Traditional Medicine for Neuronal Health 9815040200, 9789815040203

Table of contents :
Cover
Title
Copyright
End User License Agreement
Contents
Foreword
Preface
List of Contributors
Parkinson's Disease: A Phytotherapeutic Prospective
Bhargab Deka1, Bedanta Bhattacharjee1, Naveen Shivavedi2, Gireesh Kumar Singh3, Hans Raj Bhat1, Surajit Kumar Ghosh1 and Anshul Shakya1,*
INTRODUCTION
NEUROPROTECTIVE ACTIVITY OF BIOACTIVE PHYTOCOMPOUNDS FROM MEDICINAL PLANTS
M. pruriens (Kauncha)
Plant Description
Phytoconstituents of M. pruriens
Neuroprotective Activity of M. pruriens in Parkinson’s Pathology
Curcuma longa (Turmeric)
Plant Description
Phytoconstituents of Turmeric
Neuroprotective Activity of Curcumin in Parkinson’s Pathology
Zingiber officinale (Ginger)
Plant Description
Phytoconstituents of Ginger
Neuroprotective Activity of Ginger in Parkinson’s Pathology
Bacopa monnieri (Brahmi)
Phytoconstituents of “Brahmi”
Neuroprotective Activity of “Brahmi” in Parkinson’s Pathology
Nardostachys jatamansi (Jatamansi)
Plant Description
Phytoconstituents of “Jatamansi”
Neuroprotective Activity of N. jatamansi in Parkinson’s Pathology
W. somnifera (Ashwagandha)
Plant Description
Phytoconstituents of Ashwagandha
Neuroprotective Activity of Ashwagandha in Parkinson’s Pathology
Silybum marianum (Silymarin)
Plant Description
Phytoconstituets of Silymarin
Neuroprotective Activity of Silymarin in Parkinson’s Pathology
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Delineating the Neuroinflammatory Crosstalk in Neurodegeneration and Probing the Near Future Therapeutics
Vinod Tiwari1,*, Ankit Uniyal1, Vineeta Tiwari1, Vaibhav Thakur1, Mousmi Rani1 and Akhilesh1
INTRODUCTION
NEUROINFLAMMATION: A FRIEND OR A FOE?
NEUROINFLAMMATION: A CRITICAL MEDIATOR FOR NEURODEGENERATIVE DISEASES
Parkinson’s Disease
Alzheimer’s Disease
Multiple Sclerosis
Huntington’s Disease
Amyotrophic Lateral Sclerosis
THERAPEUTIC PATHWAYS FOR THE NEAR FUTURE MANAGEMENT OF NEURODEGENERATION
Microglial Responsiveness Modulation: A Potential Tool for Neuroprotection
Peroxisome Proliferator-activated Receptor Gamma (PPARγ): A Potential Target against Neuroinflammation
P2X7 Purinergic Receptor-mediated Signalling and Neurodegeneration
NF-κB Signaling and Neuroinflammation
Toll-like Receptors: The Biological Switches for Neuroinflammation
NLRP3 Inflammasome and Caspase-1 Signalling in Neurodegeneration
Neuroinflammation-associated Oxidative Stress Multimodal Cascade
Neuroinflammation and Mitochondrial Dysfunction
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Modulations of SIRTUINs and Management of Brain Disorders
Sudhir Kumar Shekhar1,*, Sarfraj Ahmad Siddiqui2,* and Girish Rai3
INTRODUCTION
SIRTUINS STRUCTURE AND TYPES
SIRT1
SIRT2
SIRT3
SIRT4
SIRT5
SIRT6
SIRT7
SIRTUINS IN DIFFERENT BRAIN FUNCTIONS
SIRTUINS AND NEURODEGENERATIVE DISORDERS
Multiple Sclerosis (MS)
AD
PD
ALS
WD
Spinal Cord Injury (SCI)
Traumatic Brain Injury (TBI)
Stroke
MODULATION OF SIRTUINS
STACs
NBMs
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Beyond the Synthetic Drugs: Fungal Endophytes Derived Bioactive Compounds in the Management of Neurodegenerative Disorders
Ashish Verma1,#, Nilesh Rai1,#, Swapnil C. Kamble2, Pradeep Mishra3, Suvakanta Barik4, Rajiv Kumar1, Santosh Kumar Singh1, Prafull Salvi5 and Vibhav Gautam1,*
INTRODUCTION
FUNGAL ENDOPHYTE AS A SOURCE OF BIOACTIVE COMPOUND FOR MANAGING HEALTH DISORDERS
ROLE OF FUNGAL ENDOPHYTE-DERIVED BIOACTIVE COMPOUNDS IN TREATING NEURODEGENERATIVE DISEASES
Fungal Endophyte-derived Bioactive Compounds having Anti-neuroinflammatory Properties
Fungal Endophyte-derived Bioactive Compounds in Managing Neuro-hydrolases
Role of Fungal Endophyte-derived Bioactive Compounds in Managing Oxidative Stress Response
Role of Fungal Endophyte-derived Bioactive Compounds in the Management of Depression
CHALLENGES IN THE APPLICATION OF BIOACTIVE COMPOUNDS FOR THE MANAGEMENT OF NEURODEGENERATIVE DISORDERS
CONCLUSION AND FUTURE PERSPECTIVE
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Neuroprotective Role of Medicinal Plants from North Eastern Region of India
Bedanta Bhattacharjee1, Bhargab Deka1, Naveen Shivavedi2, Hans Raj Bhat1, Saurabh Kumar Sinha3, Surajit Kumar Ghosh1 and Anshul Shakya1,*
INTRODUCTION
NEUROPROTECTIVE HERBS
Allium sativum
Camella sinensis
Centella asiatica
Coriandrum sativum
Crocus sativus
Glycyrrhiza glabra
Morus alba
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Tinospora cordifolia in Neurodegeneration: A Strong Antioxidant and Anti-inflammatory Phytotherapeutic Drug Candidate
Anuradha Sharma1 and Gurcharan Kaur2,*
INTRODUCTION
BRAIN HEALTH AND NEUROLOGIC DISEASE BURDEN
IMMUNOMODULATORY ROLE OF T. CORDIFOLIA
ROLE OF T. CORDIFOLIA IN NEURODEGENERATION
T. cordifolia and Oxidative Stress
T. cordifolia and Neuroinflammation
Glutamate-induced Excitotoxicity
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Mucuna pruriens and Parkinson’s Disease: A Natural Approach to Treat PD
Mamta Tiwari1,* and Anurag Pandey2
INTRODUCTION
PATHOLOGY OF PD
SIGNS AND SYMPTOMS OF PD
AETIOLOGY OF PD
AYURVEDIC UNDERSTANDING OF PD
AETIOLOGY OF PD AS PER AYURVEDA (TABLE 2)
M. pruriens in Ayurveda
Properties of M. pruriens
M. pruriens as Source of L-DOPA
Neuroprotective Activity of M. pruriens
Hypoglycaemic Activity of M. pruriens
Anti-inflammatory Activity of M. pruriens
Anti-depressant Activity of M. pruriens
Antioxidant Activity of M. pruriens
DISCUSSION
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Bacopa monnieri and Neural Health: An Indian Herb
Prachi Pattnaik1, Chetan Panda2, Tarun Minocha3, Sanjeev Kumar Yadav3, Namrata Dwivedi4 and Sandeep Kumar Singh5,*
INTRODUCTION
WHAT ARE NEURODEGENERATIVE DISEASES?
PHYTODRUGS - THE POTENTIAL ALTERNATIVE
PERKS OF PHYTOMEDICINES OVER SYNTHETIC DRUGS
WHAT ARE NOOTROPICS?
ROLE OF PHYTOMEDICINES IN NEUROPROTECTION
BACOPA MONNIERI: A REAL FORTUNE FOR NEURAL HEALTH
Taxonomic Classification
Botany
Pharmaceutical Properties and Uses
Neuroprotective Aspect of Brahmi
Role of BM in Curing AD
Effect on Curing Cancer
Other Biological Activities of BM
CURRENT RESEARCH AND SCOPE
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Role of Curcumin in the Treatment of Neurological Disorders
Bhuwan Chandra Joshi1 and Yogita Dobhal2,*
INTRODUCTION
ROLE OF CURCUMIN IN VARIOUS NEUROLOGICAL DISORDERS
ALZHEIMER’S DISEASE (AD)
PARKINSON’S DISEASE (PD)
OTHER DISEASES
Amyotrophic Lateral Sclerosis (ALS)
Huntington’s Disease (HD)
Traumatic Brain Injury (TBI)
Glioma (GBM)
Cognitive Dysfunctions
Multiple Sclerosis (MS)
CURCUMIN IN CLINICAL TRIALS
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Pharmacology of Rosmarinic Acid against Psychological Disorders
Himanshu Verma1, Naveen Shivavedi1, Mukesh Kumar1 and Prasanta Kumar Nayak1,*
INTRODUCTION
SCIENTIFIC LITERATURE
PATHOPHYSIOLOGY OF PSYCHOLOGICAL DISORDERS
EPIDEMIOLOGY
CURRENT TREATMENT STRATEGIES
ROSMARINIC ACID (RA)
PHARMACOLOGY OF RA
PHYTOCHEMISTRY OF RA
THERAPEUTIC EFFICACY OF RA IN PSYCHOLOGICAL DISORDERS
CHALLENGES AND SAFETY CONSIDERATIONS
CONCLUSION AND FUTURE PERSPECTIVE
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Neuroprotective Effects of Berberine in Neurodegenerative and Neuropsychiatric Disorders
Rupinder Kaur Sodhi1 and Anurag Kuhad1,*
INTRODUCTION
SOURCE, BIOCHEMISTRY AND PHARMACOLOGY
BERBERINE IN NEURODEGENERATIVE DISORDERS
Alzheimer’s Disease (AD)
Parkinson’s Disease (PD)
Huntington’s Disease (HD)
Cerebral Ischemia
Traumatic Brain Injury (TBI)
BERBERINE IN NEUROPSYCHIATRIC DISORDERS
Depression
Schizophrenia
Anxiety
SAFETY OF BERBERINE
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Resveratrol: A Novel Drug for the Management of Neurodegenerative Disorders
Sapna Bala1, Anamika Misra2, Upinder Kaur3 and Sankha Shubhra Chakrabarti1,*
INTRODUCTION
CHEMISTRY
DIETARY SOURCES
METABOLISM
MECHANISM OF ACTION
Antioxidant Effect
AMPK (AMP-Activated Protein Kinase) Pathway
Sirtuins
OTHER MECHANISMS
RESVERATROL IN CELL CULTURE EXPERIMENTS
RESVERATROL IN ANIMAL MODELS
Reveratrol and Alzheimer’s Disease (AD)
Resveratrol and Parkinson’s Disease (PD)
Resveratrol in Other Neurodegenerative Disorders
CONCLUSION: RESVERATROL IN CLINICAL USE
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Protective Effect of Potent Protein-like Drug Isolated from Indian Medicinal Plants over Diabetic Neuropathy
Harsha Kashyap1,*, Hagera Dilnashin2 and Mukesh Kumar3
INTRODUCTION
DN
Imbalance of Oxidative Homeostasis
Alteration in Neurotransmitters
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Natural Herbs Polishing Memory: Neuroprotection against Alzheimer's Disease
Manisha Thakkur1,*, Hagera Dilnashin2 and Priyanka Kumari Keshri2
INTRODUCTION
EPIDEMIOLOGY
PATHOPHYSIOLOGY
Autosomal Dominant AD (ADAD)
Early-Onset AD (EOAD)
Late-Onset AD (LOAD)
MAJOR HYPOTHESES
β-amyloid Hypothesis
Hyperphosporelated Tau Hypothesis
Chronic Inflammation
Cholinergic Hypothesis
Metal Ion Hypothesis
CONCLUDING REMARKS AND SCIENTIFIC EVIDENCE FOR NEUROPROTECTIVE POTENTIAL OF INDIAN HERBS OR PHYTOCHEMICALS FOR ALZHEIMER’S DISEASE
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
REFERENCES
Neuroprotective Effect of Natural Products in Attenuation of Aging-associated Neurodegeneration
Abhai Kumar1 and Rameshwar Nath Chaurasia1,*
INTRODUCTION
NATURAL PRODUCTS AND NEUROPROTECTION
Honey
Propolis
Withania somnifera
Ginseng
Curcumin
Uncaria Rhynchophylla
Cyanobacteria
CHALLENGES AND FUTURE PERSPECTIVE
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Subject Index
Back Cover

Citation preview

Traditional Medicine for Neuronal Health Edited by Surya Pratap Singh

Department of Biochemistry Institute of Science, Banaras Hindu University Varanasi-221005, India

Hareram Birla

Department of Biochemistry Institute of Science, Banaras Hindu University Varanasi-221005, India

& Chetan Keswani

Department of Biochemistry Institute of Science, Banaras Hindu University Varanasi-221005, India

Traditional Medicine for Neuronal Health Editors: Surya Pratap Singh, Hareram Birla & Chetan Keswani ISBN (Online): 978-981-5040-19-7 ISBN (Print): 978-981-5040-20-3 ISBN (Paperback): 978-981-5040-21-0 © 2023, Bentham Books imprint. Published by Bentham Science Publishers Pte. Ltd. Singapore. All Rights Reserved. First published in 2023.

BSP-EB-PRO-9789815040197-TP-307-TC-15-PD-20230309

BENTHAM SCIENCE PUBLISHERS LTD.

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CONTENTS FOREWORD ........................................................................................................................................... i PREFACE ................................................................................................................................................ ii LIST OF CONTRIBUTORS .................................................................................................................. iii CHAPTER 1 PARKINSON'S DISEASE: A PHYTOTHERAPEUTIC PROSPECTIVE ............. Bhargab Deka, Bedanta Bhattacharjee, Naveen Shivavedi, Gireesh Kumar Singh, Hans Raj Bhat, Surajit Kumar Ghosh and Anshul Shakya INTRODUCTION .......................................................................................................................... NEUROPROTECTIVE ACTIVITY OF BIOACTIVE PHYTOCOMPOUNDS FROM MEDICINAL PLANTS .................................................................................................................. M. pruriens (Kauncha) ............................................................................................................ Plant Description .......................................................................................................... Phytoconstituents of M. pruriens ................................................................................. Neuroprotective Activity of M. pruriens in Parkinson’s Pathology .............................. Curcuma longa (Turmeric) ..................................................................................................... Plant Description .......................................................................................................... Phytoconstituents of Turmeric ...................................................................................... Neuroprotective Activity of Curcumin in Parkinson’s Pathology ................................. Zingiber officinale (Ginger) .................................................................................................... Plant Description .......................................................................................................... Phytoconstituents of Ginger .......................................................................................... Neuroprotective Activity of Ginger in Parkinson’s Pathology ..................................... Bacopa monnieri (Brahmi) ..................................................................................................... Phytoconstituents of “Brahmi” ..................................................................................... Neuroprotective Activity of “Brahmi” in Parkinson’s Pathology ................................ Nardostachys jatamansi (Jatamansi) ....................................................................................... Plant Description .......................................................................................................... Phytoconstituents of “Jatamansi” ................................................................................ Neuroprotective Activity of N. jatamansi in Parkinson’s Pathology ............................ W. somnifera (Ashwagandha) ................................................................................................ Plant Description .......................................................................................................... Phytoconstituents of Ashwagandha ............................................................................... Neuroprotective Activity of Ashwagandha in Parkinson’s Pathology .......................... Silybum marianum (Silymarin) .............................................................................................. Plant Description .......................................................................................................... Phytoconstituets of Silymarin ........................................................................................ Neuroprotective Activity of Silymarin in Parkinson’s Pathology ................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ...............................................................................................................................

1 2 3 3 3 3 4 4 5 5 5 6 6 7 7 8 8 9 9 10 10 10 11 11 11 12 12 12 13 13 16 17 17 17 17

CHAPTER 2 DELINEATING THE NEUROINFLAMMATORY CROSSTALK IN NEURODEGENERATION AND PROBING THE NEAR FUTURE THERAPEUTICS ............... 24 Vinod Tiwari, Ankit Uniyal, Vineeta Tiwari, Vaibhav Thakur, Mousmi Rani and Akhilesh INTRODUCTION .......................................................................................................................... 25 NEUROINFLAMMATION: A FRIEND OR A FOE? ............................................................... 26

NEUROINFLAMMATION: A CRITICAL MEDIATOR FOR NEURODEGENERATIVE DISEASES ....................................................................................................................................... Parkinson’s Disease ................................................................................................................ Alzheimer’s Disease ............................................................................................................... Multiple Sclerosis ................................................................................................................... Huntington’s Disease .............................................................................................................. Amyotrophic Lateral Sclerosis ............................................................................................... THERAPEUTIC PATHWAYS FOR THE NEAR FUTURE MANAGEMENT OF NEURODEGENERATION ........................................................................................................... Microglial Responsiveness Modulation: A Potential Tool for Neuroprotection .................... Peroxisome Proliferator-activated Receptor Gamma (PPARγ): A Potential Target against Neuroinflammation ................................................................................................................. P2X7 Purinergic Receptor-mediated Signalling and Neurodegeneration .............................. NF-κB Signaling and Neuroinflammation .............................................................................. Toll-like Receptors: The Biological Switches for Neuroinflammation .................................. NLRP3 Inflammasome and Caspase-1 Signalling in Neurodegeneration .............................. Neuroinflammation-associated Oxidative Stress Multimodal Cascade .................................. Neuroinflammation and Mitochondrial Dysfunction .............................................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ............................................................................................................................... CHAPTER 3 MODULATIONS OF SIRTUINS AND MANAGEMENT OF BRAIN DISORDERS ............................................................................................................................................ Sudhir Kumar Shekhar, Sarfraj Ahmad Siddiqui and Girish Rai INTRODUCTION .......................................................................................................................... SIRTUINS STRUCTURE AND TYPES ...................................................................................... SIRT1 ...................................................................................................................................... SIRT2 ...................................................................................................................................... SIRT3 ...................................................................................................................................... SIRT4 ...................................................................................................................................... SIRT5 ...................................................................................................................................... SIRT6 ...................................................................................................................................... SIRT7 ...................................................................................................................................... SIRTUINS IN DIFFERENT BRAIN FUNCTIONS ................................................................... SIRTUINS AND NEURODEGENERATIVE DISORDERS ...................................................... Multiple Sclerosis (MS) .......................................................................................................... AD ........................................................................................................................................... PD ........................................................................................................................................... ALS ......................................................................................................................................... WD .......................................................................................................................................... Spinal Cord Injury (SCI) ......................................................................................................... Traumatic Brain Injury (TBI) ................................................................................................. Stroke ...................................................................................................................................... MODULATION OF SIRTUINS ................................................................................................... STACs ..................................................................................................................................... NBMs ...................................................................................................................................... CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................

27 28 29 30 31 32 32 33 35 36 37 37 38 39 39 40 41 41 41 41 47 47 48 49 50 50 51 51 51 52 52 58 58 59 61 63 64 65 66 67 68 69 70 70 71

CONFLICT OF INTEREST ......................................................................................................... 71 ACKNOWLEDGEMENTS ........................................................................................................... 71 REFERENCES ............................................................................................................................... 71 CHAPTER 4 BEYOND THE SYNTHETIC DRUGS: FUNGAL ENDOPHYTES DERIVED BIOACTIVE COMPOUNDS IN THE MANAGEMENT OF NEURODEGENERATIVE DISORDERS ............................................................................................................................................ Ashish Verma, Nilesh Rai, Swapnil C. Kamble, Pradeep Mishra, Suvakanta Barik Rajiv Kumar, Santosh Kumar Singh, Prafull Salvi and Vibhav Gautam INTRODUCTION .......................................................................................................................... FUNGAL ENDOPHYTE AS A SOURCE OF BIOACTIVE COMPOUND FOR MANAGING HEALTH DISORDERS ......................................................................................... ROLE OF FUNGAL ENDOPHYTE-DERIVED BIOACTIVE COMPOUNDS IN TREATING NEURODEGENERATIVE DISEASES ................................................................. Fungal Endophyte-derived Bioactive Compounds having Anti-neuroinflammatory Properties ................................................................................................................................ Fungal Endophyte-derived Bioactive Compounds in Managing Neuro-hydrolases .............. Role of Fungal Endophyte-derived Bioactive Compounds in Managing Oxidative Stress Response ................................................................................................................................. Role of Fungal Endophyte-derived Bioactive Compounds in the Management of Depression CHALLENGES IN THE APPLICATION OF BIOACTIVE COMPOUNDS FOR THE MANAGEMENT OF NEURODEGENERATIVE DISORDERS ............................................. CONCLUSION AND FUTURE PERSPECTIVE ....................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ............................................................................................................................... CHAPTER 5 NEUROPROTECTIVE ROLE OF MEDICINAL PLANTS FROM NORTH EASTERN REGION OF INDIA ............................................................................................................ Bedanta Bhattacharjee, Bhargab Deka, Naveen Shivavedi, Hans Raj Bhat, Saurabh Kumar Sinha, Surajit Kumar Ghosh and Anshul Shakya INTRODUCTION .......................................................................................................................... NEUROPROTECTIVE HERBS ................................................................................................... Allium sativum ........................................................................................................................ Camella sinensis ...................................................................................................................... Centella asiatica ...................................................................................................................... Coriandrum sativum ................................................................................................................ Crocus sativus ......................................................................................................................... Glycyrrhiza glabra .................................................................................................................. Morus alba .............................................................................................................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ...............................................................................................................................

82 83 84 86 88 89 91 92 94 94 95 95 95 95 103 104 105 105 107 108 111 112 113 114 117 118 118 118 118

CHAPTER 6 TINOSPORA CORDIFOLIA IN NEURODEGENERATION: A STRONG ANTIOXIDANT AND ANTI-INFLAMMATORY PHYTOTHERAPEUTIC DRUG CANDIDATE ........................................................................................................................................... 129 Anuradha Sharma1 and Gurcharan Kaur INTRODUCTION .......................................................................................................................... 129

BRAIN HEALTH AND NEUROLOGIC DISEASE BURDEN ................................................. IMMUNOMODULATORY ROLE OF T. CORDIFOLIA ....................................................... ROLE OF T. CORDIFOLIA IN NEURODEGENERATION ................................................... T. cordifolia and Oxidative Stress .......................................................................................... T. cordifolia and Neuroinflammation ..................................................................................... Glutamate-induced Excitotoxicity .......................................................................................... CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 7 MUCUNA PRURIENS AND PARKINSON’S DISEASE: A NATURAL APPROACH TO TREAT PD ................................................................................................................. Mamta Tiwari and Anurag Pandey INTRODUCTION .......................................................................................................................... PATHOLOGY OF PD ................................................................................................................... SIGNS AND SYMPTOMS OF PD ................................................................................................ AETIOLOGY OF PD ..................................................................................................................... AYURVEDIC UNDERSTANDING OF PD ................................................................................. AETIOLOGY OF PD AS PER AYURVEDA ............................................................................. M. pruriens in Ayurveda ......................................................................................................... Properties of M. pruriens ....................................................................................................... M. pruriens as Source of L-DOPA ......................................................................................... Neuroprotective Activity of M. pruriens ............................................................................... Hypoglycaemic Activity of M. pruriens ................................................................................ Anti-inflammatory Activity of M. pruriens ........................................................................... Anti-depressant Activity of M. pruriens ................................................................................ Antioxidant Activity of M. pruriens ...................................................................................... DISCUSSION .................................................................................................................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 8 BACOPA MONNIERI AND NEURAL HEALTH: AN INDIAN HERB ................. Prachi Pattnaik, Chetan Panda, Tarun Minocha, Sanjeev Kumar Yadav, Namrata Dwivedi and Sandeep Kumar Singh INTRODUCTION .......................................................................................................................... WHAT ARE NEURODEGENERATIVE DISEASES? .............................................................. PHYTODRUGS - THE POTENTIAL ALTERNATIVE ........................................................... PERKS OF PHYTOMEDICINES OVER SYNTHETIC DRUGS ............................................ WHAT ARE NOOTROPICS? ...................................................................................................... ROLE OF PHYTOMEDICINES IN NEUROPROTECTION .................................................. BACOPA MONNIERI: A REAL FORTUNE FOR NEURAL HEALTH ................................ Taxonomic Classification ....................................................................................................... Botany ..................................................................................................................................... Pharmaceutical Properties and Uses ....................................................................................... Neuroprotective Aspect of Brahmi ......................................................................................... Role of BM in Curing AD .............................................................................................. Effect on Curing Cancer ...............................................................................................

130 131 132 132 134 136 137 138 138 138 138 144 144 145 145 146 147 148 148 149 150 151 151 152 153 153 154 156 156 156 156 156 160 161 162 163 164 165 165 166 167 167 168 169 169 170

Other Biological Activities of BM .......................................................................................... CURRENT RESEARCH AND SCOPE ....................................................................................... CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 9 ROLE OF CURCUMIN IN THE TREATMENT OF NEUROLOGICAL DISORDERS ............................................................................................................................................ Bhuwan Chandra Joshi and Yogita Dobhal INTRODUCTION .......................................................................................................................... ROLE OF CURCUMIN IN VARIOUS NEUROLOGICAL DISORDERS ............................. ALZHEIMER’S DISEASE (AD) .................................................................................................. PARKINSON’S DISEASE (PD) .................................................................................................... OTHER DISEASES ........................................................................................................................ Amyotrophic Lateral Sclerosis (ALS) .................................................................................... Huntington’s Disease (HD) ..................................................................................................... Traumatic Brain Injury (TBI) ................................................................................................. Glioma (GBM) ........................................................................................................................ Cognitive Dysfunctions .......................................................................................................... Multiple Sclerosis (MS) .......................................................................................................... CURCUMIN IN CLINICAL TRIALS ......................................................................................... CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 10 PHARMACOLOGY OF ROSMARINIC ACID AGAINST PSYCHOLOGICAL DISORDERS ............................................................................................................................................ Himanshu Verma, Naveen Shivavedi, Mukesh Kumar and Prasanta Kumar Nayak INTRODUCTION .......................................................................................................................... SCIENTIFIC LITERATURE ....................................................................................................... PATHOPHYSIOLOGY OF PSYCHOLOGICAL DISORDERS .............................................. EPIDEMIOLOGY .......................................................................................................................... CURRENT TREATMENT STRATEGIES ................................................................................. ROSMARINIC ACID (RA) ........................................................................................................... PHARMACOLOGY OF RA ......................................................................................................... PHYTOCHEMISTRY OF RA ...................................................................................................... THERAPEUTIC EFFICACY OF RA IN PSYCHOLOGICAL DISORDERS ........................ CHALLENGES AND SAFETY CONSIDERATIONS ............................................................... CONCLUSION AND FUTURE PERSPECTIVE ....................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ...............................................................................................................................

171 172 172 173 173 173 173 177 177 178 178 180 181 181 181 182 182 182 182 183 183 187 187 188 188 191 191 193 193 194 194 194 195 195 196 202 203 203 203 204 204

CHAPTER 11 NEUROPROTECTIVE EFFECTS OF BERBERINE IN NEURODEGENERATIVE AND NEUROPSYCHIATRIC DISORDERS ....................................... 213 Rupinder Kaur Sodhi and Anurag Kuhad INTRODUCTION .......................................................................................................................... 213

SOURCE, BIOCHEMISTRY AND PHARMACOLOGY ......................................................... BERBERINE IN NEURODEGENERATIVE DISORDERS .................................................... Alzheimer’s Disease (AD) ..................................................................................................... Parkinson’s Disease (PD) ...................................................................................................... Huntington’s Disease (HD) .................................................................................................... Cerebral Ischemia .................................................................................................................. Traumatic Brain Injury (TBI) ................................................................................................ BERBERINE IN NEUROPSYCHIATRIC DISORDERS ......................................................... Depression .............................................................................................................................. Schizophrenia ......................................................................................................................... Anxiety ................................................................................................................................... SAFETY OF BERBERINE .......................................................................................................... CONCLUSION .............................................................................................................................. CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 12 RESVERATROL: A NOVEL DRUG FOR THE MANAGEMENT OF NEURODEGENERATIVE DISORDERS ............................................................................................ Sapna Bala, Anamika Misra, Upinder Kaur and Sankha Shubhra Chakrabarti INTRODUCTION .......................................................................................................................... CHEMISTRY .................................................................................................................................. DIETARY SOURCES .................................................................................................................... METABOLISM .............................................................................................................................. MECHANISM OF ACTION ......................................................................................................... Antioxidant Effect ................................................................................................................... AMPK (AMP-Activated Protein Kinase) Pathway ................................................................ Sirtuins .................................................................................................................................... OTHER MECHANISMS ............................................................................................................... RESVERATROL IN CELL CULTURE EXPERIMENTS ........................................................ RESVERATROL IN ANIMAL MODELS .................................................................................. Reveratrol and Alzheimer’s Disease (AD) ............................................................................. Resveratrol and Parkinson’s Disease (PD) ............................................................................. Resveratrol in Other Neurodegenerative Disorders ................................................................ CONCLUSION: RESVERATROL IN CLINICAL USE ........................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 13 PROTECTIVE EFFECT OF POTENT PROTEIN-LIKE DRUG ISOLATED FROM INDIAN MEDICINAL PLANTS OVER DIABETIC NEUROPATHY ............................... Harsha Kashyap, Hagera Dilnashin and Mukesh Kumar INTRODUCTION .......................................................................................................................... DN ..................................................................................................................................................... Imbalance of Oxidative Homeostasis ..................................................................................... Alteration in Neurotransmitters .............................................................................................. CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT .............................................................................................................

214 215 215 216 218 218 219 219 219 220 221 222 222 223 223 223 223 230 231 231 232 232 233 233 234 234 236 236 239 239 241 242 243 245 245 246 246 252 252 256 256 257 259 260 260 260

REFERENCES ............................................................................................................................... 260 CHAPTER 14 NATURAL HERBS POLISHING MEMORY: NEUROPROTECTION AGAINST ALZHEIMER'S DISEASE .................................................................................................. Manisha Thakkur, Hagera Dilnashin and Priyanka Kumari Keshri INTRODUCTION .......................................................................................................................... EPIDEMIOLOGY .......................................................................................................................... PATHOPHYSIOLOGY ................................................................................................................. Autosomal Dominant AD (ADAD) ........................................................................................ Early-Onset AD (EOAD) ........................................................................................................ Late-Onset AD (LOAD) ......................................................................................................... MAJOR HYPOTHESES ................................................................................................................ β-amyloid Hypothesis ............................................................................................................. Hyperphosporelated Tau Hypothesis ...................................................................................... Chronic Inflammation ............................................................................................................. Cholinergic Hypothesis ........................................................................................................... Metal Ion Hypothesis .............................................................................................................. CONCLUDING REMARKS AND SCIENTIFIC EVIDENCE FOR NEUROPROTECTIVE POTENTIAL OF INDIAN HERBS OR PHYTOCHEMICALS FOR ALZHEIMER’S DISEASE ......................................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENT ............................................................................................................. REFERENCES ............................................................................................................................... CHAPTER 15 NEUROPROTECTIVE EFFECT OF NATURAL PRODUCTS IN ATTENUATION OF AGING-ASSOCIATED NEURODEGENERATION ..................................... Abhai Kumar and Rameshwar Nath Chaurasia INTRODUCTION .......................................................................................................................... NATURAL PRODUCTS AND NEUROPROTECTION ............................................................ Honey ...................................................................................................................................... Propolis ................................................................................................................................... Withania somnifera ................................................................................................................. Ginseng ................................................................................................................................... Curcumin ................................................................................................................................. Uncaria rhynchophylla ........................................................................................................... Cyanobacteria ......................................................................................................................... CHALLENGES AND FUTURE PERSPECTIVE ...................................................................... CONCLUSION ............................................................................................................................... CONSENT FOR PUBLICATION ................................................................................................ CONFLICT OF INTEREST ......................................................................................................... ACKNOWLEDGEMENTS ........................................................................................................... REFERENCES ...............................................................................................................................

265 266 267 268 269 269 269 269 269 270 270 271 271 272 275 275 275 275 284 284 285 285 286 287 288 290 290 291 292 293 293 293 293 293

SUBJECT INDEX .................................................................................................................................... 

i

FOREWORD Traditional therapies, which are indigenous to India, are believed to be the world's oldest comprehensive healthcare system, and are now one of the most recognized and widely practiced disciplines of alternative medicine in the world. Medicinal herbs have been in use for treating diseases since ancient times in India. Medicinal herbs generally provide relief without any adverse effects, even after prolonged administration. Since the last decade, the therapeutic potentials of natural compounds in age-associated neurodegenerative disorders have received major attention. Within the last few years, a search for novel pharmacotherapy from medicinal plants for neurodegenerative disorders has progressed significantly. The content of the book focuses on natural agents and medicinal herbs that have shown a promising role in reversing neurodegenerative disease’s pathology. The book provides comprehensive information concerning the phytological applications of various medicinal herbs to provide sufficient baseline information that could be used in drug discovery, thereby providing new therapeutics for neurodegenerative diseases. The editors are acknowledged for synchronizing with global authorities on the subject to underline the anti-neurodegenerative effects of medicinal herbs with the potential to benefit mankind.

Prof. Ishan K. Patro Schools of Studies in Zoology and Neuroscience Jiwaji University Gwalior, India

ii

PREFACE Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss (structurally and/or functionally) in different regions of the brain. NDs represent one of the most important public health concerns, as they are the growing cause of death around the world, especially among the elderly. Aging has led to an increase in NDs, such as Alzheimer's disease, dementia, cerebrovascular impairment, seizure disorders, head injury, and Parkinson's disease, which are becoming critical due to their irreversibility, lack of effective medication, and the resulting social and financial burdens. Indeed, despite the noteworthy achievements in our understanding of NDs, there has been little achievement in formulating suitable therapies. Currently, the available treatments for NDs seem to be ineffective, as they only work to ease the symptoms but cannot prevent the disease's progression. The use of medicinal herbs is emerging as an alternative or integrative therapeutic against NDs because of the preconception that medicinal herbs are consequently safe. Phytochemicals from medicinal plants assume an indispensable job in keeping up the chemical balance of the brain by affecting the capacity of receptors for the major inhibitory neurotransmitters. In a conventional act of medication, a few plants have been accounted for to treat NDs. This book highlights various homegrown medications and their scientific validation to maintain neuronal wellbeing, utilized in Ayurveda practices and Chinese medication. This book summarizes different phytochemicals from various medicinal herbs that are used as promising therapeutic agents for NDs due to their anti-inflammatory and anti-oxidative as well as anticholinesterase activities. Even though the affinity of receptors or carriers for polyphenols or different phytochemicals of the homegrown arrangements in cerebrum tissues remains to be found out, numerous candidates show up as a potential and promising class of therapeutics for the treatment of ailments with a multifactorial etiology. Adopting the ethnomedicinal approach, this book addresses the intersection between recent therapeutics for NDs and personalized medicine that will allow a broader range of interventions, including evidence-based natural products.

Surya Pratap Singh Department of Biochemistry, Institute of Science Banaras Hindu University Varanasi-221005, India Hareram Birla Department of Biochemistry, Institute of Science Banaras Hindu University Varanasi-221005, India & Chetan Keswani Department of Biochemistry, Institute of Science Banaras Hindu University Varanasi-221005, India

iii

List of Contributors Anshul Shakya

Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh786004 (Assam), India

Anamika Misra

Department of General Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India

Abhai Kumar

Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India

Anurag Pandey

Department of Vikriti Vigyan, Faculty of Ayurveda, Banaras Hindu University, Varanasi-221005 (U.P.), India

Anurag Kuhad

Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160101 (Punjab), India

Anuradha Sharma

College of Animal Biotechnology, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana-141004 (Punjab), India

Ashish Verma

Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India

Akhilesh

Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, Uttar Pradesh, India

Ankit Uniyal

Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, Uttar Pradesh, India

Bhargab Deka

Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh786004 (Assam), India

Bedanta Bhattacharjee

Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh786004 (Assam), India

Bhuwan Chandra Joshi

Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun University, Bhimtal Campus, Nainital-263136, (Uttarakhand), India

Chetan Panda

Department of Agricultural Biotechnology, College of Agriculture, Odisha University of Agriculture & Technology, Bhubaneswar-751003 (Odisha), India

Gireesh Kumar Singh

Department of Pharmacy, Institute of Health Sciences, Central University of South Bihar, Gaya-824236 (Bihar), India

Girish Rai

Vivekanand Government PG College Maihar, Manpur- 485771 (M.P.), India

Gurcharan Kaur

Department of Biotechnology, Guru Nanak Dev University, Amritsar-143005 (Punjab), India

Hagera Dilnashin

Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005 (U.P.), India

Hans Raj Bhat

Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh786004 (Assam), India

Himanshu Verma

Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, 221005 (U.P.), India

iv Harsha Kashyap

Department of Bioscience and Biotechnology, Banasthali Vidyapith, Vanasthali-304022 (Rajasthan), India

Mamta Tiwari

Department of Swasthavritta and Yoga, Faculty of Ayurveda, Banaras Hindu University, Varanasi-221005 (U.P.), India

Manisha Thakkur

Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar-125001 (Haryana), India

Mousmi Rani

Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, Uttar Pradesh, India

Mukesh Kumar

Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, 221005 (U.P.), India School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong

Naveen Shivavedi

Shri Ram Group of Institutions, Faculty of Pharmacy, Jabalpur-482002 (M.P.), India Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, 221005 (U.P.), India

Namrata Dwivedi

Biotechnology Centre, Jawaharlal Nehru Krishi Vishwa Vidyalaya, Jabalpur482004 (M.P.), India

Nilesh Rai

Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India

Prafull Salvi

Department of Agriculture Biotechnology, National Agri-Food Biotechnology Institute, SAS Nagar, Mohali, Punjab-140306, India

Prachi Pattnaik

Department of Horticulture, Institute of Agricultural Sciences, Banaras Hindu University, Varanasi-2210005 (U.P.), India

Prasanta Kumar Nayak

Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, 221005 (U.P.), India

Priyanka Kumari Keshri

Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005 (U.P.), India

Pradeep Mishra

Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-171 77-Stockholm, Sweden

Rajiv Kumar

Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India

Rupinder Kaur Sodhi

Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160101 (Punjab), India

Rameshwar Nath Chaurasia

Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India

Surajit Kumar Ghosh

Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh786004 (Assam), India

Sudhir Kumar Shekhar

Department of Biochemistry, King George Medical University, Lucknow226003 (U.P.), India

Sarfraj Ahmad Siddiqui

Department of Zoology, University of Lucknow, Lucknow-226007 (U.P.), India

v Sarfraj Ahmad Siddiqui

Department of Zoology, University of Lucknow, Lucknow-226007 (U.P.), India

Swapnil C. Kamble

Department of Technology, Savitribai Phule Pune University, Ganeshkhind, Pune-411007, India

Suvakanta Barik

Chemical Engineering Discipline, Indian Institute of Technology Gandhinagar, Gujarat-382355, India

Santosh Kumar Singh

Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India

Saurabh Kumar Sinha

Department of Pharmaceutical Sciences, Mohanlal Shukhadia University, Udaipur, Rajasthan- 313 001, India

Sanjeev Kumar Yadav

Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi-2210005 (U.P.), India

Sandeep Kumar Singh

Indian Scientific Education and Technology Foundation, Lucknow-226002 (U.P.), India

Sankha Shubhra Chakrabarti

Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India

Sapna Bala

Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India

Tarun Minocha

Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi-2210005 (U.P.), India

Upinder Kaur

Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India

Vinod Tiwari

Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, Uttar Pradesh, India

Vineeta Tiwari

Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, Uttar Pradesh, India

Vaibhav Thakur

Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, Uttar Pradesh, India

Vibhav Gautam

Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India

Yogita Dobhal

School of Pharmaceutical Sciences and Technology, Sardar Bhagwan Singh University, Balawala, Dehradun-248001, (Uttarakhand), India

Traditional Medicine for Neuronal Health, 2023, 1-23

1

CHAPTER 1

Parkinson's Prospective

Disease:

A

Phytotherapeutic

Bhargab Deka1, Bedanta Bhattacharjee1, Naveen Shivavedi2, Gireesh Kumar Singh3, Hans Raj Bhat1, Surajit Kumar Ghosh1 and Anshul Shakya1,* Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh-786004 (Assam), India 2 Shri Ram Group of Institutions, Faculty of Pharmacy, Jabalpur-482002 (M.P.), India 3 Department of Pharmacy, Institute of Health Sciences, Central University of South Bihar, Gaya824236 (Bihar), India 1

Abstract: Parkinson's disease (PD) is a complex multi-factorial, neurodegenerative disease characterized by neurodegeneration of dopaminergic neurons in the substantia nigra (SN) of the ventral midbrain area. Loss of dopamine (DA) supply induces an imbalance of multiple neurotransmitter networks in different parts of the brain. This contributes to many motor and non-motor symptoms in PD. The main goal of modern allopathic medicine is to restore DA function with synthetic levodopa (L-DOPA) and DA agonist, which has been partially effective; however, there are still several inadequacies and adverse effects that patients often cannot cope with. In the field of herbal medicine, extensive studies on bioactive phytocompounds have shown that it has immense potential as a neuroprotective therapy for neurodegenerative disorders, such as PD. Bioactive phytocompounds are very promising because they have minimal side effects and very high anti-inflammatory, anti-oxidant, and anticholinesterase activity. Recent preclinical studies suggest that several bioactive phytocompounds can be developed into pharmaceutical formulations for the treatment of PD. Ayurvedic medicines have been used in many countries and particularly in India since ancient times to prevent or cure PD. This article focuses on the recent evidence-based neuroprotective activity of medicinal plants like Mucuna pruriens, Curcuma longa, Zingiber officinale, Bacopa monnieri, Nardostachys jatamansi, Withania somnifera, and Silybum marianum in in vivo and in vitro PD research models.

Keywords: Ayurvedic medicine, Levodopa, Neurodegeneration, Parkinson’s disease, Phytotherapy. Corresponding author Anshul Shakya: Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh786004 (Assam), India; E-mail: [email protected] *

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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INTRODUCTION Parkinson's disease (PD) is the most common type of progressive neurodegenerative disease, causes severe impairment, and impacts the quality of life [1]. It affects approximately 10 million people worldwide, and the prevalence in India is roughly 10% of the global burden. The most common cause of PD in older adults is idiopathic PD, also known as sporadic PD [2]. PD is typically related to motor symptoms, including tremors, akinesia/bradykinesia, reduced body balance, and rigidity. PD leads to neurodegeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), which is related to dopamine (DA) deficiency in basal ganglia. The most commonly recognized causes of PD are protein misfolding, aggregation, toxicity, mitochondrial dysfunction, and oxidative stress [3 - 5]. Protein misfolding, mainly alpha-synuclein (α-syn), is critically linked to PD. The small protein α-syn consisting of 140 amino acids is present in the brain and other organs, like the heart and gut [6]. The role of this protein in humans is still unclear; however, studies have shown that α-syn plays normal physiological roles, such as storage, recycling, and compartmentalization [7]. There are two very well-known hypotheses of α-syn misfolding, i.e., exposure to environmental toxins and heavy metals [8], and another is misfolding due to dysbiosis of the microbiome of the gut [9]. For metabolic requirements, neurons are largely dependent on mitochondrial integrity. Effective transport of mitochondria to the hot spots of energy demand is required, such as pre-synaptic and post-synaptic areas. It is, therefore, not shocking that mitochondrial dysfunction will promote neuronal breakdown and degeneration [10]. The generation of cellular energy (ATP) is formed in five transmembrane complexes after electron transportation in the mitochondrial membrane [11]. In this process, the electrons leak out of the chain, mainly from complexes I and III, and react with oxygen to form a superoxide ion (O2-). O2production occurs at minimum levels under normal physiological conditions; however, dysfunction of complex I and III contributes to elevated O2- generation, and may be one of the main hallmarks of neurodegeneration in SNpc of patients with PD [12, 13]. Since ancient times, PD has been known in different parts of the world. Asian countries like India, Japan, Korea, and China, which have a treasure of traditional systems of medicine, have been using different plant-based medications to treat PD for a long time [14]. In India, the Ayurvedic system of medicine is the oldest form of an alternative and holistic medicinal system. PD is described as “Kampavata” in Ayurveda. The formulation prepared from seeds of Mucuna

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pruriens has been prescribed by Ayurveda to treat symptoms that are the hallmark of PD. Scientific investigations showed that M. pruriens is used to treat long-term improvement in PD. In clinical trials, powdered seed formulation of M. pruriens has also shown positive effects with accelerated action in PD patients [15]. Long-term therapeutic and health-promising properties of bioactive phytochemicals from medicinal plants have drawn the interest of the scientific community for the prevention or treatment of different types of chronic and disabling neurological disorders [16 - 19]. Therefore, scientific examination and validation of these bioactive phytocompounds on preclinical models are very valuable for the development of neuroprotective drugs. The use of bioactive phytocompounds for these types of chronic and progressive disorders may yield more satisfactory clinical outcomes than synthetic chemical drugs [20 - 22]. NEUROPROTECTIVE ACTIVITY OF PHYTOCOMPOUNDS FROM MEDICINAL PLANTS

BIOACTIVE

M. pruriens (Kauncha) M. pruriens belongs to the Fabaceae family, and the subfamily Papilionaceae is commonly distributed in the tropical and subtropical regions of the world, characterized by 150 species of annual and perennial legumes. Among these different varieties of wild legumes, only velvet beans (M. pruriens) are used for a range of medicinal purposes [23, 24]. Plant Description The plant is a perennial, long-grown, climbing shrub that can reach more than 15 m in length. When the plant is young, it is almost entirely covered with shaggy hair, but when it is older, it is almost fully hair-free. The leaves are tripinnate, ovate, inverted, rhombus-shaped, or broadly ovate [25]. Phytoconstituents of M. pruriens Phytoanalytical screening of velvet beans has been found to have 3-(3,4dihydroxy phenyl)-l-alanine or levodopa (L-DOPA) and can be used to alleviate motor symptoms of PD [26]. It also contains glutathione (GSH), gallic acid (GA), and beta-sitosterol. It has unspecified bases, such as mucunine, mucunadine, prurienine, and prurienine. Serotonin is found in pods as well. Seeds also include palmitic, stearic, oleic, and linoleic acid oils [27].

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Neuroprotective Activity of M. pruriens in Parkinson’s Pathology In 1973, the first extraction of L-DOPA from M. pruriens seeds was achieved, and they were recognized as a significant source of L-DOPA for treating PD [28]. The effectiveness of M. pruriens was shown by Katzenschlager et al. in 2004 by contrasting it with the normal drug combination, L-DOPA/ carbidopa (C-DOPA). At weekly intervals, patients were administered single doses of 200/50 mg LDOPA/ C-DOPA and 15 g and 30 g of M. pruriens preparation in randomized order. The pharmacokinetics of L-DOPA was calculated, and the Unified PD Rating Scale and tapping speed were obtained at baseline and consistently during the 4 h after ingestion of the medication. Without worsening dyskinesia, M. pruriens acted quicker and lasted longer than L-DOPA/ C-DOPA [29]. Nagashayana et al. demonstrated a prospective clinical study where patients were divided into two separate groups, one receiving treatment consisting of a mixture of powders of M. pruriens (4.5 g), Hyoscyamus niger (0.75 g) seeds, Withania somnifera (14.5 g), and Sida cordifolia (14.5 g) roots in 200 mL cow’s milk, and other receiving palliative therapy. The group that received phytoingredients had shown better improvement in tremors, bradykinesia, stiffness, and cramps as compared to the group that underwent only palliative therapy [30]. Cilia et al. have shown a clinical study in which 18 patients with advanced PD obtained the following randomized treatments: (a) dispersible L-DOPA at 3.5 mg/kg integrated with the standard benserazide DOPA-decarboxylase inhibitor; (b) high-dose M. pruriens (17.5 mg/kg); (c) low-dose M. pruriens (12.5 mg/kg); (d) pharmaceutical preparation of L-DOPA without DOPA-decarboxylase. They observed that a single low dose of M. pruriens exhibited comparable effectiveness to a mixture of L-DOPA/C-DOPA with fewer dyskinesias [31]. A preclinical study in which a Parkinsonian rat model was developed by intrastriatal injection of 6-hydroxydopamine (6-OHDA) with amphetamine was demonstrated by Ghazala et al. They compared synthetic L-DOPA (2.5 or 5.0 g/kg) with endocarp M. pruriens and found that extract M. pruriens was more effective than that of synthetic L-DOPA [32]. Curcuma longa (Turmeric) C. longa is a member of the family of ginger (Zingiberaceae). Indian turmeric is very common compared to other countries due to the high content of curcumin. Rhizomes from C. longa are widely recognized as “Haldi” or turmeric. It is widely used for the treatment of various illnesses, viz. gastrointestinal diseases, especially for the biliary and hepatic disorders, diabetic wounds, rheumatism,

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infections, inflammation, sinusitis, anorexia, coryza, and cough by traditional medical practitioners of the Ayurvedic system of medicine, and also it is very commonly used for culinary purposes in Indian standard diet [33]. Plant Description Turmeric is a rhizome with a rootstock that possesses broadly lanceolate or oblong leaves with deep purple ferruginous. Its petiole and sheath are long. It involves a spike that emerges in front of the branches, and a flowering green bract with a ferruginous tinge, light yellow flower, and reddish outer lip [34]. Phytoconstituents of Turmeric Curcumin, demethoxycurcumin, and bisdemethoxycurcumin are the major phenolic compounds in turmeric, commonly recognized as curcuminoids (3-6%). They are responsible for the neuroprotective activities of turmeric [35]. In the 19th century, the primary coloring principle of the turmeric rhizome was isolated and named “curcumin”. Its chemical composition has been determined by Roughley and Whiting. Turmeric contains protein (6.3%), fat (5.1%), minerals (3.5%), carbohydrates (69.4%), and moisture (69.4%). (13.1%). Phenolic diketone, curcumin (diferuloylmethane) (3-4%), is responsible for the yellow color and consists of curcumin I (94%), curcumin II (6%), curcumin III (0.3%), and volatile oil (4.2%). Turmerone, ar-turmerone, curcumene, germacrone, and ar-curcumene are the primary components. Copper, zinc, campesterol, stigmasterol, betasitosterol, fatty acids, potassium, sodium magnesium, calcium, manganese, and iron are other chemical compounds [36]. Neuroprotective Activity of Curcumin in Parkinson’s Pathology In humans, α-syn is a protein encoded by the SNCA gene. People with PD are found to have abnormal clumps of misfolded α-syn called Lewy bodies (LB), which are toxic to brain cells. It is abundant in the brain but is also present significantly in the muscles of the heart, intestines, and other tissues. Abnormal clusters of α-syn have also been found in the intestines of people with PD. Researchers have suggested that α-syn may potentially misfold and accumulate in the gut. Recent studies have shown that α-syn clumps can misfold nearby normal α-syn proteins, and trigger further clumps. These results indicate that a chain reaction triggered by misfolded α-syn could migrate from the intestine to the vagus nerve, which directly affects the brain [37].

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The effect of curcumin solution (5 μL) on α-syn protein aggregation was explored by Pandey et al. An in vitro model was developed where the aggregation of α-syn was accomplished by treatment of purified α-syn protein (wild-type) with 1 mM Fe3+ (Fenton reaction). They observed that curcumin therapy inhibited α-syn aggregation in a dose-dependent manner and also improved the solubility of αsyn. They also tested the same in a cell line-based culture using the catecholaminergic cell line SH-SY5Y. It was observed that after 48 h of subsequent curcumin addition, it decreased the aggregation of mutant α-syn by 32% [38, 39]. The effect of curcumin in soybean oil (incorporated into the diet) on the motor activity of the transgenic mice model, which overexpresses wild-type human tagged α-syn protein, was investigated by Spinelli et al. They observed that curcumin diet intervention significantly improved gait impairments and contributed to an improvement in phosphorylated forms of α-syn at the cortical presynaptic terminals [40]. An experiment was carried out by Pan et al. to assess curcumin's efficacy to prevent nigrostriatal neuronal degeneration in a 1-methyl 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) model. It was shown that curcumin (50 mg/kg/day) inhibits nigrostriatal neuron degeneration by inhibiting mitochondrial dysfunction and by suppressing the hyperphosphorylation of c-Jun N-terminal kinase (JNK) caused by MPTP [41]. Zingiber officinale (Ginger) Ginger is a well-known herb native to India, a common ingredient found in every Indian kitchen for culinary purposes. It is used in dishes, such as curries, desserts, cakes, and biscuits, as a flavoring agent. Ginger is a popular herbal remedy used in the traditional medicine system for treating different ailments. Many of the pharmacological effects of ginger include anti-emetic, anti-diabetic, analgesic, anti-arthritis, anti-cancer, anti-oxidant, anti-ulcer, anti-microbial, antiinflammatory, immunomodulatory, and cardiovascular function [42]. Plant Description In the Zingiberaceae family, ginger is an upright herbaceous perennial plant cultivated for its edible rhizome (underground stem). The rhizome is brown, corky in the outer layer, and light yellow in the center. With linear leaves arranged alternately on the stem, the above-ground shoot is erect and reed-like. The shoots come from multiple bases, circling each other. The leaves can be 2.75 inches (7 cm) long and 0.7 inches (1.9 cm) wide. On shorter stems, the floral heads are borne, and the plant produces cone-shaped light yellow flowers. The ginger plant

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is grown as an annual plant and can reach a height of 0.6-1.2 m (2-4 ft) [43, 44]. Phytoconstituents of Ginger The main active ingredients in ginger, such as zingerone, gingerdiol, zingiberene, gingerols, and shogaols, are known to have an antioxidant function [45]. In several studies in the past, the shagaols have shown very strong neuroprotective activity against PD. The principal antioxidant of ginger was proved to be 6gingerol, and its derivatives contained volatile oils, shogaols, diarylheptanoids, gingerols, paradol, zerumbone, 1-dehydro- [10] gingerdi-one, terpenoids, and ginger flavonoids. Ginger pungency is due to the presence of volatile oils, nonvolatile compounds, and oleoresins. In the fresh ginger rhizome, gingerols have been established as the main active ingredients, and gingerol [5-hydroxy-1(4-hydroxy-3-methoxy phenyl) decane-3-one] is the most abundant component in the gingerol sequence [46]. Ginger dramatically reduced lipid peroxidation (LPO) by preserving the activity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), in the rat [47]. Neuroprotective Activity of Ginger in Parkinson’s Pathology Park et al. presented a preclinical experiment in which cultured mesencephalic rat cells were treated for one hour with 6-shagaol (10 mg/kg/day) and then for another 23 h with 1-methyl-4-phenylpyridium (MPP+). 6-shogaol significantly increased the number of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in MPP+ treated rat mesencephalic cultures and reduced the levels of tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO). Treatment in mice with 6shogaol reversed MPTP-induced motor control alterations and bradykinesia. In addition, 6-shogaol reversed TH-positive cell count in the SNpc and TH-IR fiber density in the striatum (ST) caused by MPTP [48]. Another experiment where ginger rhizome extract (600 mg/kg) was administered to rats was shown by Hussein et al. They suggested that ginger may be a neuroprotective agent due to the presence of polyphenolic compounds that can reduce the neurotoxic impact of monosodium glutamate through altering neurotransmitter levels and preventing the aggregation of 8-hydroxy-2'-deoxyguanosine (8-OHdg) and amyloid. This study has claimed that ginger improves the histological characteristics of the brain and attributes this effect to the antioxidant properties of ginger [49]. A study carried out by Ha et al. has demonstrated 6-shogaol to block LPS-induced microglial activation both in the primary cortical neuron-glia culture and in the in vivo neuroinflammatory model. Also, 6-shogaol has been proven to have important neuroprotective effects in vivo in transient global ischemia by inhibition

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of microglia. These findings indicate that 6-shogaol is an important therapeutic agent for the treatment of neurodegenerative diseases [50 - 53]. Bacopa monnieri (Brahmi) B. monnieri, also popularly known as “Brahmi”, is a plant traditionally used in the Ayurvedic system of medicine for treating different forms of neurological conditions. To enhance cognitive functions, it has been widely used as a nootropic agent and is more commonly defined as a brain tonic. This increases brain perfusion, leading to the improvement of general neurological functions. “Brahmi” has strong anti-oxidants, and is used for neuroprotection. For example, “Brahmi” is used to promote neuronal activity in neurodegenerative diseases, including PD, mediated by oxidative stress [54, 55]. 1.2.4.1. Plant Description B. monnieri, sometimes referred to as water hyssop, belongs to the family of Scrophulariaceae. It is a spreading, semi-succulent herb that occurs mainly in the Indian subcontinent, Southeast Asia, Australia, the subtropical United States, and tropical Africa in marshy wetlands at an altitude of 1500 m. The leaves of B. monnieri are normally oblong in shape or spatulate, thick with light purple or white flowers [56, 57]. Phytoconstituents of “Brahmi” Chemicals with complex structures, primarily triterpenoid saponins named jujubacogenin, bacosides, and psudojubacogenin glycosides, were characterized and isolated from B. monnieri. There are about 12 structural analogs in the family of bacosides that have been recognized till now. A distinct class of saponins was described and named as the sequence of compounds I to XIII in a recent study [58]. Bacoside A, Bacoside B, Bacopa saponins, D-mannitol, and monnieri sides I to III are important among the other bacoside saponins. B. monnieri has numerous pharmacological effects, mostly due to the presence of triterpenoids, saponins, and bacosides, which are widely accepted. Bacoside A is the most widely studied bioactive component, consisting of bacoside A3, bacosaponine C, bacopaside II, and bacoside X. Several chemical constituents are also present in the B. monnieri extract, such as brahminic acid, beta acid, betulinic acid, wogonin, brahamoside, oroxinide, brahminoside, isobrahmic acid, stigmasterol, and b-sitosterol [59].

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Neuroprotective Activity of “Brahmi” in Parkinson’s Pathology To relieve different symptoms of PD, “Brahmi” extract has been used since ancient times. In various animal models, including cell lines, Drosophila, zebrafish, and rodents, environmental toxin-induced (ROT, PQ, MPTP) and genetic forms (PINK 1) were successfully used to mimic behavioral and physiological symptoms of PD [60]. It is worth remembering that B. monnieri has an essential degree of anti-oxidant activity, which is why most studies have recorded its mode of action in PD by alleviating the pathways of oxidative stress [51]. Some influential studies are mentioned in Tables 1 and 2. Table 1. B. monnieri extract results in the stabilization of motor and non-motor symptoms of PD in mouse models and cell lines using toxic environmental compounds. S. No.

Extract

1.

Standardized B. monnieri extract (BME) (200 mg/kg body weight/day; three weeks)

PD Model

PQ mice model

Result

Refs.

Improved exploratory activity reduction caused by PQ, gait defects (stride duration and paw placement mismatch), and motor dysfunction (rotarod performance). Reduced [62] depletion of ST DA levels and retained activity of mitochondrial succinate dehydrogenase (SDH).

2.

Whole plant BME (48 mg/kg)

MPTP mice model

Increased voluntary movement of the locomotion and strength test. It also improved response to tyrosine hydroxylase (TH), caspase-3, and neurogenic gene expression in the SN region.

3.

Standardized dietary “Brahmi” extract for seven days

ROT-treated PD Drosophila model.

B. monnieri guarded ROT (500 mM) mortality, prevented DA depletion, and enhanced negative geotaxis assays.

[64]

Reduced α-syn aggregation, prevented DAergic neuronal death, and maintained lipid content of nematode.

[65]

Improved climbing behaviour.

[66]

4.

5.

“Brahmi” extract

“Brahmi” extract

Transgenic α-syn and 6OHDA induced PD model in Caenorhabditis elegans Phosphatase and tensininduced putative kinase 1-PINK1 Drosophila mutant genetic model of PD

[63]

Nardostachys jatamansi (Jatamansi) N. jatamansi is a small dwarf plant found in Alpine Himalayas belonging to the family Valerianacae. “Jatamansi” has a very long history. It is being used in

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traditional and alternative medicine since ancient times. “Jatamansi” exhibits different kinds of pharmacological activities, such as anti-fungal, hepatoprotective, CNS activity (enhancement in production of neurotransmitters), anti-oxidant, anti-convulsant, anti-diabetic, and anti-Parkinsonian [67]. Plant Description It is a small, perennial, dwarf, hairy, herbaceous, and rhizomatous plant. The leaves, in dense cymes, are rosy, softly pink or blue. The rhizomes have a dark grey appearance and are crowned with reddish-brown tufted fibers. The odor is highly agreeable and aromatic. The thickness of the rhizomes is 2.5-7.5 cm in height. The shape is cylindrical and elongated [68, 69]. Phytoconstituents of “Jatamansi” The plant's rhizomes and roots are of medicinal significance and have been the key subject of phytochemical studies as well. Both volatile and non-volatile components are produced by N. jatamansi. A significant portion of volatile compounds is formed by sesquiterpenes, while the main components of nonvolatile extracts are sesquiterpenes, coumarins, lignans, neolignans, and alkaloids. The chemical test conducted by Chatterjee et al. revealed a new terpenoid ester, nardo-stachysine [70]. Sesquiterpenes are present in high amounts and are responsible for the essential oil in the roots of the plant. The major sesquiterpenes present in the jatamansi plant are jatamansone or valeranone. Alpha-patch-ulense, angelicin, β-eudesem, β-atchoulense, β-sitosterol, calarene, elemol, jatamansin, and jatamansinol are also known as sesquiterpenes [71, 72]. A new sesquiterpene aldehyde, called “nardal”, was reported from the “jatamansi” plant [73]. Neuroprotective Activity of N. jatamansi in Parkinson’s Pathology Ahmad et al. conducted a study in which 6-OHDA-treated rat models were developed. Rats were treated with 200, 400, and 600 mg/kg body weight of N. jatamansi root extract for three weeks. On day 21, 2 μL of 6-OHDA (12 μg in 0.01% ascorbic acid-saline) was infused into the right ST, while 2 μL of the vehicle was infused into the sham-operated group. Three weeks after the 6-OHDA administration, the results were very promising. Due to 6-OHDA injections, the loss of locomotor activity and muscle coordination was significantly and dosedependently restored by N. jatamansi extract. The lesions due to LPO and significant depletion of the reduced GSH content in SN were also prevented by N.

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jatamansi. A significant decrease in the level of DA and its metabolites and an increase in the number of DA D2 receptors in the ST have also been found with the treatment of N. jatamansi. There is also evidence of increased density of THIR fiber in the ipsilateral ST of the lesioned rats following treatment with N. jatamansi. The data indicate that the “jatamansi” extract could help reverse the damage caused by Parkinsonism [77]. W. somnifera (Ashwagandha) W. somnifera is popularly known as Indian ginseng or Indian winter cherry. It is generally referred to as “Ashwagandha” because it smells like horse urine. Horse means “Ashwa” and gandha means “odor.” It is commonly used in Ayurveda for the treatment of stress, anxiety, arthritis, and other CNS diseases, such as PD and Alzheimer's disease. It is claimed to be an effective neuronal tonic in Ayurveda [74, 75]. Plant Description W. somnifera is a small 2 m tall and 1 m wide shrub. The short, fine silver-grey, branched hair covers almost the whole plant. The stems below are brownish, prostrate to erect, and often without leaves. The leaves are alternating (opposite to the flowering shoots), simple, complete to slightly wavy, narrowly ovate, obviate or oblong, 30-80 mm long and 20-50 mm high, narrow to 5-20 mm long, almost hairless, and green above, densely hairy below, and narrow to 5-20 mm long [76, 77]. Phytoconstituents of Ashwagandha Through laboratory study, 35 chemical constituents have been identified. Roots of W. somnifera primarily consist of compounds known as withanolides, which are believed to be responsible for their excellent medicinal properties. Withanolides are steroidal, and have similarities with the active constituents of Asian ginseng (Panax ginseng), known as ginsenosides, both in their action and appearance [78 80]. Alkaloids, isopelletierine, anaferine, cuseohygrine, anahygrine, etc., and steroidal lactones, such as withanolides and withaferins, are bioactive chemical constituents of W. somnifera. Sitoindoside VII and VIII and withanolides with a glucose moiety of carbon 27 sitoindoside IX and X are other chemical constituents of W. somnifera. Seven new withanolide glycosides I to VII were isolated and described in 2001 by Matsuda et al. [81, 82].

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Neuroprotective Activity of Ashwagandha in Parkinson’s Pathology The production of oxidative free radicals involved in the process of neurodegenerative diseases, such as PD, is increased by compromised antioxidative defense mechanisms. Several major free radical enzyme scavenging systems, such as SOD, CAT, and GPX, are present throughout the body [83]. A defect in the activity of these enzyme processes contributes to the accumulation of toxic free radicals and the consequent degeneration of cells and tissues [84]. Manjunath et al., in 2015, conducted a study to check the neuro-ameliorative effects of W. somnifera in the ROT D. melanogaster model (Oregon-K). They found significant evidence of protection against ROT-induced lethality, and the survivor flies showed significant improvement in locomotor function. Further, biochemical analysis revealed that W. somnifera significantly reduced ROTinduced oxidative stress [84, 85]. Further analysis revealed W. somnifera extract to substantially reverse dose-dependent levels of reduced GSH, GPX, SOD, and CAT compared to the 6-OHDA rat model [86]. Prakash et al., in a PD mice model, investigated the neuroprotective function of W. somnifera extract against DAergic neurodegeneration caused by Maneb-Paraquat (MB-PQ). Important evidence has been obtained that it is capable of inhibiting oxidative stress in nigrostriatal tissues and simultaneously increasing the number of positive TH cells in the SN area of the MB-PQ-mediated brain in the PD mice model [70]. Silybum marianum (Silymarin) Silymarin is a flavonoid originating from a plant belonging to the Asteraceae/Compositae family, S. marianum. As the leaves of the plant have milky veins, it is commonly known as milk thistle. Silymarin is used mostly as a hepatoprotective agent and for gall bladder disorders. But it has some impressive neuroprotective properties aside from this, which can be used with neurodegenerative disorders, such as PD. The wide pharmacological role of silymarin is primarily due to its excellent antioxidant properties [87]. Plant Description S. marianum is a rosette-forming biennial native to the Mediterranean region, generally referred to as the Blessed Thistle or Milk Thistle (Southern Europe, Western Asia, and Northern Africa). In the first year, a showy rosette of highly lobed, obviate, spiny green (up to 20' long) leaves with distinctive white marbling occurs. When sliced, the leaves and stems exude a milky sap, which is the

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common term for milk thistle. In the second year, from the foliage rosette, a large flower stalk rises to 3-5' tall, bearing thistle-like, deeply scented, purple-pink (2' across) flower heads underpinned by spiny bracts. As the plant has finished its biennial life, flowers are replaced by seeds [88, 89]. Phytoconstituets of Silymarin The main bioactive phytochemical of silymarin is silybin, constituting more than 50% of the composition. Silychristin, silydianin, and isosilybin are also present as other flavonolignans along with some unidentified polymers. Quercetin, taxifolin, and kaemferol are present in minor quantities. Silymarin's composition depends on the variety of S. marianum and the state in which it was cultivated. Since it significantly affects biological activities, the technique of plant tissue culture is considered to be the better alternative to enhancing the silymarin content. With distinct regulators, cultural dynamics can be manipulated [90]. Neuroprotective Activity of Silymarin in Parkinson’s Pathology Silymarin, which has significant antioxidant effects, is a polyphenolic flavonoid. Its major functions are free radical scavenging, raising the level of cellular GSH, and enhancing SOD activity. Since oxidative stress is one of the key triggers of neurodegenerative processes, the use of silymarin in PD treatment can be very promising [91]. In a study, silymarin has been reported to inhibit the activation of microglia as well as the synthesis of inflammatory mediators, such as a product of TNF-α and NO, reducing damage to DAergic neurons [92]. As reported, by decreasing apoptosis in the SN and preserving DAergic neurons, silymarin maintained striatal DA levels. The anti-oxidant and anti-inflammatory functions of silymarin are the reasons for these effects [93]. In the study by Singhal et al., silymarin (40 mg/Kg) and melatonin (30 mg/Kg) were found to protect against midbrain DAergic neuronal loss and associated behavioral impairments in MB-PQ-induced animal PD models [94]. An in vitro study indicated that silymarin guards against neurotoxicity caused by lipopolysaccharide (LPS) by inhibiting microglia activation, indicating its antiinflammatory behaviour [95]. Similar in vitro experiments have shown that silymarin dissolved in dimethyl sulfoxide (DMSO) also reduces the production of superoxide and TNF-α, thus inhibiting inducible NO synthase (iNOS) [96].

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In vivo PD models have shown that silymarin (100 mg/kg) in MPTP-intoxicated mice reduces apoptosis in SN, protects DAergic neurons, and thus regulates striatal DA levels [97]. Another in vivo study demonstrated that silymarin (200 mg/kg) binds to estrogen receptors β in the CNS region, and it attenuates toxininduced neurotoxicity, inhibits LPO, and works synergistically with antioxidants, such as GSH [98, 99]. Table 2. Summary of beneficial effects of different plants on in vitro and in vivo models of Parkinsonism. S. No.

Plant

Extract/Fraction Used M. pruriens seed powder (15 g and 30 g)

1.

M. pruriens (Kauncha)

Model Used

Effects Observed

Refs.

In vivo

30g of M. pruriens preparation showed a faster onset of action, which led to peak LDOPA plasma concentration without any significant dyskinesias.

[30]

Better improvement in tremors, bradykinesia, stiffness, and cramps.

[31]

Powder of M. pruriens (4.5 g), Hyoscyamus reticulatus seeds (0.75 g), W. somnifera (14.5 In vivo g), and Sida cordifolia roots (14.5 g) in 200 mL cow’s milk M. pruriens endocarp (2.5 or 5.0 g/kg)

In vitro

M. pruriens extract was more effective than [34] synthetic L‐DOPA.

M. pruriens powder at a low dose (12.5 mg/kg) showed comparable motor reactions M. pruriens powder to synthetic L-DOPA with less dyskinesia from roasted seeds (12.5 In vivo and adverse reactions. While the high dose [35] mg/kg and 17.5 mg/kg) of M. pruriens powder (17.5 mg/kg) caused greater motor change with fewer dyskinesias for a longer period. Curcumin solution (5 μL)

2.

C. longa (Turmeric)

Curcumin in soyabean oil (incorporated in the diet)

In vitro

The addition of curcumin inhibited mutant α-syn aggregation by 32% within 48 h.

[39]

Intervention with the curcumin diet substantially increased gait and culminated In vivo in an improvement in α-syn [41] (phosphorylated forms) at cortical presynaptic terminals.

Curcumin prevented nigrostriatal degeneration by inhibiting the Curcumin 50 mg/kg/day In vivo mitochondrial dysfunction through [42] suppressing the JNK hyperphosphorylation caused by MPTP.

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(Table ) cont.....

S. No.

Plant

Extract/Fraction Used

6-shogaol (10 mg/kg/day)

3.

Z. officinale (Ginger)

Ginger rhizome extract (600 mg/kg)

6-Shogaol

4.

5.

N. jatamansi (Jatamansi)

W. somnifera (Ashwagandha)

Model Used

Effects Observed

Refs.

The number of TH-IR neurons was substantially increased by treatment with 6shogaol. It suppressed TNF-α and NO levels. It also reversed alterations in motor coordination and bradykinesia in mice In vivo [43] caused by MPTP. Also, 6-shogaol reversed MPTP-induced TH-positive cell count reductions in SNpc and TH-IR fiber density in the ST. Ginger therapy substantially attenuated the neurotoxic consequences of monosodium In vivo glutamate by reducing 8-OHdG and βamyloid aggregation as well as modifying the amounts of neurotransmitters.

[44]

6-Shogaol substantially blocked NO release and LPS-induced expression of iNOS. Anti-inflammatory effect is exerted by inhibiting the development of prostaglandin E2 (PGE2) and proinflammatory cytokines, In vitro such as interleukin-1beta (IL-1β) and TNF- [41] α, and by deregulation of cyclooxygenase-2 (COX-2), p38 mitogen-activated protein kinase (MAPK), along with nuclear factor kappa B (NF-kB) expression.

Significantly improved locomotor activity and muscular coordination. Lesions owing N. jatamansi root to LPO and extensive depletion of the GSH extract (200, 400, and In vivo content have also been prevented. It also [68] 600 mg/kg/bodyweight) raised the amount of DA and its metabolites, as the number of D2 receptors increased. W. somnifera extract

In vivo

Increased GSH, GPX, SOD, and CAT levels.

[77]

W. somnifera extract

In vivo

Oxidative stress was inhibited in nigrostriatal tissues, and the number of positive TH cells in the SN area increased.

[81]

W. somnifera extract

In vivo

Improved locomotor function and reduced oxidative stress.

[86]

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(Table ) cont.....

S. No.

Plant

Extract/Fraction Used

S. marianum extract

6.

S. marianum (Silymarin)

Model Used

Effects Observed

Refs.

In PC-12 neural cells, it improved nerve growth factor (NGF)-induced neurite outgrowth neural cells and extended their In vitro cultural survival. The extract of milk thistle [84] also preserved cultured rat hippocampal neurons against cell death caused by oxidative stress.

Silymarin dissolved in DMSO

LPS-induced activation of microglia and the production of inflammatory mediators, In vitro such as TNF-α and NO, were substantially blocked by silymarin and also the damage to DAergic neurons minimized.

Silymarin (100 mg/kg)

In the SN of MPTP-intoxicated mice, 100 mg/kg silymarin therapy greatly reduced In vivo [86] the number of apoptotic cells and protected DAergic neurons.

Silymarin (200 mg/kg)

In vivo

Silymarin (40 mg/kg)

Significantly reduced locomotor activities and TH-IR. Increases in LPO, degenerating neuron count, nitrite content, cytochrome In vivo P-450 2E1 (CYP2E1), GSTA4-4 mRNA [95] expressions, CYP2E1 and GST, P-p53 catalytic activity, Bax and caspase 9 protein expressions have been attenuated.

Oxidative stress was attenuated, and the thiobarbituric acid reactive compounds caused by 6-OHDA were reduced.

[85]

[87]

CONCLUSION PD is multifactorial and has many pathological mechanisms of neurodegeneration. Till today, there are no modern allopathic drugs that have disease-modifying effects and that can target a specific pathomechanism. On the other side, plant extracts are known to have many bioactive phytochemicals that possess different kinds of biological or pharmacological effects. This combination of bioactive phytochemicals might target different molecular pathomechanisms in neurodegenerative disorders, for instance, PD. Recently, the scientific community has developed a sufficient interest in the isolation, identification, and characterization of bioactive phytochemicals to cure PD. Traditionally, these bioactive phytochemicals have been used for the treatment of CNS-related disorders, but still lack their quality control data and safety in consumption across the population, which limits their use in the modern world of medicines. Although, many bioactive compounds from natural sources have recently been

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documented to have neuroprotective effects in different laboratories. PD models from ethnobotanical and ethnopharmaceutical resources, large-scale, doubleblind, and placebo-controlled studies, and their pharmacokinetic evidence are needed to determine the dosage type and also assess the therapeutic impact of bioactive phytocompounds on PD. Here, we have surveyed the literature for the most relevant available evidence on bioactive constituents from natural sources possessing neuroprotective function in different laboratories of PD models. Although the spectrum of these studies reported is not comprehensive, all the bioactive compounds listed have shown a major neuroprotective impact on PD models. Hence, these bioactive phytocompounds can be a promising source for the treatment of PD. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT The authors thank the LNB Library, Dibrugarh University, Assam, India, for providing the facilities required to access relevant papers. REFERENCES [1]

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CHAPTER 2

Delineating the Neuroinflammatory Crosstalk in Neurodegeneration and Probing the Near Future Therapeutics Vinod Tiwari1,*, Ankit Uniyal1, Vineeta Tiwari1, Vaibhav Thakur1, Mousmi Rani1 and Akhilesh1 Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, Uttar Pradesh, India 1

Abstract: Neurodegenerative disorders are threatening mankind with significant health and economic burden. Neurodegeneration involves the deterioration of neurons in the central nervous system (CNS), resulting in decreased neuronal survival. Therefore, it is of utmost requirement to develop a promising pharmacological strategy to minimize or prevent the progression of the underlying disease pathogenesis. In neurodegenerative disease conditions, neurons and glial cells present in the specific brain regions are damaged and depraved, resulting in specified disease symptoms in the patients. Neuroinflammation plays a major role in the degeneration of neuronal cells by regulating the expression of interleukin-1 beta (IL-1β), IL-6, IL-8, IL-33, tumor necrosis factor-alpha (TNF-α), chemokines Cxcl3 (C-C motif) ligand 2 (CCL2), CXCL5, granulocyte-macrophage colony-stimulating factor (GM-CSF), glia maturation factor (GMF), substance P, reactive oxygen species (ROS), reactive nitrogen species (RNS), impaired tuning of immune cells and nuclear factor kappa-B (NF-κB). Considering this, it is very important to understand the in-depth role of neuroinflammation in the initiation and progression of various neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), as well as Multiple Sclerosis (MS). Recent shreds of evidence have suggested that using exogenous ligands to approach various biological molecules or cellular functioning that modulates the neuroinflammation, such as microglia response, P2X7 receptors, TLR receptors, oxidative stress, PPARγ, NF-κB signaling pathway, NLRP3 inflammasome, caspase-1 signaling pathway, and mitochondrial dysfunction, helps to combat neurodegeneration in a variety of diseases. Thus, targeting the neuroinflammatory drive could provide a beacon for the management of neurodegenerative diseases. Here, we have attempted to provide comprehensive literature suggesting the role of neuroinflammation in neurodegeneration and its implication in the development of near-future neurotherapeutics. * Corresponding author Vinod Tiwari: Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (B.H.U.), Varanasi-221005 (U.P.) India; E-mails: [email protected]; [email protected]

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

Crosstalk in Neurodegeneration

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Keywords: Alzheimer’s disease, Multiple sclerosis, Neuroinflammation, Neurodegeneration, Parkinson’s disease, Pro-inflammatory cytokines, Therapeutics. INTRODUCTION The global burden of neurodegenerative disease is increasing continuously as life expectancy among people increases. The major neurodegenerative disorders are Alzheimer’s disease (AD), Huntington's Disease (HD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) [1]. Risk factors accompanying neurodegeneration are of genetic, environmental, and endogenous origin. The pathophysiology of neurodegenerative disease is not clearly understood due to the complexity of the central nervous system (CNS) and the involvement of multiple cascades [2]. This has created a substantial barrier to the development of effective therapeutics for the clinical management of neurodegenerative disorders. The major theories of neurodegeneration suggest the involvement of misfolding proteins that damages cellular machinery and leads to neuronal death [3 - 5]. The misfolded proteins initiate several downstream signaling pathways, such as neuroinflammation, impaired immune cell tuning, oxidative stress, mitochondrial dysfunction, and unchecked protein interactions. Neuroinflammation-mediated neurodegeneration is one of the key theories that has evolved over several decades [6]. Inflammation is one of the defensive mechanisms of our body that fights against pathogens and helps remove cell debris, thus maintaining cellular integrity. On the other hand, neuroinflammation is the mechanism associated with the regulation of homeostasis at the neuronal level. However, chronic inflammation or sustained inflammation is detrimental to cellular health and promotes several CNS pathologies [7]. Many preclinical and clinical studies have also reflected a cross-link between neuroinflammation and neurodegeneration. The release of inflammatory molecules results in neurodegeneration via the increased stimulation of glial cells and an altered immune response [8]. The past few decades have witnessed a strong interconnection between neuroinflammation and the persistent progression of neurodegenerative diseases, such as AD, HD, PD, MS, as well as ALS. Multiple cascades are believed to be involved in neuroinflammation, such as the activation of glial cells, demolition of the blood-brain barrier (BBB), as well as CNS trafficking of the peripheral immune cells [9]. Cell death and demyelination are the two major consequences of neuroinflammation, which can be detected by electronic techniques, such as positron emission tomography (PET), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT) [10]. Microglia are

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mainly responsible for the innate immune responses in the CNS. Dysregulation of microglial autophagy is associated with the loss of CNS homeostasis and the generation of maladaptive immune responses, which leads to cell damage [11]. Thus, impairment in the functioning of microglial cells results in the pathophysiology of neurodegeneration [12]. Microglia in the resting stage are inactive, but once they have been transformed into an active state, they stimulate cytokine storm [13]. Dysfunction of mitochondria has also been linked to CNS neuroinflammatory and neurodegenerative processes. The uncoupling proteins 2 (UCP2) and 4 (UCP4) present in the mitochondria are neuroprotective, and the dynamics of their expression may influence the pathogenesis of neurodegenerative diseases. Microglia M1 state is triggered when UCP2 is downregulated [14]. Glia maturation factor (GMF), a brain protein, has been shown in many studies to stimulate glial cells, triggering the release of neuroinflammatory mediators that cause neuronal death both in vivo and in vitro [15]. Moreover, neurogenerative disease is associated with the infiltration of peripheral immune cells, which aggravates the expression of the proinflammatory cytokines. In this chapter, we have summarized various neuroinflammatory signals associated with the development of neurodegeneration and neuronal death. Further, we have discussed the comprehensive literature on the therapeutic targeting of neuroinflammatory signaling in various neurodegenerative pathologies and its near future translational potential. NEUROINFLAMMATION: A FRIEND OR A FOE? Astrocytes and microglia are the chief mediators of inflammation in the CNS. The manner of microglial activation determines the type of response elicited, i.e., neurotoxic (pro-inflammatory) or neuroprotective [16]. M1 phenotype of microglia is mostly pro-inflammatory, whereas the M2 phenotype is neuroprotective and immunosuppressive. The M1/M2 glial cell stimulation framework has been extensively studied in neurodegenerative diseases to better understand microglia’s role in neuroprotection as well as neurodegeneration [10]. Depending on the degree of activation, the microglia stimulate the release of proinflammatory mediators, like interleukin-1 (IL-1), IL-6, tumor necrosis factorα (TNF-α), nitric oxide (NO), reactive oxygen species (ROS), and proteases. The M2 phenotype of microglia is correlated with neuroprotection and antiinflammatory effects and is consistent with alternative activation [11]. Antiinflammatory cytokines, IL-4, IL-13, IL-10, and transforming growth factor-β (TGF- β) from M2 microglia inhibit pro-inflammatory cytokines' activities, enabling normal conditions to return. Pro-inflammatory cytokines (fragments of pathogens or damaged cells) elicit an inflammatory response by factors, like IL1β, IL-6, TNF-α, NO, and other proteases, thereby causing detrimental effects in

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neurodegenerative diseases [8]. Conversely, IL-4, IL-10, IL-13, and TGF-β elicit a neuroprotective response by factors, like FIZZ1, Chitinase-3-Like-3 (Chi3l3), Arginase1, Ym1, CD206, insulin-like growth factor-1 (IGF-1), and Frizzled class receptor-1 (Fzd1), thereby initiating neuroprotection and tissue healing. Similarly, astrocytes are the characteristic glial cells in the CNS that also exert proinflammatory and neuroprotective actions. Astrocytes initiate pro-inflammatory factors, like IL-1β, TNF-α, and nitric oxide via the upregulation of certain genes. In contrast to microglia, the astrocytes mediate neuroprotection by upregulating neurotrophic factors and thrombospondins [17]. Furthermore, IL-4, IL-10 as well as IL-13 elicit the neuroprotective action of astrocytes, resulting in the release of IL-4, IL-10, and also TGF-β [16]. Previously, it was considered that the brain has the privilege to restrict immune responses and that the peripheral immune system and the brain have no bidirectional signals [18]. However, it is now very well known that the peripheral immune system and brain communicate bi-directionally and modulate pathophysiological conditions. The short-term mild inflammatory responses are required to remove any infective agents, toxins, or dead cells from the tissues and prevent the body from any damage. Minimal cytokines and chemokines [TNF-α and chemokine (C-C motif) ligand 2 (CCL2)] are essential to carry out the normal physiology of the body. Mast cell mediators and growth factors are also much needed for tissue healing, angiogenesis, innate immunity, and also for the normal growth of the neurons. An upregulation of TNF-α causes an increase in brainderived neurotrophic factor (BDNF) levels, thereby providing neuroprotection. However, an increased inflammatory response for a long duration will lead to an increase in the level of inflammatory mediators. This results in accumulation as well as activation of the inflammatory cells, causing a deleterious effect on the neurons. Also, increased peripheral immune response along with inflammatory response causes dysfunction of the BBB as well as infiltration of immune cells into the brain [19]. Thus, in a nutshell, we could conclude that neuroinflammation acts as both a friend and a foe. Although, chronic and exaggerated inflammation can severely damage cellular integrity and neuronal survival [20]. NEUROINFLAMMATION: A CRITICAL NEURODEGENERATIVE DISEASES

MEDIATOR

FOR

Progressive, site-specific, and irreversible deprivation of neurons in the CNS is the hallmark of neurodegenerative diseases. Neuroinflammation is considered the most prominent underlying cause of neurodegenerative diseases, e.g., PD, AD, HD, MS, and ALS. Now, we will understand the role of this phenomenon in aggravating and maintaining neurodegenerative diseases.

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Parkinson’s Disease PD is a progressive neurodegenerative disorder of the CNS. Bradykinesia, muscular rigidity, resting tremors, and impaired postural balance are the cardinal characteristics of PD [21]. The death of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc), Lewy bodies, and α synuclein-containing intracellular aggregates are the hallmark of PD pathophysiology [22 - 28]. Over the decades, increasing clinical and preclinical evidence has suggested the role of sustained neuroinflammation, T-cells, and activated glial cells in PD conditions. Reactive microglia were observed in the SNpc of the human brain post-mortem [29]. A neuroinflammatory response can be stimulated by a variety of causes, including misfolded protein aggregation, the production of ROS/ RNS, oxidative stress, mitochondrial dysfunction, and non-functional neurotrophic factors [30, 31]. α-synuclein (α-syn) released by degenerating dopaminergic neurons activates the microglia into the pro-inflammatory phenotype [14]. Therefore, with neurodegeneration progression, more α-syn drives a more robust inflammatory response mediated by the microglia by releasing IL-1β, TNFα, and NO [32]. This leads to further neuronal damage by interference among local cellular processes, such as cellular integrity and DNA translation. The astrocytes also have a significant role in neuroinflammation-mediated neurodegeneration. In the presence of α-syn, astrocytes increase the release of IL-6 and TNF-α, and induce astrogliosis, microglial activation, and dopaminergic neuron degeneration [33]. A few studies have indicated that viral infection may cause an inflammatory response in people with PD, but no virus candidates have been formally identified yet and linked to the disease [34]. To date, the most plausible theory is that immune responses are activated in the affected nervous system regions as a result of cellular damage and/or neuronal communication failure. Based on extensive research, it is well evident that neuromelanin is a significant cause of microglial cell stimulation, activating the production of pro-inflammatory mediators and the up-regulation of NF-κB and p38. Trafficking of immune cells into the brain is also involved in the progression of the disease. Hirsch et al. recently reported an increase in the CD4+ and CD8+ levels at the SNpc of PD patients [35]. A preclinical study reported that mice lacking CD4+ cells were protected from the nigrostriatal degeneration caused by MPTP. Results from recent in-vivo studies also show that CD4+ T cells can increase microglial activation, and thus stimulate neuroinflammation [36]. CD4+/CD25+ regulatory T cells (Tregs) are also involved in the induction of microglial-mediated apoptosis. Based on the evidence, it could be concluded that neuroinflammation promotes neurodegeneration.

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Alzheimer’s Disease AD is a neurodegenerative disease that accounts for 70% of the total cases of dementia worldwide. Extracellular amyloid plaque (Amyloid-β peptide), intracellular τ peptide, and intercellular neurofibrillary tangles (INT) are the pathological hallmarks of AD [37]. Speculation dictates that neuroinflammation precedes the actual onset of AD [38]. Microglia and astrocytes take care of synaptic transmission, neuronal plasticity, adaptation, and homeostasis [39]. However, they also participate in the aberrant pathways leading to the pathogenesis of AD. These pathways include brain proteinopathies, failure of the synapses, loss of brain plasticity, neuroinflammation, damage to the axons, and neurodegeneration. Various neuroinflammatory mediators are involved in both the initiation and the progression of AD [40]. The innate immune system, which includes microglia and astrocytes, bacteria, viruses, and fungi residues, abnormal endogenous proteins, iron overload, complement factors, antibodies, cytokines, and chemokines, including toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE), emits a slew of damage signals that disrupt CNS homeostasis [41]. Microglial cells control the activity of multiple markers expression, like the major histocompatibility complex II (MHC-II) and molecular pattern recognition receptors (PPRs), which release proinflammatory cytokine drugs, including IL-1β, IL-6, IL-12, interferon-gamma (IFN-γ), and tumor necrosis factors, under these conditions. They also produce and release cytotoxic factors with a short half-life, such as superoxide radicals (O2), NO, and ROS [42, 43]. The process of microglial stimulation is based on phenotypic characteristics, and also it is functionally diverse since the response entirely depends on the form, strength, and background of the stimulus that produces it. Factors modulating microglial behaviour may induce neuroprotection in AD [44]. Under pathological circumstances, neurotoxicity can be manifested as a result of a fine balance between neurotoxic and neuroprotective impacts. Numerous inflammatory signals from compromised homeostasis, including amyloid-β peptide accumulation, cause activation of microglia, followed by neuronal apoptosis and degeneration. Such microglial stimulation is called priming and may lead to a secondary immune response resulting in an exacerbated inflammatory response. Experimental findings indicate a switch between the pro-inflammatory phenotype M1 and the anti-inflammatory phenotype M2 of the microglia, depending on the AD progression [45]; for example, during the end stage of AD, the M1 phenotype prevails over a diminished M2 phenotype. Acute stimulation of microglia by amyloid β peptides and dying/dead cells results in their elimination by phagocytosis, reducing their spread. In contrast, chronic activation leads to an extremely negative impact due to the production of pro-inflammatory cytokines, aggravating the degeneration. As a consequence, microglia induce neuroinflammation through the recruitment of astrocytes, the release of pro-

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inflammatory cytokines, and the alteration of the function of TGF-β1. Also, extracellular dephosphorylate peptide causes the activation of the p38 mitogenactivated protein kinase pathway (MAPK) to initiate a pro-inflammatory response in AD [46]. Triggering receptors expressed on myeloid cells 2 (TREM2) mediates microglial function in response to amyloid β and extracellular τ tangles. TREM2 variants minimize the phagocytic activity of the microglia through dysregulation of the pro-inflammatory responses [29]. Healthy neurons secrete fractalkine protein (CX3CL1) that binds to the microglial CX3CR1 receptor to maintain its resting state. Besides, the cerebrospinal fluid in AD patients is deficient in CX3CL1, highlighting it as a potential target for AD treatment. Synaptic degeneration and glutamate dysregulation are a result of pro-inflammatory phenotypes of astrocytes. Amyloid β peptides initiate signaling cascades via the TNF-α and c-Jun kinase (CJK) pathways. However, γ-secretase release as activated by TNF-α causes enhanced synthesis of amyloid β peptides, further escalating the production of TNF-α and other secondary mediators [2]. These results contribute to two-fold amplification, i.e., a) extreme release of TNF-α, and b) excessive amyloid β peptide synthesis. Due to inflammatory response, the microglia result in the production and liberation of the ROS as well as RNS, and the subsequent release of both species causes neuronal cell death by oxidative stress. The role of neuroinflammation is continuously being explored in AD for dissecting the pathology and establishing newer therapeutics [47]. Multiple Sclerosis MS is a neurodegenerative disease of the CNS characterized by neuroinflammation, immune intolerance to myelin and neuronal antigens, and blood-brain barrier dysfunction. It typically affects young adults [48]. Acute inflammation by TNFα as well as IL-1β released from activated microglia and astrocytes and lymphocyte infiltration result in uncontrolled glutamatergic transmission and inhibited synaptic GABAergic transmission, which may lead to neurodegeneration during the early onset of MS [49]. Such inflammationmediated excitotoxicity and the downregulation of neurotrophic factors, like BDNF and IGF1, impact neuronal function. Moreover, TNFα and IL-1β aggravate excitotoxicity via the N-methyl-d-aspartate (NMDA) and α-amino-3-hydroy-5-methyl-4-isoxazole propionic acid (AMPA) pathways. Mitochondrial dysfunction can elicit an inflammatory response via the release of apoptotic enzymes. The timeline of the evolving MS lesion is outlined in this section [1]: self-reactive CD4 T cells are activated in the periphery, transmigrated via the BBB to the CNS, and locally reactivated by APCs [2]; cytokine-releasing CD4 T cells and other successively recruited and activated immune cells cause inflammatory lesions [3]; in the proinflammatory environment, activated effector

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pathways mediate myelin, oligodendrocyte and axon damage, leading to inflammatory lesions [50]. Previous findings suggest that inflammatory or infectious contexts not only affect CD4 T cells but are likely to modulate many other essential components of MS, such as dendritic cells, BBB cells, CD8-naïve T cells, and innate immune system cells (e.g., mast cells). In addition to the theories of molecular mimicry and bystander activation, a variety of other observations support the critical role of myelin-reactive CD4 T lymphocytes in MS pathogenesis; CD4 T cells, among other cells, are present in CNS lesions and cerebrospinal fluid (CSF) of MS patients [51]. This evidence suggests the critical role of neuroinflammation and its elicited immune response in the development and maintenance of MS. Huntington’s Disease HD is a debilitating neurodegenerative genetic condition that causes progressive motor dysfunction, emotional disturbance, and mental retardation. HD is also described by a spectrum of various psychiatric features, as well as behavioral abnormalities, including depression, anxiety, irritability, apathy, obsessivecompulsive disorder (OCD), and psychosis. Besides, HD is manifested by a cognitive impairment that is associated with a significant memory decline, even at an early stage. Unfortunately, the disease progression is neither cured nor decelerated. Neuroinflammation has been suggested as a promising target for the therapeutic intervention of HD. Using 11C-PBR28 PET/MRI, it was observed that patients with HD presented regional variation in neuroinflammation in comparison to the healthy controls [52]. The preclinical evidence suggested microglial activation and changes in CSF inflammatory protein to promote the progression of HD. Further, the search for changes in the peripheral immune system is important not only to elucidate HD pathophysiology but also to identify biomarkers useful for non-invasive monitoring of disease progression and/or response to treatment. Neuroinflammation has been suggested as an important early pathological process in HD [53]. It is mainly mediated through the activation of glia and results in the formation of soluble pro-inflammatory molecules, such as cytokines, prostaglandins, and nitric oxide, following the activation of nitric oxide synthase, thereby negatively impacting the brain structure and function. Activated microglia have been found in the neostriatum, globus pallidus, cortex, and underlying white matter in post-mortem human brain tissue in Huntington’s disease patients [54]. Pro-inflammatory mediators, including IL-1β, TNF-α, IL-6, IL-8, and MMP-9, have also been reported to be up-regulated in the same brain regions [47, 55]. Therefore, neuroinflammation may play an important role in the pathological process in Huntington’s disease and may provide diagnostics as well as therapeutics in the near future.

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Amyotrophic Lateral Sclerosis ALS is a neurodegenerative disease that involves the deterioration of upper and lower motor neurons of the anterior horn in the spinal cord and the motor cortex [2]. Substantial evidence validates neuroinflammation's role in ALS via reactive astrocyte and microglial phenotypes, expression of pro-inflammatory factors, and infiltration of peripheral immune cells (T-cells) in the motor region of the CNS [15]. There is no clear explanation for ALS progression; it has been hypothesized that it occurs in 2 stages. In the 1st stage, the anti-inflammatory and neuroprotective responses attempt to relieve neuronal stress. Supportive microglia, astrocytes, T helper-2 cells, and regulatory T lymphocytes (Treg) play a significant role in neuroprotection by secreting neurotrophic factors [56]. The Treg produces high amounts of anti-inflammatory IL-4. Therefore, the M2 neuroprotective phenotype of microglia is activated, which signals astrocytes to release IL-10, IL-6, glial-derived neurotrophic factor (GDNF), and insulin-like growth factor-1 (IGF-1) [57]. In stage 2, as neuronal degeneration takes place, a cytotoxic response is elicited by the microglia and the astrocytes [58]. Suppression of Treg activity results in the helper T1 cells releasing excessive IFN-γ. IFN-γ and activating factors released by degenerating neurons lead to the activation of the M1 phenotype of the microglia [majorly by nuclear factor-κ B (NF-κB)] and prolonged astrogliosis [47]. The CSF of sporadic ALS patients shows high levels of TREM2 and may indicate a neuroprotective mechanism by slowing down ALS progression [59]. Superoxide dismutase (SOD1) causes neuronal toxicity by initiating a strong inflammatory response that is common to ALS. It accounts for direct and irreversible damage to the neurons. Hence, astrocytes with SOD1 mutations are known to release soluble toxins that negatively affect motor neurons [53]. Fig. (1) shows the neuroinflammationassociated pathophysiology of ALS. THERAPEUTIC PATHWAYS FOR THE MANAGEMENT OF NEURODEGENERATION

NEAR

FUTURE

Neuroinflammation is one of the most common pathophysiological mechanisms found behind many neurodegenerative diseases, such as PD, AD, HD, MS, and ALS (Fig. 2). Thus, it is the most suitable target approach for potential therapeutic effects in neurodegenerative disorders. Here, we have discussed different pathways that are either being targeted or have the potential to be targeted in the future for the treatment of various neurodegenerative disorders.

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Fig. (1). Neuroinflammation is a key regulator for neurodegeneration.

Activation of the microglia and astrocytes is considered one of the earliest signs of neuroinflammation in various neurodegenerative diseases, such as AD, PD, MS, and ALS. Microglia and astrocytes, upon activation, produce various proinflammatory cytokines and liberate ROS. The former molecules cause neuroinflammation and oxidative stress, further leading to neuronal death and the release of ATP. This increases the extracellular concentration of ATP, which stimulates the NF-κB signaling pathway, eventually forming a cycle of neurodegeneration in disease pathology. Microglial Responsiveness Modulation: A Potential Tool for Neuroprotection As discussed earlier, microglia are the resident macrophages of the CNS and are involved in the immune surveillance of the CNS. Credible evidence has shown that microglia stimulation is one of the early signs of neuroinflammation in many neurodegenerative diseases [60]. In chronic conditions, the M1 stage is

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predominant and often permanent, culminating in neuronal death due to a cascade of inflammatory reactions [61].

M I state

Resting microglia

PPA g agonist, PP ARb/d agonist (Pioglitazone,

M2 state

~_____~~~~~~~~~~~~~~e~~ _________________ _

_______________________________________ I I I I I I I I I

o-chlorobenzamide cyanoguanidines, quinoline moiety derivatives

!>

Inflammatory sti:li ~

:,,,,,,,,,"",""

:'\7.

' iiiiiiiiiiiii~

~----------~ TLR2~R4

Candesartan cilexetil, Rifampicin, T AK242 IpPARg agonist

+-0 !

mature ILlb

IVXf 5

K + efflux

1

MyD88

caspase-l pro TLlb pro ILlB

j

A~

1

NLRP3 inflammasome

o/igomerisa,lon

-----..--~.~

NLRP3 protein

------------------------ ~~~~~~~~-~ -------------------- ---------------------------

Fig. (2). Microglia responsiveness modulation in neurodegeneration.

This change in microglial morphology has been confirmed to occur in neurodegenerative diseases through multiple animal models. Understanding and managing changes in microglial morphology can also prevent the initiation of neuroinflammation in neurological disorders [41]. The RNA sequencing profile of single microglial cells in the preclinical study has suggested the activation of the site and disease-specific microglia in CNS. Pharmacological inhibition of microglia is proven to be effective in mitigating neuroinflammation and enhancing dopaminergic neuron survival. The neurological deficit and neurodegeneration are both improved using a variety of inhibitors of microglia. Recent strategies are being shifted from inhibition of microglia to the restoring

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M2 stage and resisting M1 (Fig. 2). Repurposing of already existing drugs for the same could help to identify potential therapeutics for the management of neurodegenerative diseases. Microglia are normally found in a resting state, but in case of infection or diseased condition, they get activated and change their morphology. Microglial activation occurs in two states, one is a damaging M1 state and the other is a protective M2 state. In the M1 state, the activated microglia release a bunch of pro-inflammatory cytokines along with prostaglandins (PGs), ROS, and RNS. Whereas in the M2 state, activated microglia produce anti-inflammatory and neuroprotective mediators. In chronic cases, the M1 state becomes predominant and sometimes permanent, hence resulting in neuronal death by a cascade of inflammatory reactions. This shift in microglial morphology has been confirmed to occur in neurodegenerative diseases in various animal models. PPARβ/δ and PPARγ agonists are reported to mediate the conversion of the M1 state to the M2 state, thus decreasing the extent of neuroinflammation and subsequent damage. Other therapeutic strategies involve blocking or inhibiting molecular factors that contribute to neuroinflammation in the system. TLR2 and TLR4 are known to activate MyD88 mediated NF-κB/NLRP3/caspase-1 inflammasome signaling pathways for the production of proinflammatory cytokines. Every step of this pathway suggests a potential target for the attenuation of neuroinflammation. Peroxisome Proliferator-activated Receptor Gamma (PPARγ): A Potential Target against Neuroinflammation Peroxisome proliferator-activated gamma receptor agonists, pioglitazone, thiazolidinedione, and rosiglitazone, which modulate microglial activity, have emerged as a potential therapy for neuroinflammation in PD [62]. The PPARγ agonists also suppress inflammatory reactions by suppressing MyD88-dependent signaling and producing pro-inflammatory cytokines, primarily IL1β, IL23, and IFNγ. Recent investigations have found PPARβ/δ agonists to be a novel approach to mitigating neuroinflammation and providing subsequent therapeutic effects in neurodegenerative disorders. They not only have strong anti-inflammatory effects but can also sustain myelin sheath homeostasis in MS and ALS as well as amyloid β clusters depletion in patients with AD. These agonists have demonstrated neuroprotective effects against MPP in PD animal models [46]. The benefit of PPARβ/δ over PPARβ/δ is that it plays a major role in the mediation of oxidative stress and inflammatory reactions through the regulation of mitochondrial function in neurons. Chemokines (CXCL1, CXCL2, CXCL10) and iNOS expression in the cell have been identified to inhibit the upregulation of proinflammatory cytokines (TNFα, IFNγ, IL6). They also reduce ROS and NO

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production and decrease oxidative stress. Similarly, in the ALS transgenic mice model, PPARβ/δ agonist has also shown promising anti-inflammatory and neuroprotective activity [63]. P2X7 Purinergic Receptor-mediated Signalling and Neurodegeneration P2X7 receptors are another over-expressed or over-regulated gene linked with many neurodegenerative disorders. They are associated with CNS inflammatory signaling. P2X7 receptors are activated by an increased concentration of extracellular ATP. Upon activation, P2X7 leads to a series of downstream events, including inflammatory activation, caspase activation of pro-inflammatory cytokines (IL1β, IL18), PGE2 synthesis and release, and ROS and RNS production [8]. All these factors eventually contribute to further cell apoptosis, inducing neuroinflammation. The dying cells also release ATP, which is again perceived as a danger signal by P2X7 receptors [54]. Therefore, this vicious cycle never ends, and only the pathological condition of the patients continues to deteriorate. Such activity of P2X7 is more found in neurodegenerative diseases. AD, MS, PD, and ALS have been shown to have P2X7 receptor upregulation. Post-mortem studies of AD patients have found overexpressed P2X7 genes in their brains. Similarly, overexpression in MS active lesions has been reported in MS patients with P2X7 upregulation. Targeting P2X7 receptors may thus be considered a possible therapeutic strategy. P2X7 antagonist could be a promising strategy against neuroinflammation (a). In the Alzheimer's disease animal model, amyloid β was found to activate P2X7 via excessive ATP release, resulting in the recruitment of cytotoxic T-cells [64]. Even in the APPPS1 mice model, the lowering of the P2X7 receptor was proven to reduce the load of amyloid β proteins. P2X7 is one of the most common antagonists for both animals and humans, as well as Brilliant Blue G (BBG). In preclinical studies, BBG has been shown to have neuroprotective effects, thus suppressing inflammatory reactions in the AD rat model [61]. Similarly, in SOD1-G93A mice, P2X7 inhibition by BBG was also found to delay the pathogenesis of ALS. In addition to the sodium ion canals, BBG antagonizes many other purinergic receptors and leads to unpredictable or divergent effects. Intensive research and testing in several major pharmaceutical companies are being conducted to find a suitable P2X7 receptor antagonist, which is BBB permeable, targeted, and of high power. Multiple molecules were prepared to block the P2X7 receptor activity. Cyanoguanidines and quinolone derivatives have, until now, been successfully investigated as possible P2X7 antagonists in the P2X7 receptor [62]. Among these heterocyclic derivatives, the o-chlorobenzamide moiety was successfully achieved in phase II clinical trials [51]. The progress in the field has proven the glory of targeting the P2X7 receptor to mitigate neuroinflammation in various neurodegenerative

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disorders. NF-κB Signaling and Neuroinflammation NF-κB is responsible for regulating genes of cytokines, chemokines, enzymes, pro-inflammatory transcription factors, and adhesion molecules, which are required for the survival of neurons. In case of inflammatory or pathogenic response inside the cell, NF-κB gets activated. NF-κB is abundant in CNS, and it can modulate neuroinflammation, neurotoxicity, and neuroprotection. Therefore, the regulation and inhibition of NF-κB play a pivotal role in controlling disease progression [61]. Inhibition of NF-κB has been significantly shown to reduce the levels of proinflammatory cytokines (TNFα, IFNγ, IL1β) and chemokines along with other inflammation-causing mediators, and repress the activation of microglia. NF-κB in AD has been proven to produce NO in the presence of amyloid β protein, further deteriorating the patient’s condition. It has also been shown that NF-κB is responsible for mediating TLR signaling in response to neuronal injury in CNS. Moreover, NF-κB expression inhibition in CNS has been found to decrease the movement of leukocytes across BBB. NF-κB-inhibiting molecules, tanshinone-I resveratrol [65], rhinacanthin C, and trans cinnamaldehyde have been investigated to successfully suppress inflammation by decreasing the level of TNFα, IFNγ, IL1β, IL1a, NO, COX-2 and PGE2 enzyme in LPS-induced neurotoxicity mice models [41]. Targeting NF-κB was proven to improve locomotor behaviors and provide neuroprotection in mice with rotenoneinduced nigral neurodegeneration. Further, preclinical studies have demonstrated NF-κB as an attractive and potential target that can be translated into the clinical setup [66]. Toll-like Receptors: The Biological Switches for Neuroinflammation Toll-like receptors (TLRs) play a major role in the innate immunity system. They activate the NF-κB pathway via the MyD88 gene to upregulate the transcription of pro-inflammatory cytokines as well as immune cells [21]. TLR4 is actively found to be involved in the release of proinflammatory cytokines, such as TNFα, IL1β, and IL6, which are heavily responsible for neuroinflammation. A variety of natural molecules targeting TLR are being tested against neurodegeneration. Flavonoids, lignans, phenolic alcohols, and phenolic acids are examples of such molecules. But because of low BBB permeability, rapid metabolism, and poor absorption, the above polyphenols are not a good candidate for a potential therapeutic approach. However, using the state-of-art approach to enhance the pharmacokinetic profile of such ligands could help to overcome such problems. In AD, activation of TLR has been reported to have both beneficial as well as

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damaging roles. TLR4 specifically can worsen the deteriorating AD condition by increasing levels of proinflammatory cytokines and ROS, whereas deficiency of TLR2 and TLR9 enhances clearance of amyloid β proteins. Moreover, MPTP mouse model with the genetic absence of TLR4 suggested the importance of this receptor in the pathogenesis of PD [67]. In another study, absence of TLR4 prevented dopamine neurons from any potential damage, reduced neuroinflammation, and also decreased the significant level of α-synuclein protein in the brain. Small molecule antagonists of TLR4 and TAK242 reduce TNFα production, α-synuclein mediated oxidative stress, and cell apoptosis in vitro [68]. Similarly, inhibiting TLR2 expressions has been shown to reverse M1 microglial phenotype and prevent P2X7-dependent inflammatory responses. In MS patients, TLR expressions were found to be upregulated in CNS and peripheral blood mononuclear cells. Also, downregulation of TLR2 and TLR9 is observed in MS [67] to deploy neuroprotective effects against inflammatory responses, whereas deficiency of TLR4 presented enhancement of neuroinflammation. Targeting TLR4 was found to be beneficial in HD by suppressing neuroinflammation. Further, the intracellular dimerization of TLR4 and TLR6 was observed to reduce the receptor assembly and inhibit microglia-mediated neurodegeneration [69]. The use of artificial intelligence-assisted drug discovery followed by in vitro and in vivo testing could provide the development of promising candidates that could modulate the TLR signaling. NLRP3 Inflammasome and Caspase-1 Signalling in Neurodegeneration NLRP3 inflammasome is highly expressed in CNS and is accountable for triggering caspase-1, eventually leading to proteolytic cleavage of precursors of inflammatory cytokines, like IL 1β and IL18, thereby mediating cell pyroptosis. NLRP3 is of critical importance in the progression of neuroinflammation. Its targeting approaches are still experimental, but recent studies provide some promising evidence of it as a near-future therapeutic target. In vitro studies have found that NF-κB and TLR are two important checkpoints that are required for activating NLRP3 inflammasome-mediated inflammatory damage. Recent studies have demonstrated NLRP3 inflammasome to contribute to the pathology of various neurodegenerative diseases. The NLRP3 and caspase 1 expressions are found to be upregulated in AD [70], ALS [71], and MS patients [15]. Small molecule inhibitors of NLRP3 are emerging to have high specificity and potency towards NLRP3 inflammasome. Pterostilbene and glyburide [72] are two such examples that have been associated with inhibiting the NLRP3 inflammasome signaling pathway in in vivo studies. Moreover, MCC950, a highly specific and potent NLRP3 inhibitor, has demonstrated a significant decline of amyloid β proteins in the AD mouse model. Benzyl isothiocyanate has also been reported to

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suppress the activation of the inflammasome, production of ROS, and other inflammatory mediators, hence hindering the secretion and regulation of IL1β cytokine. Similarly, caspase inhibitors also have the potential to attenuate inflammatory responses in neurodegenerative conditions. Caspase 1 inhibitors, such as VX-765, have been shown to have neuroprotective effects on the J20 mice model of AD [73]. Neuroinflammation-associated Oxidative Stress Multimodal Cascade Oxidative stress and neuroinflammation are the characteristic features of neurodegeneration. Innate immune responses lead to the liberation of ROS in the CNS. Further, increased ROS production leads to neuronal damage and loss through neuroinflammation [74]. The molecular mechanisms involved in immune-mediated oxidative stress as well as neurodegeneration are not yet clear. However, activation of the microglia cells is considered the prime contributor. A prolonged pro-inflammatory and pro-oxidant environment followed by persistent activation of the microglia can cause deleterious effects on the neurons. Oxidative stress is also considered to be a hallmark in progeroid conditions. In down syndrome, there is a genetic imbalance in chromosome 21 that contains the genes for the enzymes involved in oxidative stress. It is distinguished by a breach in antioxidant defense [75]. Other relevant characteristic clinical symptoms of down syndrome are impaired cognition and that individuals are more susceptible to AD [76]. Therefore, a deep understanding of the mechanisms involved in progeroid conditions might provide insight into the pathophysiology of neurodegenerative diseases. Targeting oxidative stress using endogenous ligands demonstrated a strong anti-inflammatory effect in scopolamine-induced neurodegeneration. Further, exogenous compounds, such as a natural product, were also screened against oxidative stress-induced neuroinflammation/neurodegeneration. It has been found that inhibition of oxidative stress leads to the suppression of inflammatory activity and mitigates neurodegeneration [77]. Medicinal plant and bioactive compounds found in algae and fungi play a very important role in reducing inflammation in various neurodegenerative diseases [78 - 82]. Neuroinflammation and Mitochondrial Dysfunction Mitochondria is the prime source of ROS and is liberated as a by-product during the electron transport chain activity [73]. These are also considered a direct target for ROS. Mitochondrial rearrangement caused due to oxidative stress is indicated as a contributor to neurodegeneration. Recently, it has been found that apart from providing energy and ROS signaling, mitochondria also trigger inflammation through a toxic signaling response. In response to various stressors, mitochondrial

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DNA (mtDNA) can be displaced into intra- or extra-cellular compartments [74]. The mechanism of mtDNA unloading through the mitochondria is not fully understood. Extracellular vesicle is one of the postulated theories that make the mtDNA release. Once delivered, mtDNA may associate with damage-associated molecular patterns (DAMPs) that trigger an innate immune inflammatory response. Mitochondrial plasticity is additionally affected by energy-detecting mediators, including insulin, insulin-like growth factor 1 (IGF1), mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and Sirtuins. With regards to neurodegeneration, metabolic alterations are closely associated with mitochondrial dysfunction and CNS pathologies. The mitochondrion integrity is dysregulated during neurodegeneration [72]. Neuroinflammation is related to a huge arrangement of neurological issues for which mitochondrial-derived vesicles (MDVs) may address a common thread, supporting disease progression. Failing mitochondrial fidelity pathways disserve a further layer of mitochondrial quality control (MQC) arranged by mitochondrial–lysosomal crosstalk. Reports have suggested that mitochondrial dysfunction leads to the inflammatory cascade initiation, which further damages the CNS cells [77]. CONCLUSION Neuroinflammatory conditions are caused due to immune responses that damage the nervous system. In the CNS, inputs obtained from both the innate and acquired immune systems along with glial cell responses are considered factors for altered brain tissue homeostasis. The differential activation of the microglia is involved in the regulation of neuroinflammation and can either produce a neuroprotectivity or a neurotoxic effect. Therefore, environmental exposure is a crucial element for the fate of neurons concerning degeneration or protection. Additional studies must be carried out to understand the versatility of microglia. The involvement of other cells, such as astrocytes, is also crucial for the development of neurodegeneration. A balance between pro-inflammatory and anti-inflammatory cells is critical in the progression of neurodegenerative diseases. The inflammation for a sustained period degrades the local cellular machinery and results in neuronal death. Targeting neuroinflammation is being tested in a wide variety of diseases, including neurodegeneration. Comprehensive studies using a translational approach are required to develop potential therapeutics. Targeting microglia-astrocyte axis, P2X7 and TLR receptors, oxidative stress, PPARγ, NF-κB signaling pathway, NLRP3 inflammasome, and

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caspase-1 is a potential near-future approach to modulate neuroinflammationmediated neurodegeneration. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS This work is supported by Core Research Grant (CRG/2020/002621) and SPARC grant (SPARC/2018-2019/P435/SL) awarded to Dr. Vinod Tiwari by the Science and Engineering Research Board and Ministry of Human Resource & Development, Government of India, respectively. The authors would also like to acknowledge the Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, for providing infrastructure and support. REFERENCES [1]

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CHAPTER 3

Modulations of SIRTUINs and Management of Brain Disorders Sudhir Kumar Shekhar1,*, Sarfraj Ahmad Siddiqui2,* and Girish Rai3 Department of Biochemistry, King George Medical University, Lucknow-226003 (U.P.), India Department of Zoology, University of Lucknow, Lucknow-226007 (U.P.), India 3 Vivekanand Government PG College Maihar, Manpur- 485771 (M.P.), India 1 2

Abstract: Neurodegenerative disorders are the conditions in which neurons of the central and peripheral nervous systems degenerate. Various cellular and molecular processes are associated with the progression of such degeneration, including inflammation, apoptosis, and axonal degeneration. Recently, SIRTUINs have emerged as one of the key factors associated with neurodegenerative disorders. SIRTUINs are involved in the regulation of several cellular and molecular processes in neurons of the nervous system through the deacetylation of target proteins. The chapter focuses on the modulatory role of SIRTUINs in neurodegenerative disorders and their potential therapeutic application.

Keywords: Acetylation, Brain Neurodegeneration, SIRTUINs.

disorders,

Histone

modifications,

INTRODUCTION The SIRTUINs (Silencer information regulator) or SIRT are the histone deacetylation family of proteins with both histone and non-histone targets. SIRTUINs are class III histone deacetylases that include 7 homologous subtypes (SIRT1-7) (Table 1), which are localised in either nucleus, cytoplasm, mitochondria, or more than one compartment. SIRTUINs (Sir2 SIRTUIN) were first identified in yeast (Saccharomyces cerevisiae) as a factor for enhancing the life span, but later studies have found their role in Caenorhabditis elegans, Drosophila melanogaster, and other organisms too. The main enzymatic function Corresponding authors Sudhir Kumar Shekhar and Sarfraj Ahmad Siddiqui: Department of Biochemistry, King George Medical University, Lucknow- 226003 (U.P.), India and Department of Zoology, University of Lucknow, Lucknow- 226007 (U.P.), India; E-mails: [email protected] and [email protected]

*

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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played by SIRTUINs is deacetylation of histones and non-histone both, thereby regulating the epigenetic as well as intracellular functions of cells. SIRTUINs are mainly nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that also function in the metabolic regulations of the cells. These SIRTUINs have diverse functions that vary concerning the organ as well as the organism where they are present. Table 1. SIRTUINs classification, location, and functions. SIRTUINs

Subcellular Location

Histone Targets

Non-histone Targets

Primary Functions

SIRT1

Nucleus, Cytosol

H1, H3, H4

p53, DMT1, BCL6, Tat, Ku70, HMGCS1, Tip60, p300, FOXO, NFκB

Regulation of cellular metabolism, cell survival, stress response

SIRT2

Nucleus, Cytosol

H3, H4

α- tubulin, FoxO3a, PEPCK1, p53, NFκB

Microtubule stability, cell cycle regulation, heterochromatin formation

SIRT3

Nucleus, Mitochondria

H3, H4

AceCS2, MnSOD, GD, LCAD, HMGCS2, IDH2

Regulates mitochondrial function and thermogenesis

SIRT4

Mitochondria

Glutamate dehydrogenase, Malonyl Co-A decarboxylase

Suppress insulin secretion

SIRT5

Mitochondria

CPS1

Unknown

SIRT6

Nucleus

H3

DNA polymerase-β, TNF-α, CtIP

DNA repair

SIRT7

Nucleus (especially in nucleoli)

H3

RNA polymerase I, GABPβ1, p53

Regulation of rRNA synthesis, ribosome synthesis

SIRTUINs regulate several brain functions, including basic physiology to higherorder cognitive function. Recent studies have suggested their role in the differentiation and cell division of neural precursor cells. In other studies, the role of SIRTUINs in neurodegenerative disorders has been confirmed, where their main functions are neuroprotective, anti-apoptotic, and anti-inflammatory in neurons. Several preclinical studies have supported the function of SIRTUINs in neurodegenerative disorders [1 - 3]. The chapter here discusses the role of SIRTUINs in neurodegenerative disorders and their therapeutic approaches. SIRTUINS STRUCTURE AND TYPES SIRTUINs are a family of proteins involved in several cellular processes, such as transcription, apoptosis, aging, inflammation, and stress. These SIRTUINs contain one of the most important activities, such as mono adenosine diphosphate (ADP)ribosyltransferase, deacylase activity, deacetylase, desuccinylase, demalonylase,

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demyristoylase, and depalmitoylase. SIRTUINs control cellular homeostasis through the regulation of various cellular processes. SIRTUINs require the coenzyme NAD+ for their function, which is present in all living cells. The Sir2 (silent mating-type information regulation 2) SIRTUIN from yeast was the first discovered SIRTUIN, which regulates cellular processes in yeast. Sir2 and some other SIRTUINs with deacetylase activity hydrolyse the acetyl group from lysine residues and release O-acetyl-ADP-ribose, deacetylated substrate, and nicotinamide. Nicotinamide is a regulator of SIRTUIN activity, which depends on the energy status of the cell via the cellular NAD+/nicotinamide adenine dinucleotide hydrogen (NADH) ratio, the levels of NAD+, NADH, or nicotinamide (NAM), or a combination of these molecules. SIRTUINs with histones deacetylation activity are structurally and mechanistically distinct from other classes of histone deacetylases (HDACs; classes I, IIA, IIB, and IV). These SIRTUINs have a different protein fold and use Zn2+ as a cofactor. SIRTUINs are a member of the class III protein deacetylase family, which unlike other HDACs, specifically require NAD for their activity [4]. NAD is an important cofactor for the electron transport chain and is also involved in many enzymatic reactions [3, 5]. Besides having HDAC activity, mammalian SIRTUINs also contain deacetylase activity for the non-histone protein substrates. The deacetylation activity of SIRTUINs comprises two main steps. The first step involves the cleavage of NAD to produce NAM, and the second step involves the transfer of the acetyl group from a substrate to the ADPribose moiety of NAD that produces O-acetyl-ADP ribose and the deacetylated substrate [6]. SIRT1 SIRT1 (Fig. 1), a member of the SIRTUIN family, is a NAD-dependent deacetylase that removes acetyl groups from various histones and non-histone proteins. SIRT1-subtype of SIRTUIN is present primarily in the nucleus but also shuttles to the cytoplasm. SIRT1 is involved in the regulation of a broad range of physiological functions, such as gene expression, regulation of cell division, regulation of metabolism, and aging. SIRT1 regulates p53protein, FOXO (forkhead box O transcription factors regulated by insulin/Akt), HES1 (hairy and enhancer of split 1), HEY2 (hairy/enhancer-of-split related with YRPW motif 2), PPARγ (peroxisome proliferator-activated receptor-gamma), CTIP2 [chicken ovalbumin upstream promoter transcription factor (COUP-TF) - interacting protein 2], p300, PGC-1α (PPARγ coactivator), and NF-κB (nuclear factor kappa B), stimulates autophagy, and activates TH cells.

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Fig. (1). SIRT1 protein structure (4IG9 from Protein Data Bank).

SIRT2 The SIRT2 subtype SIRTUIN is primarily found in the cytoplasm, which is transported to the nucleus. In the cytoplasm, SIRT2 regulates α- tubulin, FoxO3a, phosphoenolpyruvate carboxykinase 1 (PEPCK1), p53, and NF-κB proteins functions by deacetylation activity, thereby controlling the differentiation of oligodendroglia cells, microtubule stability, and cell cycle regulation [7, 8]. In the nucleus, it maintains the heterochromatin state and also regulates the cell cycle through histone H4K16 deacetylation. Through FOXO1 deacetylation, SIRT2 controls adipocyte differentiation [9, 10]. SIRT3 SIRT3 is present in both the nucleus and mitochondria but is principally known as mitochondrial SIRTUIN. The N-terminal of SIRT3 contains mitochondriontargeting sequences that recruit it in mitochondria [11 - 13]. It has both histone and non-histone targets. The histone targeted by the SIRT3 includes H3 and H4, while non-histone targets include acetyl-CoA synthetase 2 (AceCS2), manganesecontaining superoxide dismutase (MnSOD), glutamate dehydrogenase (GDH), long-chain acetyl-CoA dehydrogenase (LCAD), NADH: ubiquinone oxidoreductase subunit A9 (NDUFA9), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), and isocitrate dehydrogenase 2 (IDH2) protein. SIRT3 deacetylates AceCS2, which results in increased acetyl-CoA synthesis activity [14]. In mitochondria, the most important function of SIRT3 is to regulate mitochondrial functions, including thermogenesis. NDUFA9, a protein subunit of the complex I of the electron transport system, is also controlled by the SIRT3mediated deacetylation, which in turn regulates cellular ATP levels [15]. Furthermore, the SIRT3 is also known to control fatty acid oxidation through the activation of LCAD by its deacetylation [16].

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SIRT4 SIRT4 is a mitochondrial SIRTUIN having only ADP-ribosylation that exhibits NAD+-dependent deacetylase activity. It has an N-terminal mitochondrial signal sequence that guides it to mitochondria. Its main target includes GDH and malonyl Co-A decarboxylase (MCD). SIRT4 suppresses insulin secretion by pancreatic β-cells in response to calorie restriction (CR) through ADPribosylation of GDH [11]. SIRT4 inhibits fatty acid oxidation through SIRT1dependent deacetylation of MCD in muscles and liver cells [17]. SIRT4 acts as a tumor suppressor protein whose overexpression is known to suppress the proliferation of cancer cells through the inhibition of glutamine metabolism. SIRT5 SIRT5 protein is encoded by the SIRT5 gene in humans. It is primarily localised in the mitochondrial matrix due to the presence of an N-terminal mitochondrial signal sequence. It especially contains deacetylase, desuccinylase, as well as demalonylase activity that removes acetyl, succinyl, and malonyl moiety, respectively, from the lysine residues of proteins. SIRT5 regulates the urea cycle through deacetylation and activation of carbamoyl phosphate synthetase 1 (CPS1), which is an initiating and rate-limiting step of the urea cycle in the liver mitochondria [13]. An increased CPS1 activity and urea production have been observed in mice that overexpress the SIRT5 gene; however, contrary to this, SIRT5 knockout mice exhibit elevated ammonia levels [18]. In broad activity, SIRT5 regulates proteins that are involved in various cellular processes, such as glycolysis, Kreb’s cycle, fatty acid oxidation, electron transport chain (ETC), ketone body formation, nitrogenous waste management, and ROS detoxification. SIRT5 has a dual role in cancer progression as it both promotes and suppresses tumor. SIRT5 exhibits a crucial role in cardiac functions as well as stress through the regulation of energy metabolism of cardiac cells. SIRT6 SIRT6 SIRTUIN, situated in the nucleus, is an NAD+-dependent enzyme. It contains deacetylase activity that targets both histone and non-histones proteins, including histone H3, DNA polymerase-β, tumor necrosis factor-alpha (TNF-α), and C-terminal interacting proteins (CtIP) [19 - 21]. The SIRT6 regulates several molecular pathways associated with aging, stress, DNA repair, telomere stability, inflammation, neurodegeneration, cardiac hypertrophic responses, and glycolysis [22, 23]. The SIRT6 is also required for postnatal development and survival, as

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suggested by some studies on mice. The anti-aging role of SIRT6 protein was confirmed by a SIRT6 knockout mice study that showed premature aging syndrome, characterized by spinal curvature, greying of the fur, lymphopenia, and low levels of blood glucose. Furthermore, the mice with overexpression of SIRT6 protein exhibit an increased lifespan. SIRT7 SIRT7 is an NAD+-dependent deacetylase present in the nucleolus, where it functions as a positive regulator of RNA polymerase I transcription [24]. SIRT7 is a highly expressed tissue that is metabolically active (e.g., liver and spleen) and non-proliferating (e.g., heart and brain). SIRT7 helps in the transcription of DNA through the promotion of DNA polymerase I, DNA polymerase II, and DNA polymerase III. The deacetylase activity of SIRT7 SIRTUIN targets specifically H3 histone protein, while non-histone targets include RNA polymerase I, GA binding protein-beta 1 (GABP-β1), and p53. It is involved in the regulation of transcriptional machinery through controlling rRNA and ribosome synthesis. The important role of SIRT7 in anti-aging was suggested by the study showing signs of aging-related changes, such as kyphosis (an abnormal backward curve to the vertebral column), loss of subcutaneous fat, degenerative heart hypertrophy, and premature death in SIRT7-knockout mice [25]. SIRTUINS IN DIFFERENT BRAIN FUNCTIONS SIRTUINs are intracellular enzymatic proteins with NAD+-dependent deacetylases activity. The proteins were first identified as a SIRT2 factor in S. cerevisiae yeast [26] that controls the lifespan of yeast through the promotion of genomic stability. SIRTUINs are extensively conserved proteins in organisms, ranging from bacteria to humans. On account of their deacetylase activity, these are grouped with HDACs family proteins but under a separate class of class III HDACs. SIRTUINs condense chromatin through the deacetylation of lysine residues on histone proteins. Despite having sequence similarity, all SIRTUINs do not show similar deacetylase activity. In particular, some SIRTUINs, such as SIRT1, SIRT2, SIRT3, and SIRT7 contain NAD+-dependent deacetylase activity; while SIRT4, SIRT5, and SIRT6 show somehow weak or no apparent deacetylase activity. The structural analysis of the catalytic domain of human SIRT1 confirmed that the enzymatic activity of SIRT1 is regulated by the regulatory domain present at the c-terminal region [27] (Fig. 2).

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Fig. (2). Protein domain structure of SIRTUINs.

The subcellular localisation of SIRTUINs affects the functional diversity among them as some of them are localised in the nucleus, some in mitochondria, and some in cytoplasm, while some involve overlapping localisation. For example, the SIRT1 SIRTUIN is localized principally in the nucleus, where it deacetylates nuclear transcription factors, such as FOXO, p53, p300, and NF-κB. However, during neuronal differentiation events, this same SIRT1 SIRTUIN is transferred to the cytoplasm. The SIRT2, which is present predominantly in the cytosol, interacts with the microtubules and deacetylates α-tubulin, resulting in microtubular stability and cell cycle regulation. Moreover, the SIRTUIN SIRT3, SIRT4, and SIRT5 are mostly present in the mitochondria having important mitochondrial functions, such as thermogenesis. SIRT6 and SIRT7 SIRTUINs are present in the nucleus, where they are associated with DNA repair and transcription regulation [24]. Studies have suggested the role of SIRT1 in several brain functions, such as synaptic plasticity, neuronal growth, survival, lineaging of neural precursor cells, as well as the development of the nervous system [28, 29]. Several brain functions are controlled by the SIRT1, whose absence results in various types of dysfunctions in the nervous system, such as diminishing endocrine secretions and cognitive dysfunction, including impaired learning and memory [30, 31]. SIRT1 is a crucial factor for neuroprotection against neurodegenerative agents. Its protective function against neurodegeneration has been well proved through different in vivo and in vitro studies on AD, ALS, and Wallerian degeneration (WD) [32 - 34]. SIRT1 is expressed ubiquitously in the animal system and is well known for its high expression in the brain. The expression of SIRT1 occurs in both neurons and glial cells [35, 36]. Higher-level expression of SIRT1 occurs in the hippocampus

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and hypothalamus, as confirmed by the histological analysis of mouse brain tissue [37]. The early embryonic stage is characterized by higher SIRT1 expression but the level continuously decreases throughout the development stages up to the adult stage. Aging and pathological conditions also affect SIRT1 expression in the brain, as confirmed by the studies showing a decreased expression of SIRT1 both by age and in neurodegenerative conditions [38]. Furthermore, the energy input also affects SIRT1; when the input decreases, the expression increases in the brain as well as in other tissues [39]. The embryogenesis and neurogenesis development is regulated by SIRT1. SIRT1 protein is involved in major steps of neurogenesis through the regulation of potency of embryonic stem cells (ESC) and fate determination of neural precursor cells (NPCs) [40 - 42]. SIRT1 controls the expression as well as the activity of Nanog, Oct-4, Hes1, and Sox-2 proteins, which are important factors involved in the maintenance of pluripotency in stem cells [43]. Its overexpression is reported to be a negative regulator of neurogenesis, which in turn affects neurogenesis in the neural tube of a chick through inhibition of neurogenin2 (Neurog2), a neurogenesis-promoting factor, while its inhibition using NAM, a SIRT1 inhibitor, promotes differentiation of neural stem cells [44, 45]. The nuclear-cytoplasmic localization of SIRT1 is an important mechanism in determining neuronal differentiation. Its cytoplasmic localization maintains the NPCs stage, while its presence in the nucleus governs the differentiation of neurons. When in the nucleus, it suppresses the activity of the Hes1 transcription factor and activates Tuj1 proteins, which result in the promotion of neuronal differentiation, as confirmed through in vitro and in vivo studies [36]. Adult neurogenesis, which occurs mainly in the dentate gyrus (DG) of the hippocampus and sub-ventricular zone (SVZ), is under the control of SIRT1. In these regions (SVZ and DG), SIRT1 is expressed by the proliferating cells. Ablation of SIRT1 gene through the knockdown method using lentivirus enhances neurogenesis in the SVZ and DG; however, it does not affect the proliferation of NPCs [46]. Moreover, the role of SIRT1 as a negative regulator of adult NPCs differentiation is confirmed by different studies. These studies show that enhancing SIRT1 activity either by overexpression of the SIRT1 gene or through pharmacological stimulation using resveratrol results in the inhibition of NPCs differentiation. Interestingly, SIRT1 plays dual functions in the regulation of proliferation and differentiation of adult neural stem cells (NSCs). SIRT1, at one end, promotes the proliferation of adult neural stem cells, but at the same time, it inhibits their differentiation. Apart from the proliferation of NSCs, SIRT1 also regulates the growth of

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neuronal processes, such as dendritic projections and branching along with the length of the axon, as reported by the studies involving the hippocampus. These studies showed that enhanced SIRT1 activity increases axonogenesis as well as elongation of axon processes through deacetylation of Akt. The Akt protein functions through the inhibition of glycogen synthase kinase 3 (GSK3) in these neurons [47, 48]. This function of SIRT1 was further confirmed by the studies where SIRT1 knockdown enhanced the mechanistic target of rapamycin (mTOR) signaling that inhibits axon and dendritic processes and neuronal survival. Enhancing SIRT1 activity either through its overexpression or through the treatment of SIRT1 activator (resveratrol) led to increased dendrite branching. The tumor suppressor protein p53, which regulates the apoptosis of neurons, is under the control of SIRT1. The SIRT1 deactivates the p53 protein through deacetylation, which in turn reduces apoptosis and promotes the proliferation of neuronal cells during development [49 - 52]. Hypothalamus is a brain center that monitors metabolic and hormonal alterations in our body system and accordingly regulates vital functions, like temperature, hunger, thirst, sleep cycles and synthesis, and secretion of hormones [53 - 55]. It is composed of important nuclei, including the arcuate nucleus (ARC), ventromedial hypothalamic nucleus (VMH), paraventricular nucleus (PVN), and lateral hypothalamic (LH) area [56]. The ARC nuclei of the hypothalamus contain two types of neurons that control feeding behaviour. These neurons include (a) anorexigenic pro-opiomelanocortin (POMC) neurons that secrete alphamelanocyte-stimulating hormone (α-MSH) and cocaine and amphetamineregulated transcript peptide (CART); and (b) orexigenic agouti-related peptide (AgRP) neurons that secrete neuropeptide Y (NPY), AgRP, and gammaaminobutyric acid (GABA). Of these, the α-MSH hormone increases satiety by stimulation of melanocortin receptors (MCR) (type 3 and 4) while AgRP inhibits these receptors and increases intake of food or hunger [57]. These POMC and orexigenic AgRP neurons that regulate hunger and food intake express SIRT1. The SIRT1 is not only restricted to only ARC nuclei but also expressed in other hypothalamic nuclei. Although the role of SIRT1 in hunger and feeding behaviour is well known, studies have found a different association of SIRT1 in the hippocampus with feeding behaviour. Inhibition of SIRT1 either by using an intraventricular injection of Ex-527, a SIRT1 inhibitor, or by siRNAmediated knockdown of SIRT1 decreases food intake through increased expression of POMC and decreased expression of AgRP [58]. Although POMC neuron’s specific knockout of SIRT1 shows a higher association for diet-induced obesity through decreasing energy consumption, it does not affect feeding behaviour [31]. Fasting is associated with the SIRT1, but its association is inconsistent in different studies. It has been reported by one study that fasting

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increases the ubiquitination-mediated decrement of SIRT1 in the hypothalamus [59]. While, another study showed increased SIRT1 in the dorsomedial hypothalamus and LH under fasting conditions. Similarly, adenovirus-mediated overexpression of SIRT1 in the mediobasal hypothalamus nuclei of mice results in a decrease in food intake behaviour [59 - 61]. Although the SIRT1 is considered an important factor that regulates hunger and consumption of food, the exact function of the SIRT1 receptor is requisite to be worked out. SIRTUINs are well known for their role in controlling several brain functions, including basic metabolism to complex activities, such as learning and memory and cognitive functions. SIRT1 and SIRT2 are the most widely studied SIRTUINs that are associated with various types of brain functions [3, 62]. Numerous brain functions, including synaptic plasticity, neurogenesis, dendritic arborisation, and cognitive functions, are under the control of these SIRTUINs. The studies have confirmed the role of SIRT1 in cognitive functions where SIRT1 deleted mice exhibited impaired cognitive functions, such as spatial learning as well as associative memory. This impaired cognitive function was associated with the decrement in dendritic branching in the hippocampal neurons, including alterations of the genes associated with the myelination, synaptic plasticity, membrane fusion, and metabolism of amino acids and lipids [37]. The exact role of SRT1 in brain function was confirmed by the studies of Gao et al., where deletion of the SIRT1 gene in nestin-positive NPC diminished synaptic plasticity and memory function [30]. The mice with deletion of the SIRT1 gene exhibited impaired memory functions in novel object recognition tasks and fear conditioning behaviour. These neuropsychological changes are associated with the reduction in neurotrophic factors, such as cAMP response binding protein (CREB) and brain-derived neurotrophic factor (BDNF), associated with synaptic plasticity. Decreased SIRT1 expression is under the regulation of miRNAs, which contributes to diminishing memory. SIRT1 increases the expression of CREB and BDNF by downregulating miR-134 microRNA expression in the normal brain. This is one of the crucial factors for the regulation of synaptic plasticity as well as memory formation in our brain, where SIRT1, in combination with the Yin Yang1 (YY1) factor, decreases the expression of 134 miR [30]. Furthermore, the activation of SIRT1 SIRTUIN using an intraventricular injection of resveratrol activates synaptic plasticity and memory formation through the activation of CREB and BDNF expression while decreasing miR-124 and miR-134 expression [63]. The SIRT1 expression decreases under the influence of miR-34c that inhibits SIRT1. Increased miR-34c expression, together with the decreased SIRT1 condition, is observed with the pathological condition of AD, as observed in the APPPS-21 mice model [64, 65]. Impaired memory caused by obesity through the

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downregulation of SIRT1 expression results in a decrease in synaptic plasticity and hippocampal-dependent spatial memory [66]. SIRT1 also controls behavioral and neuropsychological aspects of our brain. Studies have found an association of SIRT1 with stress and anxiety behaviour in brain-specific SIRT1 knockout mice [67]. These SIRT1-KO mice exhibited a lowering in stress and anxiety response together with an enhanced explorative behaviour. SIRT1 promotes stress and anxiety through the inhibition of serotonin levels. SIRT1 stimulates MAO-A (monoamine oxidase A) expression, which degrades serotonin as well as noradrenaline levels, leading to anxiety and stress conditions. Psychiatric disorders with stress and anxiety are often associated with the genetic polymorphic in the SIRT1 gene [68, 69]. Some genome-wide study has shown an association of genetic variations for the SIRT1 gene with major depressive disorder [70]. The genetic association of SIRT1 with psychiatric disorders is supported by other studies where single nucleotide polymorphisms (SNPs) in the SIRT1 gene were related to SIRT1 activity [69]. The region-specific association of SIRT1 with neuropsychiatric disorders has been confirmed in various studies. Nucleus accumbens (NAc), which is a brain region associated with reward and motivation, exhibited an increased SIRT1 expression in a mouse model of depression disorder. Stimulation of SIRT1 in NAc either by bilateral infusion of the SIRT1 agonist resveratrol or viral-mediated overexpression of SIRT1 resulted in increased anxiety and depression-like behaviour in mice in the elevated plus-maze test and forced swim test. However, inhibition of SIRT1 through Intra-NAc introduction of SIRT1 antagonist EX-527 or SIRT1 knockdown decreased anxiety and depression behaviour. Similarly, a decreased SIRT1 expression in the hippocampus correlates with the depression behaviour caused by chronic stress conditions [71]. This chronic stress-mediated downregulation of SIRT1 protein results in reduced spine density and dendritic length in hippocampal neurons, while SIRT1 overexpression reduces the effect caused by chronic stress [71]. The reward circuitry is associated with the SIRT1 and SIRT2-mediated changes in NAc. There is increased histone acetylation and decreased methylation in SIRT1 and SIRT2 genes that activate SIRTUIN activity in cocaine-induced reward circuitry in NAc [72 - 76]. Furthermore, virus-induced overexpression of SIRT1 or SIRT2 in the NAc induces reward effects caused by cocaine and morphine; contrary to this, genetic ablation of SIRT1 in the NAc inhibited this reward [77]. Overall, diverse brain functions are associated with the SIRTUINs, which regulate basic metabolic functions to higher-order functions, such as learning and memory, stress and anxiety, the release of neurotransmitters, synaptic activity and reward, etc.

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SIRTUINS AND NEURODEGENERATIVE DISORDERS SIRTUINs regulate pluripotency and fate determination of embryonic NPCs, including adult neurogenesis in the hippocampus and ventricles. The role of SIRTUIN in neurodegenerative disorders has been proven by various studies [1 3]. Neurodegenerative disorders are the heterogeneous group of disorders associated with the degeneration of neurons of CNS and PNS that result in the deformation of structures of the nervous system [78]. There has been an altered expression of SIRTUINs in different neurodegenerative disorders, which is supported by several pharmacological as well as genetic alteration studies. These studies have shown a neuroprotective effect of SIRTUINs in CNS and PNS. Of these studies, SIRT1 and SIRT2 are the most studied SIRTUINs in these neurodegenerative disorders. We will discuss here in detail some of the neurodegenerative disorders and their associations with the SIRTUINs. Multiple Sclerosis (MS) MS is a disease of CNS that involves demyelination of the myelin sheath of neurons caused by autoimmune disease. In MS, the immune cells attack the myelin sheath, causing inflammation and damage to the axon and disrupting the neuronal signaling in CNS [79, 80]. The most common immune mediator in the progression of MS is CD4+ T helper cells. The enhanced immune response caused due to T-cell activation leads to damage to the axon, and ultimately, the death of neurons of the CNS as well as of cranial nerves. SIRTUINs play a crucial role in neuronal protection in mouse models of MS. Pharmacological activation of SIRTUINs using resveratrol (a SIRT1 activator) protects retinal ganglionic cells from neurodegeneration in mice [81, 82]. SIRT1 is one of the most studied SIRTUINs associated with MS, yet the involvement of other SIRTUINs is required for the study. In an experimental autoimmune encephalomyelitis (EAE) model of MS, the role of SIRT1, SIRT2 and SIRT6 has been found. The role of SIRT1 as a neuroprotective factor has been reported by several studies, where activation or inhibition of SIRT1 results in neuroprotection and neuronal death, respectively [83 - 86] (Fig. 3). Besides this, other studies have found contradictory effects of SIRT1. A study by Prozorovski et al. has shown a suppressive effect of SIRT1 on NPCs proliferation in cells from EAE lesions. Similarly, other studies have suggested a SIRT1mediated activation of TH-cells in the EAE model of MS. These studies have shown that SIRT1-mediated deacetylation and activation of retinoic acid receptorrelated orphan receptors gamma (RORɣt) stimulate differentiation of TH-cells [87].

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The post-mortem tissue samples from the patients suffering from MS show a reduced SIRT2 level in their lesions, suggesting the role of SIRT2 in MS. Some of the recent studies showed a decreased SIRT2 expression in EAE animal models of MS. SIRT2 is well known for its role in the regulation of axon myelination, axon branching, and differentiation of oligodendrocytes [88]. Mitochondrial SIRTUINs SIRT3, SIRT4 and SIRT5 are very less studied SIRTUINs in MS. Studies on post-mortem brain by Rice et al. have shown a reduced SIRT3 expression in MS patients [89]. Single nucleotide polymorphism study on SIRT4 and SIRT5, performed by Inkster et al., has pointed out the role of SIRT4 and SIRT5-associated mitochondrial dysfunction in MS patients [90]. Although SIRT6 and SIRT7 have a neuroprotective effect, their role is not associated with MS so far. Among all SIRTUINs, SIRT1 and SIRT2 are the most studied SIRTUINs associated with the MS. These SIRTUINs may be targeted by using activators and inhibitors for the therapeutic application of MS. Currently available therapeutics include immunological targets by suppressing them in MS but their efficacy does not protect the patients from neurodegeneration of neurons. All SIRTUINs (SIRT1-7) have somehow different cellular functions as these are associated with the different cellular processes, such as neurodegeneration, epigenetic regulation, signaling cascades, autoimmunity, and metabolism. So, targeting specifically a single or couple of types of SIRTUINs will have better therapeutic applications. Despite the availability of SIRTUINs activator and inhibitor, none of the drugs have been approved to be used as a drug for MS treatment, but some drugs targeting SIRTUINs are promising for therapeutics in MS [91, 92]. AD AD is a neurodegenerative disorder characterized by the degeneration of neurons due to the formation of neurofibrillary tangles made up of tau proteins in older people. The disease affects neurobiological functions that result in cognitive disability, memory loss, as well as diminished brain functions [93, 94]. The main cause behind AD progression is the mutation in two genes, i.e., amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2). The PSEN1and PSEN2 genes encode a γ-secretase protein, which cleaves APP protein after cleavage by β-secretase [93, 95]. This cleavage of APP generates small amyloid peptides (Aβ-40/42), whose accumulation creates amyloid plaques in AD. Similarly, tauopathy states that the neurofibrillary tangles (NFTs) are formed from hyperphosphorylation of tau protein, which is a microtubule-associated protein guiding cellular molecules in the cells. The role of SIRTUINs in AD has

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been reported in several studies (Table 2). Out of other SIRTUINs, the SIRT1 is downregulated, while the SIRT2, SIRT3, and SIERT5 SIRTUINs are upregulated in AD. The neuroprotective function of SIRT1 in AD has been discussed in several animal studies [3, 62, 96, 97]. These studies show that using SIRT1 activator resveratrol and/or genetic upregulation protected the formation of amyloid plaque in the brain [33, 98 - 100]. SIRT1 also regulates the formation of neurofibrillary tau proteins in CNS by reducing their expression (Fig. 3). The SIRT3 and SIRT5 levels were found to be upregulated in brain microglial cells in the tissues of Alzheimer’s patients. Furthermore, in their study, Lee et al. have reported a decreased level of SIRT3 SIRTUIN in the frontal cortex of AD patients that results in activation of p53, and finally, neuronal damage [101, 102]. Treatment of cultural neuronal cells showed an increased SIRT3, SIRT4, and SIRT5 SIRTUINs expression upon treatment with the APP. SIRT1 degrades Aβ proteins and upregulates the expression of α-secretase ADAM10. SIRT1 protects neurons from neurodegeneration by inhibiting oxidative stress, NF-κB signalling, as well as the levels of Aβ (Fig. 3). However, it also inhibits the formation of tau tangle by deacetylation of tau protein that results in decreased tauphosphorylation and tauopathy [103] (Fig. 4). SIRT2 has an opposing detrimental effect compared to SIRT1 in AD, where it is positively correlated with the Aβ pathology. The studies have reported an increased SIRT2 level in AD. Further, SIRT2 inhibition either using pharmacological approaches or the knockout method provides a neuroprotective effect. Other SIRTUINs are not well known for their roles in AD; however, few studies have suggested their role in AD. Cieslik et al. have shown in their study that extracellular Aβ1-42 oligomers treatment increased the expression of SIRT3, SIRT4, and SIRT5, suggesting their association with AD [104, 105]. The role of SIRT6 has been reported by some studies, where a decreased SIRT6 expression was observed in AD patients. SIRT6 is associated with the repair of DNA by controlling the base excision repair pathway [106, 107]. Further, the mice with brain-specific knockout of SIRT6 exhibited enhanced DNA damage, neuronal death, and deficit in learning and memory [105]. SIRT6 suppresses tau protein level and its phosphorylation, thus regulating AD, as patients with AD exhibit a lower SIRT6 level. Table 2. Hippocampal SIRTUIN functions in AD [108, 109]. Increased SIRTUINs in AD

Decreased SIRTUINs in AD

Function Unknown in AD

SIRT2, SIRT5

SIRT1, SIRT3

SIRT4, SIRT6, SIRT7

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Fig. (3). SIRT1 pathways in neuroprotection.

Fig. (4). s SIRT1 pathway inhibition in AD.

PD PD is a neurodegenerative disease characterized by impaired motor neuron function in the brain of older persons. The person with PD shows aberration in the

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dopaminergic (DAergic) neuron system, most commonly in substantia nigra (SN) and striatum (ST) of the brain. The main cause of PD is abnormal accumulation and misfolding of α-synuclein (α-syn) protein [Lewy body (LB) formation] [110 112]. Some recent studies have suggested the role of SIRTUINs in PD. The postmortem brain studies have revealed a significant decrease in the expression of SIRT1 in PD, suggesting a role of SIRTUINs in PD. In vitro studies using induced pluripotent stem cell (iPSC)-derived DAergic neurons with a mutation in leucine-rich repeat kinase 2 (LRRK2) show a decreased SIRT1 expression [113, 114]. Mutation in the LRRK2 region is a characteristic feature of PD, where mitochondrial functions are diminished. Mostly, SIRT1 and SIRT3 have been reported to have a neuroprotective effect, while SIRT2 worsens PD condition as its inhibition protects from pathology in PD (Fig. 5). In general, the SIRT1 SIRTUIN has a neuroprotective function in PD [3, 115, 116] with few exceptions (Fig. 3). The implication of SIRT1 in PD has been confirmed by several studies. The study by Ham et al. suggests that the C. elegans with transgenic α-syn expression correlate with SIRT2. SIRT2 SIRTUIN expression (a homolog to human SIRT1 and SIRT3) acts as a suppressor of α-syn formation [117]. The role of SIRT1 in PD was further confirmed in the study of Mudo et al. using PPARγ co-activator-1 alpha (PGC-1 α), which is activated by SIRT1 deacetylation [118, 119]. They showed that the mice with overexpression of PGC-1α were irresponsive toward MPTP-mediated neurotoxicity [120]. Another study by Takahashi-Niki et al. has suggested an activation of SIRT1 SIRTUIN by PD susceptibility gene [121], suggesting a feedback mechanism of SIRT1 activity in PD.

Fig. (5). SIRT1 and SIRT2 mediated cellular death in PD.

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SIRT2, a cytosolic SIRTUIN, mostly shows its association with the pathological condition of PD. SIRT2 inducing neurotoxicity in nerve cells in PD has been suggested by several studies. Studies by Outeiro et al. have proved that the inhibition of SIRT2, either by using an inhibitor or by gene silencing, reduces neurotoxicity as well as α-syn inclusion formation [122]. Similarly, this role of SIRT2 has also been supported by other studies using SIRT inhibitors [123]. Moreover, the SIRT3 and SIRT5 mitochondrial SIRTUINs are probably associated with the regulation of mitochondrial oxidative damage, which is also the basis of the PD condition and suggests a neuroprotective function of SIRT3 and SIRT5 [124]. ALS ALS is a complex disorder of the nervous system that affects motor neuron function in the CNS. It is a fast-progressing neurodegenerative neuromuscular disease that reduces motor neurons in the cortex and spinal cord [125, 126]. It is the most common motor neuron disease that affects control over voluntary muscles. The symptoms start from the weakening of arms or legs (i.e., limbonset), and difficulty in swallowing and/or speaking (i.e., bulbar-onset). The loss of motor neurons lasts till the basic physiological functions, such as body movement, speaking, eating, and breathing, start to diminish. Currently, there is no available therapeutic available for its treatment. Several molecular alterations, including superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP43), as well as SIRTUINs, have been reported to be in ALS conditions by various studies involving rodents and human ALS patients [127 - 132]. The neuroprotective role of SIRTUINs in ALS has been supported by different studies (Fig. 6). It has been found in the studies that the neurodegenerative effect caused by SOD is protected, either by using resveratrol treatment and/or overexpression of SIRT1 SIRTUIN [41, 133]. Similarly, SOD-KO mice exhibited enhanced pan expression of SIRT1 along with enhanced survival [134]. Contrary to SIRT1 function as a neuroprotector in ALS, SIRT2 exhibits no association with the disease [135]. Although, the role of SIRT2 is well-known to promote neuronal death [136]. Further study is requisite to suggest its role in ALS disorder. The neuroprotective role of SIRT3 is supported by the studies where there is a decreased SIRT3 expression in CNS in the ALS mouse model; however, the mitochondrial isoform shows an increased SIRT3 expression in the muscles and spinal cord [137, 138].

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Fig. (6). SIRT1 and SIRT3 pathway in ALS.

WD WD is a neuronal process characterized by axonal degeneration due to nerve injury in CNS and PNS. This WD is followed by the degeneration of myelin sheath and further infiltration of macrophages at the site, followed by induction of axonal degeneration of nearby neurons. This situation is also characteristic of some other diseases, such as ALS and AD. The event of axonal degeneration in WD starts after 30-40 h of the injury. SIRTUINs are well known for their neuroprotective functions, but the involvement of SIRT1 and SIRT2 in these neurodegenerative disorders is the most important. The primary function of SIRT1, as suggested by different studies, is in delaying neuronal degeneration in WD. The involvement of SIRT1 with the WD has been confirmed by some indirect studies that involved upstream elements, such as nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) and NAD. The study involving overexpression of NAD biosynthetic enzyme Nmnat1 exhibited a delayed onset of WD condition in the trimmed axon. The Nmnat1function in delaying WD is through NAD-mediated promotion of SIRT1 activity. This upstream Nmnat1 activity in WD has been further confirmed by other studies, where suppressing SIRT1 activity either through SIRT1-knockdown or sirtinol (a SIRT1 inhibitor) enhanced axonal degeneration. The increased axonal degeneration was correlated

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with decreased NAD production. Additionally, treating neurons with resveratrol (a SIRT1 activator) or NAD decreased axonal degeneration. However, other studies have suggested the role of NAD only instead of SIRT1 in the protection of axonal degeneration in WD. Further, the role of SIRT2 as a promotor of axonal degeneration has been confirmed by different studies. In one of the studies, the SIRT2 overexpression enhanced axonal degeneration by hyperacetylationmediated depolarization of microtubules. Likewise, SIRT2-KO mice exhibited protection from axonal degeneration together with increased microtubule acetylation in cerebellar granule cells [139]. Spinal Cord Injury (SCI) SCI is an injury to the spinal cord that may develop into short- or long-term functional changes. It may have a varying degree of severity that ranges from apathy to total paralysis. Following SCI, tissue injury starts that causes further injury to the neurons and glial cells, generation of oxidative stress, tissue edema, and inflammation. This generation of oxidative stress and tissue inflammation increases spinal cord injury and diminishes functions of the nervous system [140]. The most important symptoms of spinal injury include loss of sensation, impaired muscle functions, and an imbalance in autonomic body functions in those parts of the body where the injured spinal cord has innervations. The main cause of spinal damage is the physical damage to the body, such as accidents, sports injury, and from nonphysical damage, such as pathological infections, cancer, inadequate blood supply, etc. Most commonly, the SCI is followed by the inflammation of the nervous system that leads to neuron degeneration. Although the role of SIRTUINs is well known in protection from neurodegeneration conditions, their role in the protection of neuroinflammation is still unknown. Most importantly, the function of SIRT1 SIRTUIN has been suggested by some studies. The SIRT1 expression has been reported to be decreased in a study during the progression of SCI (Fig. 7), while the level of proinflammatory cytokines, such as β-catenin and NF-κB p65, and TNF-α and interleukin 12 (IL-12), has been found to be increased in SCI. SIRT1 treatment in vitro decreased β-catenin expression in microglia cells, suggesting an inhibiting role of SIRT1 over β-catenin. Further, treatment with SRT1720 (a SIRT1 activator) improved recovery in the SCI condition together with the lowering of inflammatory cytokines [141]. Overall, the role of SIRT1 as a neuroprotector is supported by these studies in SCI through the inhibition of the β-catenin pathway. The anti-inflammatory function of SIRT1 was confirmed by SIRT1-KO mice having impaired SIRT1 in inflammatory cells, including T-cells, B-cells, macrophages, dendritic cells, and

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neutrophils, together with an enhanced inflammation activity. SIRT1 functions through the activation of the p53 pathway that prevents neuronal cells from apoptosis during SCI condition (Fig. 7). The SIRT1 activity is regulated by the miR-494, which inhibits its activity and promotes neurodegeneration. In other SIRTUINs, SIRT2 and SIRT6 have some predictable association with the SCI; however, there exists very limited information.

Fig. (7). SIRT1 inhibition in SCI; SIRT1 inhibition promotes apoptosis and halts the cell cycle.

Traumatic Brain Injury (TBI) TBI is abrupt brain damage that causes intracranial injury. The main cause of TBI is the external physical forces, such as road accidents, sports injuries, etc., that may cause very mild to severe damage to the brain. TBI impairs a wide range of body functions, such as physical damage, cognitive and social impairment, including functional disability and/or death. TBI is followed by two types of injury, first is a primary injury that is the first sudden physical injury caused by an external force, and the secondary injury that occurs hours or days after the injury. The secondary injury includes different types of damage, such as damage to the blood-brain barrier (BBB), the release of inflammatory factors, extensive generation of free radicals, excitotoxicity caused by a higher amount of the neurotransmitter release, sodium and calcium ions influx into neurons, mitochondria dysfunction, etc. SIRTUINs, a neuronal protector, also function in TBI conditions. Recent studies have found that the expression level of SIRTUINs increased significantly following TBI. Similarly, other studies have suggested a neuroprotective function of SIRTUINs following TBI [142, 143]. SIRT1 plays a critical role in the

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reduction of inflammation, as observed in TBI conditions. The high mobility group box 1 (HMGB1) protein, which is elevated in TBI-associated inflammation through microglia activation, is regulated and suppressed by the SIRT1-mediated acetylation. However, contrary to this, SIRT2 increases inflammatory conditions. NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome that induces interleukin-1β (IL-1β) cytokine production is under the inhibitory control of SIRT1. SIRT1 suppresses NLRP3 inflammasome activity to prevent inflammation during TBI. Further, SIRT1 prevents inflammation by inhibiting microglia activation (a TBI-associated event) through inhibiting the p38 mitogen-activated protein kinase (MAPK) signaling pathway [144]. SIRTUIN (especially SIRT1, SIRT3, and SIRT4) also decreases excitotoxicity, which is a common condition in TBI and other neurodegenerative diseases [145]. SIRT1 functions in another way to prevent glutamate-associated excitotoxicity through deacetylation-mediated inhibition of PGC1α. Studies have also supported the neuroprotective role of SIRT3 and SIRT4 against excitotoxicity [32, 146]. Moreover, other studies have found a downstream effect of SIRT1 to prevent TBI injury through the activation of ERK1/2. Inhibition of either SIRT1 or ERK1/2 progresses towards enhanced apoptosis following TBI [147, 148]. In conclusion, the role of SIRTUINs is beyond the neuroprotection of our nervous system, where it has diverse functions, such as anti-inflammation, synaptic plasticity, and neuronal survival, including regulation of basic neuronal functions. It is one of the most important potential targets for further studies to treat TBI and other related diseases. Stroke A stroke is a situation where the blood supply to the brain is reduced in such a way that the brain does not receive enough supply of nutrients and oxygen. Due to this stroke condition, the neurons die and cause severe damage to the brain. The stroke is of two types, one is an ischemic stroke, in which there is a lack of blood flow to the brain, and the second is hemorrhagic stroke, which occurs due to excessive bleeding into the brain. The major risk factors for strokes are high blood pressure, obesity, smoking, increased blood cholesterol level, diabetes mellitus, kidney diseases, atrial dysfunctions, etc. Different studies have suggested a neuroprotective function of SIRTUINs in stroke conditions. The SIRT1 is an important neuroprotective molecule that functions to delay the stroke. Animals that lack SIRT1 show a robust displayed larger infarct volume along with cerebral ischemia condition; however, SIRT1 overexpression shows delayed brain damage. SIRT1 provides neuroprotection through the upregulation of NF-κB, as reported by different studies. SIRT1 also

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activates anti-oxidant production, such as SOD, that in turn reduces oxidative stress condition of the brain during stroke. SIRT1 also activates the production of hypoxia-inducible factor-2alpha (HIF-2α), which is one of the most important mechanisms for reducing oxidative stress. The role of SIRT1 is also confirmed by the activity of NAD, whose expression decreases in hypoxia/ischemic conditions while its overexpression reverses ischemic. Further confirmation of SIRT1 in ischemic stroke comes from the activity of estrogen. The estrogen protects neurodegeneration by activating the SIRT1 and AMP-activated protein kinase (AMPK) pathway. Interestingly, the SIRT2 SIRTUIN exerts an opposite function in ischemia, where studies involving SIRT2-KO animals have exhibited an improvement in ischemia condition together with reduced infarct size. Furthermore, studies involving in vitro conditions have shown an increased SIRT2 level in oxidative stress conditions, including cellular death. Similar to SIRT1, SIRT3 has an anti-apoptotic function in ischemic stroke conditions. Several in vitro and in vivo studies have confirmed a protective role of SIRT3 in ischemic stroke and/or oxidative stress conditions. However, its overexpression has been shown to prevent oxidative damage and ROS production in several studies. Furthermore, the SIRT3 also regulates ketone body formation following an ischemic stroke through the regulation of its downstream targets FOXO3a and SOD2. The studies have confirmed the protective function of SIRT4 from glutamate excitotoxicity. The SIRT4 activation and knockout have glutamate-dependent anti-excitotoxic and excitotoxic effects, respectively, via regulation of glutamate transporter-1 (GLT-1) expression. Although the function of SIRT5 in stroke is not well studied, some of the studies have suggested neuroprotective and anti-excitotoxic effect with ischemic stroke. However, SIRT5 is well known for its function in mitophagy during starvation. Furthermore, the role of SIRT6 and SIRT7 in stroke is suggested by some of the studies; however, their neuroprotective and anti-apoptotic functions in the nervous system are well known. MODULATION OF SIRTUINS SIRTUINs are the HDAC family of deacetylation enzymes that regulate several proteins’ functions. The enzymatic activity of SIRTUIN is regulated in two ways. The first is to use SIRTUIN activating compounds (STACs) that allosterically modulate their activity (Fig. 8), and the second is by using NAD+ boosting molecules (NBMs) that regulate NAD+ level, which indirectly modulates SIRTUIN activity (Fig. 8).

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STACs The STACs, which modulate SIRTUINs, have a beneficial effect on our body functions, such as anti-inflammation, protection from diabetes, improved heart functions, extended lifespan, delayed aging, improved cognitive functions, etc. Naturally occurring resveratrol and other related synthetic drugs are well-known SIRTUIN activating compounds (polyphenol nature). Resveratrol (3, 5, 4`trihydroxystilbene), a natural constituent from grapes, activates the SIRT1 fold more than the untreated one. Stilbene derivative with some modification (especially at 4` position) has improved SIRT1 promotion activity. One of the next generations of chemically synthesised STACs oxazolo[4,5-b] pyridine, thiazolopyridine, and bridged urea, has improved function over naturally occurring STACs. Likewise, another SIRTUIN activator 1, 4-dihydropyridine with attached benzyl group at the N1 position, has the potency to stimulate SIRT1, SIRT2, and SIRT3. The third-generation STACs, such as SRT1720 and SRT2104, have thousand-time improved SIRTUIN activation activity as compared to resveratrol.

Fig. (8). Sirtuins modulators; (A) STACs activator, (B) NAD+ activators.

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NBMs NAD+ is a co-substrate required for SIRTUIN functions as it helps in deacetylase activity. It is evidenced from the studies that NAD+ modulation modulates SIRTUIN activity and is supposed to be a potential therapeutic in the treatment of neurodegenerative disorders. MBs class of drugs function either by supplying NAD+ precursor [NAM, NAM riboside (NR), and nicotinic acid] or by activation of those enzymes (i.e., nicotinamide mononucleotide adenylyltransferases, nicotinamide phosphoribosyltransferase, and indoleamine 2, 3-dioxygenase) that are required for the synthesis of NAD+. Preclinical and clinical studies using NAM, NR, and nicotinic acid introduction have shown increased NAD+ level. However, these drugs have less stability together with side effects, but the current study focuses on the therapeutic applicability of nicotinamide mononucleotide (NMN) in the treatment of neurodegenerative disorders. Furthermore, NR has potential applicability as it has lower side effects as well as oral administration possibilities. The studies have reported the involvement of glucocorticoids in the improvement of MS condition. The rate-limiting first step of NAD+ synthesis catalyzed by indoleamine 2,3-dioxygenase (IDO) enzyme is regulated by glucocorticoid. Furthermore, the naturally obtained compound, epigallocatechin gallate (EGCG, an antioxidant) containing green tea, promotes neuroprotection by activation of nicotinamide mononucleotide adenylyltransferase (NMNATs) enzyme. However, other compounds, P7C3 (an aminopropyl carbazoles class of compound), that activate nicotinamide phosphoribosyltransferase, have neuroprotective function. Apart from this, reducing the degradation of NAD+ is another strategy to treat neurodegenerative disorders. For this, NADases family enzymes can be targeted. For example, using flavonoids (e.g., quercetin, apigenin, or luteolinidin) or thiazoloquin(az)olinones (e.g., 78c) to inhibit CD38 (primary NADase in mammals) resulted in increased NAD+ levels in rodents. Furthermore, poly ADP-ribose polymerases (PARPs) utilize NAD+, whose inhibition also raises cellular NAD+ level using PARPs inhibitors (PJ34, olaparib, and some flavonoids). In conclusion, NADase inhibitors are the most important therapeutic targets for the treatment of neurodegenerative disorders. CONCLUSION SIRTUINs are one of the most important classes of biomolecules associated with diverse types of body functions. Their role in neurodegenerative disorders is interesting as they protect neurons of the nervous system by regulating various pathways. Modulation of SIRTUINs using available natural and/or synthetic compounds is a remarkable strategy for therapeutic application in the treatment of neurodegenerative disorders. The most important strategy to modulate SIRTUINs

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is the use of either STACs or NBMs. The varied beneficial effect of STACs and NBMs has been supported by several preclinical studies. The results from these studies have been started to be utilized in clinical studies also. For understanding the therapeutic application of these drugs, future research is requisite in clinical studies through modulation of selected SIRTUINs subtypes. It is also mandatory to develop better therapeutic drugs that specifically target those SIRTUINs that have a beneficial effect on neurodegenerative disorders, as some SIRTUINs, like SIRT2, promote apoptosis and neurodegeneration. Furthermore, preclinical and clinical studies utilizing the combinatorial effect of STACs and NBMs over any of these drugs alone should be done to get a better therapeutic application. The validation of these drugs in preclinical and clinical studies is very much needed to get an effective strategy for neuroprotection in these disorders. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS The authors received financial support from ICMR and UGC for the research, authorship, and publication of this article. REFERENCES [1]

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CHAPTER 4

Beyond the Synthetic Drugs: Fungal Endophytes Derived Bioactive Compounds in the Management of Neurodegenerative Disorders Ashish Verma1,#, Nilesh Rai1,#, Swapnil C. Kamble2, Pradeep Mishra3, Suvakanta Barik4, Rajiv Kumar1, Santosh Kumar Singh1, Prafull Salvi5 and Vibhav Gautam1,* Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India 2 Department of Technology, Savitribai Phule Pune University, Ganeshkhind, Pune-411007, India 3 Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-171 77-Stockholm, Sweden 4 Chemical Engineering Discipline, Indian Institute of Technology Gandhinagar, Gujarat-382355, India 5 Department of Agriculture Biotechnology, National Agri-Food Biotechnology Institute, SAS Nagar, Mohali, Punjab-140306, India 1

Abstract: Fungal endophytes are a group of fungi that reside in plant tissues and show a symbiotic relationship with the host plants. They protect against pathogens and increase food availability without causing any harmful effects on the host plant. Fungal endophytes are known to produce a wide range of bioactive compounds with several biological activities, including neuroprotective effects. Neurodegenerative disorders lead to miscommunication between nerve cells, damage or loss in structure and function of the central nervous system (CNS) or peripheral nervous system (PNS). Reactive oxygen species, neuroinflammation, protein degradation or aggregation, familial history, mutation in mitochondrial genes, and aging contribute to neurodegenerative disorders. Plant-associated fungal endophytes produce bioactive compounds, which show anti-neuroinflammatory, antioxidant, and anti-cholinesterase activities. Several pro-inflammatory (TNF-α and NF-κB) and depressant (serotonin, dopamine, and noradrenaline) molecules or neuronal signaling pathways leading to neurodegenerative disorders are known to be inhibited or down-regulated by fungal endophyte-derived bioactive compounds. Therefore, bioactive compounds produced from fungal endophytes could be a promising approach to treating various health * Corresponding author Vibhav Gautam: Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India; E-mail: [email protected] # Authors contributed equally to this work

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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ailments. The present chapter discusses selected fungal endophyte-derived potential bioactive compounds with neuroprotective effects for managing neurodegenerative disorders.

Keywords: Depression, Fungal endophytes, Neurodegenerative disorders, Neuroinflammation, Oxidative stress. INTRODUCTION Endophytes are microbes that reside in intracellular spaces of the stem, root, petiole, and leaves of the plant, and live in a symbiotic relationship. The term endophyte was coined by De Barry in 1866 [1]. Endophytes primarily include fungi and bacteria [2, 3]. In the present chapter, we will mainly discuss fungal endophyte-derived bioactive compounds for managing neurodegenerative disorders. The quality and efficacy of the fungal endophyte-derived bioactive compounds mainly depend on environmental factors, such as temperature, humidity, and geographical location [4]. Microbial endophytes provide several benefits to the plants, such as protection against invading pathogens, nutrient availability to the plants, and shaping the proper growth and development of the plant body [5, 6]. In mycological literature, the term endophytic fungi is used to explain the internal mycota of living plants [7, 8]. In the recent past, several bioactive compounds have been isolated from medicinal plants, which are of great importance, but due to the continuous and prolonged use of selected medicinal plants (such as Huperzia serrata, Bauhinia forficate, and Taxus brevifolia), their existence is in danger due to the loss of their natural habitats. To overcome this, fungal endophytes could play a major role in the isolation of bioactive compounds having medicinal importance similar to the host plants [9]. Mounting pieces of evidence have shown that around 70% of the antiinflammatory, anti-neoplastic, anti-diabetic, anti-cancer, and anti-microbial compounds are obtained from fungal endophytes [10]. Still, a majority of fungal endophytes and their associated bioactive compounds need to be explored for their medicinal properties [11 - 14]. The present chapter aims to discuss the role of fungal endophytes and their associated bioactive compounds in treating neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’ disease (AD), Huntington’s disease (HD), and Prion disease, showing similar mechanism involving aggregation and deposition of misfolded proteins, leading to central nervous system (CNS) diseases [15]. As per the reports, around 30 million people are globally affected by neurodegenerative diseases [16, 17]. PD is caused due to missense mutation in

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the alpha-synuclein (α-syn) gene, resulting in the aggregation of α-syn called Lewy bodies (LB), and hampers the dopamine (DA) activity [18]. AD is caused by the self-aggregation of α-syn and tau protein into larger inclusion bodies, such as LB and neurofibrillary tangles (NFT) [19]. HD is caused due to the mutation in the huntingtin gene on chromosome 4 and CAG repeat expansion [20]. Prion’s disease is mainly caused due to the deposition of PrPSc, an abnormally misfolded protein derived from normal prion protein PrPc [21]. Neurodegenerative diseases are mainly caused due to the abnormal accumulation and degradation of proteins in CNS, neuroinflammation, microglial activation [22], excess production of reactive oxygen species (ROS) [23], a mutation in genes involved in iron metabolism [24], and oxidative stress [25 - 27]. Despite advancement in understanding the pathology of disease, currently available drugs are limited to treating neurological disorders. Researchers are now shifting their research interest towards other safe alternatives, i.e., fungal endophyte-derived bioactive compounds. Fungal endophytes are a very good source of glycosides, steroids, alkaloids, terpenoids, flavonoids, phenolic acids, and many bioactive molecules [28, 29]. In past decades, several studies have shown possible anti-inflammatory, neuroplastic and immunomodulatory activity of fungal endophyte-derived bioactive compounds. In one of the reports, Alternaria alternata, associated with Vinca rosea (Catharanthus roseus), was tested for inhibitory compound production, which inhibits acetylcholinesterase activity (AChE) up to 78% and butyrylcholinesterase (BuChE) activity up to 73%. These two enzymes are responsible for the reduction of acetylcholine (ACh) and butyrylcholine (BuCh) levels in cholinergic synapses in the CNS and peripheral nervous system (PNS), responsible for maintaining proper locomotion and coordination in the body [30]. Another bioactive compound, phomol, which is an antibiotic obtained from Phomopsis species associated with Erythrina crista-galli, exhibits antiinflammatory and neuroleptic activity [31]. Fusarium subglutinans associated with the plant Tripterygium wilfordii are known to secrete immunosuppressive compounds subglutinol A and B [32]. These examples further suggest that the fungal endophyte-derived bioactive compounds could be an excellent source for treating neurodegenerative diseases. FUNGAL ENDOPHYTE AS A SOURCE OF BIOACTIVE COMPOUND FOR MANAGING HEALTH DISORDERS In the plant kingdom, fungi are heterotrophic groups of an organism with a different life cycle; some of the fungi live in a symbiotic relationship with their host plant, referred to as endophytic fungi [33]. Isolation of the fungal endophyte from the associated medicinal plants in laboratory conditions can be performed by culturing the desired plant explants (leaf, flower, twig, stem, and fruit) on the

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media supplemented with antibiotics and necessary growth factors. The media plates containing plant explants are further incubated in a controlled condition till the appearance of fungal colonies. Further, subculturing of the fungal colonies is performed in order to isolate the single colony corresponding to single fungal species. In order to identify the details of the species, phenotypic screening (colony characteristics, morphological properties through microscopy) and molecular identification (genomic DNA isolation followed by polymerase chain reaction (PCR) amplification of conserved internal transcribed spacer (ITS) region, purified PCR products are further subjected to DNA sequencing to identify the fungal strain) can be performed. After the isolation of the single colony, a large-scale fermentation for the fungal strain is carried out till the emergence of fungal mycelia. Both extracellular and intracellular fungal endophytes could be used as per the need of the experiment for the extraction of bioactive compounds. Purification of the bioactive compounds could be performed through high-pressure liquid chromatography (HPLC) [34] and other chromatographic techniques; structural elucidation of the bioactive compound can be performed using nuclear magnetic resonance (NMR). For functional characterization of the bioactive compound, in vitro and in vivo studies need to be performed using the isolated bioactive compound. Fungal endophytes are classified into two major groups based on their phylogeny and life history: clavicipitaceous (for example, Epichloe, Neotyphoidium) and noncalvicipitaceous (for example, Mycophycia ascophylli, Fusarium culmorum, Colletotrichum magna). Clavicipitaceous fungal endophytes are found in cold habitats and are associated with grasses. Non-calvicipitaceous fungal endophytes (mainly Ascomycota or Basidiomycota) are found in internal tissues of nonvascular plants, ferns, and angiosperms [35, 36]. In the present section, we discuss the medicinal importance of selected bioactive compounds derived from fungal endophytes. Fusarium oxysporum associated with the mangrove plant Rhizophora annamalayana is known to produce taxol (also known as paclitaxel) and its derivatives [37]. Taxol is an anti-cancer drug (cytotoxic and anti-neoplastic) that is used for the treatment of prostate cancer, breast cancer, ovarian cancer, and lung cancer. Another bioactive compound, cryptocandin, obtained from Cryptosporiopsis cf. quercina, associated with T. wilfordii, inhibits the growth of many human fungal pathogens, such as Candida albicans and Trichophyton spp [38]. Podophyllotoxin isolated from fungal endophytes associated with Sinopodophyllum hexandrum, Diphylleia sinensis, and Dysosma veitchii is used for the treatment of cancer, rheumatoid arthritis, bacterial and viral infections [39]. Camptothecin and its analog (10-hydroxycamptothecin) are isolated from Entrophospora infrequens associated with Nothapodytes foetida, and are very effective anti-neoplastic agents [40, 41]. Bioactive compounds, Subglutinol A and

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B produced by F. subglutinans and associated with T. wilfordi, show immunosuppressive activity [42]. In a study, crude fungal extract of Colletotrichum spp. was shown to have antibacterial activity against Bacillus subtilis, Streptococcus lutea and Streptococcus aureus with MIC value ranging from 25-75 µg/mL, and antifungal activity against C. albicans and Aspergillus niger with MIC value ranging from 50-100 µg/mL [43]. Another endophytic fungus, Talaromyces pinophilus, associated with the strawberry tree (Arbutus unedo), is known to secrete platelet-aggregation inhibitory bioactive compounds, herquiline B and antibiotic 3-O-methylfunicon [44]. Another report shows that withanolide produced by T. pinophilus and isolated from the leaves of Withania somnifera helps in the treatment of cardiovascular diseases and AD [45]. Fusarium proliferatum, associated with Syzygium cordatum, is known to produce ergosta-5,7,22-trien-3β-ol, nectriafurone-8-methyl ether, 9-O-methyl fusarubin, bostrycoidin, bostrycoidin-9-methyl ether and 8hydroxy-5,6-dimethoxy-2-methyl-3-(2-oxo-propyl)-1,4-naphthoquinone; these bioactive compounds show potent cytotoxic activity with LD50 value < 100 μg/mL [46]. ROLE OF FUNGAL ENDOPHYTE-DERIVED BIOACTIVE COMPOUNDS IN TREATING NEURODEGENERATIVE DISEASES Neurodegenerative disease in humans is caused by intracellular or extracellular aggregation of misfolded proteins, such as superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), optineurin (OPTN), and ubiquilin-2 (UBQLN2), which leads to the continuous alteration in nerve and glial cells [47]. Different synthetic drugs, such as Rivastigmine, Galantamine, Donepezil, and Memantine, are available with neuroprotective effects. However, these drugs have various limitations and side effects, such as skin reaction, neuropsychiatric adverse effects, agitation, depression, anxiety, confusion, cholinergic stimulation in CNS and PNS. Therefore, it is necessary to look for an alternative compound that is safe to consume with greater potency in managing health-associated disorders. Fungal endophytes-derived bioactive compounds are known to have a neuroprotective effect by targeting neuronal molecular pathways (Table 1, Fig. 1). Pseudomassaria species is known to produce non-peptidyl bioactive compounds L-783,281, which show neurorestorative effects by stimulating the Trk family of tyrosine kinase receptors and other signaling pathways [48].

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Table 1. Bioactive compounds isolated from plant-associated fungal endophytes for the treatment of neurodegenerative diseases. S. No.

Host Plant

Fungal Endophyte

Bioactive Compound/s

1.

Kandelia candel (L.)

Paecilomyces sp.

Secalonic acid A

2.

Artemisia annua

Aspergillus terreus

16α-hydroxy-5N-acetylardeemin

Acetylcholinesterase inhibitory activity

[50]

3.

Pongamia pinnata (L.) Pierre

Phomopsis occulta

ME0-W-F1

Inhibitory effects on the aggregation of Aβ42 in mammalian cells

[51]

4.

Tabebuia argentea

A. alternata and A. niger

Phenolic compounds

Antioxidant activity

[52]

5.

Acanthus ilicifolius Linn.

Penicillium sp. (2R,3S)-Pinobanksin-3-cinnamate FJ-1

6.

Everniastrum sp.

Nodulisporium sp. (No. 65-1-2-1)

Nodulisporiviridin G

Aβ42 aggregation inhibitory activities

[54]

7.

Psychotria condensa

Cytospora rhizophorae

HAB16R26

Inhibit beta-secretase (BACE1)

[55]

8.

Glehnia littoralis

Neosartorya fischeri JS0553

Fischerin

Glutamate-mediated HT22 cell death through inhibition of ROS, Ca2+ influx

[56]

9.

Morus alba

Colletotrichum sp. JS-0367

Evariquinone

Neuroprotection against HT22 cell death induced by glutamate

[57]

10.

Imperata cylindrical

Chaetomiun globosum

Cytochalasans

Inhibit H2O2-induced damage in PC12 cells

[58]

Mode of Action

Refs.

Inhibit phosphorylation of [49] JNK and p38

Neuroprotective effects on corticosterone-damaged [53] PC12 cells

After the collection of the plant sample, surface sterilization is carried out using disinfectant for the removal of epiphytic microbes and dust particles present on the surface. Plant sample is further placed on the selected solid media amended with antibiotic, incubated at 27±2 °C till the appearance of fungal mycelia. Individual fungal species can be isolated from the primary culture after subculturing onto the solid media plate. Fungal endophytes derived bioactive compounds can be produced at larger scale by growing them in selected liquid culture medium with constant shaking for about 21-24 days at 27±2 °C. Further, fungal endophyte derived bioactive compounds are extracted in selected solvents such as ethyl acetate, chloroform, methanol or ethanol. Extracted fungal crude

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extract could be used to evaluate the potential neuroprotective activity. On the other hand, extracted crude extract are subjected for HPLC, gas chromatographymass spectrometry (GC-MS) and NMR based studies for the purification, molecular identification and characterization of bioactive compounds.

Fig. (1). Neuroprotective role of fungal endophyte derived bioactive compounds.

Fungal Endophyte-derived neuroinflammatory Properties

Bioactive

Compounds

having

Anti-

Inflammatory responses generated during infection of CNS by toxic substances or by brain injuries activate residential glial cells of the brain, which leads to the production of ROS and other inflammatory molecules, such as cytokines, chemokines, and prostaglandins [59, 60]. Due to these inflammations, a variety of neurodegenerative disorders occur, such as AD, PD, multiple sclerosis (MS), and many others. In the recent past, anti-inflammatory synthetic chemical therapies have been tested, but due to the lack of high accuracy, the focus has been shifted toward the usage of naturally existing bioactive compounds. Anti-inflammatory activities have been shown by various bioactive compounds, which may act as a safer alternative in comparison to synthetic drugs [61 - 64]. Bioactive compounds derived from Penicillium spp. show anti-neuroinflammatory activity. In one of the recent reports, Penicillium polonicum, a fungal endophyte associated with Taxus fauna, is known to secrete a dimeric anthraquinone (R)-1,1′,3,3′,5,5-hexahydroxy-7,7′- dimethyl[2,2′-bianthracene]-9,9′,10,10′-tetraone (Fig. 2a). A steroidal furanoid, (-)-wortmannolone (Fig. 2b), shows potent anti-inflammatory

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activities, which have been validated through tumor necrosis factor-alpha (TNF-α) induced nuclear factor kappa light chain enhancer of activated B cells (NF-κB) assay with IC50 value of 0.47 µM [65]. Another naturally produced phenolic compound, gallic acid (GA), is known to show anti-inflammatory activity [66]. In one of the studies, Penicillium sp., associated with Acer ginnala secretes GA (Fig. 2c), was found to show potent anti-inflammatory activity [67]. Indole alkaloid derivatives, diketopiperazine type neoechinulin-A (Fig. 2d) and B (Fig. 2e), isolated from Eurotium sp., associated with Hibiscus tiliaceus and Microsporum species, also show anti-inflammatory effect [68]. Neoechinulin A inhibits the generation of nitric oxide (NO) and prostaglandin E2 (PGE2) and the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in a dose-dependent manner (12.5 µM to 100 µM) without causing any alteration in the cell viability. Neoechinulin B is known to show similar inhibitory activity against NO production at 25 µM, with alteration in the cell viability. Neoechinulin A is also known to regulate the secretion of proinflammatory cytokines, such as interleukin-1β (IL-1β) and TNF-α. In another report, it was also observed that neoechinulin A blocks the activation of NF-κB in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and prevents the degradation of inhibitor of kappa B-alpha (IκB-α). Due to the inhibition of NF-κB and p38 MAPK pathways, it can be confirmed that neoechinulin A is one of the potent molecules having anti-inflammatory activity [69]. Another report shows that Talaromyces wortmannii, associated with Aloe vera (Asphodeloideae), produces bioactive compounds B and C, which can suppress the TNF-α induced intercellular adhesion molecules-1 (ICAM-1) expression, suggesting the anti-inflammatory activities of compounds B and C [70]. Similarly, Periconia sp. F-31, associated with Annonsa muricata, secretes three important bioactive compounds, periconianone A, periconianone B, and dihydro naphthalene-2,6-dione. These compounds have anti-neuroinflammatory activities by using LPS-induced NO generation [71]. Periconianone A (Fig. 2f), periconianone B (Fig. 2g), and dihydro naphthalene-2,6-dione (Fig. 2h) are known to demonstrate anti-neuroinflammatory activity with IC50 values of 0.15 μM, 0.38 μM, and 0.23 μM, respectively [72]. The aforementioned studies clearly show how fungal endophyte-derived bioactive compounds could be a better alternative for the treatment of neurodegenerative disorders. Fungal Endophyte-derived Bioactive Compounds in Managing Neurohydrolases Neurodegenerative disorders, such as AD, are associated with the loss of memory and analytical indebtedness and low level of ACh [73]. AChE enzyme having

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esterase activity plays a major role in the functioning of the nervous system via cholinergic pathways. The cholinergic pathway works in the synaptic clefts of CNS and PNS, where it regulates nerve impulses by stimulating the hydrolysis of ACh [74]. Presently, there is no effective therapy for the treatment of AD; various drugs exist for the prevention of AD, which work by suppressing the AChE breakdown in nerve cells [75]. In one of the studies, it was found that in AD patients, the level of AChE and BuChE increases; 80% contribution is due to an increased level of AchE, whereas an increase in the level of BuChE plays a minor role in the regulation of ACh level in the brain. In the brain of AD patients, AChE activity remains unchanged or declines, but BuChE activity increases [76]. In one of the recent reports, acetylcholinesterase inhibitors (AChEIs), donepezil, rivastigmine, and galantamine, have been shown to maintain the ACh level to its normal threshold. However, these drugs also lead to numerous side effects, such as gastrointestinal complaints and hepatotoxicity [77]. Due to the use of synthetic drugs, various side effects, such as nausea, dizziness, insomnia, gastrointestinal disturbances, abnormal heartbeat, dry mouth, and many more, have been reported in patients suffering from neurodegenerative disorders. Therefore, fungal endophyte-derived bioactive compounds could be a safer approach for the development of drugs that can cure neurodegenerative disorders. Chaetomium globosum, associated with the leaves of Adiantum capillus-veneris, is known to secrete a bioactive compound that inhibits the activity of the BuChE enzyme [78]. In another report, two novel bioactive compounds, asperterpenol A (Fig. 2i) and asperterpenol B (Fig. 2j), obtained from mangrove plants associated endophytic fungi Aspergillus sp. 085242, collected from the South China Sea, are known to demonstrate BuChE and AChE inhibitory activity with IC50 value of 2.3 μM for asperterpeneol A and 3.0 μM for asperterpeneol B [79]. In another study, Huperzine A (Hup-A) (Fig. 2k), a Lycopodium alkaloid isolated from Acremonium sp. 2F09P03B, associated with H. serrata (Thunb. ex Murray), was shown to exhibit anti-AChE activity with long-term effect, high oral bioavailability, and lesser side effects [80]. Another study showed colletotrichine A (Fig. 2l), isolated from Collechotricum gloeosporioides GT-7 (GenBank Accession No. KR911618), associated with Uncaria rhynchophulla, to exert inhibitory activity against monoamine oxidase (MAO) and AChE with an IC50 value of 17.79 μg/mL and 28 μg/mL, respectively [81]. MAO inhibitors are used in the treatment of neurodegenerative disorders, such as PD and AD. Another form of colletotrichine has also been reported, named colletotrichine B (Fig. 2m), from the same endophytic fungi with inhibitory activity against MAO, AChE, and PI3Kα. AChE inhibitory activity was also calc-

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ulated with an IC50 value of 38.0 ± 2.67 μg/mL, suggesting that colletotrichine B is more potent than colletotrichine A [82]. Role of Fungal Endophyte-derived Bioactive Compounds in Managing Oxidative Stress Response Oxidative stress is caused by an imbalance in ROS production and due to the abolition of the anti-oxidant property of the existing molecules [83]. It has been noted that a large amount of oxygen is required for the proper functioning of the CNS. In the human body, free radical is generated due to the variation in various metabolic pathways. Various factors are responsible for making CNS sensitive to ROS attacks, such as increased concentration of polyunsaturated fatty acid, alteration in anti-oxidant mechanisms, and selectivity of the blood-brain barrier [84 - 86]. The role of oxidative stress in neurodegenerative diseases, such as PD [87 - 89], AD [90], and amyotrophiclateral sclerosis (ALS) [91], has been studied, which suggests that free radicals may be one of the major reasons behind the progression of neurodegenerative diseases. The use of antioxidants, such as vitamin C and E, for the treatment of neurodegenerative diseases is less effective [92]. Therefore, fungal endophyte-derived bioactive compounds could be an important tool in managing oxidative stress responses. In another study, a bioactive compound (Z)-7,4-dimethoxy-6-hydroxy-aurone-4-O-β-glucopyranoside, isolated from Penicillium citrinum, associated with Burguiera gymnorrhiza, showed anti-oxidant activity in 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative damage to PC12 cells [93]. Chrysogenamide A (Fig. 2n), a member of the macfortine group of alkaloids, obtained from Penicillium chrysogenum, associated with Cistanche deserticola (Orobanchaceae), shows neuroprotective activity by inhibiting the oxidative damage in nerve cells (SHSY5Y cells) [94]. Lasiodiplodia theobromae, associated with Saraca asoca, secretes a bioactive compound, cholestanol glucoside (Fig. 2o), which shows neuroprotective activity against oxidative damage in nerve cells. Cholestanol glucoside is known to exhibit 50% and 100% free radical scavenging activity at a concentration of 16.2 µM and 27 µM, respectively [95]. Withanolide (Fig. 2p), obtained from Penicillium oxalicum, associated with W. somnifera, is known to restore the free radical scavenging enzyme system and hypoxia-induced depleted anti-oxidant glutathione (GSH) level in the brain [96]. Penicillium spp. YY-20, associated with the root of Ginkgo biloba, is known to secrete adenosine, adenine, and 2’-deoxyadenosine, showing DPPH-scavenging activities [97]. Penicitriketo (Fig. 2q), isolated from Penicillium spp., associated with the plants, has also been reported to show 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity with an IC50 value of 85.33 μM [98]. Epicoccum spp., associated with the marine brown alga, Fucus vesiculosus, is known to secrete bioactive compounds

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derived from isobenzofuranone, such as 4,5,6-trihydroxy-7-methylpthalide (Fig. 2r) 5-(acetoxymethyl)-furan-2-carboxylic acid (Fig. 2s) (-)-(3R,4S)-4 hydroxymelliein (Fig. 2t) and (-)-(3R)-5-hydroxymellein (Fig. 2u). These bioactive compounds are reported for their anti-oxidative property by DPPH free radical scavenging assay and thiobarbituric acid reactive substance (TBARS) assay [99]. Role of Fungal Endophyte-derived Bioactive Compounds in the Management of Depression Depression is a very common condition today, which is majorly caused due to a deficiency in biogenic monamines, such as serotonin (5-HT), noradrenaline (NA), and DA [100]. With the aid of modern diagnostic tools, such as brain-imaging techniques, positron emission tomography (PET), and single positron emission tomography (SPET), the detection of neurological disorders is presently possible [101]. Due to the availability of these modern diagnostic tools, the exact reason for neurodegenerative disorders can also be determined. These tools are helpful in the detection of 5-HT receptors in the human brain; it has been found that the binding density of the 5-HT1A receptor decreases in depressed patients as compared to normal individuals [102]. In the case of patients suffering from panic disorders, 5-HT1A receptor binding decreases [103]. Bioactive compounds belonging to chalcones, flavonoids, polyphenol and flavone groups are more suitable for the treatment of depression in humans. Hypericin and pseudohypericin, which belong to the polyphenol group, extracted from Hyericium perforatum L., show anti-depressant activity [104]. In one of the studies, Thielavia subthermophila, associated with H. perforatum L., is known to secrete a bioactive compound, ‘hypericin’ (Fig. 2v) [105]. It was observed that hypericin showed MAO-A and MAO-B inhibitory activity with 50% inhibition [106]. However, hypericin binds with GABAA and 5-HT1 receptors [107], and alters the expression of the genes that may regulate the hypothalamic-pituitary-adrenal axis. Due to this, the expression level of corticotropin-releasing factor (CRF) and 5HT1A receptor was found to be reduced in the hippocampus and hypothalamic paraventricular nucleus, respectively [108]. In another report, a bioactive compound from Aspergillus terreus-F7, associated with Hyptis suaveolens (L.) Poit, showed anti-depressant activity [109]. In another study, it was found that vincamine (Fig. 2w), a bioactive compound, used in the pharmaceutical industry as a cerebral stimulant and vasodilator, was isolated from a fungal endophyte associated with Vinca minor [110].

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Fig. (2 a-w). Chemical structures of fungal endophyte-derived bioactive compounds used in the management of neurodegenerative disorders.

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CHALLENGES IN THE APPLICATION OF BIOACTIVE COMPOUNDS FOR THE MANAGEMENT OF NEURODEGENERATIVE DISORDERS Fungal endophytes produce a broad range of bioactive compounds. However, one of the major challenges in drug development for commercial application is the production of bioactive compounds in very low quantities. Therefore, more study is required on the importance of plant-endophyte interaction, geographical location of plants, and identification of elicitors in the production of bioactive compounds by endophytes under the strategy of OSMAC (one strain many compounds) to counter the low yield and attenuation problem [111, 112]. Attenuation of product formation is due to the lack of elicitor molecules secreted from plant-endophyte interaction in axenic monoculture, leading to gene silencing [113, 114]. Besides this, several ongoing researches are focused on finding effective bioactive compounds with the ability to manage neurodegenerative disorders [93]. Therefore, researchers are trying to identify highly productive fungal endophyte strains by using strategies, such as genetic manipulation, the use of elicitors, and co-culturing. Such modifications make fungal endophytes a suitable candidate for drug development in the management of neurodegenerative disorders. Moreover, a better understanding is required regarding the biosynthetic pathways, including key enzymes and associated genes, which help to enhance the production of bioactive compounds. Therefore, genes involved in the biosynthetic pathways of the bioactive compounds need to be studied via omics-based studies, such as genomics, transcriptomics, proteomics, and metabolomics for the desired fungal endophyte [114]. Several reports have shown the neuroprotective role of bioactive compounds produced from fungal endophytes; however, a mechanism-based study is still lacking. CONCLUSION AND FUTURE PERSPECTIVE The medicinal plant produces a large number of bioactive molecules. In the last few decades, it has been found that fungal endophyte-derived bioactive compounds mimic the bioactive compounds produced by the host plant. These bioactive compounds may have anti-oxidant, anti-cancer, anti-bacterial, antidiabetic, and many other activities. In addition to this, various other bioactive compounds have been reported for the treatment of neurodegenerative diseases with greater efficacy and potency. An increasing body of evidence has also shown that a wide number of fungal endophytes have not been cultured in laboratory conditions (e.g., fungus clone AE34), due to which a vast variety of bioactive compounds remain unexplored. Therefore, the identification of fungal endophytederived novel bioactive compounds and culturing them using alternative ways are

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an area of prime research presently. Even after extensive research, the relationship between fungal endophytes and their host remains unclear, which creates ample future research opportunities in this field. Bioactive compounds, isolated from fungal endophytes, are less explored and need to be checked for their medicinal importance. With the progress in the molecular biology approaches, such as TALEN (Transcription Activator-Like Effector Nucleases) and CRISPR (Clustered Regulatory Interspaced Short Palindromic Repeats)-Cas9, improvement in the fungal strain can also be performed which will increase the production of bioactive compounds. Additionally, it would be a matter of great interest to devise the nanoencapsulation method for the delivery of the bioactive compounds in order to mediate their slow and efficient release. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS AV, NR, and VG would like to acknowledge the Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, for funding and internal grants. NR would also like to thank the University Grants Commission, New Delhi, for Junior Research Fellowship. Research in the VG laboratory is supported by the SERB-EMEQ project (EEQ/2019/000025), University Grants Commission, New Delhi, India, and internal funding from Banaras Hindu University, Varanasi (under the Institute of Eminence Scheme). REFERENCES [1]

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Neuroprotective Role of Medicinal Plants from North Eastern Region of India Bedanta Bhattacharjee1, Bhargab Deka1, Naveen Shivavedi2, Hans Raj Bhat1, Saurabh Kumar Sinha3, Surajit Kumar Ghosh1 and Anshul Shakya1,* Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh-786004, Assam, India 2 Shri Ram Group of Institutions, Faculty of Pharmacy, Jabalpur-482002, Madhya Pradesh, India 3 Department of Pharmaceutical Sciences, Mohanlal Shukhadia University, Udaipur, Rajasthan313 001, India 1

Abstract: The term neurodegenerative disease means the loss of neuronal cells in the brain, including Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Huntington's disease. It is one of the most common types of disease associated with elevated rates of mortality and morbidity worldwide. At the same time, modern allopathic medicines have a large number of synthetic chemicals for the symptomatic treatment and control of these diseases. These drugs have failed miserably due to clinical insufficiency and debilitating adverse effects. In the past decade, natural ingredients have gained notable interest in the prevention and treatment of neurodegeneration due to their powerful anti-inflammatory and anti-oxidant properties with minimal side effects. However, there is also an issue of safety and effectiveness due to the absence of an ample amount of research findings. The most common cellular mechanism for every neurodegenerative disorder is neuroinflammation and oxidative stress. Several preclinical and clinical studies conducted across the world have demonstrated that different bioactive compounds of herbal origin can potentially arrest these processes to prevent or treat neurodegeneration and can be developed into promising pharmaceutical formulations. This article discusses and analyses the various herbal compounds, such as Allium sativum, Camella sinensis, Centella asiatica, Coriandrum sativum, Crocus sativus, Glycyrrhiza glabra, and Morus alba used for phytotherapy of neurodegenerative diseases by combining recent in vitro and in vivo models.

Keywords: Alzheimer’s disease, Amyloid-beta, Huntington’s disease, Multiple sclerosis, Parkinson’s disease. Corresponding author Anshul Shakya: Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh786004 (Assam), India; E-mail: [email protected] *

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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INTRODUCTION Neurodegenerative disorders are characterized by progressive neurodegeneration and loss in particular regions of the brain. These disorders involve Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), and Multiple Sclerosis (MS) [1 - 3]. AD is a progressive neuron-related brain disorder in which dementia occurs. This seems to be age-related neurodegeneration. The onset of the illness occurs with AD after 65 years of age and older. AD symptoms include memory loss, learning problems, apathy, and confusion [4]. It affects approximately 46.8 million people worldwide. According to a 2020 study, 13.8 million people in America suffer from AD, and statistics from official death records show that 122,019 deaths occur due to AD [5, 6]. The primary neurological complication in AD contributes to the extracellular accumulation of amyloid-beta (Aβ) plaques and aggregation of hyperphosphorylated tau protein. PD is a steadily progressing, extrapyramidal motor condition in which dopaminergic (DAergic) nerve cell loss occurs in the substantia nigra (SN) region of the brain. PD is known to be the world's second most common neurodegenerative disease. PD is associated with tremors in arms, hands, jaw, and legs, rigidity of the limbs, impaired postural balance and coordination, and bradykinesia [7]. It affects approximately 100-200 per 1,00,000 persons, with an average rate of 15 per 1,00,000 globally. The neuropathological complication concerns the irregular development of Lewy bodies (LB) within the cytoplasmic glial inclusion [8 - 10]. HD is the most common neurodegenerative condition, characterized by repeat expansion of inherited cytosine-adenosine-guanine trinucleotide in the huntingtin gene on chromosome 4, encoding polyQ at the end of 5' [11 - 13]. In the basal ganglia, loss of neurons and dysfunction are attributed to cognitive decline and progressive motor dysfunction in the HD. In the western population, the occurrence rate of HD is 10.6-13.7 individuals per 100,000. The disease usually begins between the ages of 30 to 40 years, having greater than 39 CAG repeats. In the United States, as of 2020 reports, 30,000 people are suffering from HD. Symptoms of HD include impaired cognitive function, chorea, mood swings, and gait abnormality [14]. MS is characterized by chronic autoimmune nervous system disorder that targets the neuronal myelin sheath in the central nerve system (CNS). The major neuropathology of complications of MS includes the formation of lesions in the spinal cord and brain region and neuronal destruction of myelin sheaths. After hindering the myelin sheath, the levels of proinflammatory cytokines increase dramatically, and the blood oligoclonal band and the blood-brain barrier (BBB)

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are damaged [15]. Most people develop MS between the ages of 20-50 years, and women are more affected than men. Globally, it affects approximately 2.3 million people worldwide [16]. The major clinical symptoms include sensation, coordination problems, double vision, and muscle weakness. NEUROPROTECTIVE HERBS The information on northeastern-based neuroprotective [17 - 21] herbs has been compiled in Table 1. Allium sativum A. sativum is a natural spice commonly known as garlic and has many health benefits. It contains a variety of phytometabolites, including organosulfur compounds, polysaccharides, saponins, and phenolic compounds. The reported active constituents of garlic include S-allyl cysteine, diallyl disulfide, allicin, and ajoene. It has been demonstrated that garlic exhibits neuroprotective activities. A research group found that inhibiting the production of nitric oxide (NO) induced by lipopolysaccharide (LPS)-activated microglial cells BV2 on treatment with aged garlic extract and activated garlic L-arginine led to attenuated neuroinflammation [21]. In a study, it was revealed that organosulfur compounds were responsible for the anti-neuritis activity of garlic in lipopolysaccharide-stimulated microglial cells BV2 [22]. In addition, in the hippocampal regions of rats, aged garlic extract mitigated cholinergic deficit neurons, and increased level 1 vesicular glutamate transporter, glutamate decarboxylase, which attenuated memory loss [23]. Similarly, the ethanolic garlic extracts were shown to improve memory [24]. The garlic extract activated glutamine synthetase, Ca2+ ATPase, and Na+/K+ ATPase in the hippocampus region of the diabetic Wistar rats [24]. In addition, the memory loss induced by monosodium glutamate was effectively reversed by ethanolic garlic extract [25]. Garlic-derived active constituent, including Z-ajoene, has been shown to avoid gliosis, lower lipid peroxidation (LPO), and delay neuronal cell death in the hippocampus CA1 area [26]. Similarly, by reducing the acetylcholinesterase activity, oxidative stress, neuroinflammation, and astrogliosis, S-allyl cysteine improved memory impairment in rats. The diagnostic characteristic of AD is the brain deposition of Aβ peptide and tau protein phosphorylation. The deficiency of acetylcholine (ACh) levels in the CNS has been associated with AD pathogenesis. Haider et al. indicated that the prolonged uptake of garlic is consequently linked with improved memory function by lowering the levels of the neurotransmitter serotonin [27]. It was shown that in

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vivo consumption of garlic extract was able to enhance memory by inhibiting acetylcholinesterase (AChE) enzyme levels and eliminating free radicals that cause oxidative damage [28]. S-allyl cysteine is a promising candidate that possesses anti-amyloidogenic and anti-oxidant activities. By various mechanisms, S-allyl cysteine can arrest the continuation of AD [29, 30]. S-allyl cysteine reduces Aβ formation and increases its clearance by decreasing amyloid precursor protein (APP) and reducing beta-site APP cleaving enzyme 1 (BACE1) and mRNA expression [31]. S-allyl cysteine inhibits the fibrillation of Aβ, but it also destabilizes the formation of preformed Aβ fibrils [32]. S-allyl cysteine lessens the activity of phosphorylation of tau2, which involves glycogen synthase kinase beta (GSK-3β) protein and possesses anti-amyloidogenic activity [33]. The Aβ pathways sequentially elaborate activation of c-Jun N terminal kinase (JNK) by neuronal apoptosis, reduced BCL-W regulation, and release apoptogenic factor caspase followed by neuronal death [34]. Biswas et al. found the level of Bim to be significantly increased in AD neurons, and being necessary for Aβ-induced apoptosis [35]. In an experimental model, when rat pheochromocytoma cells line (PC12) was exposed to Aβ, a significant increase in ROS occurred [36]. Garlicderived compounds, such as S-allyl cysteine and diallyl disulfide, have been found to protect against neuronal cell death induced by apoptosis and Aβ toxicity [37, 38]. S-allyl cysteine and aged garlic extract also lessened DNA fragmentation, and protected the neurons against Aβ-induced apoptosis and caspase 3 activations. In an experimental model, 1-methyl-4-phenylpyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) were used to induce nigrostriatal DAergic neurotoxicity. Treatment with S-allyl cysteine increased DAergic levels, and reduced oxidative damage and LPO caused by MPP+ and 6-OHDA. The superoxide dismutase (SOD) level was simultaneously higher in the MPP+ model [39, 40]. In animal models, quinolic acid and 3-nitropropionic acid are used to induce HD. S-allyl cysteine administration lowered the level of mitochondrial dysfunction and LPO. It also improved behavioral alteration and the levels of Mn and Zn/Cu as well as SOD activity [41, 42]. It was reported that allicin inhibited the enzymes AChE and butyrylcholinesterase, which greatly increased the concentration of Ach levels in the hippocampus region of the brain [43]. In an experimental model of HD, a neurotoxin, 3-nitropropionic, reduced succinate dehydrogenase levels, producing massive oxidative/nitrosative stress. Administration of S-allyl cysteine reduced mitochondrial stress, LPO, and the hypokinetic pattern generated by the toxin, and increased SOD, Mn, and Cu activities, suggesting S-allyl cysteine to show neuroprotective effect due to its anti-oxidant role [44]. Thus, the constituents of garlic may also be responsible for its neuroprotective effect. Organosulfur compounds of garlic play a key role in neuroprotection.

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Camella sinensis C. sinensis, also known as green tea, has been shown to be useful against neurodegenerative disorders, such as AD and PD. The epicatechin, epigallocatechin, and epigallocatechin gallate (EGCG) are the active constituents of green tea [45]. The molecular models of PD disease are neurotoxins 6-OHDA and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which disrupt the SN region of the brain and contribute to DAergic neuronal failure [46]. The Parkinson’s model was induced by MPTP in cynomolgus monkeys; the administration of catechin-derived polyphenols increased the levels of dopamine (DA), decreased α-synuclein (α-syn) oligomers, and maintained tyrosine hydroxylase (TH) [47, 48]. Pre-administration of EGCG in MPTP-treated C57/BL mice model showed to increase the expression of Bax and decrease the expression of Bcl-2 and α-syn. EGCG demonstrates neuroprotective activity by substantially increasing the level of protein kinase C alpha (PKCα) in the striatum (ST) [49]. The long-term use of levodopa (L- DOPA) has shown an adverse effect in PD treatment, which would further inhibit the uptake of DA, reduce DA turnover, and inhibit dopamine transporters (DAT). Catecholamine-O-methyl transferase (COMT) inhibitors block the conversion of L-DOPA to 3-O-methyl DOPA and are used widely for the treatment of PD. Under in vitro and in vivo conditions, EGCG inhibits COMT, which further inhibits the methylation of L- DOPA, proposing that the EGCG may also be given in combination with existing drugs of PD to increase their efficiency and availability in the brain [50]. The oral administration of EGCG at a dose of 25 mg/kg prevented the depletion of DAergic neurons in the brain region and retained DA levels [51]. In MPTPtreated mice, EGCG prevented the accumulation of α-syn. These effects showed the antioxidant activity of EGCG [49]. A study demonstrated that phytoextracts from green tea prevented DAergic neurons against inducible ROS, nitrite/ nitrate content, and LPO due to the exposure of rats to 6-OHDA. In in vitro conditions, the tea polyphenols have been shown to exhibit free radical scavenging activity, and inhibit xanthine oxidase (XO), lipooxygenase, cyclooxygenase, NO, and nuclear factor-kappa B (NF-κB). In transgenic nematode strains, phytoextract of green tea was found to retard Aβ protein in AD [52]. In AD mice models, feeding with EGCG at a dose of 2-6 mg/kg showed a substantial reduction in the aggregation of Aβ [53]. In an Alzheimer's transgenic mouse model exposed to APP, EGCG at doses of 50 mg/kg showed a marked reduction in Aβ levels. Similarly, green tea epicatechins have been able to inhibit tau proteins and improve cognitive ability, thus minimizing Aβ levels [54]. In the Swedish mutant APP transgenic mouse model in AD, intraperitoneal (20 mg/kg) or oral (50 mg/kg) administration of EGCG significantly reduced Aβ and plaque formation levels [55]. Oral administration of EGCG (20 mg/kg) for up to 3 months showed a 60% decrease in Aβ deposits in the hippocampus and frontal cortex areas of the

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brain in transgenic mice with AD [56]. EGCG was found to activate GSK-3β in the Aβ-induced neurotoxicity model by inhibiting cytoplasmic non-receptor tyrosine kinase (TRK) involved in nuclear translocation and nervous system development [57]. In an investigation, EGCG was seen to inhibit the expression of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and inducible nitric oxide synthase (iNOS), enhancing the levels of intracellular anti-oxidants against proinflammatory effects caused by free radicals in heme oxygenase-1, microglia, and factor 2-related nuclear erythroid 2 [58]. EGCG attenuated ROS-mediated NF-κB activation in Aβ-induced cytotoxicity, including p38 and JNK signaling [59]. In an AD rat model, a polyphenol from green tea was shown to improve cognitive function and prevent oxidative stress in the hippocampus regions [60]. Oral administration of tea polyphenol could reduce DAergic neuronal injury, motor impairment, DAergic neurons, and DA depletion in monkeys associated with PD, thus enhancing the motor function of the brain [26]. In China, a cross-section study was performed on 215 participants, in which daily tea intake decreased the risk of AD and increased cognitive decline [61]. Another research found that the risk of PD was decreased by daily tea intake [62]. Polyphenols from green tea also have a beneficial impact on anti-oxidant enzymes. Regular intake of green tea by patients with PD has indicated a significant increase in the level of antioxidant enzymes, such as catalase (CAT) and SOD, and decreased protein and lipid oxidation [63]. EGCG greatly decreased oxidative stress-mediated apoptosis, LPO, and restored locomotors’ function in the mutant Drosophila model of PD expressing α-syn [64]. Administration of EGCG dose-dependently decreased the aggregation of PolyQmediated Htt protein in the experimental model of HD and prevented the aggregation of Htt protein exon 1. In Drosophila models of HD, administration of EGCG reduced toxicity, decreased photoreceptor degeneration, and improved motor function. It also stabilized the hypoxia-inducible factor (HIF-1α) pathway and inhibited heat shock protein 90 (HSP90), which is directly associated with the suppression of hydroxyl radical scavenging. In MS people, it also improved muscle metabolism [55, 65 - 68]. Thus, green tea extract exhibits a neuroprotective role in HD, PD, AD, and MS. Centella asiatica C. asiatica, referred to as “Gotu kola”, is frequently used as a neuroprotective herb with beneficial properties, such as behavioral, memory enhancing, and performance learning. The active phytoconstituents of C. asiatica are madecassoside, asiaticosides in which trisaccharide moiety is connected with aglycone portion of asiatic acid, madecassic acid, and asiatic acid. Copper et al. have also suggested that C. asiatica is a promising candidate as it manifests

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neuroprotective activity via various mechanisms, such as inhibiting enzymes, preventing Aβ plaques formation and oxidative stress [69]. C. asiatica possesses anti-oxidant activity, arresting free radical mechanisms and restoring glutathione (GSH) levels by increasing anti-oxidant enzymes glutathione-s-transferase (GST) activity. It also decreases the brain's Aβ deposition. A group of studies conducted by Chen et al. demonstrated that C. asiatica ethanol extract inhibited the Aβinduced neurotoxicity in PC12 and IMR32 cell lines [70, 71]. Asiatic acid from C. asiatica has an important neuroprotective impact on cultural cortical cells by restoring the cellular oxidative protection mechanism [72]. It may thus prove to be efficient in protecting neurons from oxidative damage induced by excessive glutamate exposure [73]. In a rat model, administration of colchicine resulted in marked devastation of septohippocampal pathways and hippocampal granule cells, which resulted in decreased activities of choline acetyltransferase, AChE, and loss of cholinergic neurons. So, C. asiatica prevented oxidative stress and cognitive impairment induced by colchicine [74]. In the prenatal stress model of rats, postnatal treatment of fresh leaves extract of C. asiatica protected the hippocampal regions, and improved memory and learning performance [75]. The AChE inhibitory activity of C. asiatica has been revealed by several in vitro experiments. The inhibitory activity of AChE enzymes with an IC50 value of 106.55 ± 9.96 μg/mL was shown by hydroalcoholic extracts of C. asiatica [76]. Similarly, long-term therapy of C. asiatica extract reduced the pathology of Aβ in transgenic mice [77]. In aged Sprague-Dawley rats-induced neurotoxicity models, extract of C. asiatica exhibited effectiveness against neurodegenerative disease [78]. In SH-SY5Y cell lines, asiatic acid extracted from C. asiatica protected against glutamate-induced apoptosis in vitro and reduced glutamate-induced cognitive deficiencies in mice, which suggests the possible role of asiatic acid in treating neuronal damage [79]. The effects of ethanolic and aqueous extracts of C. asiatica on nerve regeneration in human SH-SY5Y cells showed that the ethanolic extract greatly increased neurite outgrowth in the presence of nerve growth factor [71]. In male SpragueDawley rats, ethanolic extract of C. asitica was orally given to increase axonal regeneration and induce rapid recovery of memory. In vivo studies showed that asiaticoside and both C. asiatica methanolic and ethanolic extracts exhibited anxiolytic action [80]. Oral administration of C. asiatica extract increased memory retention and learning skills in rats [81]. In a rat model of cerebral ischemia-reperfusion, an important triterpene, madecassoside acid, showed neuroprotective activity [82]. This study found that madecassoside decreased neuroinflammation significantly and improved the response to oxidative stress. In a rat model, it was revealed that madecassoside could be effective in the early stage of PD [83]. The effect of C. asiatica water extract on the phospholipase A2 enzyme was studied by Defillipo et al. [84]; it particularly inhibited cPLA2 and

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sPLA2, which are involved in neurotoxicity induced by Aβ. Caffeoylquinic acid from water extracts of C. asiatica is one of the major substances having antioxidant activity, preventing Aβ-induced cell death, and improving mitochondrial dysfunction [85, 86]. C. asiatica has been shown to enhance phosphorylation of the cAMP response element-binding protein in neuroblastoma cells expressing Aβ, possibly conciliated by the extracellular signal-regulated kinase (ERK)/ ribosomal S6 kinase (RSK) signaling pathway [86]. C. asiatica was thus suggested as a supportive herb for oxidative stress and neuroinflammation induced by Aβ. A group of researchers systematically assessed the inhibitory potency of C. asiatica towards enzyme γ-aminobutyric acid (GABA) transaminase and glutamic acid decarboxylase, both of which are responsible for the metabolism of GABA, and it was shown that C. asiatica extract stimulated 40% glutamic acid decarboxylase activity [87]. Lee et al. investigated the neuroprotective properties of 36 lead asiatic acid molecules prepared by structural alteration, rearrangement, and testing of rat cortical neurons overexpressing glutamate, a well-known neurotoxin, in a cell culture medium. Out of 36, 3 lead molecules were found to possess beneficial neuroprotective activity than asiatic acid and greatly decrease enzymes levels, viz. glutathione peroxidase (GPX), GSH, as well as NO-induced glutamate production [71]. In the brain of male prepubertal mice induced with mitochondrial dysfunction and oxidative stress by 3-nitropropionic acid, which is a fungal-derived neurotoxin, it was found that C. asiatica extract decreased the level of oxidative stress markers, like radical oxygen species and malondialdehyde (MDA) [88]. In old rat models, C. asiatica extract was administered orally at a dose of 300 mg/kg per day for up to 60 days, and the hippocampus, hypothalamus, cerebellum, cortex, and ST regions of the rat brain were analyzed in terms of LPO and protein carbonyl contents. The researchers concluded that by decreasing LPO and protein carbonyl content, the C. asiatica extract demonstrated neuroprotective activity in rats [89]. The chloroform-methanol extract (4:1) of the plant exhibited radical scavenging activity in Sprague-Dawley female rats treated with monosodium glutamate at doses of 100 and 200 mg/kg [90]. In another research work, the C. asiatica triterpene derivative, asiatic acid, orally administered at a dose of 30, 75, and 165 mg/kg, demonstrated neuroprotective activity in mice with permanent cerebral ischemia by estimating the amount of the infarction and behavioral improvements from the 1st and 7th days [91]. Asiaticosides from C. asiatica demonstrated promising neuroprotective activity against PD in rats induced by MPTP by reversing neurotoxicity via balancing the levels of DA and several anti-oxidant mechanisms [92].

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Coriandrum sativum This plant belongs to the Apiaceae family. The main active phytoconstituents of C. sativum are polyphenolic compounds, like protocatechuic acid, caffeic acid, linalool, glycitin, and flavonoids, including quercetin-3-glucuronide [93, 94]. In a study, it was reported that the C. sativum extract significantly increased the enzyme levels of CAT, SOD, and GSH, and reduced the levels of LPO and cerebral infarct size in rats. An experimental model of scopolamine and diazepam-induced memory deficits was altered by C. sativum leaves extract [95]. The C. sativum leaves extract also exhibited anti-oxidant property, 2,2-dipheny-2-picryl hydrazyl radical scavenging activity, inhibition of phospholipid peroxidation, and inhibition of lipooxygenase, which may also lead to its memory enhancement impact [96]. The neuroprotective effects of C. sativum have been assessed against brain ischemia-reperfusion insult. In albino rats, by blocking the carotid arteries for 30 min, global cerebral ischemia was observed, followed by reperfusion of 45 min. After the reperfusion phase, certain biochemical and histological changes were observed, and levels of LPO, CAT, SOD, GSH activity were measured. Bilateral complete blockage of the carotid artery causes a notable increase in the levels of LPO, infarct size, and a decrease in certain anti-oxidant enzymes levels, such as GSH, SOD, and CAT. Pre-administration with the methanolic extract of C. sativum leaves (200 mg/kg) for up to 15 days enhanced the levels of antioxidant enzymes, such as CAT, SOD, and GSH total protein, and decreased cerebral infarct size and LPO. Similarly, C. sativum has a protective effect in cerebrovascular insufficiency states and ischemic reperfusion injury [97]. In vitro study was conducted to find out the neuroprotective activity of C. sativum against glucose/serum deprivation-induced cytotoxicity. At the end of the procedure, the cell viability was analyzed using the tetrazolium-based colorimetric assay. A concentration of 1.6 mg/mL N-butanol fraction and ethyl acetate fraction of C. sativum reduced cell survival, and the hydroalcoholic fraction did not exhibit cytotoxicity under standard conditions. The researcher concluded that water-soluble extract of C. sativum possesses neuroprotective activity [98]. In transgenic AD mice, linalool-derived from C. sativum reduced tauopathy and β amyloidosis in the CA1 hippocampus region of the brain. In transgenic AD mice, regular treatment with linalool prevented Aβ accumulation and age-related cognitive impairments [99, 100]. Similarly, in transgenic mice with AD, oral treatment with linalool reduced proinflammatory mediator (IL-1β) and downregulated iNOS activity of COX-2. Linalool also shows anti-oxidant action and shows beneficial effect against H2O2-induced oxidative stress in the brain [101] A toxic chemical that is an unsaturated water-soluble carbonyl compound mostly used in industries is acrylamide. More focus has been given to neurotoxicity induced by acrylamide [102]. It hinders the anti-oxidant mechanisms of the brain and increases the level of LPO [103]. It also activates

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caspase 3, which is responsible for apoptosis of neuronal cells [104]. An in vivo study demonstrated that in Wistar rats, linalool displayed neuroprotective activity in dose and time-dependent manners in the acrylamide neurotoxicity model. The level of LPO is decreased, and elevated GSH levels have also been found in the brain of treated rats [105]. Crocus sativus One of the most prominent neuroprotective herbs, belonging to the family Iridaceae, is commonly known as saffron that is available in some of the regions of northeastern India. The reported active constituents include crocin, crocetin, and safranal. The C. sativus extract protects neurons from neurodegenerative diseases due to its anti-oxidant and anti-inflammatory effects [106, 107]. In the hippocampus region of the brain, Ghadrdoost et al. suggested that crocin, a diester-disaccharide derivative from C. sativus, activates anti-oxidant mechanisms and improves oxidative stress [108]. In a study conducted by Soeda et al., it was reported that the administration of crocin decreased oxidative stress-mediated neuronal cell death by preventing the activation of ceramide production, neutral sphingomyelinase, and JNK phosphorylation [109]. Crocin administration can prevent neurodegeneration and increase the levels of oxidative stress markers in an experimental model of AD [110]. The possible pathological complication of AD is the deposition of neurofibrillary tangles (NFTs) and Aβ plaques in the brain. The anti-oxidant and anti-apoptotic activities of C. sativus and its phytoconstituents are reported by different authors [111, 112]. In a randomized double-blind study, it was found that C. sativus stigma extract has potential antioxidant mechanisms, and its impact on Aβ1-40 fibrillogenesis has been determined and carried out on 46 AD participants [113]. In a clinical study, C. sativus (15 mg) administration for about 16 weeks twice daily in treated groups showed improvement in memory retention compared to placebo groups [114]. In addition, treatment with C. sativus in a single-blind randomized trial of 12 months study showed improvement in the cognitive decline in 17 patients with amnesia [114]. In an animal model, the neuroprotective effects of crocetin on brain injury are primarily linked to the ability to facilitate sub-acute angiogenesis and inhibition of early stages apoptosis as governed by significantly increased levels of vascular endothelial growth factor receptor-2 and serum response factor [115]. In glucose/serum deprivation-induced cytotoxicity, crocin may inhibit the increased levels of LPO [116]. In PC12 cell lines, treatment with C. sativus extract (5 and 25 mg/mL) and crocin (10 and 50 μg/mL) could reduce the neurotoxic impact of glucose [117]. Treatment with C. sativus extract (200 mg/kg) decreased the neurotoxicity caused by aluminum chloride in mice [118]. In anesthetized rat models, administration of safranal followed by kainic acid

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administration reduced the extracellular concentration of aspartate and glutamate in the hippocampus region [119]. Administration of crocin increased the activity of SOD and GPx, and significantly decreased the level of MDA in the ischemic cortex region in the ischemic stroke rat [120]. In AD, Ebrahim and Habib et al. suggested that C. sativus has the ability to prevent short-term memory problems and inhibit Aβ aggregation in the brain of mice [121]. C. sativus has the ability to inhibit Aβ fibrillogenesis in a time and concentration-dependent manner due to its anti-oxidant properties. As a result, the amphiphilic nature of crocin makes it more efficacious and effective in preventing the development of Aβ [122]. As compared to a low concentration of dimethylcrocetin, the digentibiosyl ester derivative of crocetin i.e., trans-crocin-4, inhibits Aβ fibrillogenesis [123]. Treatment with C. sativus extract 30 mg/kg for up to 3 weeks in rats with sporadic AD model induced by intracerebrovascular streptozotocin injection could significantly improve memory deficits [124]. Geromichalos et al. reported that C. sativus extract has an inhibitory action on AChE and that it prevented ACh breakdown, which is the primary treatment approach for AD [125]. Under the amyloidogenic condition, safranal and crocin have an inhibitory effect on fibrillation of Apo α-lactalbumin, where crocin was found to be more potent than safranal [121]. In the PD rat’s model induced by 6-OHDA, intraperitoneal administration of crocetin (75 μg/kg, b.w.) for up to 7 days showed neuroprotective effects via reduction in DA levels [126]. In human neuroblastoma cells, an in vitro study demonstrated by Papandreous et al. showed that crocin and C. sativus have protective effects against H2O2-induced toxicity [123]. Preadministration of C. sativus prevented the formation of DAergic cells in SN by increasing the levels of TH in cells (25-35%) in a mouse model of PD induced by MPTP [127]. Glycyrrhiza glabra G. glabra is an herbaceous perennial plant, commonly named licorice, which belongs to the Fabaceae family. The major pharmacoactive constituents of G. glabra are glycyrrhizic acid, glycyrrhetinic acid, monoglucoronide, isoliquiritigenin, liquiritigenin, and glabridin, an isoflavonoid derivative that possesses neuroprotective activity [128]. Administration of glabridin profoundly reduced the levels of MDA in the brain, and it elevated the levels of SOD and GSH [129]. Treatment with glabridin was shown to hinder staurosporine induced apoptosis and DNA fragmentation in cortical neurons [129]. The in vivo neuroprotective effects of glabridin were assessed in mid-cerebral artery occlusion rat models, where treatment with glabridin rats showed decreased MDA levels and it elevated levels of SOD and GSH [129]. Oral administration of G. glabra extract was shown to improve the memory and learning behavior in mice at a

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varying concentration (75-300 mg/kg) for 14 days [130]. The neuroprotective effect of G. glabra extract is primarily associated with its anti-oxidant properties, resulting in the improvement of memory, neuronal function, and reduced brain damage. The activation of the NF-κB signaling pathway is linked with the neuropathology of MS [131]. In this connection, the effects of glycyrrhetinic acid, monoglucoronide and glycyrrhizic acid are shown to inhibit NF-κB signaling pathways as well as other inflammatory signaling molecules, including ROS, TNF-α, PGE2, NO, IL-1, and IL-1β through LPS induced inflammation [131]. Both glycyrrhetinic acid, monoglucoronide and glycyrrhizic acid were shown to decrease the mitochondrial activity of Bcl-2 and increase the activity of phosphoinositol-3 kinase (PI3K), which inhibited the cell death process [130]. Mitogen-activated protein kinase (MAPK), also known as ERK pathway, is involved in the neuroprotection of glycyrrhizic acid. The initial process starts with the binding of an extracellular signal to a TRK protein. At the end of this process, molecules of ERK enter the nucleus and promote signal transcription, which results in cell survival and protection against stress-induced apoptosis. Glycyrrhizic acid was shown to increase ERK pathway activity in neuronal culture [132]. The active constituents of licorice include isoliquiritigenin and liquiritigenin, which have been studied for neuroprotective properties. On glutamate-induced neurotoxicity, the inhibitory effect of isoliquiritigenin is similar to that of glycyrrhizic acid. Isoliquiritigenin reduces the levels of expression of mitochondrial Bax, apoptosis-inducing factor (AIF), and LPO, and increases the levels of signaling molecules, including Bcl-2, p53, ERK, and JNK, which inhibit apoptosis and promote cell survival [133, 134]. On cortical neural cells, the administration of isoliquiritigenin substantially reduced the impact of neurotoxicity caused by Aβ [25 - 35] in vitro [134]. Another study showed that water extract of licorice exerted a decrease in neurotoxic effects of Aβ protein in PC12 cell lines [135]. Licorice has been shown to enhance learning and memory behavior in animal models. In an experimental model with amnesia induced by diazepam and scopolamine, licorice was found to reverse the amnesia and have anti-cholinesterase activity [135] in the PD mouse model induced by 6-OHDA, which is known to induce apoptosis and stress in neurons. Administration of isoliquiritigenin extract from G. glabra showed decreased levels of NO and ROS [124] Similarly, inhibition of cytochrome C, Bax, JNK, intracellular signals, and caspase3 was also noted in the 6-OHDA treated with isoliquiritigenin [136]. In cultured neural tissue, isoliquiritigenin and liquiritigenin have been shown to prevent aggregation of α-syn fibrils [137]. Morus alba M. alba has long been used as a neuroprotective medicinal plant in the ayurvedic

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and western systems of medicine. This herb belonging to the family Moraceae contains active phytoconstituents, including glycosides, steroids, tannins, flavonoids, volatile oils, terpenoids, and alkaloids. The reported active constituents include cyanidin-3-O-β-d-glucopyranoside, artoindonesianin O, mulberroside A, morachalcone A, astragalin, quercetin, rutin, isobavachalcone, and isoquercetin [138]. The protective effects of fruits, bark, and leaves of white mulberry improved neuronal activity [139, 140]. It was shown that anthocyanins in mulberry fruit extract prevented the DAergic neurons from neurotoxicity [141]. The neuroprotective activity was seen due to the presence of high amounts of total phenolic compounds in matured mulberry fruit extract [142]. In a rat model, mulberry fruit extract could enhance memory retention, improve cholinergic activity and densities of neurons suffering from hippocampal damage, and memory impairment. Therefore, this research validates the neuroprotective effects of mulberry fruit extract against memory impairment [143]. One of the major active phytoconstituents isolated from mulberry fruit extract was cyanidin-3--β-d-glucopyranoside. It has been reported that cyanidin-3-O-β-d-glucopyranoside showed neuroprotective effects on H2O2-induced neurotoxicity in PC12 cell lines and cerebral ischemia in mice. In an animal model with middle cerebral artery occlusion, cyanidin-3-O-β-d-glucopyranoside showed a more neuroprotective effect than mulberry fruit extract against cerebral ischemia [141]. In PD, the antiapoptotic and anti-oxidant effects of mulberry fruit extract significantly prevented the loss of neurons from neurotoxins in in vivo and in vitro models [141]. Mulberry fruit extract has been able to protect against the degeneration of DAergic neurons and olfactory dysfunction, inhibit α-syn, improve motor deficits and ubiquitin upregulation mechanisms [144]. Treatment with mulberry extract exerted a beneficial effect against PD-like symptoms, including tremor and bradykinesia in the PD model induced by MPTP, and protected loss of DAergic neuron damage induced by MPTP [144]. Another phytocompound-derived from mulberry wood (M. alba), oxyresveratrol, possesses potent antioxidant activity and free radical scavenging against cerebral ischemia [145]. Administration of oxyresveratrol showed neuroprotective activities via significantly increasing the basal levels of SIRT1 and regulated the phosphorylation of JNK in the PD model induced by 6-OHDA neurotoxicity [146]. After high exposure to trauma and glutamate, administrations with oxyresveratrol exert a neuroprotective effect due to its blood-brain permeability and anti-oxidant effects. In rodent PD models, a monomeric derivative of proanthocyanidin, catechin, showed a neuroprotective effect against the peroxynitrite-induced formation of 5-S-cysteinyl DA, which is an endogenous neurotoxin involved in the early development of PD [146]. Similarly, supplementation of mulberry fruit extract in animal models showed a beneficial effect on Bcl-2 immunopositive neuron density and anti-oxidant activity. Qio et al. isolated and identified a dietary phenolic compound derived

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from mulberry, artoindonesian O [147]. In neuronal cells, treatment with artoindonesianin O reduced the okadaic acid-induced tau hyperphosphorylation and lowered the N-methyl-D-aspartate (NMDA) or Aβ42-induced neurotoxicity. The authors suggested that the mechanisms involved with the inhibition of p-ERK 1/2 expression [147] Additionally, after treatment with artoindonesianin O, the numbers of dendritic spines also increased [147]. This study revealed that artoindonesianin O showed neuroprotective effects on neurons [148]. Wang et al. revealed the neuroprotective effects of mulberroside A, polyhydroxylated stilbene derivative compound derived from the twigs and roots of M. alba against brainischemic damage using in vitro primary culture of rat cortical neurons. Mulberroside A has been reported to have anti-apoptotic and anti-inflammatory effects [148]. In HT22 hippocampal cells, isolated compounds from the fruits of M. alba, including morachalcone A, astragalin, artoindonesianin O, quercetin, rutin, isobavachalcone, and isoquercetin, have shown neuroprotection effects on glutamate-induced oxidative stress [149]. On primary hippocampal cultures of rat cortical neurons, preadministration with quercetin, a flavonol glycoside, reduced LPO, apoptosis, protein oxidation process, and Aβ-induced toxicity [150, 151]. Table 1. List of neuroprotective herbs from North-Eastern origin of India. S. Herbs No. A. 1. sativum

Regional Names Assamese-Nohoru, Manipuri- Chanam, Mizo- Purunvar

Assamese- Chah paat, C. Bengali- Chaa pata, 2. sinensis Manipuri-Cha, MizoThingpui

3.

C. asiatica

C. 4. sativum L.

Assamese-Manimun, Bengali- Thanakun, Mizo- Lambak

Assamese- Dhaniya

Family

Pharmacoactive Constituents

Possible Mechanisms

Refs.

Amaryllidaceae

Allicin, S-allyl -cysteine, diallyl sulfide, ajoene

Reduced ROS production, LPO, decreased formation of Aβ.

[21, 25, 26]

Theaceae

Prevent apoptosis of neurons by increasing Catechin, epigallo catechin gallate, Bax and decreasing [52 the Bcl-2 expression, 54] epigallo catechin and lowering α-syn expression.

Apiaceae

Asiatic acid, asiaticosides, madecassic acid, madecossides.

Inhibitory AChE activity, inhibited Aβ peptide formation, [79 and improved 81] memory learning abilities.

Geranyl acetate, borneol, αphellandrene, linalool

Anti-oxidant mechanisms, reduced levels of [96, proinflammatory 100, mediators, 103] downregulated COX2 and iNOS.

Apiaceae

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(Table ) cont.....

S. Herbs No.

Regional Names

Family

Pharmacoactive Constituents

Assamese- Kunkum, Jafaran, Kungkum

Iridaceae

Crocin, crocetin, safranal

Leguminosae

Glycyrrhizic acid, glycyrrhetinic acid monoglucoronide, dehydroglyasperin C, liquiritigenin

5.

C. sativus L.

6.

G. Assamese-Zostimodhu, glabra Bengali- Yasthimadhu

7.

Assamese- Kiskuri, M. alba Nuni, ManipuriL. Kabrangchakangouba, Mizo- Thing-theihmu

Moraceae

Possible Mechanisms

Refs.

Improved level of oxidative stress [112 markers, and inhibited Aβ fibrillogenesis. 114] Improved neuronal function, memory, anti-oxidant mechanisms, etc.

[129, 130]

Inhibited tau hyperphosphorylation, Cyanidin-3-o-β-d-glucopyranoside, [142, free radical artoindonesianin O, mulberroside 144, scavenging A, morachalcone A, mechanisms, inhibited 149] oxyresveratrol, Isobavachalcone ubiquitin downregulation, etc.

CONCLUSION Neurodegenerative disorders have skyrocketed in the past decades, but the cause of most neurodegenerative disorders remains unclear. The use of medicinal herbs has gained a great deal of interest in recent years due to their therapeutic effectiveness. In the future, the use of phytochemicals may be a promising alternative due to their anti-inflammatory, anti-oxidant, and anti-cholinesterase activities. Neurodegenerative diseases, such as AD, PD, HD, MS, and others share similar features at the cell and subcellular levels and most other common molecular signaling mechanisms that may contribute to oxidative damage, apoptosis, necroptosis, and neuroinflammation. To date, there are no modern synthetic drugs to effectively treat or reverse neurodegeneration. Medicinal herbs provide promising alternatives to the current therapies because the diverse bioactive phytochemicals possess different kinds of biological or pharmacological effects. This combination of bioactive phytochemicals may target different molecular mechanisms. Although herbal medicines have been in use for neurodegeneration for years, they still lack quality control data and safety in consumption across the population, and their potential is greatly hindered by their poor pharmacokinetic properties. In order to overcome these limitations, herbal medicines have to undergo quality control, safety evaluation, and better formulation for consumption. Here, in this review, we have collected the data from the most relevant evidence (literature) that demonstrates a neuroprotective function in animal models. Although the mentioned studies are not comprehensive, the listed medicinal herbs have shown very promising results in animal models.

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CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT The authors thank the LNB Library, Dibrugarh University, Assam, India, for providing facilities required to access relevant papers. REFERENCES [1]

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CHAPTER 6

Tinospora cordifolia in Neurodegeneration: A Strong Antioxidant and Anti-inflammatory Phytotherapeutic Drug Candidate Anuradha Sharma1 and Gurcharan Kaur2,* College of Animal Biotechnology, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana-141004 (Punjab), India 2 Department of Biotechnology, Guru Nanak Dev University, Amritsar-143005 (Punjab), India 1

Abstract: Tinospora cordifolia is a Rasayana herb of Ayurveda, commonly known as “Heavenly Elixir” or “Amrita”, and one of the most exploited herbs in herbal medicines. T. cordifolia is well reported for its various pharmacological properties, such as anti-diabetic, anti-inflammatory, antipyretic, immunomodulatory, anti-cancer, cardioprotective, neuroprotective, and hepatoprotective activities. The prevalence of neurodegenerative diseases and other neurologic disorders is increasing worldwide. Oxidative stress and neuroinflammation are among the major pathologic mechanisms underlying neurodegenerative diseases. This chapter discusses the pieces of scientific evidence of the beneficial effects of T. cordifolia in various brain-related ailments. Various research groups have demonstrated the ability of T. cordifolia and its extracts to normalize oxidative stress and suppress the inflammatory response against various causative agents, and thus suggested that T. cordifolia has the potential to be a neurotherapeutic drug candidate in the future.

Keywords: Herbal medicine, Neuroinflammation, Neurologic disorders, Oxidative stress, T. cordifolia.

Neurodegeneration,

INTRODUCTION Tinospora cordifolia is used as one of the important components of herbal formulations in the Indian system of medicine, i.e., Ayurveda, due to its exceptional pharmacological properties. T. cordifolia is a climber shrub of the family Menispermaceae and grows throughout India, Myanmar, Sri Lanka, China, and also in tropical regions of Africa and Australia [1]. T. cordifolia is known by Giloy, Guduchi, Amrita, Amarvel, Rasakinda, and many other vernacular names Corresponding author Gurcharan Kaur: Department of Biotechnology, Guru Nanak Dev University, Amritsar143005 (Punjab), India; E-mail: [email protected]

*

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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in different regions of India. It has been referred to as ‘Heavenly Elixir’ and ‘Nectar of Immortality’ in the literature of herbal medicine and is being used for the treatment of various ailments, such as gout, fever, arthritis, dysentery, diabetes, diarrhea, asthma, anemia, and psoriasis [2 - 5]. T. cordifolia is known as ‘Amrita’ due to its ability to provide vitality, longevity, and youthfulness [6 - 8]. Medicinal/pharmacological properties of this plant have been attributed to its phytoconstituents, such as glycosides, steroids, alkaloids, diterpenoid lactones, and aliphatic compounds [9 - 12]. A long list of anti-diabetic, immune-stimulant, anti-oxidant, anti-inflammatory, memory enhancer, neuroprotective and anticancer activities in the scientific literature witness its importance for disease treatment in the modern era [13 - 16]. T. cordifolia has also been reported to be beneficial against microbial infections. T. cordifolia got a special mention recently in immune-potentiating herbal formulations and kadas (liquid drinks) against the COVID-19 epidemic [15]. BRAIN HEALTH AND NEUROLOGIC DISEASE BURDEN The brain, being a command center of the body, facilitates the formation of memories, processing of thoughts and emotions, and control of bodily movements. A healthy brain is considered a state in which individuals can optimise their psychological, emotional, and cognitive abilities, and thus behavioral responses to cope with different stresses/situations in life. Maintaining good mental health is the topmost goal for achieving health and longevity; however, it becomes challenging with increasing age as well as increasing neurological disease burden [17]. Neurological disorders are classified into three groups: (a) diseases that cause damage or alteration to brain structures, such as brain cancers, traumatic brain injuries, cerebrovascular diseases, meningitis, etc.; (b) diseases that affect brain function, such as neurodegenerative and mental diseases. These functional disorders are because of the significant destruction of neuronal connections and networks; (c) other brain diseases with detectable functional or structural impairments, such as sleep disorders and migraine. All of these disorders affect the brain in different but overlapping ways. For example, neurodegenerative diseases mainly induce dementia and cognitive impairment, whereas mental disorders affect rewards, emotions, and execution. According to the Global burden of disease study 2016, neurological disorders are the 2nd most prevalent cause of death worldwide (9 million); however, in terms of disabilityadjusted life years (DALYs), neurological disorders are the 1st leading contributor (276 million) [17 - 19]. This global disease burden is expected to increase exponentially with increasing age. Population above 60 years of age is expected to be 2 billion by 2050, which was around 900 million in 2015 (WHO global health

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ethics team). Individuals with neurological ailments having physical, cognitive, mental, and functional disabilities pose an economic burden to healthcare systems worldwide. To promote healthy aging and brain health in general, new technological tools and developments for brain health assessment as well as novel therapeutic strategies are warranted. IMMUNOMODULATORY ROLE OF T. CORDIFOLIA T. cordifolia is reported to stimulate the non-specific immune systems and its immunomodulatory potential is well documented. The macrophage cell line J774A.1 treated with T. cordifolia directly showed macrophage activation and enhanced lysozyme secretion into the culture medium, which further exhibited microbicidal activity against E. coli [20]. Treatment with aqueous extract of T. cordifolia was reported to exhibit dose-dependent cytotoxicity in mouse melanoma B16F10 cells as well as activation of cultured splenocytes by upregulating the cytokine secretion, enhancement of nitric oxide generation, and boosting the phagocytic action of macrophages, which was suggestive of multifaceted immunomodulatory potential of this herb [21]. In in vitro as well as in vivo models of skeletal muscle atrophy, T. cordifolia treatment stimulated myogenic differentiation of C2C12 skeletal muscle myoblasts and enhanced proliferation of lymphocytes by reducing oxidative stress, neuroinflammation, and modulating the expression of different enzymes of anti-oxidant system. Prophylactic and immunomodulatory activities of T. cordifolia were also observed against experimentally induced anemia in chickens, where herbal treatment containing T. cordifolia and other herbs attenuated the Chicken infectious anemia virus (CIAV) induced immunosuppression and modulated the proliferation of CD4+/CD8+ cells [22]. The immunomodulatory activity of T. cordifolia was attributed to polysaccharides-rich fraction of T. cordifolia. Some phytoconstituents of this herb that have been reported to have immunomodulatory potential include magnoflorine, 11-hydroxymustakone, N-Formylannonain, tinocordiside, cordifolioside A, G1-4A arabinogalactan, and syringin [13]. There are different patents filed and granted for the immunomodulatory potential of T. cordifolia for treatment and prophylaxis of different disorders, like AIDS, flu, hepatitis, TB, etc., by enhancing cell-mediated and humoral immunity as well as suppressing the histamine release [13]. In a recent study by Aranha and Venkatesh, an immunomodulatory protein of 25kDa, characterized as ImP from T. cordifolia stem, was reported to show an immunogenic response upon intranasal administration to mice by significantly enhancing the serum levels of IgE and IgA. The immunogenic response of this protein was further found to be enhanced by conjugating it with adjuvant ovalbumin [23].

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ROLE OF T. CORDIFOLIA IN NEURODEGENERATION Neurodegenerative diseases are progressive disorders of the neurological system characterized by loss of structure and function of neurons leading to neuronal miscommunications and degeneration. Neurodegenerative diseases, such as Parkinson’s (PD), Alzheimer’s (AD), Huntington’s (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias, have diverse pathophysiology [19, 24, 25]. Accumulation of defective proteins, protein misfolding, and protein aggregation are considered hallmarks of neurodegenerative diseases. Major pathogenic mechanisms underlying neurodegenerative diseases are altered protein dynamics, oxidative stress, excitotoxicity, mitochondrial dysfunction, free radical generation, neuroinflammation, altered bioenergetics, and axonal transport [26], which are complex phenomena and collectively result in neurodegeneration. T. cordifolia and Oxidative Stress Oxidative stress plays a major role in the pathophysiology of neurodegenerative diseases, and it prevails when a generation of free radicals and associated products exceeds the rate of oxidant scavenging by the antioxidant system. Biological molecules, like DNA, protein, lipids, and other macromolecules, become the target of oxidative stress, which leads to the initiation of a series of events, such as mitochondrial dysfunction, nitric oxide synthesis, and ROS generation leading to excitotoxicity, which further results in structural damage, deteriorated signaling, and untimely cell death [27 - 29]. The major pool of ROS in brain cells forms from the un-neutralized oxidizing species generated from the respiratory chain, lipid peroxidation, Fenton reactions, and protein nitrosylation [29, 30]. Oxidative damage to mitochondrial and nuclear DNA occurs during the earlier phases of PD, ALS, AD, and aging [31, 32]. In AD, the mutated APP and derivatives lead to the generation of ROS in mitochondria, thus resulting in apoptosis and neuronal death [33, 34]. T. cordifolia is well-reported to have antioxidant properties. Lipid peroxidation due to high ROS production is considered the underlying mechanism of gentamicin-induced renal failure, and T. cordifolia treatment ameliorated the structural alterations as well as exhibited curative effects, but detailed mechanisms were not studied [35]. Another recent study on skeletal muscle atrophy and inflammatory condition in human monocytic cells (THP-1) showed the beneficial effects of T. cordifolia by neutralizing ROS, ameliorating lipid peroxidation, and modulating the expression of antioxidant enzymes [35, 36]. Further, another study by Prince et al. reported that treatment with an alcoholic extract of T. cordifolia to alloxan-treated diabetic rats restored the antioxidant

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status of the heart and brain, and this extract was more effective than glibenclamide and insulin. They have also reported similar observations previously with 6 weeks of T. cordifolia root extract treatment [37, 38]. T. cordifolia was also reported to attenuate oxidative damage induced due to oxygen-glucose deprivation to hippocampal slices by reducing ROS production, enhancing glutathione (GSH) levels, and modulating the superoxide dismutase gene expression [39]. Jagetia and Baliga evaluated the nitric oxide scavenging activity of methanol and dichloromethane extracts of T. cordifolia in an in vitro study along with extracts of other medicinal plants and suggested its potential antioxidant activity [40]. A study examining the activity of different enzymes related to oxidative stress on erythrocytes membrane and liver of alloxan-treated diabetic rats also showed that treatment with methanolic T. cordifolia stem extract normalized the oxidative stress by reducing the elevated lipid peroxidase and catalase and by upregulating the expression of glutathione peroxidase and superoxide dismutase enzymes [41]. In a disease model of PD, 6-OHDA treatment reduced the levels of dopamine and glutathione (GSH). Glutathione depletion results in the dysfunctional clearance of hydrogen peroxide, and thus elevates the rate of formation of hydroxyl free radicals (OH), which leads to oxidative stress. Oral treatment with T. cordifolia ethanolic extract for 30 days exhibited neuroprotection and amelioration of oxidative degeneration by normalizing the dopamine levels as well as GSH and complex-I activity [42 - 44]. Extended wakefulness or sleep deprivation also induces oxidative stress. Oral administration of aqueous ethanolic extract of T. cordifolia to Wistar albino rats in the sleep deprivation model attenuated sleepinduced high expression of chaperones HSP70 and mortalin, which act as main response elements to oxidative stress [45]. Similarly, T. cordifolia exhibited beneficial effects against glutamate-induced oxidative stress and neurodegeneration in primary neuronal cultures by attenuating iNOS expression and mitochondrial dysfunction [46]. Another study using ethanolic extract of T. cordifolia by Trigunayat and Mishra (2017) showed that T. cordifolia extract treatment attenuated reperfusion-induced oxidative stress and showed a protective effect against acute cerebellar ischemia [47]. The strong antioxidant activity of T. cordifolia is also supported by studies on heavy metal-induced stress in experimental rats. Cadmium-induced nephrotoxicity and hepatotoxicity were also prevented by T. cordifolia methanolic extract treatment, which restored the levels and activities of endogenous antioxidants (SOD, GSH, CAT, GST, GPX) [48, 49]. In a recent study on MPTPinduced Parkinsonism in mice, water extract of T. cordifolia was used, which reduced the oxidative stress and enhanced the levels of antioxidant enzymes in substantia nigra of MPTP-intoxicated mice, suppressing lipid peroxidation and

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increasing glutathione levels [8]. Neuroleptic and antipsychotic drugs, haloperidol and sulpiride, to Wistar albino rats induced hyperprolactinemia along with reducing dopamine levels and increasing oxidative stress [50]. T. cordifolia methanolic extract treatment for 28 days showed beneficial effects by restoring the dopamine and prolactin levels in serum and also ameliorating oxidative stress by regulating the expression of superoxide dismutase and catalase. The antioxidative potential of T. cordifolia has also been demonstrated to play a significant role in stressful conditions [51]. The anti-oxidative property of T. cordifolia is attributed to polysaccharides, particularly arabinogalactan and phenolic compound epicatechin [52, 53]. The antioxidative potential of leaf extract is suggested as superior to extract obtained from the stem of T. cordifolia [13, 54]. Kaur et al. (2019) compared the antioxidant potential of five different herbs, including T. cordifolia, using principal component analysis based on its polyphenolic content [55]. Pachayiappan et al. also found some bioactive peptides from T. cordifolia, including papain, pepsin, trypsin, and α-chymotrypsin, and suggested them to be contributing to the anti-oxidative activity of this herb [56]. T. cordifolia and Neuroinflammation Chronic inflammation and immune activation in CNS, along with expression of MHC-II, altered blood-brain barrier, glial activation, and T-cell infiltration, are hallmark features of pathogenesis and development of neurodegenerative diseases [57]. CNS is considered an immune-privileged organ, with immune response being controlled by the peripheral system. Studies suggest that peripheral inflammation in response to viral infections or systemic LPS induces leukocyte infiltration into CNS from the periphery, which subsequently results in neuroinflammation and neurodegeneration [58, 59]. The initial insult, that is, leukocyte infiltration, causes microglial activation and induces secretion of various pro-inflammatory factors as well as blood-brain barrier (BBB) dysfunction. As infiltrated peripheral cells, T-cells and macrophages, have similar functional properties, these cells, in addition to glial cells, also play a role in neuroinflammation [58, 60]. Acute neuroinflammation is considered beneficial for brain functioning and coping with stress, e.g., to minimize the infection or injury by innate immune system activation. However, chronic neuroinflammation involves long-term activation of microglial cells that implies the long-term release of inflammatory mediators, which induce serious oxidative stress and prolong the neuroinflammation, resulting in neurodegeneration [61 - 64]. In addition to microglia, astrocytes and neurons also participate in the activation of innate

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immunity, thus triggering the constant insult during ongoing infection or inflammation [65]. Various reports suggest that microglial activation and chronic neuroinflammation are major underlying factors in neurodegenerative diseases pathophysiology, e.g., activated microglia (IL-1 positive) were observed in motor neuron regions undergoing degeneration in ALS patients and also co-localized with neurofibrillary tangles or β-amyloid plaques in AD [66]. Neurotropic viruses were also reviewed to induce chronic neuroinflammation underlying viral neurodegeneration [67]. Further, neuroinflammation is also associated with oxidative stress either as a cause or a consequence. Activated microglial cells release high levels of ROS, nitric oxide species, TNF-α, and glutamate, which are neurotoxic and cause neurodegeneration in AD, PD, and ALS [61, 64, 68]. T. cordifolia possesses beneficial anti-inflammatory properties both against peripheral inflammation and neuroinflammation [8, 18]. We have recently reviewed the beneficial effects of T. cordifolia in neurological disorders along with reports of its anti-neuroinflammatory activity from different extracts of this herb [18]. In a recent study by Prakash et al. (2017), ethanolic extract of T. cordifolia was shown to exert neuroprotection against LPS-induced neuroinflammation in male Wistar rats. LPS-induced behavioral alterations were ascertained from locomotion and passive avoidance test and neuronal damage, which were significantly attenuated by T. cordifolia ethanolic extract treatment [69]. Another recent study showed the anti-neuroinflammatory effect of an aqueous extract of T. cordifolia in MPTP induced PD model. T. cordifolia extract treatment significantly downregulated MPTP-induced activation of NF-κB and pro-inflammatory cytokine TNF-α expression [8]. MPTP-induced activation of microglial-specific marker Iba-1 and astroglial specific GFAP was also suppressed by T. cordifolia extract treatment along with upregulation of the expression of anti-inflammatory cytokine IL-10 as well as tyrosine hydroxylase, which is an enzyme catalysing dopamine biosynthesis. IL-10 and tyrosine hydroxylase were significantly reduced by MPTP intoxication in mice brains [8]. Intake of a high-fat diet (HFD) results in high levels of circulating fatty acids, which cause systemic inflammation and further lead to the onset of neuroinflammation and neuronal damage [70, 71]. A recent study by Singh et al. (2021) showed the beneficial effects of T. cordifolia against HFD and obesityinduced brain function impairments/alterations. T. cordifolia powder supplementation to HFD resulted in attenuation of the increase in body weight due to HFD despite high-calorie intake and also ameliorated HFD-induced anxiety and motor co-ordination impairments, which are suggested to be caused by reactive gliosis and neuroinflammation. T. cordifolia exhibited anxiolytic and neuro-inflammatory activity by suppressing the expression of pro-inflammatory

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cytokine IL-6 as well as reactive gliosis and microgliosis, which was evident from downregulated expression of GFAP, Iba-1, and NF-κB. Additionally, T. cordifolia supplementation also averted HFD-induced changes in apoptosis and synaptic plasticity pathways, thus inhibiting memory and cognition alterations as well as neuronal damage [72]. In another study, Singh et al. studied the synergistic effects of Ayurvedic herbs supplementation and intermittent fasting-dietary restriction (IFDR) in middle-aged female rats and co-related the findings with aging-induced neuroinflammation [73]. T. cordifolia and W. somnifera supplementation to animal feed plus IFDR regimen practice for 5 weeks was seen to ameliorate anxiety, modulate the stress response, and suppress inflammatory pathways as suggested by outcomes of elevated plus maze (EPM) test and expression of various molecular markers, like GFAP, HSP70, NF-κB, Iba-1 and proinflammatory cytokines [73]. T. cordifolia also suppressed sleep-induced neuroinflammation in the piriform cortex and hippocampus regions of the rat brain [45]. Sleep deprivation was observed to activate the inflammatory pathway, induce reactive gliosis and apoptosis, which resulted in neurodegeneration. Orally administered aqueous ethanolic extract of T. cordifolia modulated all these altered pathways as well as suppressed behavioral anxiety and promoted cell survival [45]. Although studies of anti-neuroinflammatory activity are limited, there are many reports that have shown the anti-inflammatory effect of T. cordifolia against peripheral inflammation, such as hind paw edema and skeletal muscle dystrophy [13, 14, 18]. The anti-oxidative property of this herb is suggested to play a major role against neuroinflammation and thus suggested as the basic mechanism underlying the anti-inflammatory activity of T. cordifolia [18]. Alkaloids, diterpenoid lactones, and aliphatic compounds of T. cordifolia are reviewed to exert anti-inflammatory activity (Saha and Ghosh, 2012). Further, steroids identified from chloroform extract of T. cordifolia, stigmasterol and β-sitosterol, were also suggested to exhibit anti-inflammatory potential by inhibiting NF-κB pathway activation and prostaglandin synthesis [5]. Glutamate-induced Excitotoxicity Glutamate-induced excitotoxicity is a common final destructive pathway of all neurodegenerative diseases and other disorders of the CNS. Glutamate excitotoxicity leads to imbalanced cellular homeostasis, elevated oxidative stress, mitochondrial dysfunction, neuroinflammation, and alterations in synaptic plasticity, which results in structural and functional impairments in CNS as well as neuronal damage. We studied the potential beneficial effects of butanol extract

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of T. cordifolia on glutamate-treated primary cerebellar and hippocampal neurons and found that pre-treatment with B-TCE suppressed glutamate-induced structural alterations and promoted neuronal differentiation as evident from morphometry studies as well as from the expression of MAP-2, NF200, and GAP-43. B-TCE further downregulated the expression of neuroinflammatory markers (proinflammatory cytokines, NF-κB and AP-1), suppressed mitochondrial dysfunction (iNOS and Mitotracker Green FM), and regulated cell cycle markers (CyclinD1, PCNA). Additionally, B-TCE treatment promoted cellular migration as suggested by primary explants and wound scratch assays, suppressed apoptotic pathway, and promoted cell survival and synaptic plasticity (Bcl-xL, PSA-NCAM, and NCAM) [18, 46]. The study was further extended to in vivo model system of glutamateinduced excitotoxicity. Behavioral function alterations caused by glutamate exposure, such as anxiety, impaired motor coordination, memory, and cognition, were ameliorated by B-TCE treatment, which was also reflected at molecular levels. B-TCE treatment suppressed alterations in synaptic plasticity and cell survival markers, and attenuated the reactive gliosis and expression of proinflammatory cytokines in glutamate-exposed Wistar albino rats as well. The neuroprotective and neuroregenerative activities of B-TCE were suggested to be due to glycosides and some of the alkaloids detected from LCMS/MS examination of the extract [74, 75]. In addition to neurodegeneration, T. cordifolia also exhibited beneficial effects on other parameters of brain health, such as brain cancers, stress, and depression [74]. Hexane and chloroform fractions of aqueous extract of T. cordifolia exhibited anti-brain cancer activity and inhibited proliferation and metastasis of glioblastoma as well as neuroblastoma cell lines [45, 76]. Anti-stress and antidepressant activity of T. cordifolia were evident from amelioration of behavioural anxiety and stress, modulated levels of MAOA and MAOB, as well as increased levels of monoamines in the brain of experimental animals [77, 78]. CONCLUSION T. cordifolia, due to its multiple pharmacological properties, the bioavailability of its active constituents, and low toxicity, has received much attention in the research arena of natural products. Further, various pre-clinical in vitro and in vivo studies have evidenced the neurotherapeutic role of this miraculous herb (Fig. 1). Based on these experimental data, an exhaustive and targeted approach should be used for the development of novel therapeutics based on T. cordifolia. The major focus of future research should be aimed at the identification and purification of the active constituents of T. cordifolia. For this purpose, bioassay-guided fractionation, chemical characterization of actives, the study of their mechanisms

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of action, and structure-activity relationship by advanced chemical, molecular and pharmacological techniques need to be carried out. These aspects will be particularly important and also challenging since the multiple components simultaneously influence multiple target pathways. Future studies may also be planned to address the pharmacokinetics of the extracts and their active compounds to know their absorption, distribution, and metabolism in the body by making use of suitable animal models before planning systematic clinical studies on this important medicinal plant. Aging Genetic factors Environmental factors

ROS, Inflammatory mediators, Excitotoxicity

Stress, sleep deprivation Neurodegeneration

T. cordifolia

Anti-oxidant, Anti-inflammatory, Neuroprotective, Immunomodulatory

Fig. (1). Representation of beneficial pharmacological activities of T. cordifolia against neurodegeneration.

CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT Declared none. REFERENCES [1]

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CHAPTER 7

Mucuna pruriens and Parkinson’s Disease: A Natural Approach to Treat PD Mamta Tiwari1,* and Anurag Pandey2 Department of Swasthavritta and Yoga, Faculty of Ayurveda, Banaras Hindu University, Varanasi-221005 (U.P.), India 2 Department of Vikriti Vigyan, Faculty of Ayurveda, Banaras Hindu University, Varanasi-221005 (U.P.), India 1

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease affecting the aged population. The variable loss of dopaminergic neurons within substantia nigra pars compacta (SNpc) of the brain, which controls movement, and the presence of intracellular protein aggregates called Lewy bodies are major pathological findings. The recent years’ research in PD is directed to herbal drug discovery for PD as a large number of patients, particularly in western countries, prefer to use “natural therapies” and drugs instead of pharmaceuticals. Kapikachhu (Mucuna pruriens Linn.) is one of the popular drugs in Ayurveda, the classical system of medicine in India. The seeds of M. pruriens contain 5% L-3, 4-dihydroxyphenylalanine (L-DOPA), and it has emerged as a promising single drug treatment of PD. The present manuscript is an attempt at obtaining complete knowledge regarding Parkinson’s disease as mentioned in Ayurveda for achieving a natural and holistic approach to better management and prevention of disease with herbal drugs, such as M. pruriens.

Keywords: Ayurveda, Levodopa, Mucuna pruriens, Parkinson's disease. INTRODUCTION Parkinson's disease (PD) is a complex disorder of the central nervous system (CNS), affecting a large number of aged population throughout the world. PD is a progressive degenerative disorder predominantly affecting the motor system, leading to shaking, stiffness, difficulty in walking, and difficulty in maintaining balance and coordination. The motor symptoms of PD are due to the death of dopamine (DA)-generating cells in the substantia nigra pars compacta (SN) Corresponding author Mamta Tiwari: Department of Swasthavritta and Yoga, Faculty of Ayurveda, Banaras Hindu University, Varanasi-221005 (U.P.), India; E-mail: [email protected] *

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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located in the midbrain [1 - 3]. The medical system of Ayurveda PD is well described under the name Kampavata, which is characterized by Kampa (Tremors), Stambha (Rigidity), Chesthahani (Akinesia), and Gativikriti (Gait disorders). According to Ayurveda, most of the diseases associated with Vata vitiation in old age are essential conditions of degenerative nervous system diseases. One such condition caused by the Vata imbalance is Kampavata. Kapikachhu (Mucuna pruriens Linn.) is a popular drug in the Ayurvedic system of medicine generally used to treat impotence. Mucuna pruriens has been used in Ayurvedic medicine since ancient times to treat symptoms associated with PD [4 6]. The treatment of PD with natural remedies of Ayurveda requires an in-depth understanding of the disease and the properties of the drugs mentioned for the treatment of this disease [7]. .

PATHOLOGY OF PD Depilation of dopaminergic (DAergic) neurons of substantia nigra pars compacta (SNpc) results in the deficiency of striatal DA, which is the main biochemical abnormality of PD. Loss of DA in these areas is associated with a reduction in the concentration of the DA metabolite homovanillic acid (HVA), suggesting that the turnover of DA is decreased with reduced activity of dopa-decarboxylase (which converts dopa to DA) and tyrosine hydroxylase (TH) (which converts tyrosine to dopa) [8]. Acetylcholine (Ach) concentration is normal, but cerebral cortical choline acetyltransferase activity is reduced. The definitive diagnosis is made by histopathological assessment with the identification of aggregates of the protein alpha-synuclein (α-syn), known as Lewy bodies (LB), found in nigrostriatal neurons. SIGNS AND SYMPTOMS OF PD The mean age of onset of PD is between 55 and 70 years. The symptoms are insidious in onset. The common presenting symptoms include tremors in the hands, legs, and head, and stiffness of limbs. Other presentation includes difficulty in walking, fatigue, depression, softness of voice, and dysarthria. These may be poor emotional and motor responses characteristic of akinesia. The typical form of PD presents with reduced facial expressions, a reduction in spontaneous blink rate, soft monotonous voice, flexed posture, and the patient has difficulty in walking or changing directions. Tremor is present in many patients that usually start in one upper limb. The rigidity of PD is evident in nearly all cases; it produces resistance to passive movements in all muscle groups. Voluntary movements are slow (bradykinetic) and of reduced amplitude (hypokinetic). Autonomic features, such as constipation, mild urinary frequency, and occasional

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incontinence, may occur. The non-motor symptoms are present in the early stage, but as the disease progresses, it becomes more challenging. The non-motor symptoms include impaired sensory ability, sleep disorders, fatigue, sleep disorders, and cognitive and psychiatric disturbances. These symptoms may affect a patient’s quality of life greatly. AETIOLOGY OF PD The genetic and environmental components play a crucial part in the pathophysiology of PD. Age is the major risk factor for this disorder, with the median age being 60 years of age [9]. Several studies have suggested that abnormal protein clearance, mitochondrial dysfunction, oxidative stress, altered protein handling, and neuro-inflammatory alterations lead to cell dysfunction and the onset and progression of PD. Although PD is generally an idiopathic disease in a minority of cases (10-15%), family history is reported, and about 5% cases have mendelian inheritance [10]. The recent development in the understanding of the genetic component of PD is the identification of some genes involved in familial PD. These include α-syn (SNCA), leucine-rich repeat kinase-2 (LRRK2), and Grb10 interacting GYF protein 2 (GIGYF2); these are autosomal dominant genes. While PINK1, DJ-1, and ATP13A2 mutations in parkin are related to autosomal recessive PD. The mutation in the LRRK2 protein is the most commonly inherited form of PD, a kinase whose substrate has been elusive [11]. Mutant LRRK2 has been associated with dysregulation of macroautophagy as well as mitochondrial abnormalities. The reactive oxygen species (ROS), superoxide anion (O2−), hydroxyl radical (OH•), hydrogen peroxide (H2O2), and singlet oxygen species are produced naturally as a product of mitochondrial respiration within neurons [12]. These are detoxified by compensatory mechanisms, such as anti-oxidant and reactive oxygen scavenger or protein [e.g., glutathione peroxidase (GPX), superoxide dismutase (SOD), catalase (CAT)] in healthy neurons. But even in a normal state, nigrostriatal DA neurons exist in a more oxidized state as compared to other neurons. These compensatory mechanisms can be depleted in the dopamine neuron under pathological conditions, and increased ROS production becomes a source of cellular oxidative stress [13]. The H2O2 is not a free radical, but at a relatively low concentration, it can cause cell damage, and in conditions of impaired detoxification or enhanced production, the free radicals may play a vital role in modifying cellular processes. Nitric Oxide (NO), which is abundant in the brain, when combined with H2O2, it leads to the production of peroxynitrite (ONOO−) and OH−, and these OH• are highly toxic and can bind to a cellular macromolecule, causing widespread protein dysfunction, lipid oxidation, and breaking of DNA strands. In microglia, inflammatory gene expression is dynamically regulated; occupation of the surface

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receptor for cell damage or pathogens can induce the transcription of protein inflammatory genes [14]. Redox transcription factors, such as NF-κβ, can unregulate hundreds of protein inflammatory mediators, as inducible nitric oxide synthase (iNOS), and may also promote the expression of proteins that are neurotoxic, such as tumor necrosis factor (TNF)-α, interleukin (IL-1), and interferon (IFN-γ) [15]. Thus, PD is due to multiple causes, and an understanding of key player and cellular pathway that lead to neurodegeneration is essential to devise new therapeutic strategies in order to slow down the disease process. AYURVEDIC UNDERSTANDING OF PD The medical system of Ayurveda PD is well described under the name Kampavata in Ayurveda classics, but no single disease is mentioned with such a name. However, we have attempted to view the symptoms observed in patients of PD with respect to the symptoms mentioned in Ayurveda, as shown in Table 1. Table 1. Symptoms of PD, which are more similar to the symptoms of the “Vata Dosha Kshya” mentioned in the “Charak Samhita” and “Sushruta Samhita”. S. No.

Classical Symptoms in PD

Ayurvedic Correlation

Ref. in Ayurveda

1.

Tremors

Kamp (symptom by Vata dosha in Tridoshaj Headache), a symptom of Rasa Kshaya Vepathu (one of 80 Vata diseases)

[Charak Samhita, 2011, p.100; Sushruta Samhita, 2016, p.76]; C.S. Su. 20/11; [Charak Samhita, 2011, p.113]

2.

Rigidity

Stambha (Symptoms of abnormal Vata)

[Charak Samhita, 2011, p.113,114] C.S. Su. 20/11, 12

3.

Depression

Vishada (one of 80 Vata diseases)

[Charak Samhita, 2011, p.114] C.S. Su. 20/ 12

4.

Loss of voluntary movements

Mand Chestata (Symptom due to decreased VataDosha) Praytna Hani (Decrease in functional loss Of UdanVayu)

[Charak Samhita, 2011, p.616] C.S. Ch. 28/7

5.

Reduced blink rate

Nimesha Kriyahani (Decrease in functional loss of Vyana Vayu)

[Charak Samhita, 2011, p.616] C.S. Ch 28/ 9

6.

Softness of voice

[Sushruta Samhita, 2016, p.219] Vaak Pravrtti hani (Decrease in functional loss [Charak Samhita, 2011, p.616] of Udan Vayu) S.S Ni.1/15, VaakSvaraGraha C.S. Ch. 28/7 [Charak Samhita, 2011, p.626] C.S. Ch 28/224

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(Table ) cont.....

S. No.

Classical Symptoms in PD

Ayurvedic Correlation

Ref. in Ayurveda

7.

Difficulty in walking

Gatihani (Decrease in functional loss of VyanaVayu) Gatisanga (KaphaAvratVyana Vayu)

[Charak Samhita, 2011, p.616] C.S. Ch 28/ 9 [Charak Samhita, 2011, p.626] Ch. Chi. 28/228

8.

Constipation

Mala Pravrtti Graha (Decrease in functional loss of Apana Vayu)

[Charak Samhita, 2011, p.616] C.S. Ch 28/ 10

Sthivan –Decrease in functional loss of Prana [Charak Samhita, 2011, p.616] Vayu (Prana Vayu is functional Vayu in C.S. Ch. 28/ 6 mouth) Note: [C.S. Su. – Charak Samhita Sutra Sthan, C.S. Ni. – Charak Samhita Nidana Sthan, C.S. Ch. – Charak Samhita ChikitsaSthan, S.S.Su.- Sushruta Samhita Sutra Sthan, S.S.Ni.- Sushruta Samhita Nidana Sthan] 9.

Drooling of saliva

AETIOLOGY OF PD AS PER AYURVEDA (TABLE 2) M. pruriens in Ayurveda M. pruriens (velvet bean or cowhage) is a leguminous plant belonging to the Fabaceae family that grows in the world's tropical and subtropical areas (Table 3). In the Ayurvedic and Unani systems of medicine, M. pruriens is commonly referred to as a 'cowhage plant' or 'kapikacchu' or 'kevach' in Hindi. Table 2. Correlation of Ayurveda with classical PD etiology. S. No.

Classical PD etiology

Possible Ayurvedic Correlation

1.

Dopamine deficiency

Vatakshaya (Neuro-hormonal deficiency) RasaKshaya in old age

2.

Unknown

Yaadricchika (idiopathic)/Dosha-Karmajvyadhi, diet, lifestyle, mental status

3.

Environmental toxins

Polluted air, water, land, time (factors of the epidemic in Ayurveda, DushiVisha, GaraVisha, ViruddhaAhara)

4.

Decreased free radicals

Arm formation in body

5.

Deficient detoxification pathway

KhaVaigunya, Deha-Ashudhi, Dosha Adhikya (accumulations of toxins in the body)

Table 3. Samanya Karma of Mucuna pruriens (Pharmacological actions mentioned in various Ayurvedic texts). Karma (Pharmacological Actions)

C.S.

Balya (Strengthening)

+

Brmhna (Nourishment)

S.S.

A.S.

B.N. +

+

+

+

SO.N.

R.N.

D.N.

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(Table ) cont.....

Karma (Pharmacological Actions)

C.S.

Hridya (Cardio-tonic) Purisavirajaniya (To form normal stool)

S.S.

A.S.

+

+

B.N.

SO.N.

R.N.

D.N.

+

Shukrakara (Spermatogenic)

+

Vajikara (Aphrodisiac)

+

Vrisya (Aphrodisiac)

+

+ +

+

+

Yonisankirnikara + Note: [C.S. – Charak Samhita, S.S. - Sushruta Samhita, A.S. - AshtangHridayam, B.N. - BhavPrakash, SO.N.-SodhalaNighantuh, R.N. - Raj Nighantu, D.N. - Dhanvantri Nighantu.]

Sanskrit names: Aatmagupta, Rishabhi, Shookshimba, Vrishya, Markati, Ajara, Kandura, Vyanga, Duhsparsha, Pravrshayani Hindi name: Kapikacchu, Kevanch, Kaunch Properties of M. pruriens “Santarpan” (nutritive), “Stanyajanana” (lactogenic), “Balprad” (tonic for strength) “Shukrakafavah” (increase sperm and produce good kafa). Ayurvedic Properties: Ras (Madhur); TiktaGuna (Guru); SnighdhaVeerya (UshnaVipaak); Madhur Karma (Vatahar and Pittahar). Due to its nutrient content and biologically active compounds, it has a high nutritional value. The analysis of nutrients present in this plant shows the presence of phytates, tannins, saponins, and compounds with potentially toxic properties, such as alkaloids. In Ayurvedic medicine, velvet bean has been used to relieve conditions, including psychogenic impotence and unexplained infertility, for resilience against stress, general resistance against infection, retardation of the aging process, and subsequent enhancement of male sexual function. A variety of bioactive substances, including tryptamine, alkylamines, steroids, etc., are found in the seeds and are also a good source of l-3,4 dihydroxyphenylalanine (L-DOPA). It is reported that M. pruriens contains LDOPA, 40 mg/g of a plant, which is a large percentage of plant products [17]. The gold standard treatment of PD is the enhancement of DA transmission by exogenous L-DOPA and DA agonists. Unlike synthetic L-DOPA treatment, M. pruriens cotyledon powder treatment significantly restored the endogenous LDOPA, DA, norepinephrine, and serotonin content in the SN [18].

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M. pruriens as Source of L-DOPA Clinical studies have shown the positive outcome of M. pruriens in motor symptoms of patients with PD. M. pruriens is the natural source of L-DOPA with the yield of 30g amino acid from 2 kg seed powder [19]. The study on the animal model has revealed that M. pruriens seed powder with no additives in 12 mg/Kg and 20 mg/Kg LD equivalent dose alone is superior to LD alone or LD+BZ combinational therapy to improve the symptoms of parkinsonism with a significantly reduced risk of drug-induced dyskinesias [20]. Yet another study reported 15 g of crude M. pruriens seed to effectively inhibit the chlorpromazine injection prolactin response as effectively as 0.5 g of L-DOPA [21, 22]. In a randomized, controlled, double-blind crossover trial in patients with PD, standard treatment with L-DOPA/ carbidopa (C-DOPA) resulted in a substantially faster onset of effect, expressed in shorter latencies at peak plasma L-DOPA concentrations, compared to 30 g of M. pruriens. The mean time was 21.9% (37 min) longer with 30 g M. pruriens than with normal L-DOPA/ C-DOPA, suggesting that this is a natural source of M. pruriens. However, the period of ontime achieved with 30 g M. pruriens was significantly longer, suggesting higher bioavailability than standard L-DOPA preparations. The quality of motor improvements was equivalent to that seen with synthetic L-DOPA/C-DOPA, but the onset of action was longer [23]. In an animal study on rats, the vibrissaeevoked forelimb positioning test showed that M. pruriens substantially enhanced the placement of the forelimb, indicating a strong antagonistic operation on both motor and sensory-motor deficits [24]. Another advantage is M. pruriens does not cause dyskinesia. Interestingly, no dyskinesia was observed in monkeys as models of PD, i.e., the group who had just taken M. pruriens, while those with L-DOPA and C-DOPA had maximum dyskinesia [25]. These clinical studies strongly substantiate the fact that M. pruriens is a good source of L-DOPA, and thus, increases the levels of DA in the brain. In an animal model study, oral administration of M. pruriens endocarp in the form of HP-200 had a significant effect on DA content in the cortex with no significant effect on L-DOPA, norepinephrine, or DA, serotonin, and their metabolites, HVA, DOPAC, and 5-HIAA in the nigrostriatal tract. The failure of M. pruriens endocarp to significantly affect DA metabolism in the striatonigral tract, along with its ability to improve Parkinsonian symptoms in the 6-hydroxy dopamine (6OHDA) animal model and humans, may suggest that its anti-parkinsonian effect may be due to components other than levodopa or that it has an L-DOPA enhancing effect [22].

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Neuroprotective Activity of M. pruriens Mitochondrial dysfunction and oxidative stress are two prime factors for increased free radical production, and greater evidence is available that supports the free radical theory responsible for symptoms of PD. In Parkinsonian patients, the oxidized-to-reduced type ratio of CoQ10 is elevated, indicating that increased oxidative stress in PD and CoQ10 depletion may lead to cellular dysfunction in PD. These findings show the dual function of CoQ10 as both an electron acceptor for complexes I and II and a strong anti-oxidant; thus, CoQ10 may be an important part of the PD therapeutic strategy. Nicotinamide adenine dinucleotide (NADH) and coenzyme Q-10, which have been revealed to have a therapeutic benefit in PD, were found to be present in M. pruriens cotyledon powder. This additional finding of a neurorestorative benefit of M. pruriens cotyledon powder on the degenerating DAergic neurons in the SN may be due to increased complex-I activity and the presence of NADH and coenzyme Q-10 [18]. M. pruriens cotyledon powder treatment significantly restored the endogenous LDOPA, DA, norepinephrine, and serotonin content in the SN. ROS interacts with lipid membrane polyunsaturated fatty acids (PUFAs), causing lipid peroxidation (LPO) and leading to cell death. In a study, 0.1-0.5 mg powder of M. pruriens cotyledon LPO in rat brain exhibited a neuroprotective effect against toxicity induced by H2O2 significantly as compared to control [26]. Also, ROS are produced when the rat brain is incubated with t-butyl hydroperoxide; this experiment’s results show that one thousand micrograms of M. pruriens powder scavenged 70% of the ROS induced by t-butyl hydroperoxide compared to the controls [26]. The study findings revealed that the nigrostriatal portion of Parkinson's mouse brain showed significantly higher levels of nitrite, malondialdehyde (MDA), and lower levels of catalase compared to the control. The aqueous seed extract of MP substantially improved catalase activity and decreased MDA and nitrite levels compared to the untreated Parkinson's mouse brain, thereby sustaining the neuroprotective property of M. pruriens [27]. The MPTP model of PD seeds of M. pruriens shows the recovery of DA neurons in SN, down-regulates the development of NO, neuroinflammation, and activation of microglia, all of which contribute to the neuroprotective activity of MP [28 - 30]. Hypoglycaemic Activity of M. pruriens The epidemiological studies suggest a link between hyperglycemia and PD. Hyperglycaemia causes oxidative stress in vulnerable tissues, like the brain [31]. The crude ethanolic extract of M. pruriens seeds administered to alloxan-induced diabetic rats (plasma glucose > 450 mg/dL) resulted in a dose-dependent reduction in blood glucose level after 8 h of treatment. The anti-diabetic activity

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of M. pruriens seeds was also shown to be due to the methanolic and ethanolic fractions of the extract [32]. The pharmacological study on M. pruriens ethanol extract has shown it to be a rich source of dietary fiber and anti-oxidants, and contain anti-diabetic components, such as saponins, squalene, D-chiro-inositol, and oligocyclitol [33]. The M. pruriens seeds were found to possess hypoglycemic and hypolipidemic properties and reduce diabetes lesions in the liver and pancreas in a streptozotocin-induced animal model [34]. A comparative study on the hypoglycaemic effect of aqueous extract of the seeds of M. pruriens between normal and glucose load conditions in streptozotocin-induced diabetic rats was conducted. The results showed that in normal rats, the aqueous extract of the seeds of M. pruriens significantly reduced the blood glucose levels from 127.5 ± 3.2 to 75.6 ± 4.8 mg 2 h after oral administration of M. pruriens seed extract [35]. Anti-inflammatory Activity of M. pruriens The elevated plasma levels of proinflammatory cytokines, such as IL-6, TNFalpha, IL-1-b, IL-2, and IL-6, enzymes, such as cyclooxygenase-1 (COX-2), and activated microglial cells are associated with greater risk for PD, thus supporting the role of immunity in PD. The activation of microglia directly or indirectly is a sign of neuroinflammation. The experiments done in vivo have also shown that activated microglia selectively damage DAergic neurons with the subsequent release of several neurotoxic factors. The key components of M. pruriens found using the high-performance thin-layer chromatography (HPTLC) system are Ursolic acid (UA) and L-DOPA [36, 37]. UA has many biological activities, including anti-tumor, anti-oxidant, and anti-inflammatory properties [38]. In a study done by Naima et al., carrageenan-induced paw edema was used to assess anti-inflammatory function and to decrease paw edema after 1, 2, 3, and 4 h. The study concluded that the whole seed powder of M. pruriens has anti-inflammatory attributes that are mediated by the inhibition of prostaglandin synthesis as well as central mechanisms that may be of potential benefit to the management of inflammatory disorders [39]. The 250 and 500 mg/kg methanolic extract produced significant inhibition of delayed hypersensitivity reaction in mice by 33.33% and 28.89%, respectively. The same dose of the extract caused elevation of secondary RBCs specific antibody titer when compared to control [40]. Activated microglial cells and T lymphocytes have been reported in SN expression. The antiinflammatory property of M. pruriens also modulates the activity of the NF-κB transcription factor and immune components, such as TNF-α, IL-6, IFN-λ, IL-1β, iNOS, and IL-2 in the CNS, which play an important role in the progression of PD. Thus, M. pruriens immunomodulatory activity can prevent neuroinflammation, which is thought to accelerate nigrostriatal degeneration in PD.

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Anti-depressant Activity of M. pruriens Depression is one of the most frequently encountered neuropsychiatric conditions in PD. There are mild to severe depressive symptoms in significant numbers of PD patients. Depressive symptoms are often more likely to accompany anxiety disorders, cognitive impairment, and psychosis. The haloperidol-induced cataleptic mice model showed the reversal of depression and motor functions by 200 mg/kg isolated L-DOPA for 14 days [41]. Forced swim tests (FSTs) are quite sensitive and widely used in rodents to predict anti-depressant potential by reducing the immobility period. 14 days of treatment with M. pruriens seed powder decreased the duration of immobility in the FST and the tail suspension test (TST) conducted on mice, reflecting the anti-depressant property of M. pruriens. Open field test (OFT) of olfactory bulbectomy in rats reversed the hyperactivity with the administration of 10-20 mg/kg M. pruriens [42]. The antidepressant action is mediated by noradrenergic and serotonergic systems, as proved in a study on hydroalcoholic extract of the M. pruriens seeds extract (200 mg/Kg, orally), which was carried out using FST and TST in mice. The neurotransmitter estimations revealed the levels of noradrenaline and serotonin to be increased with 14 days of M. pruriens extract treatments [43]. The study was done using neuroleptic-induced cataleptic models. The cataleptic effects of haloperidol depend on the balance between the DAergic and serotonergic systems, and the serotonergic system has an inhibitory effect on the DAergic system. Isolated L-DOPA and alkaloid fractions of M. pruriens seeds have been shown to significantly increase levels of brain DA, noradrenaline, and serotonin in mice, indicating the anti-depressant activity of these bioactive constituents [41]. Antioxidant Activity of M. pruriens Oxidative alterations are viewed as an important factor in the genesis of PD, with the principal reason for oxidative stress being glial cell activation. The production of ROS can induce LPO, protein oxidation, and DNA oxidation, which eventually damages SN. ROS-mediated DNA damage in the PD brain is indicated by increased 4-hydroxyl-2-nominal (HNE) levels, carbonyl soluble protein modifications, and 8-hydroxy-deoxyguanosine, a DNA and RNA oxidation product. In PD, GSH is depleted in the nigrostriatal tract [44]. GSH works mainly by reducing the enzyme's inactive disulfide bonds to the active sulfhydryl group, thus oxidizing the sulfhydryl GSH group. GSH, therefore, plays a significant role in protection against membrane peroxidation and also reduction by GPX into H2O2. Down-regulation of GSH production in rat brain tissue has been shown to contribute to progressive degeneration of nigral DAergic neurons. NADPH is an

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important reduction equivalent for the regeneration of GSH by GR and NADPHdependent thioredoxin system activity, both of which play an important role in protecting cells against oxidative harm. The presence of polyphenols and GSH may have a direct impact on the anti-oxidant activities of M. pruriens [26]. On 7, 14 and 21 days of therapy, the M. pruriens methanol extracts actively increased the ferric reduction potential of the plasma. A substantial decrease in the amount of TBARS reactive substances was observed in addition to an upturn in the level of SOD in the liver and kidney at two separate plant doses [38]. In this view, we can conclude that it may be helpful to treat “VataKshaya” symptoms by the properties of M. pruriens discussed above. DISCUSSION PD is believed to be due to a combination of genetic and environmental factors. The genetic factors, including PARKIN and LRRK2 genes, and environmental factors, such as toxins, accelerate aging and neurodegenerative changes in SN, and increase free radical and iron content, contributing to the pathogenesis of this disease. In Ayurveda, “Kampavata” is a “Vataja” disease condition, so etiological factors mentioned under “Vata Vyadhi” can be regarded as “Kampavata's” etiological factors. The various factors that may be responsible for the disease may be grouped under various heads as dietetic factors “Rukshanna” (unctuous diet), “Laghuanna” (light diet), “Kashayanna” (astringent taste), “Katuanna” (acrid taste), “Tiktanna” (bitter taste), “Abhojana” (starvation), “Alpasana”, and “Pramitasana” (less quantity food). These factors relate to under-nourishment as elderly persons are frequently devoid of essential dietary factors both in terms of macro and micronutrients especially vitamin B 12, B6, folic acid, and Omega-3fatty acids. “Viharaja” (regimen factors) that are equally important are “Atilanghana” (leaping over the ditch), “Atipradhavana” (excessive running), “Atiprajagara” (excessive awakening), “Ativyavaya” (excessive sexual intercourse), “Ativyayama” (violent exercise); these factors are responsible for vitiation of “Vatadosha” in the body. The psychological factors as “Bhaya” (fear), “Chinta” (thinking), “Shoka” (grief), and “Utkantha” (anxiety) are important contributing factors. These factors fit in the concept of stress as a crucial trigger for the initiation of disease and suggest that chronic anxiety might conceivably cause irreversible changes to nerve cells in the brain. Ayurveda considers whole-body physiology by explaining the physiology of the body in terms of “Tridosa” (Vata, Pitta, Kapha), the three biofactors. The applied aspect considers “Vata” to represent neuroscience in Ayurveda. A wide array of etiological factors, including “Dhatu Kshaya” (tissue degeneration and damage) and “Margavarana” (neuroobstructive diathesis), disturb the equilibrium of “Vata”, thereby leading to the development of “Kampvata” (PD). The fractions of

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Vata responsible for the Cheshta (voluntary motor action) and “Gati” (movement) involve the property of “Vyana Vata”. The “Bala” is the contribution of “Udana Vata”. In Parkinsonism, both the functions of “Udana Vata”, and “Vyana Vata” seem to be deranged. As for the status of “Doshas”, it is seen that for the symptoms of this disease to manifest, “Vata” is “Vridha” or “Kupitha” (vitiated) state. “Caraka” mentions that, in conditions where “Pitta” and “Kapha” are in the stage of diminution, the increased “Vata” affecting the “Marma” (Vital parts) affects the consciousness and causes trembling in the patients. This concept provides a base for understanding the pathology of tremors relating to the brain. Ayurvedic treatment for this condition centers on the treatment of “Vata” disturbance. The very first one is “Nidana Parivarjana” (avoidance of aetiological factors), which emphasizes that modifiable causative factors, like environmental toxins, drugs, head injuries, and infections, should be avoided. The second line of treatment makes use of balanced and nourishing diet along with “Vata” shaman therapies, such as “Snehana” (oleation) done with medicated oils, including “Sarvang swedana” (whole body purification and removal of toxic material from the body by “Virechana” with erand tail and “Basti” (medicated oil enema). “Nasya karma” is also an important treatment modality that refers to the therapeutic measure in which the drug (medicated oils/ghee/decoction/powder/ smoke) is administered by “Nasa” (nose) essentially to remove the vitiated “Dosha” found in “Shira” and its constituent parts. The various properties of M. pruriens, as described in Ayurveda and studied in different experimental and clinical studies, may be helpful in PD when treating “Vata Kshaya” symptoms by “Balya” (strengthening), “Brimhna” (nourishment), and “Rasayana” properties of M. pruriens. Along with M. pruriens, other drugs in combination as “Ashwagandha” (Withania somnifera), “Brahmi” (Bacopa monnieri), and “Bala” (Sida cordifolia Linn.), are useful in the prevention and management of PD. These drugs in combination could be investigated for their combined effect in preclinical and clinical studies. The various animal and human studies indicate a wide spectrum of biological and pharmacological potentials of M. pruriens as an anti-inflammatory, anti-oxidant, anti-depressant, and hypoglycemic agent. The polyphenols, flavonoids, and other nutrient content of M. pruriens are responsible for the wide spectrum of the therapeutic utility of M. pruriens in neurodegenerative diseases, such as PD. M. pruriens has shown the potential to modulate the concentrations of neurotransmitters, such as DA, norepinephrine, and serotonin content in the SN of the brain. These findings reaffirm the use of M. pruriens in “Vata” (nervous system) disorders. The active metabolites of M. pruriens cross the blood-brain barrier (BBB) and exert the major changes related to anti-oxidant and anti-inflammatory effects in order to improve the motor and non-motor symptoms in the animal models of PD. These studies provide a strong base for further exploration of M. pruriens and other

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nootropic drugs in animal models and human clinical trials. CONCLUSION The chapter indicates that PD is well described in Ayurveda texts. The etiological factors, symptoms, pathogenesis, and treatment are well documented in ancient knowledge. The physiology of PD in Ayurveda involves a unique approach. The use of the natural L-DOPA-containing herb “Kapikacchu” (M. pruriens) has received much attention; the comprehensive treatment of PD requires a much more holistic approach involving the use of preventive as well as treatment modalities of Ayurveda and Yoga for PD. The Ayurveda system of medicine has a holistic approach that goes far beyond the effect of herbal medicines only as the source of L-DOPA as well as the other bioactive compounds of plants, such as alkaloids, flavonoids, tannins, and phenolic compounds, have many effects beneficial to PD. Ayurvedic treatment's efficacy depends on an individual’s inner and subtle energies, which are gained through proper diet and lifestyle choices. The wide array of therapies and drug combinations may be future targets for the treatment of PD. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT Declared none. REFERENCES [1]

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CHAPTER 8

Bacopa monnieri and Neural Health: An Indian Herb Prachi Pattnaik1, Chetan Panda2, Tarun Minocha3, Sanjeev Kumar Yadav3, Namrata Dwivedi4 and Sandeep Kumar Singh5,* Department of Horticulture, Institute of Agricultural Sciences, Banaras Hindu University, Varanasi-2210005 (U.P.), India 2 Department of Agricultural Biotechnology, College of Agriculture, Odisha University of Agriculture & Technology, Bhubaneswar-751003 (Odisha), India 3 Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi-2210005 (U.P.), India 4 Biotechnology Centre, Jawaharlal Nehru Krishi Vishwa Vidyalaya, Jabalpur-482004 (M.P.), India 5 Indian Scientific Education and Technology Foundation, Lucknow-226002 (U.P.), India 1

Abstract: The disorders of the central nervous system are increasingly recognized as one of the most prevalent disorders in the present world. It has been envisaged that neurological disorders will be of great concern in the present and future populations worldwide. The different neurological disorders may be associated with signs, such as loss of memory, impaired brain function, cognitive deficits, etc. The occurrence of such degenerative diseases of the nervous system certainly imposes medical and public health burdens on populations worldwide. The multifactorial nature of such neural disorders entails the use of modern medicine in combination with conventional medicines for treatment. There has been undeniably a revolution in the foundation of existing medical facilities, which have been strengthened by the amalgamation of phytomedicine. In recent times, the use of medicinal herbs to improve mental function has come into the limelight in both developed and developing countries. Increased research is being carried out to discover Ayurvedic medications owing to their biosafety profile and utility in cognitive impairment. The current chapter deals with the depiction of one such plant, that is Bacopa monnieri, which possesses neuroprotective properties, and is considered to be Medhya Rasayana (a nootropic drug). This Indian herb, being a dietary anti-oxidant, has several modes of action to protect the brain against oxidative damage and age-related issues. A majority of the plant compounds, such as polyphenols, alkaloids, and terpenes, present in medicinal plants, have been known to have therapeutic properties against neurodegeneration mainly by virtue of their antioxidant, anti-inflammatory, and anti-amyloidogenic effects. Corresponding author Sandeep Kumar Singh: Indian Scientific Education and Technology Foundation, Lucknow-226002 (U.P.), India; E-mail: [email protected]

*

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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Keywords: Antioxidant, Bacopa monnieri, Neurological disorders, Nootropic, Therapeutic. INTRODUCTION The world comprises an incredible diversity of flora and fauna. India is one of the most religiously and ethnically diverse nations in the world that encompasses an endless variety of plant and animal species that have an aesthetic and medicinal value [1 - 3]. Our ecosystem encompasses an amazing diversity of 17,000 species of plants, of which approximately 8,000 species are considered medicinal plants [4]. In India, medicinal plants and their natural products are important sources of medicine, hence they are of great importance for the health of individuals and communities. According to the World Health Organization (WHO), 80% of the world’s population counts on such traditional medicinal plants to provide them with primary health care [5]. Nowadays, there is a great demand for medicinal plants worldwide because of the increasing disease burden across the globe. Medicinal plants have always been used as a source of various traditional medicines to combat and prevent the progression of various diseases. More than 3.3 billion individuals in less developed or developing nations are dependent on medicinal plants because of their medicinal values [6]. Medicinal plants are not only used in the human culture but are also used as a source for the synthesis of new herbal drugs for therapeutic purposes [7]. The brain is the most significant and complex structure in the human body, comprising neurons and neuroglia. Neurons normally cannot be replaced by the body when they are damaged or die due to certain conditions. The neurons are responsible for sending and receiving nerve signals, whereas the microglia and astrocytes ensure the proper functioning of neurons. Neurological disorders are progressively recognized as one of the most prevalent disorders in the present world. Presently people all over the world suffer from different neurodegenerative diseases, which result in cell death in the brain. Neurodegeneration is a rising medical issue, including many debilitating, incurable diseases. The diverse pathophysiological mechanisms involved in neurodegenerative disorders in human beings have gained increased attention [8]. The major neurodegenerative diseases include Alzheimer's disease (AD), Huntington's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD), causing disability and death worldwide [8, 9]. Globally, the amplifying number of population aging over the past 25 years has considerably increased the burden of neural disorders. Neurological diseases are now being considered as the root cause of disabilityadjusted life years (DALYs) or years of healthy life lost due to death or disability, according to a systematic analysis conducted for the Global Burden of Disease

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Study for the year 2015 to study the way these diseases affect people around the world. The medical complications concerned with the central and peripheral nervous systems, including the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, and neuromuscular junction, are generally categorized as neurological disorders. The present changing lifestyles have a significant effect on the physical and mental health of people. There is an imperative need to develop new and more effective therapeutic strategies in combination with modern drugs to combat these devastating diseases. Researches are particularly focused on discerning the mechanisms underlying neurodegenerative diseases and searching for effective therapeutic avenues. In the recent past, interest has been focused on exploiting traditional plant medicine that may be complementary to the existing modern healthcare applicable to public health both in developed and developing countries. The diversity, relatively low cost, flexibility, lower side effects as well as acceptance by the people are some of the positive features leading the researchers’ attention toward the role of traditional medicine [10 - 12]. Since time immemorial, the herbal compounds extracted from medicinal plants have proved to be a medical resource and play a vital role in regulating the chemical balance in our brain by influencing the function of receptors for the major inhibitory neurotransmitters [2, 3, 13]. Several such herbs have been reported whose extracts help treat neural disorders and enhance neural health. Research into one of the highly potent medicinal herbs, Bacopa monnieri (L.), has reported improvements in cognitive disorders in the human population. It has a long history of use in Ayurveda, best known as a neural tonic and memory enhancer. This review summarizes the role of B. monnieri as a neuroprotector against multiple chronic diseases, including neurological disorders. WHAT ARE NEURODEGENERATIVE DISEASES? Neurodegenerative diseases are a multifarious group of disorders that are delineated by the progressive declension of the structure and function of the central or peripheral nervous system. Neurological disorders can be broadly categorized as neurodegenerative disorders (AD and PD), seizure disorders (epilepsy), mood disorders (anxiety and depression), genetic disorders (HD and Schizophrenia), and others, including an eating disorder, addiction, etc. Neurodegenerative diseases are a blanket term encompassing all those conditions arising when neurons in the brain are affected. The terminology “neurodegenerative” can be cleaved into “neuro”, meaning brain, and “degenerative”, meaning breaking down. These disorders are a great example of the disastrous effects of miscommunications occurring between brain cells. These disorders highly influence an individual’s speech, memory, intelligence, movement, and much more. Neurodegenerative diseases (NDs), such as PD, AD,

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ALS, and multiple sclerosis (MS), primarily affect the neurons in the human brain and are defined by the degradation of neurons or myelin sheath, sensory information transmission disruption, and movement control [14]. Immune activation within the central nervous system (CNS) is a classic example of NDs, immune-mediated disorders, ischemia, infections, and trauma [15]. PHYTODRUGS - THE POTENTIAL ALTERNATIVE Phytodrugs can be described as plant-based or herbal medicine with therapeutic and curative properties. Phytomedicines essentially involve the use of active plant ingredients or their derivatives, but when any kind of external non-plant substance from any source is added, it takes away the essence of the herbal product [16]. Phytomedicine involves the use of herb-based traditional medicines encompassing different plant materials with both preventive and healing properties. The role of phytomedicines has come into existence since the advent of human civilization. The Sheng Nong’s Herbal Book, dating back to 3000 BC, is known to be one of the primary sources of traditional knowledge, which is based on the use of herbs in China. The WHO estimated that the traditional herbal medicines are one of the most preferred, accounting for around 3.5-4 billion people across the world, and a major portion of traditional medicine involves medicines derived from plant extracts and decoction, which may also be termed as the “modern herbal medicine” [17]. A phytopharmaceutical preparation of herbal medicine can be described as a drug derived specifically from a whole plant or parts of plants and produced in a crude form or as a refined pharmaceutical formulation. The WHO specified that in developing countries, approximately 70% of the population still believe more in traditional herbal medicines for their basic medication against diseases [18]. Since the last few decades, there has been a significant rise in the products produced from medicinal plants. Thus, earlier, what was used exclusively as healthy or special food has now gained considerable popularity as a boon for health care, and is being introduced into the mainstream market in the area of phytomedicines as evident by their publicity and acceptance by people [19]. Phytomedicine, along with many other healthcare fields, has indeed helped in revolutionizing and strengthening the efficiency of the existing healthcare system, and holds a major stake in the industry. The future of drugs derived from plants, therefore, seems to have vast scope for exploring some advanced and novel therapeutic products and strategies [20, 21]. Herbal medicine for ages has been utilized to treat neural symptoms. Although the accurate mechanisms of action of phytomedicines are yet to be figured out, some of them have been found to exert anti-inflammatory and/or anti-oxidant effects in a range of peripheral systems.

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The medicinal herbs act as a significant source of novel compounds against therapeutic targets due to their diversity in structure. Such therapeutic targets include problems that are newly discovered by genomics, proteomics, and highthroughput sequencing. Thus, the plant-derived extracts that may help enhance brain function have attracted enormous research to conclude their probable effectiveness as nootropics. Significant scientific literature is now concentrating on psychoactive herbal extracts, and their phytochemicals, comprising thousands of scientific papers, have surfaced over recent decades. Traditional knowledge of medicinal plants as a complementary and alternative therapy has additionally acquired great significance, and has interestingly led to the development of future potential drugs [10, 22 - 24]. Due to its safe nature and no major side effect, nearly 80% of the total world population relies on plant-extracted medicine as first line of primary health care. Nevertheless, there is a lack of compatibility and upgradations in the regulating processes and usage that can be solely attributed to a combination of scientific interpretations and the available traditional knowledge. Consequently, the progress in terms of domestication of wild plants, biotechnological approaches, and genetic enrichment of medicinal herbs, instead of just utilizing the plants growing in the wild, is promising for potential advantages. Thus, the inclusion of herbal drugs and phytomedicine in conventional therapy is a much-proposed concept now. PERKS OF PHYTOMEDICINES OVER SYNTHETIC DRUGS The usage of phytomedicines has gained immense popularity in the pharmaceutical market due to many reasons: ●

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The plant extracts are therapeutically more efficient as compared to chemically derived drugs because of the combined action of all therapeutic constituents; also, the bioequivalence of phytomedicines is in sync with synthetic chemotherapeutics. Presently focus is being shifted from the orthodox monodrug methods to multidrug therapy. Many health disorders, like cancer, diabetes, AIDS, hypertension, malaria, etc., are being treated using multidrug therapy. This is based on many reviews and observations that point towards targeting multiple diseases and their etiologies because this approach is more efficient in treating a disease rather than the concept of single-drug theory. Herbal therapy is also considered an easily achievable, therapeutic, and pocketfriendly approach without having any adverse effects associated with them under normal conditions as compared to chemically derived medicines [25].

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In most medical cases, synthetic drugs are known to provide symptomatic relief, as reported by various research works. However, herbal medicines try to improve the body’s healing mechanism [12]. Herbal medicines are gentle in action and they try to re-establish the damaged systems and processes to get rid of the deficiency present in the system. Generally, a pharmaceutical drug aims to evoke a certain reaction against certain physiological oddities, and there are side effects associated with it which are usually considered as a demerit for the benefits bestowed by these medicines over human health. Herbal medicines, on the other hand, are based upon synergistic action mechanism through which they offer therapeutic benefits with hardly any side effect [26].

WHAT ARE NOOTROPICS? Nootropics primarily comprise those smart drugs that are predominantly bestowed for treating cognitive deficits in people. This term has been derived from two words- “noos,” meaning “to mind”, and “tropein,” referring “to monitor”. It pertains to any substance that influences the functioning ability of our mind in a positive way [27]. They act by regulating the levels of neurotransmitters, enzymes, and hormones available to the brain, and by boosting the level of the brain’s oxygen supply or by stimulating nerve growth. There are extracts of certain herbs which help in enhancing the level of chemical messengers like ACh, and also which increase the blood flow towards the brain, thereby nurturing it with ample supply of oxygen and nutrients, which further regulates the brain function and memory [28]. Herbal nootropics also act as vasodilators against the small arteries and veins present in the brain. When they are introduced into the system, they tend to boost the blood circulation towards the brain with an upsurge in the vital nutrients, energy, and oxygen flow in the brain. They also help alleviate the inflammatory responses in the brain. Herbal nootropics help in modulating neurotransmitter concentration in the brain and stimulate the release of various neurotransmitters, like DA, as well as uptake of choline. A number of neurodegenerative diseases and cognitive dysfunctions can be treated with such potential nootropics. ROLE OF PHYTOMEDICINES IN NEUROPROTECTION Ayurveda, an ancient Indian practice of traditional medicine, involves extensive use of herbs and their extracts that are known to treat various psychiatric disorders. These natural herbal medicines are being used for decades in India as well as other parts of the world for relieving any kind of stress and anxiety in our mind, thereby positively influencing the mood. Various studies indicate the

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extensive use of Ayurvedic medicine as an alternative therapy against several diseases in both developing as well as developed countries of the world [29]. Due to the diverse structure of medicinal herbs, they are considered as one of the valuable sources for exploiting lead chemical compounds that can function against known therapeutic targets by making use of various genomics and proteomics techniques [30]. These herbal medicines are comparatively safer in treating chronic illnesses involving fewer side effects as compared to chemically derived medicines. The current therapeutic ideology, like interventional procedures, chemical drugs, and surgery, has so far not been completely successful in boosting normal neural functions due to their inability to regenerate or repair the neurons that have already been damaged. Due to this lagging feature of conventional therapy for recovering neural damage along with the harmful side effects associated with these drugs, there is an urgent need to look for an alternative combination of treatments with herbal or plant-derived healing products and drugs to cure such perilous disorders. The limited or total absence of side effects associated with herbal formulations provides an additional advantage. Flavonoids, which are naturally anxiolytic as well as anti-oxidative in nature, are the primary choice to be employed as neuroprotective agents. As far as oxidative stress is concerned, the brain is one of the most vulnerable organs of our body as compared to other organs due to the presence of less efficient and active anti-oxidant defense systems in the brain [31]. Some of the neurotransmitters sometimes get autoxidized, leading to the release of ROS. Although the brain as an organ is a major metabolizer of oxygen due to relatively feeble protective anti-oxidant mechanisms, it is very vulnerable to oxidative stress. This oxidative stress is one of the key features responsible for causing neurodegenerative diseases, such as PD, AD, HD, and ischemic diseases [9, 32]. In addition to this, aging is a well-known stimulant that further contributes to disease pathogenicity [33]. Certain plant-based polyphenolic compounds possessing scavenging activity that can help activate the key enzymes required for the anti-oxidant mechanism in the brain may be exploited and utilized, thus eliminating the ever-rising oxidative stress in the diseased brain and recovering the damaged tissue [33, 34]. Thus, the excessive production of oxidative stress is one of the root causes of various neural diseases, so the compounds generally possessing inherent anti-oxidant and free radical scavenging properties seem to be the best possible therapeutic option against such diseases [13]. BACOPA MONNIERI: A REAL FORTUNE FOR NEURAL HEALTH The Ayurvedic system employs a holistic approach towards health and wellbeing, especially exploiting the coadjuvant properties of natural resources. Reports on

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the Ayurvedic herb Bacopa Monnier (L.) suggest its role in improving cognitive outcomes in child and adult populations. Complementary and alternative medicines (CAM) have been widely used throughout history, and one of them from the Ayurveda is “Brahmi” or B. monnieri, from the family Scrophulariaceae. B. monnieri is a perennial creeper that thrives in damp places and marshes throughout the subcontinent and is classified as a nootropic, i.e., a cognitive enhancer [35]. The significance of Brahmi in bettering our memory as well as learning skills was first published in 1982 [36]. Several researches following this have been conducted in animals to determine various properties of a medicinal herb and its potential to shield neuronal structure and function. Taxonomic Classification Kingdom: Plantae Division: Tracheophyta Class: Magnoliopsida Order: Lamiales Family: Scrophulariaceae Genus: Bacopa Species: monnieri (L.) Botany B. monnieri Linn. is an aquatic perennial medicinal creeper with a long history of use in Ayurveda, especially in curing the treatment of cognitive deficits and poor memory, belonging to the family Scrophulariaceae. This medicinal herb has been used in Ayurvedic treatments as a remedy for various diseases, including anxiety, poor memory, and cognitive deficits [37]. Also acknowledged by the name ‘Brahmi’ or ‘Jalanimba’ in Hindi and water hyssop in English, this herb has small leaves with white or purple flowers. The name ‘Brahmi’ has originated from the word ‘Brahma’, the mythical ‘creator’ in Hinduism. Because the brain is the center for major activity, any compound that improves brain health is called ‘Brahmi’, which also means ‘bringing knowledge of the supreme reality. It is known to be native to India and Australia, and is also found growing in the United States and generally in warm wetlands [38]. Warm temperatures (30-40 °C) and humid (65-80%) climatic conditions with abundant sunshine and rainfall are considered ideal for its growth [39].

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The genus Bacopa comprises about 100 species scattered throughout the warmer wetlands of the world, including India, Nepal, Sri Lanka, China, Taiwan, and Vietnam [40]. It was originally described around 6th century A.D. in texts, like Charaka Samhita, Atharva- Ved, and Susurtu Samhita, in which it is recommended for the healing of mental conditions, including anxiety, poor cognition, and lack of concentration; it also acts as a diuretic and energizer for the nervous system and the heart [41]. The plant extract has been used in various health ailments, especially for ameliorating memory [36]. B. monnieri comprises a number of active components, such as alkaloids and saponin glycosides, especially bacoside A. Studies suggest that B. monnieri extract (BME) enhances cognitive functions and memory via bacoside A [42]. Pharmaceutical Properties and Uses The main pharmacological properties of this medicinal herb encompass antioxidant properties, anti-convulsant, cardiotonic, anti-inflammatory, bronchodilator, and peptic ulcer protection. Various indications have been described in Ayurveda for the use of Brahmi for various ailments, such as memory improvement, epilepsy, insomnia, and anxiolytic activity [43]. Historically plants have always proved to be a good anti-infective source. Medicinal plants are increasingly shoving their way into pharmaceuticals, nutraceuticals, cosmetics, and food supplements [2]. The current well-known belief that ‘Green Medicine’ is safer and more reliable than synthetic drugs, having lesser or no adverse side effects, has urged various pharmaceutical companies to invest in plant-derived drugs [3, 44]. The BM extracts comprising bacosides have been broadly investigated for their neuropharmacological effects. The compounds, triterpenoid saponins and bacosides, are known to be responsible for BM’s ability to enhance nerve impulse transmission leading to improvement in memory-related functions. Elaborate research carried out on this plant extract has proved that B. monnieri is capable of treating poor cognitive function as well as anxiety and depression, and it has also been shown to be effective against Alzheimer’s disease. Apart from its various neuroprotective functions, this plant also has other pharmacological activities, such as potential antioxidant capacity, helping in digestive aid, and curing ulcers. The herb demonstrates antioxidant, hepatoprotective [45], and neuroprotective activities. It also has hepatoprotective, anti-depressant, and anti-oxidant properties. All the parts of the plant have been used for their therapeutic beneficiary effects from ancient times as memory enhancer, anti-depressant, analgesic, anti-inflammatory, and anti-epileptic agents, and as nervine tonic, anti-Parkinson's agent, cardiotonic agent [46], antiAlzheimer's drug, anti-amnesic agent, anti-tumor agent, and for anti-oxidant effects. The constituent which has been mostly focused is bacoside A, a blend of

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bacoside A3, bacopacide II, bacopasaponin C, and a jujubogenin isomer of bacosaponin C [47] (Fig. 1). Neuroprotective Aspect of Brahmi The neuroprotective effects of B. monnieri extract have been evaluated against various toxicants, including glutamate, aluminum, beta-amyloid, nitric oxide, etc. The anti-oxidant and anti-stress activities of BM extract also contribute significantly to its neuroprotective function. It was shown that this phytoextract inhibits multiple components related to the beta-amyloid-induced oxidative stress pathway that can lead to Alzheimer’s pathology.

Fig. (1). Neuroprotective effect of bacosides from B. monnieri (Adapted from Abdul et al., 2019).

Role of BM in Curing AD AD is one of the major devastating disorders in the elderly (> 60 years) that is signified by erratic behavior, cognitive decline, and memory loss. There are various genetic and lifestyle factors involved in the pathogenesis of AD. Nowadays, some environmental factors, including heavy metals, also contribute to the progression of AD that affects neuronal cells to degenerate over a period of

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time [48]. It is generally irreversible, which is clinically characterized by disorientation, increased confusion, deterioration of memory, and other psychological as well as physical phenomena [49]. To date, no competent cure for Alzheimer’s exists, and the current medications for Alzheimer’s have limited effectiveness. But treatment with herbal drugs has been found effective in slowing down the disease’s progression, thereby highly reducing the number of cases in the years to come. Numerous studies have been carried out to characterize the neuroprotective properties of plants belonging to the Scrophulariaceae family, particularly B. monnieri and its key polyphenolic compounds known as bacosides. Due to the lack of effective treatments for such disorders, findings based on pharmacological or nonpharmacological strategies to slow down the disease progression are of significant importance. The lack of effective treatments and pharmaceuticals for Alzheimer’s has led to the assessment of alternative therapeutics, such as nutraceuticals, because they have an effect on various neurodegenerative diseases by modulating signaling pathways [50]. Bacosides are examples of such valuable therapeutic agents due to their anti-inflammatory, antioxidant, and Aβ aggregation inhibitor properties. Effect on Curing Cancer The use of multitargeted phyto-medications obtained from traditional medicine for chemoprevention and therapy of cancer treatment is reportedly more effective than using synthetic agents that target a single molecule [51]. However, with cancers being a socioeconomic burden on the patients, several alternatives have been suggested to reduce the cost of treatment along with improved outcomes. Presently medicinal herbs and their extracts are being recognized as a vital complementary therapy for cancer. A chunk of clinical investigations suggest the superiority of herbal medicines for the immune modulation, survival, and quality of life of cancer patients when these herbal medicines are administered along with conventional drugs [52]. Extensive research has been conducted to determine the constituents of BM, and in one of the studies conducted by Bose and Bose as early as 1931, an alkaloid was isolated, which they named “brahmine”. Further studies reported the presence of other alkaloids, such as nicotine and herpestine from BM, and since then, several active ingredients have been identified (Table 1), among which the characteristic compound “bacosides” are the major saponin present. Bacosides represent a mixture of structurally closely related compounds (dammarane type triterpenoid saponins) with jujubogenin or psuedojujubogenin moieties as

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aglycones [53]. Bacoside A (Fig. 2) is composed of bacopaside X, bacopaside III, bacoside A3, and bacopasaponin C. The additional components present in the herb include apigenin, cucurbitacin, brahmine, monnierin, hersaponin, monnierasides I-III, d-mannitol, nicotine, and herpestine. The pharmacological properties of B. monnieri are mainly attributed to these saponins, especially bacoside A and bacoside B, which have emerged to be bioactive marker compounds of this species [42]. Several other saponins and glycosides, such as cucurbitacins, bacobitacin A-D as well as cucurbitacin E together with three known phenylethanoid glycosides, monnieriside I, III, and plantioside B, have also been isolated from BM.

Fig. (2). Chemical structure of Bacoside A. Table 1. Active constituents of Bacopa monnieri extract (EBm) (data adapted from Chaudhari et al., 2017). Chemical groups

Contents

Saponins

Bacoside A, bacoside B, bacopasaponins, monnierin, D-mannitol, acid A

Flavonoids

Luteonin, apigenin

Alkaloids

Brahmine, hydrocotyline herpestine

Glycosides

Asiaticoside

Phytochemicals

Betulinic acid, oroxindin, stigmastarol, betulic acid, wogonin, β-sitosterol

Sapogenin

Jujubacogenin, pseudojujubacogenin

Other constituents

Brahmic acid, brahamoside, isobrahmic acid, brahminoside

Other Biological Activities of BM Besides mental functioning, Ayurvedic medications also advocate the use of BM extracts for other physiological conditions due to the presence of various other pharmacological effects of BM, such as anti-inflammatory properties,

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hepatoprotective properties, anti-ulcerogenic activity, bronchitis and asthma, cardiovascular effects, hypothyroidism, etc. CURRENT RESEARCH AND SCOPE It has now become strikingly apparent that the available psychotherapies do not suitably meet multiple therapeutic demands of a majority of neural deficit patients, and that herbal remedies have proven to be the ultimate unexplored hope for many such people in the present world. Recently, the interest in the use of herbal products has dramatically escalated in developed as well as in developing nations [54]. BM has largely been valued as a revitalizing herb used by Ayurvedic medical practitioners for almost about 3000 years. Apart from its valuable impact on curing neural deficits, the specific other uses include the treatment of asthma, insanity, and epilepsy [55]. The plant is being extensively utilized as a nootropic, digestive aid, and medication to improve learning, memory as well as respiratory function. This particular ancient medicinal plant is an excellent reservoir of various bioactive phytochemicals, mostly belonging to the saponin group of plant secondary metabolites [56, 57]. There is a gap lurking between ancient ayurvedic knowledge, experimental proof, and translational research into modern clinical studies for the acceptance of traditional medicine. Consequently, the interest of the scientific community is a paradigm shift from monotherapy involving isolated phytocompounds to target a specific cellular pathway to multitherapy based on various targets with a greater probability for success. CONCLUSION Modern medicine functions include the use of a distinct, well-defined chemical molecule(s) for pharmacotherapy. Certainly, the biggest challenge faced by scientists now is to come up with a multifaceted drug that could target multiple disease pathways without significant side effects, be non-toxic at higher concentrations, and have the ability to cross the blood-brain barrier as well. Plants are the ultimate storehouse of an unlimited source of compounds that may be exploited for improving human health. A single plant may contain hundreds of secondary bioactive metabolites and chemical diversity; however, their benefits are yet to be explored and utilized. The presently discussed medicinal herb B. monnieri has intricate mixtures of chemical compounds, which exhibit various pharmacological and biological activities. It has been used as traditional medicine for curing cognitive deficits in humans and for anti-aging. According to long-established theories, phytocompounds aid in maintaining the fundamental vigor in the body, and have

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numerous neuroprotective mechanisms that help maintain our well-being. Several diseases and aging-related neural degenerative disorders are closely associated with oxidative processes in the body. The medicinal herbs and spices play a major role as a source of anti-oxidants to combat oxidation, and thus warrant further attention. Further studies should now focus on validating the anti-oxidant properties of herbs as well as testing their effects as markers of oxidation. Thus, traditional herbal medicine will work in parallel with modern medications that aim to establish anti-oxidants as mediators of disease prevention. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT Declared none. REFERENCES [1]

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CHAPTER 9

Role of Curcumin in the Treatment of Neurological Disorders Bhuwan Chandra Joshi1 and Yogita Dobhal2,* Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun University, Bhimtal Campus, Nainital-263136, (Uttarakhand), India 2 School of Pharmaceutical Sciences and Technology, Sardar Bhagwan Singh University, Balawala, Dehradun-248001, (Uttarakhand), India 1

Abstract: The global burden of neurological diseases is increasing at a much faster rate causing a social and economic impact on the people. Neurological diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and many more, are the current hot topics. The current treatment strategy in combating neurological diseases only focuses on symptomatic relief and thus causes severe side effects. Therefore, the therapeutic approach to combating neurological diseases has shifted towards herbal plants. One such plant of great importance is Curcuma longa L. and its associated active constituent curcumin. In this book chapter, we have focused on the important role of curcumin in neurological diseases, in which we have summarized data from 10 years (2010-2020) to get a comprehensive idea for further research in this field. We have also described the role of curcumin in the treatment of neurological diseases, including its cellular and common molecular mechanisms.

Keywords: Neurological diseases, Pharmacological effects, Turmeric. INTRODUCTION Turmeric (Curcuma longa L.,) has been traditionally used as a spice of medicinal value both in India and China. It is used largely in spices, medicine, dyes, and as an herbal supplement all around the world [1]. More than 100 species of Curcuma have been reported, with India alone having origin of more than 40 species. Turmeric is also known as the cousin of ginger and is widely called Indian saffron because of its distinctive yellow color. It belongs to the family Zingiberaceae [2]. Corresponding author Yogita Dobhal: School of Pharmaceutical Sciences and Technology, Sardar Bhagwan Singh University, Balawala, Dehradun-248001 (Uttarakhand), India; E-mail: [email protected] *

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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The main active component present in turmeric is Curcumin (1,7-bis(4-hydroy-3-methoxyphenyl)-1,6-heptadiene-2,5-dione), which is a polyphenolic compound [3]. Both keto and enol forms are found in nature. A number of pharmacological activities have been reported of curcumin, like anti-oxidant, antiinflammatory, anti-cancer, anti-viral and anti-diabetic. Curcumin has shown antioxidant activities because of its property of scavenging reactive oxygen species (ROS) [4]. It has also shown modification in the expression of various factors, like chemokines, cytokines, and apoptotic factors. The second leading cause of death in the world are various neurological disorders. These can also result in indifferent disabilities in humans. Various initiatives have been developed by United Nations to reduce the neurological disorders prevailing all around the globe with sustainable development goal targets [5]. Curcumin has been found to be useful in treating various neurological diseases [6]. Long-term studies have shown that there is a decreased incidence of Alzheimer’s and memory-related diseases with continuous use of curcumin. Research has shown that the incidence or frequency of Alzheimer’s in India is about one-fourth of that in the United States (0.7% vs. 3.1% between the ages of 70 and 79), indicating the influence of genetic, environmental as well as dietary factors [7]. ROLE OF CURCUMIN IN VARIOUS NEUROLOGICAL DISORDERS Curcumin imparts a neuroprotective role in the brain by targeting at various molecular and cellular levels. The major mechanisms and targets associated with various neurological diseases are shown in Fig. (1). ALZHEIMER’S DISEASE (AD) According to a report by WHO, around 48.6 million population in the world is suffering from AD. The drugs currently in use only reduce the symptoms of the disease, whereas the underlying causes remain the same. Hence, there is a need for drugs that could act by disease modification for the treatment of this neurological disorder. The histological study has shown prominent neurofibrillary tangles, senile plaques, and neuronal loss of the affected brain tissue [7]. Further studies on curcumin have shown that it could reduce the excessive phosphorylation of tau protein, which has been implicated in AD [6]. Aβ accumulation has also been observed in AD. The property of curcumin to bind with Aβ makes it an important molecule for the development of a significant drug molecule for the treatment of AD [8]. The binding of curcumin to Aβ makes it a useful diagnostic tool in near-infrared fluorescence (NIRF), positron emission tomography (PET), two-photon microscopy, and magnetic resonance imaging (MRI), as this complex emits highly fluorescent signals, thus making it useful for AD [9, 10].

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Fig. (1). Major effects of curcumin, an active constituent of Curcuma longa L., in combating brain-related neurological diseases, including Alzheimer’s disease, Parkinson’s disease, epilepsy, and neuroinflammation.

Oxidative stress is an important factor involved in the pathogenesis of AD, accompanied by an increase in lipid peroxidation (LPO) in the brain of early AD patients. Oxidative stress also leads to mitochondrial dysfunction and has also been shown to modulate Aβ accumulation and tau phosphorylation [4, 7]. Curcumin prevents DNA-oxidative damage by scavenging the hydroxyl radicals. Neuro-inflammation is also involved in the pathogenesis of AD. It is characterized by a local cytokine-mediated acute-phase response, activation of the complement cascade, and induction of inflammatory enzyme systems, such as the inducible nitric oxide synthase (iNOS) and the prostanoid generating cyclooxygenase-2 (COX-2). In addition to this, Aβ also activates the nuclear factor κB (NF-κB)-dependent cytokine production pathway. Curcumin has been reported to inhibit NF-κB-mediated transcription of inflammatory cytokines (Fig. 2) [7]. Curcumin blocks extracellular signal-regulated kinase 2 (ERK1/2) and p38 kinase signaling in βA-activated microglia in vitro, reducing the synthesis of IL1β, tumor

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necrosis factor α (TNFα), IL6, mRNAs, and proteins [9]. In addition to this, curcumin also inhibits the activation of MAPK in microglia cells, causing a decrease in the levels of various inflammatory mediators, including TNF, IL-1β, IL-6, and many more [11] (Fig. 2).

Fig. (2). Common pathways associated with various neurological disorders and effects of curcumin on these pathways. Curcumin binds to the cellular receptors and inhibits/inactivates the following pathways: JNK, NFκB, and MAPK. Note: JNK - Janus Kinase; NF-κB - Nuclear factor kappa light chain enhancer of activated B cells; MAPK - Mitogen-activated protein kinases; ROS - Reactive oxygen species; COX - Cyclooxygenase; MMP9 - Matrix metalloproteinases; TNF - Tumour necrosis factor; IL-2/6 - Interleukins.

PARKINSON’S DISEASE (PD) PD is the second most common neurodegenerative disease that affects 2-3% of the population above 65 years of age. It is characterized by the deficiency of

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dopamine (DA) in the striatum (ST) and loss of dopaminergic (DAergic) neurons in the substantia nigra (SN), leading to abnormal DAergic neurotransmission in the basal ganglia motor circuit causing resting tremor, rigidity, bradykinesia, posture, and difficulty in swallowing. The α-synuclein (α-syn), a 140-amino acid protein (mol mass 14 kDa), is accumulated intracellularly that represents the hallmark of this neurodegenerative disease. In PD, curcumin may also produce beneficial effects by inhibiting monoamine oxidase (MAO-B), which is involved in the metabolism of dopamine, preventing mitochondrial dysfunction. Its glucoside form (curcumin-glucoside) could inhibit the fibrillization and aggregation of α-syn, preventing DA deficit and blocking neuroinflammation [6, 12]. Curcumin also protects neuronal cells from MPTP (1-methyl-4-phenyl-1, 2, 3, 6tetrahydropyridine)-induced toxicity. MPTP is a prodrug of MPP+, a neurotoxin that induces PD-like symptoms [13 - 15]. In primary astrocytes, this turmericderived polyphenol prevented the activation of MPP+; inhibited the production of TNF, IL-6, and ROS; and increased the level of IL-10 and GSH [4]. OTHER DISEASES Amyotrophic Lateral Sclerosis (ALS) It is a neurodegenerative disease that affects motor neurons. Affected nerve cytoplasm shows the aggregation of TDP-43 in most ALS patients. The decrease in the threshold of action potentials (APs) due to mutant TDP-43 was reported along with slow inactivation of voltage-gated sodium (Nav) channels in a motor neuron-like cellular model of ALS. Treatment with curcumin (15 μM) reduced the abnormalities of APs and Nav channels [7]. Huntington’s Disease (HD) It is an inherited rare neurological disorder with progressive degeneration of nerve cells in the brain, causing symptoms like loss of cognition and affected movements. An abnormal increase in polyglutamine (poly Q) sequence occurs in the Huntingtin protein. In a study on the Drosophila model of HD, a significant decrease in the disease symptoms, like reduced loss of motor function and morphological defects in the internal eye due to the suppression of cell death, was reported [7, 16].

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Traumatic Brain Injury (TBI) External factors, like mechanical forces, can also result in trauma to the brain. The role of curcumin in protecting against TBI by exerting antioxidant activity has been reported. It has been shown to modulate certain signaling pathways that are mediated through nuclear factor erythroid 2-related factor 2 (Nrf2), which is a redox-sensitive transcription factor. Another study has shown upregulation of Bcl-2 expression while the expression of caspase 3 was down-regulated in the ipsilateral cortex of TBI-induced animal models; thus, it could be assumed that curcumin, a polyphenol, can exhibit protection in TBI models by modulating the antioxidant defensive system [4]. Glioma (GBM) It is a rare type of tumor that occurs in the glial cells of the brain and spinal cord. ROS and oxidative stress are seen to be involved in the development and progression of GBMs. There is a reduction in the number of glioblastoma cells with the use of curcumin. The possible mechanism can be the suppression of signal transducer and activator of transcription (STAT) 3 and STAT3-dependent gene [4]. Cognitive Dysfunctions Cognitive function refers to the mental abilities or processes that are involved in reasoning, manipulation of information, and acquiring knowledge. The factors known to be responsible for controlling cognitive functions involve changes in neuronal and glial interactions, oxidative stress, neuroinflammation changes in the synapses, and neurochemical functions. Curcumin has shown anti-inflammatory and antioxidant activities, which result in improving cognition, memory, and intelligence. It also causes an increase in the expression of brain-derived neurotrophic factors (BNDF) and associated genes, and thus improves synaptic plasticity and cell survival. The process of cell survival is further enhanced by superoxide dismutase-2, an antioxidant enzyme, and the expression of the antiapoptotic protein-Bcl-2. Neurogenesis can be promoted by BDNF, proving its usefulness in improving cognition [1, 17]. Multiple Sclerosis (MS) It is an inflammatory autoimmune and chronic disorder, affecting the central nervous system (CNS). The disorder is characterized by the formation of

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inflammatory lesions leading to neurological damage, disruption in the bloodbrain barrier (BBB), and formation of multiple plaques in the white and grey matter of the brain and spinal cord. Free radical-induced oxidative stress also enhances the onset of MS. Curcumin has been shown to provide significant neuroprotective effects in MS by interacting with different transcription factors, growth factors, enzymes, proteins, and the cytokines involved in inflammation due to its antiproliferative, antioxidant, and anti-inflammatory properties. In a study, the administration of curcumin nanoparticles (NPs) in a lysolecithininduced focal demyelination model showed a reduction in inflammation and presented with improved glial cells. Curcumin has also been shown to protect axon degeneration, reducing NO release and JNK phosphorylation (Fig. 2). The research is still in progress to identify the exact mechanism of curcumin in preventing the degeneration of axons [18]. Numerous in vitro and in vivo studies have been performed for testing the effects of curcumin. Most of them have aimed to determine its effects and potential dose for various neurological diseases (Table 1). CURCUMIN IN CLINICAL TRIALS Clinical trials are being conducted to check the efficacy, safety, and potency of the active molecule in human subjects. Therefore, comprehensive clinical trial data of curcumin are presented in Table 2. CONCLUSION In conclusion, curcumin possesses neuroprotective properties, imparting antioxidant and anti-inflammatory activities. It is one of the most promising compounds for targeting neurodegenerative diseases associated with the abnormal aggregation of proteins. It exerts its effect by the modulation of several key molecules that are determinants in the pathophysiology of neurological diseases. It is beyond doubt that curcumin still has untapped potential that could be used for the treatment and cure of different diseases. This demands further experimental studies and clinical trials that are necessary to establish the efficacy of curcumin for the prevention and cure of various neurological diseases.

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Table 1. List of neurological diseases showing the potential role of curcumin. Experimental Setup S. No.

Neurological Disorder

In vitro Cell line

Refs.

In vivo

Comments

Animal model

APP/PS1 double transgenic mice model

Potential dose

-

Comments Improves spatial learning and memory abilities and reduces [19] the amyloid plaque burden in the hippocampus

Improves spatial learning and memory Curcumin deficits. It increases APP/PS1 mouse model (50 mg/kg/day) [20] brain lactate content i.p. and MCT2 protein levels

1.

Alzheimer’s Disease

-

APP/PS1 transgenic mice model

Male NMRI mice

Curcumin (150 mg/kg) intra-gastrically

It activated NSCs proliferation, improved neurogenesis, and ameliorated cognitive impairment. It upregulated the expression of selfrenewal genes, Notch1 and Hes1, and augmented CDK4, Cyclin D1, NICD, and Hes1 proteins.

[21]

It prevented scopolamine-induced memory retrieval Curcumin (50 deficit and restored or 100 [22] Akt and GSK mg/kg/p.o.) dephosphorylation caused by scopolamine

2.

Autism spectrum disorders (ASDs)

-

-

BTBRT+ltpr3tf/J (BTBR) mice model

Curcumin (20 mg/kg)

3.

CNS defective myelination

-

-

BPA-induced rats

Curcumin (20mg/kg b.w.) i.p.

Improved autismrelated symptoms, enhancing sociability, reducing repetitive [23] behaviours, and ameliorating cognitive impairments Neuroprotective effects but induces Notch-signalling pathway

[24]

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(Table ) cont.....

Experimental Setup S. No.

Neurological Disorder

Refs.

-

4.

Epilepsy

-

5.

6.

7.

Glioblastoma

Ischemic stroke

Multiple sclerosis

Curcumin (100 mg/kg b.w.)

KA-induced SD rats model

Curcumin (100 mg/kg/day)

It inhibits epileptic syndromes via suppression of NLRP3 inflammasome activation

[26]

-

-

-

[27]

-

Human It suppresses the MAPK fetal pathway and also reduces astrocytes the levels of IL-6 and and the COX-2 in cultured neuronal astrocytes. It also reduces cell line ROS levels SH-SY5Y

-

It markedly reduces epileptiform activity and reduces mRNA [25] and protein levels of Nav1.1

FeCl3-induced SD epileptic rat model

SD rats with pups

-

It suppresses spontaneous seizurelike events (SLEs). It also lowers the pS6 [28] expression at one phosphorylation site

Inhibition of proliferation, migration, and invasion; Decreases tumor U251 and downregulates p-AKT and Curcumin volume and necrosis Glioblastoma-xenograft U87 GB p-mTOR protein (60 mg/kg) i.p. of tumor tissues [29] mouse model cells expression for 14 days ↑ PTEN and p53 ↑ PTEN and p53 expression expression Alleviates OGD/R-induced mitochondrial dysfunction Mouse in mouse N2a cells and N2a cells promotes neuron survival, leading to neuroprotective effects.

-

-

Male C57BL/6 mice

C57BL/6 EAE mice model

-

Inhibits Bax activation after cerebral I/R injury in the periinfarct cortex [30] of ischemia-induced mitochondrial apoptosis

It significantly reduces the expression levels of pro-inflammatory cytokines, including Curcumin IL-6, IL-17, TNF-α, (20 mg/kg) i.p. and INF-γ; along for 21 days with this, it also increases the expression level of TNF-β (antiinflammatory cytokine)

[31]

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(Table ) cont.....

Experimental Setup S. No.

Neurological Disorder

Refs. Increases mechanical withdrawal threshold, MNCV, SNCV, SOD, GSHPx, CAT, and MDA Curcumin ↓ paw-withdrawal Oxaliplatin-induced SD (12.5, 25, and [32] times of cold rats 50 mg/kg b.w.) allodynia for 28 days Injured neurons of the spinal cord were repaired (-) NF-κB, TNF-α, IL-1β and IL-6

8.

Neuropathic pain

-

-

BV2 microglial cells

It attenuates neuroinflammation induced by LPS by regulating miR-199-5p/IKκB/NF-κB axis in microglia

Murine BV2 microglia cell line

It inhibits the phosphorylation of JAK2 and STAT3 in LPS-activated microglia and increased expression of SOCS-1, suppressing the activation of the JAK/STAT signal

9. Neuroinflammation

SNL-induced female Wistar rats model

Anti-allodynic effect Curcumin (oral by NO-cyclic GMPand spinal [33] ATP-sensitive K+ administration) channels pathway

BPA-induced SD rats

It significantly reduces the levels of TNF-α and IL-6 in rat spinal cords. In addition to this, protein levels of c- [34] Fos and NGF ↓. It also reduced the number of GFAPpositive cells and GFAP expression

Curcumin (60 mg/kg b.w.) i.p.

[35]

-

-

-

[36]

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(Table ) cont.....

Experimental Setup S. No.

Neurological Disorder

Parkinson’s Disease

10.

Refs. It rescued the toxicity effects of MPP+ by controlling morphological change, promoting cell proliferation, and SH-SY5Y inhibiting apoptosis. It also cells significantly reduces the adverse effects of MPP+ on dopaminergic neurons via up-regulation of HSP90

-

-

-

-

-

[37]

Drosophila model of PD with knockdown of dUCH

Curcumin 0.037%

Reduces oxidative stress

[38]

Curcumin It shows LPS-induced male SD (40 mg/kg b.w. neuroprotection and rats (i.p.)) for 21 inhibits α-synuclein days aggregation

11.

Pseudorabies virus (PRV) infection

-

-

PRV-induced rat model

12.

Traumatic brain injury

-

-

Male ICR mice

Curcumin (10 µM)

[39]

Neuroprotective effects and improved cell viability [40] by upregulating the BDNF/TrkB pathway

Neuroprotective Curcumin (50 effect by activating and 100 mg/kg) Nrf2-ARE pathway

[41]

Table 2. Recent clinical trials on curcumin for different neurodegenerative diseases. S. No.

Type of Neurological Disorder

Phase

Type of Trial

Current Status

1.

Alzheimer’s disease

II

Interventional and randomized

Active, not recruiting

NCT01811381

[36]

2.

Subdural hematomas recurrence

Early Phase I

Double-blind, randomized, and interventional

Recruiting

NCT03845322

[37]

NIH Clinical Trial Refs. Ref.

CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise.

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CHAPTER 10

Pharmacology of Rosmarinic Psychological Disorders

Acid

against

Himanshu Verma1, Naveen Shivavedi1, Mukesh Kumar1 and Prasanta Kumar Nayak1,* Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, 221005 (U.P.), India 1

Abstract: Anxiety and depression are the major psychological disorders globally, increasing the risk of morbidity and mortality and considerably leading to a socioeconomic burden by 2030. Both disorders impact day-to-day life via several symptoms (fear, insomnia, anorexia, irritability, loss of concentration, and inability to think). The available treatment strategy for psychological disorders has shown major adverse effects, which limits its use and paves the way for the development of the herbal drug-based novel drug. Natural compounds are offered as the most contented option because they possess very least side effects, are easily available, and are of low cost with high therapeutic activity. In the present chapter, we focus on the pharmacology of a plant polyphenol, Rosmarinic acid (RA), against psychological disorders. Specific plant constituents of Rosmarinus officinalis (rosmarinic acid) help treat anxiety and depression by reducing oxidative stress and inflammatory mediators. Other important targets, such as neurotransmitters (noradrenaline, 5-HT, and dopamine), neuroendocrine (Hypothalamus-pituitary-adrenal-axis), brain-derived neurotrophic factor, T-type calcium channels, mitogen kinase protein-1, and phosphorylated extracellular regulated kinase 1 and 2 protein, are also involved in the pathophysiology of psychological disorders (anxiety and depression). Thus, in this chapter, we have illustrated the pharmacology of RA in major psychological disorders, including anxiety and depression.

Keywords: Anxiety, Depression, Psychological disorders, Rosmarinic acid. INTRODUCTION Psychological disorders, such as depression, anxiety, and bipolar disorder, are highly prevalent due to their severe negative emotional impact with cognitive, beCorresponding author Prasanta Kumar Nayak: Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U.), Varanasi, 221005 (U.P.), India; E-mail: [email protected] *

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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havioral, psychological, and biochemical changes [1]. Recent worldwide epidemiological data show that nearly 800 million people have psychological disorders, with women (11.9%) having a slightly higher prevalence than men (9.3%) [2]. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is used worldwide to diagnose anxiety and depression in clinical settings [3]. In the DSM-5, psychological disorders are divided into broad categories, as anxiety disorder and depressive disorders, and are diagnosed according to the symptoms [3]. Diagnostic criteria of anxiety and depression are restlessness, panic, constant worry, thoughts, energy loss, nervousness, insomnia, difficulty in concentration, fatigue, self-esteem problem, and suicidal mood [4, 5]. Anxiety and depression refer to a group of mental disorders. These are characterized by fear, excessive avoidance, worrying about the future, difficulty in concentrating, tension headache, inability to relax, sweating, tachycardia, epigastric discomfort, dizziness, reduced self-esteem, tiredness, feel guilt, abnormal appetite, disturbed sleep, and ideas of self-harm leading eventually to suicide, which has an impact on multiple biological systems [6, 7]. Several recent changes and controversies have been developed in DSM-5 diagnostic criteria, such as agoraphobia (fear of certain places) distinct from panic disorder, cultural syndromes (significant factor for anxiety disorder), and lowering the diagnostic threshold with the limiting of dichotomous view of anxiety and depression [8, 9]. This chapter focuses on two major psychological disorders, anxiety and depression [10]. The dose-limiting adverse effects of conventional drugs have led to an exploration of novel phytochemicals, such as L-theanine [11], valerian [11], and Phelodendrone [12]. In this context, several studies have reported naturally occurring drugs as promising to treat psychological disorders without any limitations. Oxidative stress, inflammation, and cytotoxicity are significant factors in the development of anxiety and depression [13, 14]. An excessive amount of reactive oxygen species and depletion of the anti-oxidative mechanism increase the release of pro-inflammatory mediators (tumor necrosis factor-α and interleukin-6), leading to programmed cell death. Oxidative stress is a major risk factor for the brain because it has high lipid content and oxygen consumption with less antioxidative protection [13, 15 - 18]. Therefore, suitable antioxidants and antiinflammatory agents would be a curative strategy against psychiatric disorders. Since ancient times, herbal medicines have been used against psychological disorders because of several advantages described elsewhere [19].

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SCIENTIFIC LITERATURE We have done an extensive literature search on PubMed, Science Direct, Google Scholar, and Scopus databases by using keywords as rosmarinic acid (RA), depression, rosmarinic acid and anxiety, rosmarinic acid, and psychological disorders. All types of relevant research articles, review articles, and books were included. In this book chapter, we have discussed the experimental and clinical studies related to rosmarinic acid in psychological disorders. PATHOPHYSIOLOGY OF PSYCHOLOGICAL DISORDERS Anxiety and depression are widespread mental health problems, leading to a massive impact on health worldwide. The human body adapts to changes in both the external and internal environment for survival, which is known as homeostasis. For maintaining homeostasis, the endocrine system of the body releases hormones, such as cortisol, adrenaline, and noradrenaline [20]. The released hormones control the autonomic nervous system and central nervous system to prepare the body to adapt and respond accordingly [20]. However, when the body fails to adapt, it leads to health issues and sometimes death [21]. The psychological disorders badly affect the hypothalamus-pituitary-adrenal axis (HPA axis), gene expression, and autonomic nervous system (ANS) [22]. Anxiety disorders are severe, excessive, and widespread forms of childhood and adult psychiatric disorders [23]. Panic attacks reach a peak within minutes through repeated episodes of sudden feelings of fear and anxiety. The etiology of anxiety disorders is multifactorial and includes neurobiological abnormalities of noradrenergic, glutamatergic, GABAergic, and serotonergic transmission, with an interaction of genetic and environmental influences [24]. Psychological and social factors, such as loss of support, medical infirmity, loss of mastery control, and sensory loss, also play an essential role in developing anxiety [25]. Anxiety has several signs, such as nausea, urination, palpitation, cramp, perspiration, fear about the future, sorrow, and sleeplessness [26]. Depression is a significant psychological disorder with high social cost and is the primary cause of disability worldwide [27, 28]. Depression is a common, longlasting, and reoccurring illness characterized by depressed mood, anhedonia, insomnia, anorexia, low energy, loss of interest in activities, hyperphagia, and polysomnia [29, 30]. The abnormality in brain neurotransmitters, such as serotonin and norepinephrine, is the leading cause of depressive disorder [31]. Furthermore, in the pathophysiology of depression, some more factors are involved, such as inflammatory response (interleukin-1β, tumor necrosis factor-α, and interleukin-6), hyperactivity of HPA axis, imbalance of the ANS system, and

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endothelial dysfunction platelet activation [32]. Besides, gamma-aminobutyric acid (GABA), dopaminergic system, glutamatergic system, and BDNF are also included in the pathophysiology of depression [33 - 35]. EPIDEMIOLOGY Recent epidemic reports have shown that 284 million people are affected by anxiety disorder worldwide [36]. In females (179 million), the prevalence of anxiety is higher than males (105 million) [36]. In contrast, the prevalence of depression was up to 21% in 2006 [37], which increased to 49.86% of the population worldwide in the year 2020 [38]. According to recent research, more than 300 million people suffer from depression, dramatically increasing the risk of suicide [39]. Like anxiety, depression is twice as prevalent in females as in males [40]. Moreover, depression is a significant issue in developed countries due to the higher durability of depression than in developing countries [41]. Therefore, a better understanding and better management strategies for these psychological disorders are warranted. CURRENT TREATMENT STRATEGIES Several classes of drugs (serotonin reuptake inhibitors, benzodiazepines, tricarboxylic anti-depressant, and monoamine oxidase inhibitors) are available for the management of anxiety and depression [42, 43]. Nevertheless, most of the drugs, such as benzodiazepines (diazepam and lorazepam), serotonin reuptake inhibitors (fluoxetine and paroxetine), tricarboxylic anti-depressants (amitriptyline and imipramine), and monoamine oxidase inhibitors (iprozide and isocarboxazid), have limitations (drug resistance, dependence, toxic effect on organs, slow onset, low response rate, and sleep disturbance) and dangerous side effects (cognitive impairment, sexual dysfunction, and hypertensive crisis) [44 - 48]. Therefore, alternative strategies with fewer side effects and better efficacy due to using active phytochemicals have gained more attention these days. Natural compounds have gained remarkably great attention of researchers worldwide because of the diversity in their chemical profile, safety and better efficacy [49]. This chapter has discussed the pharmacological activity of a plant polyphenol, RA, which has been reported to possess anti-oxidative and anti-inflammatory properties. ROSMARINIC ACID (RA) RA (polyphenolic phytochemical) is a caffeic acid ester, a prevailing phenol present in several plants, namely Rosmarinus officinalis L., Origanum vulgare,

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and Melissa officinalis [50]. The chemical analysis of rosemary extract composition reveals that the utmost active components are phenolic diterpenes and triterpenes [51, 52]. In this context, RA exerts the most beneficial effect than other phenolic acid compounds [52]. PHARMACOLOGY OF RA RA was isolated and purified in 1958 by Scarpti and Oriente (Italian chemists) from R. officinalis, who then named it according to the plant they isolated it from [53]. The biosynthetic pathway of RA was first reported in 1970 by Ellis and Towers [54]. They demonstrated L-tyrosine and L-phenylalanine (two amino acids) to make up the RA structure [54] (Fig. 1). R. officinalis belongs to the family Lamiaceae, the primary source of RA [55]. Mentha spicata is also one of the herbs that contain the highest amount of RA comprising 29 species of the Lamiaceae family than other species studied by researchers, who stated that this herb could be a good source for extraction of RA [56]. Pharmacologically, previous research exhibits that RA contains several pharmacological effects, such as anti-oxidative [57], anti-inflammatory [58], antiapoptotic [59], anti-mutagenic, and anti-cyclooxygenase properties [60]. PHYTOCHEMISTRY OF RA RA possesses highly lipophilic and slightly hydrophilic properties [61]. RA is highly soluble in utmost organic solvents (tween 80, dimethyl sulfoxide, and ethyl acetate) [62]. The melting point and molar mass of RA are 171-175 °C (340-374 °F) and 360.32 gm mol-1, respectively [63]. Chemically, the structure of RA (3,4 di-hydroxyphenyl acetic acid) is derived from hydroxycinnamic acid [64].

Fig. (1). Chemical structure of RA (C18 H16 O8 from PubChem).

L-tyrosine and L- phenylalanine (amino acids) are mainly responsible for RA biosynthesis [65]. In the catalyzation of L-phenylalanine to 4-coumaroyl-CoA, some enzymes are involved, such as 4-coumaric acid CoA-ligase, cinnamic acid

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4-hydroxylase, and phenylalanine ammonia-lyase, which further proceed the biosynthesis of RA [63]. In human urine, RA and its metabolites (methylated RA, caffeic acid, ferulic acid, and m-coumaric acid) are detected after administration of RA [66], while in plasma, highly methylated RA is detected [66]. In the excretion, only 6.3% of RA and its derivatives are observed [66]. Nanoparticle-based RA was recently studied to bypass gastric degradation for increasing the bioavailability of rosmarinic acid [67]. In this study, RA was found not to produce in vitro cytotoxicity or genotoxicity and in vivo toxicity in rats [67]. For ocular administration of RA, chitosan-based nanoparticle delivery of RA has also been evaluated [68]. In view of numerous beneficial and non-beneficial constituents in medicinal plants, it is required to focus on determining herbal extracts' clinical effectiveness. THERAPEUTIC EFFICACY OF RA IN PSYCHOLOGICAL DISORDERS Several studies have reported that RA shows antioxidant properties and protects from anxiety in rats [69, 70] (Fig. 2, and Table 1). Abdelhalim et al. reported RA anxiolytic activity at 50-200 mg/kg by modulating gamma-aminobutyric acid (GABA) receptors and HPA axis mechanism in mice. Moreover, RA administration in mice decreased the serum corticosterone level and immobility time while increasing dopamine levels in mice [72]. Besides, the same research group observed that modulation of acetylcholine and growthassociated protein (Gap43) gene expression level exhibited an anxiolytic effect [72]. In 1996, researchers reported that a Chinese herbal extract mixture (Saiboku-To containing RA) showed an anxiolytic effect by increasing open-arm and decreasing closed-arm exploration in an elevated plus-maze test (EPM) [73]. Furthermore, the researcher also found that RA contains several positive effects on psychiatric disorders, such as anti-anxiety, anti-depressive, and neuroprotective effects [74]. In another study, rosemary tea (2% w/w orally) significantly inhibited cholinesterase activity. It reduced closed-arm exploration in the elevated plus-maze test, exerting anti-depressant and anxiolytic effects in mice [75]. In post-traumatic stress disorder laboratory, increased neuronal apoptosis rate in rats led to inhibition of hippocampus cell proliferation followed by anxiety behavior and fear responses [76, 77]. The researcher estimated that enhanced single exposure to prolonged stress induces post-traumatic stress disorder by two

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pathways (inhibition of neurogenesis in the hippocampus), exerting the negative effect on phosphorylated extracellular regulated kinase (pERK1/2) expressions and leading to anxiety behavior and fear responses recorded. RA (5 and 10 mg/kg for 14 days; intraperitoneally) exhibited an anxiolytic effect by significantly reducing post-traumatic stress disorder symptoms by restoring phosphorylated extracellular-regulated kinase expression and hippocampal proliferation [78]. Li man et al. reported anxiety to be induced by hypoxia-ischemia injury. RA (20 mg/kg, five consecutive days, intraperitoneally) showed an anxiolytic effect by improving remyelination in the corpus callosum in rats. In the subventricular zone, RA increased the proliferation of oligodendrocyte progenitor cells and also reversed the reduction of myelin sheath in the corpus callosum, which is part of the white matter structure. RA also decreased oligodendrocyte marker and myelin protein levels while increasing the oligodendrocyte apoptosis markers in rats [79]. Moreover, in a recent study, RA administration (6 weeks per oral) reduced corticosterone levels, pro-inflammatory cytokines, and macrophage chemotactic protein-1, and prevented the damage caused by angiotensin-II, showing an anxiolytic effect in mice [80]. Zhang M. et al. reported that rosmarinic acid protected locomotor ability and cognitive ability in cerebral ischemia-reperfusion, and provided relief from anxiety behavior in rats [81]. Furthermore, M. officinalis L. extract containing RA exhibited an anti-anxiety effect in an EPM test without an open field test. RA increased GABA level by inhibiting the GABA transaminase enzyme in the brain, showing an anti-anxiety effect [82]. In a randomized clinical trial, scientists used several scales (depression scale and hospital anxiety and prospective or retrospective memory questionnaire, and Pittsburgh sleep quality inventory) to measure anxiety, sleep quality, and depressive behavior [83]. In this context, the researchers randomly selected 68 participants and administered 500 mg of rosemary tea (containing RA) and placebo for 30 days [83]. The study concluded that RA could be used as an anxiolytic, anti-depressant, and a memory enhancer in humans [83]. T-type calcium channels (low voltage-activated calcium channels) are present in brain regions, such as stress-responsive areas (hippocampus), that regulate the functions of the central nervous system (CNS) in the brain [84]. In stressful conditions, these channels may produce anxiety-like behavior [85]. Therefore, by inhibiting T-type calcium channels, RA showed an anxiolytic effect [86]. In a cell culture study, the researcher used the whole-cell patch-clamp technique and identified RA activity [86]. In this study, the electrophysiological properties of Ttype calcium channels (Cav3.3) are the molecular target of RA (10-300 µg/ml) in

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HEK-293T cells, exhibiting an anxiolytic effect. It can be concluded that inhibition of T-type calcium channels leads to an anti-anxiety and neuroprotective effect of rosmarinic acid [86]. Depression is a significant and severe illness globally [38]. Some experimental research proposed that alteration in the neuronal serotonergic and noradrenergic systems, neurotrophins (BDNF, glial cell-derived neurotrophic factor and insulinlike growth factor-1), and neuropeptides (substance-P and corticotropin-releasin-factor), are the major aspects in the development of depression [87, 88]. Moreover, neurodegeneration in the dentate gyrus (DGs) of the hippocampus is also one factor that causes depression [89]. To treat this abnormality, re-regulation of neurogenesis in the hippocampus is required by anti-depressant drugs [90, 91]. Several research studies indicate that compounds containing anti-depressant property upgrade the cell proliferation in the DGs of the hippocampus by antiapoptotic and neuroprotective mechanisms [92, 93]. In the hippocampus of mice, the effect of RA was evaluated on newborn cells in the dentate gyrus by immunohistochemistry (IHC) investigation with bromodeoxyuridine (100 mg/kg) given intraperitoneally (detection of proliferating cells) [94]. These results showed that RA treatments for 1-2 weeks upregulated the quantity of bromodeoxyuridine-positive cells and reduced the immobility period in the forced swimming test without influencing locomotor activity in the open field test [94]. The surge in the amount of newborn cells in the DGs due to RA administration correlated with anti-depressant property [94]. Furthermore, in a current study, the researcher used aerial parts of the plant (Micromeria myrtifolia Boiss. & Hohen medicinal) [95]. The components isolated from these plants were myricetin, RA, apigenin, and naringenin. However, only RA exhibited statistically significant anti-depression activity on tail suspension test and FST test in rodents [95]. Amaghnouje A. et al. reported the subacute evaluation of toxicity and antidepression-like effect of Origanum majorana L. polyphenols [96]. In this research, phytochemical screening revealed the presence of 12 compounds that belonged to polyphenols. RA was also one of the 12 components, which showed a statistically significant anti-depression-like effect using the tail suspension test and forced swim test in Swiss albino mice [96]. In another study, the researcher used the water extract of M. officinalis L. and RA, which showed an anti-depressant effect by reducing the immobility period in FST test and modulating serotonergic neurotransmitters in rats [97]. Sasaki et al. reported that RA augmented the level of two numerous genes

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correlated with GABA, serotonin, and dopamine pathway called pyruvate carboxylase and tyrosine hydroxylase [98]. The study concluded that rosmarinic acid works by controlling cholinergic monoamine function in in vitro PC12 cells line and in in vivo mice, showing anti-depressant activity [98]. In this connection, identifying the mechanism of RA properties could assist in manufacturing some medicines for the treatment of major depressive disorder. In one more research, chronic unpredictable stress (CUS) was used to assess the anti-depressant property of RA in rats by the assessment of BDNF expressions in the hippocampus and astrocytes [99]. Researchers also identified that RA (10 mg/kg for two weeks) treatment exhibited anti-depressant properties by upregulation of phosphorylated extracellular-regulated kinase (ERK1/2) protein expression and BDNF expression in the hippocampus of rats. Besides, in vitro studies illustrated that RA amplified BDNF and phosphorylated ERK1/2 expression in the astrocytes [99]. This observation concluded that RA might be a novel pharmacological strategy against depression by distinguishing BDNF expression and phosphorylating ERK1/2 pathway. However, an underlying mechanism through which RA affects the phosphorylation of ERK1/2 is not entirely understood. Likewise, mitogen-activated protein kinase phosphatase-1 (MKP-1) is included in the pathophysiology of depression, recognized by assessments of preclinical and postmortem studies [100]. RA administration deactivates extracellular regulated kinase (ERK) and MKP-1 genes [101, 102]. Researchers also stated that inhibition of MKP-1 and regulating the HPA axis resulted in the anti-depressant property of RA [98]. However, additional clinical researches are needed to assess the use of RA in depressed patients. Furthermore, in the extrapyramidal system (brain), dopamine (DA) is a precursor to noradrenaline (NA) and adrenaline, which is involved in behavior regulation [103]. Thus, the regulation of dopamine and its pathway is an essential target for maintaining and controlling depression. One research reported that the hydroalcoholic extract of leaves and stems of rosemary (100 mg/kg per oral) for 14 days exhibited an antidepressant-like effect in behavioral tests, modulating noradrenergic (α-1), dopaminergic (D1 and D2 receptors), and serotonergic (5HT1A, 2A, and 5HT3 receptors) systems [104]. The same research group has also shown that in olfactory bulbectomized mice, the hydroalcoholic extract of rosemary (10-300 mg/kg) for 14 days reduced anhedonic-like behavior and upregulated hippocampal acetylcholinesterase activity, exhibiting the antidepressant property of rosmarinic acid [105]. In another study, the administration of RA (2 mg/kg, i.p.) pointedly reduced the

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duration of the immobility period and showed anti-depression-like activity [106]. The same research team used RA (0.25 mg/kg, i.p.) to reduce the duration of defensive freezing responses in an animal model of conditioned-free stress paradigm and exhibited anti-depressant activity by inhibiting emotional abnormality in mice [107]. Furthermore, a tail suspension test was used to induce depression in mice and bupropion was used as a standard drug, RA (doses 5 mg/kg and 10 mg/kg; orally for one week) exhibited a beneficial effect and significantly decreased MKP-1 and corticosterone synthesis. While, an increase in the level of BDNF and dopamine synthesis resulted in anti-depressant activity in mice [108]. Increases BDNF, cell proliferation in the dentate gyrus of hippocampus and pERK1/2 expression

Decreases T-type calcium channels

Upregulation of pyruvate carboxylase and tyrosine carboxylase

Inhibition of Mitogenactivated protein Kinase Phosphatase-1

Pharmacology of Rosmarinic acid in psychological disorders

Decreases immobility period, anhedonia symptoms, and anxiety behaviors

Decreases serum corticosterone level and promoted brain dopamine level and cholinergic activity

Modulation of Hypothalamus Pituitary Adrenal axis and GABAA receptor

Modulation of receptors (α-1 receptor, D1, D2 receptors, 5HT-1A, 5HT-2A, 5HT-3A receptors)

Fig. (2). Pharmacology of RA in psychological disorders anxiety and depression. Table 1. Representative list of experimental studies. In vitro/In vivo Animal Studies

Dose and Dose Regimen

Mechanism of Action

Refs.

In vivo (mice)

Rosemary tea (2% (w/w); 4 weeks oral)

It exerts an anxiolytic effect through the inhibition of cholinesterase activity in mice.

[75]

In vivo (rats)

5 to 10 mg/kg; 14 days intraperitoneally

Rosmarinic acid significantly improved PTSD-like symptoms induced by traumatic stress by ameliorating hippocampal cell proliferation and augmenting phosphorylated extracellular regulated kinase 1/2 expression.

[78]

Students

500 mg/twice; 30 days

Rosmarinic acid significantly decreased the score of all scales except for PSQI, which exhibited that rosmarinic acid has anxiolytic and anti-depressant properties.

[83]

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(Table ) cont.....

In vitro/In vivo Animal Studies

Dose and Dose Regimen

Mechanism of Action

Refs.

In vitro (HEK-293T cells)

10-300 µg/ml

Rosmarinic acid significantly inhibited T-type calcium channels (TTCCs), which exhibited anxiolytic and neuroprotective activity and demonstrated TTCCs as one of the novel targets expressed in HEK-293T cells.

[86]

In vivo (rats)

10 mg/kg/day; 14 days intraperitoneally

In vivo (mice)

Hydroalcoholic Rosmarinic acid showed an anxiolytic effect using the tail extract/1-300 mg/kg; 14 suspension test (10-100 mg/kg) and forced swimming test [104] days per oral (100 mg/kg).

In vivo (mice)

The hydroalcoholic extract of fluoxetine was used, which Hydroalcoholic reversed olfactory bulbectomy-induced amplified [105] extract/10-300 mg/kg; 14 exploratory, hyperactivity, and anhedonic behavior, days oral reduced serum glucose level, and increased hippocampal acetylcholine esterase activity.

Rosmarinic acid exhibited antidepressive behavior in rats by reversing phosphorylated extracellular regulated kinase [99] 1/2 protein expression brain-derived neurotrophic factor.

In vivo (mice)

Ethanol extract (50 and 100 mg/kg, oral)

Rosmarinic acid reduced the immobility period and regulated neurotransmitters (serotonin, norepinephrine, dopamine, dopamine, and acetylcholine) and brain gene expression (tyrosine hydroxylase, pyruvate carboxylase, and MAPK phosphatase).

In vivo (mice)

1.0, 2.0, 4.0 mg/kg (7 or 14 days, intraperitoneally)

Rosmarinic acid exhibited up-regulatory action in the newborn cell proliferation in the dentate gyrus (DGs) of the hippocampus in the brain.

[94]

In vivo (mice)

2 mg/kg, intraperitoneally

Significantly reduced the immobility period in the FST test but did not induce any significant effect on monoamine transporter and oxidase uptake.

[106]

In vivo (mice)

0.25 – 4 mg/kg, intraperitoneally

Rosmarinic acid significantly decreased the duration of freezing behavior and inhibited emotional abnormality produced by stress.

[107]

In vivo (mice) In vivo (rats) In vivo (mice)

[98]

Rosmarinic acid exhibited upregulation of BDNF but 5 mg/kg and 10 mg/kg; 7 downregulation of MKP-1 and regulated dopamine and [108] days oral CORT synthesis, showing anti-depressant activity in mice brain. 20 mg/kg, five consecutive days, intraperitoneally 6 weeks per oral

Rosmarinic acid showed an anxiolytic effect by improving remyelination in the corpus callosum induced by hypoxia- [79] ischemia injury in rats RA reduced corticosterone levels, pro-inflammatory cytokines, and macrophage chemotactic protein-1, and prevented the damage caused by angiotensin-II that showed an anxiolytic effect in mice

[80]

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(Table ) cont.....

In vitro/In vivo Animal Studies

Dose and Dose Regimen

Mechanism of Action

Refs.

In vivo (mice)

15 consecutive days of treatment

Melissa officinalis L. extract containing rosmarinic acid exhibited an anti-anxiety effect in elevated plus-maze test and increased gamma-aminobutyric acid level by the inhibition of gamma-aminobutyric acid transaminase enzyme in the brain.

[82]

In vivo (mice)

100 mg/kg, orally

RA exhibited statistically significant antidepression activity on the FST test and tail suspension test in mice.

[95]

In vivo (mice)

RA showed a statistically significant antidepression-like 50 and 100 mg/kg for 21 effect using forced swim and tail suspension test in Swiss days albino mice

In vivo (rats)

Three times a day for 10 days of treatment

RA showed an anti-depressant effect by reducing immobility time in the forced swim test and modulating serotonergic neurotransmitters in rats.

[96]

[97]

CHALLENGES AND SAFETY CONSIDERATIONS Nowadays, scientists focus on the discovery and development of phytopharmaceuticals to treat psychological disorders, including anxiety and depression [109 - 112]. Because of the high cost and dangerous side effects of conventional medicines, more attention is needed to discover phytopharmaceuticals with better safety profiles [113, 114]. Moreover, herbal medicines would be affordable for the populations who cannot afford conventional drugs due to the high cost and unavailability in their regions. Phytopharmaceuticals exert beneficial effects on human health due to the presence of secondary metabolites, such as polyphenols [115 - 117]. Previous evidence reports the beneficial role of polyphenols in clinical studies [118]. Data exhibit that polyphenols’ chronic administration reduces the risk of several diseases, such as cardiovascular diseases, osteoporosis, cancers, and viral diseases [119, 120]. Therefore, polyphenol plays a vital role clinically, and its consumption seems beneficial for human health [118, 121]. Therefore, in this chapter, we have focused on a polyphenol, RA, which has been found to exhibit beneficial effects against anxiety and depression with low or no side effects. In psychiatric disorders, stressors occur for a prolonged time, leading to anxiety and depression. The accumulation of free radicals leads to several other diseases, such as neurological disorders [17, 122, 123], cardiovascular diseases [124], diabetes [125], cancer [126], and atherosclerosis [127].

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Oxidative stress and inflammation are the two major known causes of anxiety and depression [128]. The supplementation of herbs containing higher antioxidants and anti-inflammatory properties may positively alleviate depression and anxiety [128 - 130]. In recent research, RA exhibited anti-inflammatory effects by reducing tumor necrosis factor-α and interleukin-1β induced by lipopolysaccharides in the zebrafish model [131]. RA also works as an antioxidative drug by augmenting superoxide dismutase (SOD) level and reducing glutathione (GSH) level along with a reduction of malondialdehyde (MDA) level and prevention of oxidative stress in mice [132]. Still, some challenges exist in using herbs because they may also interact with synthetic drugs, leading to the toxicity of formulations [133, 134]. However, caution should also be taken during clinical uses because not all herbs are safe [135, 136]. CONCLUSION AND FUTURE PERSPECTIVE Scientific knowledge of medicinal herbs has been progressing in the last centuries [110, 137]. The anxiolytic and anti-depressant activity of RA was allied with the modulation of the HPA axis, monoamines, and pro-inflammatory mediators and neurogenesis [138]. In this chapter, we have summarized the preclinical and clinical researches exploring RA as a promising therapeutic target against anxiety and depression. Overall studies indicate that RA produces its pharmacological actions through augmentation of anti-oxidative stress enzymes (superoxide dismutase, reduced glutathione, and catalase), reduction of pro-inflammatory cytokines (TNF-α and IL-6), neurotransmitters (noradrenaline, 5-HT, and dopamine), neuroendocrine pathway (HPA axis), growth factor (brain-derived neurotrophic factor), ion channels (T-type calcium channels), and protein kinases (mitogen kinase protein1 and phosphorylated extracellular regulated kinase 1/2 protein) [16, 48, 139]. All the available information suggests that the effect of RA is promising in preclinical settings. However, more well-designed clinical trials are required to prove its therapeutic potential against psychological disorders. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise.

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CHAPTER 11

Neuroprotective Effects of Berberine in Neurodegenerative and Neuropsychiatric Disorders Rupinder Kaur Sodhi1 and Anurag Kuhad1,* Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160101 (Punjab), India 1

Abstract: Berberine is an isoquinoline alkaloid obtained naturally from the roots, rhizomes, and bark of various plant species, such as Berberis, Phellodendron, etc. It is an integral part of various medical systems, such as Ayurveda, Chinese traditional medicine, and Yunani medicine. It possesses various properties, such as anti-diabetic and anti-obesity properties, controls lipid profile, and is a strong antioxidant that helps in protecting against oxidative stress. It acts on multiple pathways throughout the brain and periphery to exert a wide variety of effects that can be beneficial for human use. Berberine is effective in protecting against neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and ischemia, and it also protects against neuropsychiatric disorders, such as schizophrenia, mania, anxiety, and depression. It is a potent PI3K/Akt pathway activator, decreases proinflammatory cytokine production, reduces glutamate excitotoxicity, triggers the synthesis of neurotrophic factors, increases levels of biogenic monoamines, such as serotonin, dopamine, and norepinephrine, and shows anxiolytic effects by modulating GABA levels. In this chapter, we discuss how berberine mediates these effects, modulates which pathways in the brain and body, and how does it provide a wide array of responses.

Keywords: Berberine, Neuroprotection, Neurodegenerative diseases, Neuropsychiatric disorders, Alzheimer’s disease, Parkinson’s disease, Depression, Schizophrenia. INTRODUCTION Berberine is an alkaloid belonging to the benzylisoquinoline category of alkaloids found in roots, rhizomes, bark, and stems of plants, such as Berberis aristata, Berberis vulgaris, Xanthorhiza simplicissima, Tinospora cordifolia, Mahonia aquifolium, Eschscholzia californica, and Coptis chinensis. Over the years, berbeCorresponding author Anurag Kuhad: Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160101 (Punjab), India; E-mail: [email protected]

*

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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rine has found its use in the treatment of many diseases, such as diabetes, hyperlipidemia, cancer, and skin-related conditions. In the past decade, berberine has also shown strong neuroprotective potential in preventing the neurodegeneration of neurons and providing nourishment to them [1]. Today, a large number of dietary supplements contain berberine as their constituent and are used for conditions, such as cold, fever, influenza, and others. Berberine has been used for centuries in various traditional medicine systems, such as traditional Chinese medicine, Yunani medicine, and Ayurveda, and to date, more than 500 plant species have been identified to contain berberine [2]. The major plant families that contain berberine are Annonaceae, Berberidaceae, Menispermaceae, Papaveraceae, Ranunculaceae, and Rutaceae. Berberine is a potent antioxidant and is helpful in reducing lipid peroxidation in rats [3]. Berberine has also shown cardioprotective effects [4], helps in preventing hyperlipidemia [5], improves glucose metabolism [6], has hepatoprotective [7] and nephroprotective [8] properties, and also modulates the immune system to reduce inflammation [9], and is also used in chronic inflammatory conditions, such as inflammatory bowel disease [10]. Along with all these effects, berberine has also shown potential as a neuroprotective compound, and in this chapter, we will discuss its use/activity in various neurodegenerative and neuropsychiatric disorders. SOURCE, BIOCHEMISTRY AND PHARMACOLOGY Berberine belongs to the benzylisoquinoline type of alkaloid category and contains quaternary ammonium salt of isoquinoline (Fig. 1). It was discovered in 1830 by Buchner and Herberger. It is an important part of Chinese traditional medicine and is widely used in China. Countries with the highest production of berberine include China, India, and Iran. It is present in various plant parts, such as roots, rhizomes, stems, and bark, but the highest yield is obtained from the roots. The most common salt form available of berberine, i.e., berberine hydrochloride, is orally bioavailable and is a yellow-colored crystalline powder.

Fig. (1). Structure of berberine [16,17-dimethoxy-5,7-dioxa-13-azoniapentacyclo (11.8.0.02,10.04,8.015, 20)henicosa -1(13),2,4(8),9,14,16, 18,20-octaene] (C20H18NO4+ from PubChem).

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It is soluble in organic solvents as DMSO, ethanol, and dimethylformamide (DMF), and is slightly soluble in water; however, the salt form has better solubility. It is present in plants, such as European barberry, goldenseal, goldthread, Oregon grape, Phellodendron, and tree turmeric. After administration, berberine acts on various pathways in the body to modulate its diverse effects, such as suppression of genes encoding for inflammatory markers, including NF-κB, Bcl-2, COX-2, TNF-α, IL-6, IL-12, iNOS, DNA topoisomerase I and II, and others [11 - 14]. By modulating gene expression, it interferes with the normal cell cycle, and causes apoptosis of cancer cells and inhibits their proliferation. It also possesses antimicrobial [15] and antifungal [9] properties. It is a known AMP-activated protein kinase (AMPK) activator [16]. It is metabolized in the liver by the cytochrome P450 enzyme and undergoes phase I metabolism. It inhibits mitochondrial respiration [17] as well as choline esterase (chE) [18]. Its major uses include hepatoprotective, immunomodulatory, antimicrobial, antidiarrheal, and antidepressant. It has also shown potential anticancer activity and is an important natural alkaloid used in the treatment of diabetes and dyslipidemia. BERBERINE IN NEURODEGENERATIVE DISORDERS Neurodegenerative diseases pose a huge crisis in the healthcare system as, to date, no cure has been established to regenerate the neurons. The only possible way is to protect the neurons from further degeneration. These are incurable and debilitating conditions and require deeper investigations to target the neurological pathways involved and hence produce a possible treatment option. Alzheimer’s Disease (AD) AD is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) polymers and neurofibrillary tangles formed by tau hyperphosphorylation. Although the detailed etiology is still to be elucidated, these two characteristics have been a target for various therapies to prevent neurodegeneration and enhance memory. Various studies have shown the efficacy of berberine in preventing neurofibrillary tangles formation as well as Aβ plaque formation (Fig. 2). Tau hyperphosphorylation is caused as a result of an imbalance between tau phosphatases and tau kinases. Glycogen synthase kinase 3β (GSK-3β) overactivation and reduction in protein phosphatase 2A (PP2A) lead to an increase in tau phosphorylation [19], and therefore, targeting GSK-3β has proven to be beneficial in AD treatment. Berberine has been shown to regulate GSK-3β activity in cell lines [20] as well as rodents [21]. These studies report that

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berberine reduces phosphorylated GSK-3β and induces PI3K/Akt phosphorylation [22] by AchE, and preventing its breakdown could potentially serve as a treatment option for AD [27]. Berberine also protects the animals from streptozotocin (STZ)-induced insulin resistance in rats [26]. It improves animal performance scores in the elevated plus-maze, water maze, and open field tests, and also reduces apoptosis induced by intracerebroventricular (ICV) administration of streptozotocin. ICV-STZ has been considered a sporadic model of AD wherein brain insulin resistance leads to AD-like symptoms in animals and causes neurodegeneration. Another widely used chemical-induced model of AD, i.e., scopolamine, has also been investigated for the efficacy of berberine. Scopolamine is an anticholinergic drug that impairs learning and memory by disrupting cholinergic transmission in the brain. It increases AchE activity in the brain, and berberine was found to protect the animals against scopolamineinduced neuronal impairment and memory dysfunction [28]. The study reported enhanced memory in rats as tested by the Morris water maze test, passive avoidance test, and reduced AchE immunoreactivity while increasing choline acetyltransferase (ChAT) immunoreactivity in the hippocampus of rats. The mechanism behind all these effects on the molecular basis is mostly investigated to be related to the GSK-3β pathway as it is majorly involved in tau phosphorylation. Even in transgenic models of AD, such as TgCRND8 mice, that are related to the Aβ pathology, long-term treatment with berberine helped in improving learning deficits and retention of long-term spatial memory while inhibiting GSK phosphorylation in the first 30 minutes of administration. Akt phosphorylation is enhanced after berberine treatment, which has inhibitory effects on GSK-3β phosphorylation, ultimately leading to the inhibition of tau hyperphosphorylation [29]. Not only tau, but berberine also inhibits APP phosphorylation and helps improve memory. Parkinson’s Disease (PD) Parkinson’s is the second most common neurodegenerative disorder affecting more than 20 million people worldwide. Though over 80% of the cases are idiopathic in nature with unknown etiology, pathways are being investigated to explore neurodegenerative pathways as well as treatment. Till date, no specific cure has become available, but only symptomatic treatments targeting dopamine are available. New therapies targeting neurodegeneration and neuroinflammation in PD are being investigated on a huge scale to prevent/reduce neurodegeneration [30 - 32]. Berberine has been found to be effective in preventing neurodegeneration caused by 6-OHDA in PC12 cells owing mainly to its antioxidant effects, and hence protecting against PD. Berberine, by acting through the

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Nrf2/HO-1 and PI3K/Akt/Bcl-2 pathways, protects the cells as well as zebrafish against apoptosis and inflammation [33]. PI3K/Akt/Bcl-2 pathway plays an important role in cell proliferation and survival [34], whereas Nrf2/HO-1 pathway is known to modulate oxidative stress [35] in the body. Activation of both these pathways leads to enhanced neuronal survival and the increased ability of the body to combat oxidative stress. Berberine treatment in mice has been shown to improve short-term memory, enhance motor balance and coordination, inhibit apoptosis, and prevent dopaminergic cell death induced by MPTP in mice [36]. Though some researchers have provided conflicting data that suggest negative effects of berberine, i.e., enhancement in deleterious effects of 6-OHDA after berberine treatment in PC12 cell lines [37], by and large, berberine has been reported to be effective in reducing dopaminergic neuronal damage by inhibiting MAO activity as well [38]. Berberine has also shown efficacy in another model of chemical-induced PD. Rotenone, a pesticide, is also a potent mitochondrial complex-I inhibitor. Berberine also helps in protecting neuronal cell lines against rotenone-induced toxicity [39].

Fig. (2). Schematic representation of the possible molecular mechanism of action of berberine in Alzheimer’s disease.

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Huntington’s Disease (HD) HD is characterized by the accumulation of misfolded proteins in the brain, which leads to neurodegeneration. Most commonly used transgenic models involve mutations in huntingtin protein, which leads to enhanced folding of the protein, thus triggering HD. Berberine has been reported to prevent the accumulation of modified/mutant huntingtin protein in the HEK293 cells [40, 41]. Similarly, transgenic N171-82Q mice containing mutant HTT protein have also shown improvement in motor function and reduced HTT aggregation, while enhancing autophagy to reduce the HD phenotype in mice [40]. This is in agreement with the fact that berberine helps in the clearance of misfolded proteins that are neurotoxic in nature [42]. Cerebral Ischemia Cerebral ischemia or stroke is a leading cause of death, which does not even provide sufficient time for diagnosis and treatment of the patient after an injury, and thus poses a huge burden on the healthcare system as a very small time window is available for treatment. The neurons damaged by injury undergo rapid cell death, and this disease thus has a huge mortality rate. Studies have reported potential neuroprotective effects of berberine against brain ischemia as well, wherein berberine protected the hippocampal CA1 cells from the ischemic damage caused due to reperfusion [43]. Another study mimicking global cerebral ischemia in vitro by oxygen and glucose deprivation also revealed the neuroprotective potential of berberine in preventing cell death. Apparently, berberine protects the hippocampal slices against ischemic cell death by activating GSK-3β phosphorylation and also increasing Akt protein content as this pathway is vital for neuronal survival after global ischemia [44]. A study in rats reported reduced infarct volume and diminished brain edema after berberine treatment along with a reduction in pro-inflammatory cytokine production in the brain [45]. The underlying mechanisms of the effect of berberine in ischemia have been attributed to berberine-mediated (a) reduction in oxidative stress, which is caused by activation of the SIRT1/p53 signaling pathway; (b) anti-apoptotic effects of berberine by suppressing p53/cyclin D1 pathway; (c) reduction in inflammation by diminishing NF-κB production; (d) reduction in endoplasmic reticulum stress by activating JAK2/STAT3 pathway, and (e) increasing autophagy [46]. Furthermore, berberine also prevents platelet aggregation [47] after ischemiareperfusion injury.

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Traumatic Brain Injury (TBI) TBI is a physical injury that disrupts brain blood flow and leads to neurological impairments by a decrease in tissue oxygen levels and brain edema. TBI triggers inflammatory cytokines activating the neuroinflammatory cascade and producing cognitive decline, neurodegeneration, apoptosis, microglial activation, etc. Berberine protects the mouse cortical neurons against neuronal death, apoptosis, and matrix metalloproteinase-9 activation [48]. Berberine reduces NF-κB signaling in cultured neurons and helps protect against injury [48]. Another study reported the neuroprotective effects of berberine in cognitive impairment and learning memory by increasing the Sirt1/p38 pathway [49]. It also protects the cells from post-injury neural death. BERBERINE IN NEUROPSYCHIATRIC DISORDERS Depression With increasing stress in daily life, a worsening economy, and an enhanced workload, more and more people are now going into depression. It causes a feeling of sadness, hopelessness, and worthlessness in the person, and the patient loses interest in daily or otherwise pleasurable activities. The monoaminergic theory of depression suggests that it occurs due to a deficiency of monoamines in the brain, such as serotonin, dopamine, and norepinephrine, while studies also suggest potential glutamate excitotoxicity to be the cause behind depression [50]. Various monoamine oxidase (MAO) inhibitors, such as phenelzine and isocarboxazid, are clinically used to treat depression as they increase the synaptic levels of monoamines. As described above, berberine also possesses MAO inhibitory activity [51]. Berberine can inhibit both MAO-A as well as MAO-B, and is thus helpful in treating depression [52]. Berberine has been shown to improve the antidepressant efficacy of typical antidepressants, such as fluoxetine and tranylcypromine [53]. It improves antidepressant behavior in animals as tested by tail suspension test and forced swim test, and its efficacy was found comparable to that of imipramine. It also increases the levels of dopamine, serotonin, and norepinephrine in the whole brain, frontal cortex, and hippocampus [54]. It can also inhibit the release of norepinephrine by activating α2 adrenergic autoreceptors. Sigma receptors are also vital in modulating neurotransmitter levels in the brain as ligands binding on sigma receptors have shown an increase in dopamine levels [55]. Given the fact that sigma agonists possess antidepressant activity, berberine has been shown to modulate sigma receptors in ways similar to antidepressants [56], thus providing room for further deeper studies investigating its role as an antidepressant via sigma receptors.

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Other than affecting neurotransmitters in the brain, berberine has a multi mechanism effect in depression as it can modulate various factors involved in depression etiology, such as oxidative stress, neurotrophic factors, hormone levels, neuroinflammation, and nitric oxide synthesis. Depression patients show increased oxidative stress, lipid peroxidation, and reduced antioxidants, such as superoxide dismutase [57]. Berberine, owing to its anti-oxidant activity, helps in reducing lipid peroxidation and reactive oxygen species in the cortex of rats in the reserpine-induced depression model [58]. It also reduces NF-κB (a proinflammatory cytokine transcription factor) as well as caspase-3 in the hippocampus. Nitric oxide synthase inhibition has also shown potential antidepressant action specifically in the hippocampus. AMPK is vital for regulating nitric oxide synthesis from the endothelial cells as it stimulates endothelial nitric oxide synthase (eNOS) phosphorylation [59]. As berberine acts as an AMPK activator, it helps in increasing NO synthesis, and thus helps in coping with depression. As neuroinflammation plays an important role in manifesting various neurological disorders, studies have reported enhanced neuroinflammation in the brain leading to activation of the kynurenine pathway in the brain, which produces more inflammation, as well as compounds, such as quinolinic acid, which induce depression [60]. Indolamine-2,3-dioxygenase (IDO) is an important rate-limiting enzyme of the kynurenine pathway, and berberine has been reported to inhibit IDO activity in A549 cells [61]. Berberine also helps protect the neurons by potentiating neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) [62, 63]. Additionally, berberine also reduces corticosterone levels [64], showing antidepressant effects against corticosterone injection [65]. Berberine thus shows antidepressant activity by acting on numerous pathologies in the brain leading to depression (Fig. 3). Schizophrenia Schizophrenia is another debilitating neuropsychiatric disorder on the rise in the past decade. It alters the person’s ability to perceive reality, often resulting in hallucinations and delusions while severely affecting concentration and memory. A family of cytosolic serine peptidases, that is propyl oligopeptidase, regulates peptide hormones and other biologically active peptides in the body that are involved in diseases, such as schizophrenia, diabetes, depression, and mania. The activity of these enzymes is increased in schizophrenia and mania [66], whereas none of the antipsychotics clinically used act on these enzymes. However,

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berberine has been shown to inhibit propyl oligopeptidase [67], and thus can be explored as a treatment option in schizophrenia. Other than this, berberine has also shown protective effects in motor activity and cognition against MK801 [68]. Furthermore, berberine is currently undergoing clinical trials for use as an adjuvant in schizophrenia treatment [69].

Fig. (3). Molecular pathways modulated by berberine in depression.

Berberine has also shown efficacy in preventing atypical antipsychotics-induced metabolic complications, such as hyperglycemia, weight gain, adiposity, dyslipidemia, and increased appetite in mice, which are major side effects of atypical antipsychotics, reducing the patient compliance and increasing cardiovascular complications [70]. Anxiety Anxiety is an emotional state that negatively affects more than 1/8th of the total world population. Persistent panic attacks or obsessive-compulsive disorder affect

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the patient’s normal life by hampering their daily routine activities and also troubling their loved ones. Berberine has shown anxiolytic properties as depicted in an elevated plus-maze with effects comparable to that of clinically used anxiolytics, diazepam and buspirone [71]. This effect could be related to its efficacy in improving biogenic monoamines, such as serotonin, dopamine, and norepinephrine. Berberine also possesses an inhibitory effect on glutamate receptors, and is known to reduce glutamate levels [72]. Another neurotransmitter involved in anxiety [73], i.e., ϒ-aminobutyric acid (GABA), is also modulated by berberine. Berberine has shown anxiolytic effects in various other conditions, such as depression, post-traumatic stress disorder, and AD [74, 75]. SAFETY OF BERBERINE Natural products are generally considered to be safe. Similarly, berberine also has a large window for therapeutic efficacy. In clinical conditions, berberine can be safely used at a dose ranging from 200-1000mg two to three times daily [76]. Berberine at a dose of 1200-2000 mg/day used chronically for around 2 months helps in preventing dyslipidemia [77]. For diabetes, it can be used at doses of 500-1500mg daily for about 3-4 months [78]. It does not possess any mutagenic, cytotoxic, or genotoxic potential [53]. However, it shows cytotoxicity in cancer cell lines. High doses of berberine have been reported to show hypotension, discomfort in the gastrointestinal tract, and some flu-like symptoms [79]. As it possesses antihypertensive and antidiabetic effects, it should be given with care to patients taking other antihypertensives or antidiabetics as it may potentiate the response. It should be avoided in patients with jaundice as well as infants as it poses a risk of kernicterus by displacing bilirubin [80 - 84]. Berberine also improves left ventricle ejection fraction in cardiovascular patients upon chronic administration for up to 8 weeks at a dose of 1200-2000mg/day [85]. CONCLUSION Berberine, a potent antioxidant, has shown potential as a neuroprotective agent in various neurodegenerative and neuropsychiatric disorders, and is relatively safe (Fig. 4). It can be further investigated to draw clinical correlations for patient use.

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Fig. (4). Various effects of berberine reported in different preclinical/cell culture studies.

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CHAPTER 12

Resveratrol: A Novel Drug for the Management of Neurodegenerative Disorders Sapna Bala1, Anamika Misra2, Upinder Kaur3 and Sankha Shubhra Chakrabarti1,* Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India 2 Department of General Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India 3 Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India 1

Abstract: Resveratrol is a naturally occurring polyphenol (stilbenoid) that works as a phytoalexin, a part of plants’ defense system against infection, ultraviolet radiation, stress and injury. Common dietary sources of resveratrol include grapes, berries, peanuts, red wine, and some herbal preparations. In animal models, resveratrol exhibits a wide spectrum of potential therapeutic activities, including antioxidant, antiinflammatory, neuroprotective, and longevity-promoting properties. Resveratrol mimics the antioxidant, anti-aging, and neuroprotective effects of caloric restriction, mainly mediated through the increased expression of genes encoding antioxidants and the anti-aging factors (AMPK and Sirtuin 1). Therapeutic strategies for the treatment of neurodegenerative diseases currently have several shortcomings. Naturally occurring compounds may play a significant role in augmenting these therapeutic options. Resveratrol has been shown to maintain homeostasis, protect the brain against oxidative stress, preserve neuronal function, and ultimately minimize age-related neurological decline. It has shown positive effects in animal models and cell culturebased experiments in treating Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, Huntington’s disease, and other neurodegenerative diseases. Resveratrol enhances learning memory and neurogenesis and alleviates neural apoptosis in the hippocampus of AD mice. Beneficial effects of resveratrol in PD result from the inhibition of α-synuclein aggregation and cytotoxicity, lowering of total and oligomeric α-synuclein levels, reduction of neuroinflammation, and oxidative stress. Clinical trials are also evaluating the role of the drug in the major neurodegenerative disorders.

Keywords: Antioxidant, Brain health, Neurological disease, Polyphenol, Resveratrol. * Corresponding author Sankha Shubhra Chakrabarti: Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi-2210005 (U.P.), India; E-mail: [email protected]

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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INTRODUCTION Resveratrol (trans-3,5,4’-trihydroxystilbene) is a naturally occurring polyphenol that functions as a phytoalexin, a specialized metabolite that plays an important role in the plant’s defense system against stress-inducing conditions or other interspecies threats. It is produced in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Isolation and identification of resveratrol were first done in 1940 from the roots of the white hellebore (Veratrum grandiflorum O. Loes) [1]. Later in 1963, it was isolated from the roots of Polygonum cuspidatum, a plant used in traditional Japanese and Chinese medicine having anti-inflammatory, antibacterial, antiviral, anti-fungal, and anticarcinogenic properties, and is said to promote heart health [2 - 4]. Its potential benefits were first revealed in the 1990s through the “French Paradox” [3], in which European populations with high red wine consumption showed a lower incidence of coronary heart disease despite their fat-rich diets [4]. Resveratrol has been detected in more than 70 plant species and has also been found in various amounts in red wines and nutritional supplements. 92 resveratrol compounds, including 6 monomers, 39 dimers, 23 trimers, 13 tetramers, 4 pentamers, 6 hexamers, and 1 octamer, have been reported from plant families, including Dipterocarpaceae, Gnetaceae, Cyperaceae, Paeoniaceae, Leguminosae, Vitaceae, Polygonaceae, Gramineae, and Poaceae. Dipterocarpaceae, containing 50 resveratrol compounds, accounts for most of the resveratrol content among these plant families [5]. CHEMISTRY Resveratrol has the chemical formula C14H12O3. Its formal chemical name is E--(4-hydroxystyryl) benzene-1, 3-diol. It is composed of two phenol rings connected by an ethylene bridge. The chemical structure of resveratrol is exhibited in two isomeric forms, cis- and trans-resveratrol (Fig. 1) [6]. Ultraviolet radiation (UV) can cause isomerization of trans- to cis- resveratrol, subsequently leading to loss of potency and therapeutic effects [7]. In different biological activities, such as cell cycle arrest, differentiation, inhibition of cancer cell proliferation, and apoptosis, its trans form is generally dominant. Transresveratrol has been found to be stable at 75% humidity and up to 40 °C [5]. In addition, an aromatic hydrophobic ring of resveratrol is capable of absorbing UV radiation in the range of 270–320 nm, thus protecting the DNA of plant cells from damage [1].

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Fig. (1). Chemical structure of resveratrol (cis and trans isomers).

Pterostilbene is a resveratrol analog, natural dietary compound, and antioxidant. It was first isolated from Pterocarpus santalinus (red sandalwood) [8], a plant used in traditional Chinese medicine for diabetes treatment, and in Pterocarpus marsupium (Indian kino), which has been known for thousands of years by practitioners of Ayurvedic medicine [9]. The active ingredient pterostilbene is mainly found in blueberries, grapes, and several wood plants. Pterostilbene has a structure similar to resveratrol except that in the A ring, the 3rd and 5th positions are replaced by a methoxy group [5]. Pterostilbene treatment has been shown to attenuate glutamate-induced oxidative stress injury by reducing ROS production as well as increasing superoxide dismutase (SOD) and glutathione (GSH) levels, and activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in neuronal cells. In animal models subject to intraventricular injection of resveratrol, both learning and memory are improved. DIETARY SOURCES Plants that synthesize resveratrol include knotweeds, pine trees, including Scots pine and Eastern white pine, grapevines, peanut plants, cocoa bushes, and Vaccinium shrubs that produce berries, including blueberries, raspberries, mulberries, cranberries, and bilberries. In dietary products, resveratrol is present in glycosylated forms known as piceid. METABOLISM Since intestinal cells can absorb only resveratrol aglycone form, its absorption process requires glycosidases. Although plants and pathogens and even the human digestive tract possess enzymes able to trigger polyphenol oxidation (and subsequent inactivation), the glycosylation prevents enzymatic oxidation of resveratrol, thereby preserving its biological effects and increasing its overall

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stability and bioavailability [10]. Therefore, the proportion of aglycone and glycosylated resveratrol in foods and beverages may modulate its absorption rate. In humans, ingested resveratrol can also be rapidly conjugated into monosulfate and disulfate forms and can be entirely metabolized within eight hours after absorption in the hepatocytes and HepG2 cells. Resveratrol-3-sulfate, resveratrol3-O-glucuronide, and dihydro-resveratrol are some abundant metabolites of resveratrol in mammals, but they are not completely identified [7]. Human liver cytochrome P450 is involved in the conversion of trans-resveratrol to piceatannol and another trihydroxystilbene named M1 [11]. In the bloodstream, it is converted to sulphite derivatives, which are finally excreted in urine and feces [12]. Clinical studies have indicated that resveratrol can easily penetrate the blood-brain barrier (BBB) [1]. MECHANISM OF ACTION Resveratrol has been observed to exert its effects through diverse mechanisms. It has shown potential for cardioprotection, neuroprotection, and prevention of metabolic syndrome, stroke-induced brain damage, and cancer [13]. It functions through multiple pathways, and the evidence regarding the same is discussed subsequently. Antioxidant Effect Reactive oxygen species (ROS) exert deleterious effects on living organisms [14]. Intracellular accumulation of ROS, be it in the form of superoxide anions, hydrogen peroxide, singlet oxygen, hydroxyl radicals, or peroxy-radicals, can arise from toxic insults and normal metabolic processes [15]. The high metabolic demand of neurons gives them three typical traits: a large number of mitochondria, intense oxygen metabolism, and a fairly large production of ROS [16]. Neuroprotective effects of resveratrol are primarily attributed to its antioxidative action. It exerts its antioxidant effect mainly by acting as a scavenger of hydroxyl, superoxide, and other free radicals [17]. Due to the presence of the –OH group, resveratrol can neutralize ROS as well as reactive forms of nitrogen [1]. It clears mitochondrial ROS, one of the main cellular sources of these damaging molecules [18]. There are numerous reports employing both in vitro and in vivo models of neurodegeneration, including AD, in which red wine/resveratrol has been recognized for its antioxidant properties [15]. In cultured rat pheochromocytoma (PC12) cells, resveratrol pre-treatment leads to decreased expression of Aβ 25-35 and Bcl- XL and β-amyloid-induced oxidative cell death (attenuated β-amyloi-

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-induced cytotoxicity, apoptotic features, and intracellular reactive oxygen intermediate accumulation) [19]. Trans-resveratrol significantly prevents cognitive impairment and attenuates oxidative stress in rat brain tissue in intracerebroventricular streptozotocin (ICV STZ) treated rats [20]. Treatment with resveratrol can prevent the increase of oxidative stress in human umbilical vein endothelial cells (HUVECs) exposed to oxidized low-density lipoprotein (oxLDL) [21]. Consistent with this finding, Cabernet Sauvignon (red wine) treatment, compared to ethanol controls, also decreased neocortical AD-type amyloid plaque burden [22]. AMPK (AMP-Activated Protein Kinase) Pathway Resveratrol has been proven to act as an activator of AMP-activated protein kinase (AMPK). It increases Ca2+ levels in the cell by activating Ca2+/CaMdependent protein kinase β (CaMKKβ), which leads to AMPK activation, further activating the downstream PI3K/Akt signaling cascade [23, 24]. This causes activation of eukaryotic elongation factor (eIF) 4E/4G mediated AMPAR (αamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor) protein translation [25]. Finally, resveratrol upregulates AMPAR by activating the AMPK and PI3K/Akt pathways, which include AMPAR trafficking and synaptic plasticity, while increasing AMPAR protein synaptic localization, thereby leading to the enhancement of synaptic transmission power and regulated brain function. The role of resveratrol in regulating brain function by promoting AMPAR biosynthesis and synaptic transmission may be the reason for its potential in the treatment of AD [23]. In addition, AMPK activation by resveratrol leads to the inhibition of mTOR (mammalian target of rapamycin) signaling, which is one of two key pathways by which resveratrol modulates cellular growth, autophagy, and immune responses, and the other being sirtuin-mediated [26]. The mechanisms of action of resveratrol through major pathways are demonstrated in Fig. (2). Sirtuins Sirtuin 1 (SIRT1, silent mating type information regulation 2 homologs) is a key deacetylase. It is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD+) dependent deacetylase and is involved in the regulations of cell cycle arrest, apoptosis, and tumor suppression through the p53 protein pathway [27, 23]. In mammals, SIRT1 is located in the nucleus [15]. Recent studies suggest that resveratrol acts as a caloric restriction mimic [28]. In yeast, both caloric restriction and resveratrol activate stress response pathways, including overexpression of SIRT2, a NAD-dependent class III histone deacetylase [29], [6]. Furthermore, in obese humans, thirty days of resveratrol supplementation has

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been shown to induce caloric restriction-like effects on energy metabolism and metabolic profile [30]. Resveratrol supplementation also decreases oxidative stress and inflammation caused by the consumption of a high-calorie meal [31]. SIRT1 activation by resveratrol may protect neurons from reactive oxygen species (ROS), hydrogen peroxide free radicals, NO, Aβ, and other intra- and extracellular toxins and insults associated with neurodegenerative disorders [32]. SIRT1 decreases the production of reactive oxygen species by modulating mitochondrial activity [15].

Resveratrol

Oxidative Stress Sirtuin 1

mTOR

AMPK

Deacetylase acitivity

ROS accumulation

P13/Akt

p53

Apoptosis

Cell Survival Fig. (2). Schematic image of the mechanism of neuroprotective effects of resveratrol.

Other independent investigations have shown that enhanced SIRT1 activity not only protects against axonal degeneration but also decreases the accumulation of Aβ in cultured murine embryonic neurons [15]. Reduction in AD pathologies by SIRT1 overexpression in the brain occurs via two putative mechanisms. First, the cleavage of amyloid precursor protein (APP) produced from amyloid by activating α-secretase is directed by SIRT1. Second, SIRT1 deacetylates tau, which results in its ubiquitination and proteasomal cleavage, thus reducing tangles

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[23]. Biochemical modeling studies suggest that when resveratrol binds to SIRT1, it promotes conformational change that better accommodates the attached coumarin group of the artificial substrate p53-AMC peptide. If indeed resveratrol acts directly on SIRT1 in vivo, one could imagine that the conformational change induced by resveratrol could lead to tighter binding and more efficient turnover of native acetylated proteins [33]. OTHER MECHANISMS The blood−brain barrier (BBB) is a barrier between the brain’s blood vessels (capillaries) and the cells that make up brain tissue. It allows the entry of essential nutrients and is effective at protecting against the passage of foreign substances. The bioavailability of oral resveratrol is poor [32]. However, it is capable of crossing the BBB, so it can act effectively act in the CNS [1], resulting in detectable but low concentrations of the parent molecule in the brain, while much higher concentrations of resveratrol metabolites are found in the blood. This ability of resveratrol to cross the BBB may aid its role in protecting against stroke and brain damage, preventing cognitive decline, and promoting general neuroprotection in mice [4]. RESVERATROL IN CELL CULTURE EXPERIMENTS At the cellular level, resveratrol has demonstrated protective effects against Aβ in the pheochromocytoma (PC12) cell line [19]. In PC12 cells, Aβ induces the degradation of cytoplasmic nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), and increases the translocation of p65 to the nucleus. Oxidative stress and inflammatory processes are reversed when the cells are treated with resveratrol (25 μM), suggesting that NF-κB, in addition to its upstream signal transduction, is affected by resveratrol treatment [19, 34]. Antioxidants have been shown to protect cells from β-amyloid toxicity; it has been demonstrated that β-amyloid-induced apoptotic death via oxidative stress in PC12 cells was suppressed by pre-treatment with resveratrol. β-amyloid cytotoxicity was evaluated by determining the percentage of MTT [3-(4,-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] reduction and a protective effect against cytotoxicity induced by a full-length peptide Aβ1–42, whose accumulation is considered to be more relevant to the pathogenesis of Alzheimer’s disease [19]. Similarly, in another interesting in vitro research, in PC12 cells as an AD cellular model, the authors tried to find whether resveratrol could significantly reduce Aβ-induced oxidative damage, and also investigated whether the protective effect of resveratrol is associated with mitophagy. Here, reduced apoptosis decreased oxidative status, and alleviated mitochondrial

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damage in Aβ1-42-treated PC12 cells was observed [35]. Resveratrol has been shown to protect SHSY5Y neuroblastoma cells from both H2O2 and Aβ-induced toxicity [36] and also protect hippocampal mixed neuronal/glial cultures against sodium nitroprusside (SNP)-induced nitric oxide (NO) toxicity [37, 3] . Besides its anti-oxidative properties, resveratrol may suppress oxidative stress and induce cellular defense mechanisms against ROS in midbrain culture. Resveratrol activates the transcription factor Nrf2, resulting in the upregulation of cellular anti-oxidative factors, such as glutathione and heme-oxygenase-1, in PC12 cells. Resveratrol-induced protein kinase C (PKC) in hippocampal neuronal cell cultures of Sprague–Dawley rats has also been found to protect cells from Aβinduced toxicity [38]. Treatment with trans-resveratrol attenuates the hypoxia-induced increase in reactive oxygen species generation and increases the expression of superoxide dismutase and catalase in a dose-dependent manner [39]. Resveratrol also attenuates H2O2-induced PC12 cell death through the induction of glutamatecysteine ligase (GCLC). The administration of resveratrol or quercetin to LPSactivated microglia reduces the amount of neuronal PC12 cell death by 58% and 61% for resveratrol and quercetin, respectively. Besides these mechanisms, resveratrol also affects DNA synthesis. In rat T-I cells, resveratrol alone has been shown to induce a potent concentration-dependent inhibition of cell growth by inhibiting DNA synthesis. Treatment resulted in a dose-dependent decrease in the number of cells with a 35% reduction in the viable cell number at the highest concentration of resveratrol and increased the activity of executioner caspases 3 and 7; these effects of resveratrol counteracted the pro-proliferative and antiapoptotic effects of insulin [40]. There has been some conflicting evidence with respect to the role of resveratrol in preventing oxidative damage and glutamate-induced neuronal death. In a study involving glutamate-sensitive HT22 murine hippocampal neuronal cells, unexpectedly, resveratrol could not offer protection against hydrogen peroxideinduced cytotoxicity, whereas α-tocopherol, a well-known antioxidant, effectively protected these cells from hydrogen peroxide-induced cell death. However, pretreatment with resveratrol effectively protected these cells from glutamate cytotoxicity. Resveratrol alone or resveratrol plus glutamate resulted in Akt activation, GSK-3β inactivation, and β-catenin stabilization in a time-dependent manner [41]. Hence, the protective effect of resveratrol against glutamate-induced oxidative toxicity may not be attributable to its direct antioxidant property. Resveratrol also attenuated apoptosis in cultured cortical neurons of neonatal Sprague-Dawley rats induced by oxygen-glucose deprivation/reperfusion

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(OGD/RP), a stimulus that could induce an increase in the apoptotic rate of neurons (11.1% to 49%) with morphological changes. Pre-treatment was done with resveratrol (0.1, 1.0, and 10.0 µmol/L), and OGD/RP with oxygen and glucose was initiated on day-10 in vitro. Cortical neuronal apoptosis mechanisms were partly attenuated due to the inhibition of calcium overload and the overexpression of caspases-3 and caspase-12 mRNA [42]. The action of resveratrol in cell culture models has been studied with respect to prion proteins and neurotrophic factors. Prion hypothesis is one of the pathological hypotheses for AD. In SMB-S15 cells, three chemicals (resveratrol, piceatannol, and pterostilbene) have been demonstrated to cause suppression of prion protein scrapie (PrPSc) replication; resveratrol being the most active one, followed by Pic and Pte [43]. Resveratrol has been shown to increase brainderived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in astroglia-enriched cultures prepared from the whole brains of one-da-old rat pups treated with 25–100 mmol/L resveratrol for 12–48 h. In addition, the production of BDNF in the supernatant of cultures was found to be increased five-fold over controls 24 h after resveratrol treatment and then remained high 36 h later [44]. Considering the tentative protective role of resveratrol in AD, when human umbilical vein endothelial cells (HUVECs) were challenged with Aβ25–35 toxicity, red wine micronutrients (presumably containing vitamin E, vitamin C, resveratrol, and quercetin) protected the cells from oxidative damage, reduced ROS production, and prevented cellular DNA fragmentation [34]. Resveratrol attenuates Aβ-induced toxicity in several neuronal cell culture models and shows anti-aggregation effects in vitro [38, 19, 36]. Similarly, resveratrol exerts protective effects on the PD pathogenetic process [45, 46]. It increases the degradation of abnormal α-synuclein via AMPK and/or SIRT1-dependent autophagy in α-synuclein overexpressing PC12 cells [47]. Primary cultures of mouse cortical neurons were derived from 15-day-old embryonic mice, harvested with cesarean section from anesthetized pregnant C57Bl/6 dams (Charles River, Italy). Pre-treatment of polyphenol-enriched micronutrient mixture showed increased resilience to brain damage derived from potential ischemic events. Chromatin immunoprecipitation (ChIP) assays and all experiments carried out for 11 days in vitro demonstrated an increase in H3 acetylation (K9/18) at the Bim promoter in neurons exposed to OGD [48]. Resveratrol administration has also been able to significantly extend both female and male SOD1G93A mice lifespan [49]. Resveratrol reduces cell death in primary SOD1G93A cultures of neurons overexpressing the mutant protein.

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Alzheimer's Disease

Parkinsons's Disease

↓

↓

Aβ Amyloid plaque, Hyperphosphorylated tau protiens

α-synuclien misfolding, Neuroinflammation

Resveratrol benefits in

Huntington's Disease ↓ Mitochondrial dysfunction, Altered Huntingtin protein accumulation

Amyotrophic Lateral Sclerosis ↓ SOD1 aggreagates, Cytoskeleton disruption

Fig. (3). Resveratrol and neurodegenerative disorders.

RESVERATROL IN ANIMAL MODELS In this section, we discuss the aspects of resveratrol action in neurological disorders as demonstrated in animal models and how it exhibits a large spectrum of potential therapeutic activities, including antioxidant, anti-inflammatory, neuroprotective, and longevity-promoting properties [50] (Fig. 3). In vivo studies indicate that resveratrol is absorbed and distributed to a number of highly perfused tissues (liver, kidney, heart, and brain) and in the plasma, depending on the exposure time and concentration. Reveratrol and Alzheimer’s Disease (AD) Resveratrol action in AD involves inhibition of β-amyloid production and aggregation, destabilization of the Aβ fibril, inhibition of tau

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hyperphosphorylation, powerful antioxidant action, and anti-inflammatory properties. In resveratrol-treated AD rats, the downregulated activities of enzymes, like catalase and SOD, have been found to be significantly restored [51]. Tau plays a major role in the assembly of microtubules and in bridging these polymers with other cytoskeletal filaments. Glycogen synthase kinase-3 (GSK3β) increases tau hyperphosphorylation at sites that transform tau into a protein and lack the ability to associate with the cytoskeleton [52]. Notably, previous studies have demonstrated that resveratrol can cross the blood-brain barrier, thus making oral gavage an efficient route of administration in animal models [53]. Table 1 illustrates some animal experiments where resveratrol was shown to have beneficial effects on the AD pathogenetic process. Table 1. Resveratrol in animal experiments and its role in Alzheimer’s disease. Model

Intervention

Results

Refs.

Tg199589 mice

Oral supplementation of transresveratrol (AIN 93G diet 0.2% resveratrol) at 300 mg/kg for 45 days

Tg2576 transgenic mouse model of AD

Cabernet Sauvignon diluted to a final 6% ethanol concentration in drinking water

Significant reduction in AD-type amyloid neuropathology and attenuated Aβ-associated spatial memory deterioration

[22]

Tg6799 mice

Administration of resveratrol for 60 consecutive days

Protection against Aβ plaque formation

[54]

Mouse model of AD

Orally administered resveratrol

Reduction in amyloid plaques

[55]

Tg19959 transgenic mouse model of AD

Daily dosage (Diet-300 mg/kg of resveratrol in food)

Protection against Aβ plaque formation

[55]

AβPP/PS1 mice

Oral resveratrol administration - fed with mouse chow (Harlam Diet) containing 1% resveratrol

Significant improvement in memory capabilities and a significant reduction in plaque counts and plaque burden in the hippocampus and medial cortex

[56]

p25 transgenic mouse model of AD

Intracerebroventricular (ICV) injection of resveratrol at a dose of 5 μg/μl, 0.5μl bilateral injections injected every 2–3 days

Decrease in levels of acetylation of the SIRT1 substrate PGC-1α, prevention of cognitive decline, protection from neuronal loss and tau pathologies

[48]

Decrease in β-amyloid plaque deposits in the medial cortex, striatum, and hypothalamus, [52] reduced Aβ pathology, and altered brain glutathione status

Transgenic strain Too young–adult nematodes, a volume CL2006 of the of 6 μl resveratrol Decreased amount of Aβ induced nematode in 10% EtOH/Tween 20 (92/8 v/v) was toxicity through targeting proteins [57] Caenorhabditis elegans added containing tenfold enriched involved in UPRmt and UPRER (model of AD) resveratrol concentrations

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(Table ) cont.....

Model

Intervention

Results

Refs.

Ovariectomized (OVX) OVX, D-galactose, and resveratrol 20, rat model of AD 40, 80 mg/kg treated groups

Improvement in spatial memory

[58]

Ovariectomized (OVX) OVX, D-galactose, and resveratrol 20, rat model of AD 40, 80 mg/kg treated groups

Reduced level of insoluble Aβ1–42 in the hippocampus, protection to the integrity of the blood-brain barrier

[59]

Resveratrol and Parkinson’s Disease (PD) PD is a movement disorder, phenotypically characterized by the progressive impairment of motor functions, selective degeneration of the nigral dopaminergic neurons, and accumulation of fibrillar a-synuclein aggregates, thus leading to the formation of Lewy bodies and Lewy neurite [60, 63]. Resveratrol may decrease αsynuclein protein expression in cellular models of PD through its downregulation and partial inhibition of GSK-3β [49]. Resveratrol may simultaneously disturb hydrophobic interactions within α-synuclein molecules and inhibit oligomerization and fibrillation through hydrogen bond formation between the hydroxyl groups of the phenolic rings of resveratrol and α-synuclein [62, 64]. Resveratrol attenuates neuroinflammation in PD mice by decreasing α-synuclein levels [65, 69]. Table 2 illustrates some animal experiments where resveratrol has been demonstrated to have beneficial effects on PD pathogenesis. Table 2. Resveratrol in animal experiments and its role in Parkinson’s disease. Model

Intervention

A53T α-synuclein mice

High to low dose of resveratrol (50-10mg/kg body weight) given via single oral gavage of 100 μl solution per 10 g body weight respectively.

PGC-1a transgenic mice

0.2 ml of intraperitoneal injection (50% DMSO/70% ethanol, diluted in saline)

PD rat model (rat pups)

Resveratrol was injected Reduced TNF and COX-2 levels in intraperitoneally at the dose of 100 the substantia nigra mg/kg of body weight

MPTP-treated mouse model of PD

Saline or resveratrol injection (10 mg/kg/day)

Results

Refs.

Attenuated neuroinflammation; Iba1 & GFAP immunoactivity was markedly increased, high dosage of [61] resveratrol also reduced the level of LB509-positive α-synuclein Decrease in oxidative stress

[62]

[64]

Resveratrol can synergize with low doses of L-DOPA to improve [65] MPTP-induced Parkinson’s disease

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(Table ) cont.....

Model

Intervention

Results

Refs.

Drosophila (transgenic flies)

Grape extract fortified with resveratrol (0.08-0.064 mg extract/100 grams) was fed

Male flies - significant improvement in the climbing response Female flies - significant extension in average lifespan

[66]

6-hydroxydopamine (6OHDA)-induced PD in male Sprague–Dawley (SD) rats

The neuroprotective effect Two weeks administration of significantly decreased the levels of resveratrol (10, 20, and 40 mg/kg) [67] COX-2 and TNF-mRNA in the given orally substantia nigra

Caenorhabditis elegans, Drosophila

a) Concentration of 100 μ M resveratrol dissolved in DMSO was added 1:1000 to molten agar NGM (C. elegans) b) Concentration of resveratrol in the food was 0, 1, 3.2, 10, 32, 100, 200, and 1000 mM (Drosophila)

Male C57BL/6NIA mice

Fed AIN-93G diet modified to provide 60% of calories from fat (HC) plus 0, 0.01%, or 0.04% resveratrol

Lifespan extension

[68]

Enhanced expression of SOD2mRNA; long-term resveratrol treatment can mimic transcriptional [52] changes induced by dietary restriction

Resveratrol in Other Neurodegenerative Disorders Huntington’s disease (HD) is associated with the downregulation of the peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) activity [71]. Neuronal degeneration is reduced by resveratrol treatment in many HD animal models, including Caenorhabditis elegans, Drosophila, and multiple rodent models. As in PD models, resveratrol acts through SIRT1 to increase neuronal viability in HD models. Furthermore, increased PGC-1α expression may also increase SIRT1 activation. PGC-1α contributes towards reducing mitochondrial defects in HD because it is involved in mitochondrial biogenesis and function [69, 70]. A recent study published in Experimental Neurology [71] examined the therapeutic potential of resveratrol formulation with micronized proprietary SRT501 in the N171-82Q transgenic mouse model of Huntington's disease (HD). When SRT501 resveratrol formulation was given orally, it did not significantly improve HD-type pathology in the N171-82Q mouse model. Enhanced mitochondrial function triggered by resveratrol justified the improvement in motor function in HD YAC128 transgenic mice [72]. Resveratrol and NAM modify mRNA expression of candidate mitochondrial-encoded genes of complexes I and IV in mice cortex. One of the most robust effects of resveratrol is the increase in mitochondrial mass [73].

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In two HD models, HdhQ111 knock-in mice 26 and in transgenic C. elegans resveratrol rescued mutant polyglutamine-specific cell death in neuronal cells [74]. Amyotrophic sclerosis (ALS) is the most common adult-onset motor neuron disease, caused by degeneration of upper and lower motor neurons, leading to loss of voluntary movement [75]. Apoptosis activation is the terminal process of motor neuron death in ALS [76]. In animal models like SOD1G93A ALS mice, resveratrol could delay the onset of disease and prolong the lifespan by significantly attenuating motor neuron loss and reducing muscle atrophy and dysfunction. The presumed major beneficial roles may be its antioxidant and antiapoptotic effects. CONCLUSION: RESVERATROL IN CLINICAL USE There have been only a few clinical trials of resveratrol in the management of neurodegenerative disorders. The completed trials in AD and PD found on ClinicalTrials.gov are mentioned in Table 3. Several resveratrol-based supplements with other antioxidant and protective compounds are marketed. However, most of the clinical trials have failed to give dramatic results, and there has been little follow-up on these studies. Despite this, the potential of resveratrol may be untapped as yet, and future work may be focused on delineating the molecular mechanisms of the drug and carrying out focused clinical trials in neurodegenerative disorders, such as AD and PD. Table 3. Clinical trials involving resveratrol. Country, NCT

Sponsor

Assistance France Publique NCT02336633 Hôpitaux de Paris

Portugal NCT03095092

Bial Portela C S.A.

Phase

NA

Diagnosis

Study Design

Sample Size and Age

Treatment

Outcome

Rate of caudate atrophy before and after one year of Patients with HD, treatment N=120, positive genetic UHDRS (Unified Randomized, ≥ 18 test with CAG Huntington Oral capsule double-blind, years repeat length ≥ 39 80mg/day resveratrol Disease Rating placebo-controlled and in HTT gene Scale) older • TFC (Total Functional Capacity) and others

Cmax (maximum plasma concentration), Tmax (time of Single-centre, occurrence of open-label, N=24, Phase 400 mg oral dose of Cmax), Healthy volunteers randomized, two- ≥ 18-45 1 trans-resveratrol AUC0-t (area way crossover years under the plasma study concentration-time curve from time zero to the last sampling time)

Duration

Results and Status

4.5 yr

Completed Results not posted

1.5 months

Completed Results not posted

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(Table ) cont.....

Country, NCT

Portugal NCT03093389

Portugal NCT03095105

Portugal NCT03091543

Portugal NCT03094156

Portugal NCT03097211

Sample Size and Age

Outcome

Duration

Results and Status

Cmax (maximum plasma concentration), Tmax (time of occurrence of Cmax), AUC0-t (area under the plasma concentration-time curve from time zero to the last sampling time), and others

2.5 months

Completed Results not posted

Bial Portela C S.A.

Phase 1

Cmax (maximum plasma concentration), AUCτ (area under the plasma concentration versus time curve over the dosing interval), and others

1.5 months

Completed Results not posted

Bial Portela C S.A.

Cmax (maximum observed plasma Single-center, Four single-doses of drug double-blind, BIA 6-512 (Transconcentration), randomized, resveratrol) and their AUC0-∞ N=20, placebo-controlled, effect on levodopa (area under the Phase Healthy volunteers ≥ 18-45 crossover study pharmacokinetics plasma 1 years with five singlewhen administered in concentration dose treatment combination versus time curve periods from time zero to infinity), and others

2.5 months

Completed Results not posted

Bial Portela C S.A.

Effect of BIA 6-512 at steady-state on levodopa pharmacokinetics when administered in Double-blind, combination with a randomized, N=39, single dose of Phase Healthy volunteers placebo-controlled, ≥ 18-45 levodopa/benserazide 1 rising multipleyears 200mg/50 mg or doses with a single-dose of levodopa/benserazide 200mg/50 mg plus a single-dose of entacapone 200mg

AUC0-τ (AUC from time zero to 8 h post-dose), AUC0-∞ (Area under the plasma concentration versus time curve from time zero to infinity), and others

2.5 months

Completed Results not posted

Bial Portela C S.A.

Effect of BIA 6-512 at steady-state on levodopa pharmacokinetics when administered in Double-blind, combination with a randomized, N=38, Phase single dose of Healthy volunteers placebo-controlled, ≥ 18-45 1 levodopa/benserazide rising multipleyears 200mg/50 mg or doses with a single-dose of levodopa/benserazide 200mg/50 mg plus a single-dose of nebicapone 150mg

AUC0-τ (AUC from time zero to 8 h post-dose), AUC0-∞ (Area under the plasma 3 months concentration versus time curve from time zero to infinity), and others

Sponsor

Bial Portela C S.A.

Phase

Diagnosis

Study Design

Treatment

Four multiple-rising Single-centre, doses (25 mg, 50 mg, double-blind, N=40, 100 mg, and 150 mg Phase Healthy volunteers randomized, ≥ 18-45 6 times daily) of BIA 1 placebo-controlled years 6-512 (Transstudy resveratrol)

Healthy elderly subjects versus healthy young subjects after single and repeated oral administration

Open-label, parallel-group Study

N=25, ≥ 18-45 years

Single oral dose of 200 mg BIA 6-512 (Trans-resveratrol)

Completed Results not posted

Resveratrol: A Novel Drug

Traditional Medicine for Neuronal Health 245

(Table ) cont.....

Country, NCT

Sponsor

Phase

US ADCS, NCT01504854 National Phase (Turner RS, Institute on 2 2015) Ageing

Diagnosis

Mild-moderate AD

Study Design

Sample Size and Age

Randomized, N=120, double-blind, ≥50 placebo-controlled years

US AD patients with Randomized, US Department Phase MMSE scores 12double-blind, NCT00678431 of Veterans 3 26 placebo-controlled Affairs

Life AD as per United States Extension Phase NINCDS-ADRDA NCT01716637 Foundation 1 diagnostic criteria Inc

An open label, crossover

Treatment

Oral Resveratrol (500 mg/day; maximum 2g/day)

Outcome

10: Adverse events, volumetric MRI brain changes 20: ADCS-ADL, CSF-Aβ42 levels

Duration

Results and Status

13 months

Nausea, diarrhea, weight loss common with resveratrol; CSF and plasma Aβ declined more in the placebo group. Brain volume loss and ventricular volume increased more in the resveratrol group.

N=27, 50-90 years

Resveratrol, glucose, and malate

10: ADAS 20: CGIC

12 months

Completed change scores on ADAS-cog, MMSE, A DCSADL, Neuropsychiatric Inventory all showed less deterioration in the treatment, none of the change scores reached statistical significance. Low-dose oral resveratrol is safe and welltolerated

N=12, 60-85 years

Peri-spinal etanercept injection subcutaneously and dietary supplements having curcumin, quercetin, resveratrol, ω-3 fatty acids

10: MMSE, 20: ADAS-Cog, MoCA

6 weeks

Completed Results not posted

Abbreviations: ADAS- Cog; Alzheimer’s Disease Assessment Scale-cognitive subscale, ADCS-PACC; Alzheimer’s Disease Cooperative Study- Preclinical Alzheimer Cognitive Composite, ADL; Activities of Daily Living, MMSE; Mini-Mental State Examination, Mo CA; Montreal Cognitive Assessment, NINCDSADRDA; National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease and Related Disorders Association, CGIC; Clinical Global Impression of Change, AUC; area under the curve, MPTP; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 6-OHDA; 6-hydroxydopamine, NGM; Nematode growth medium, UPRmt; Unfolded protein response in mitochondria, UPRER; Unfolded protein response in the endoplasmic reticulum.

CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise.

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CHAPTER 13

Protective Effect of Potent Protein-like Drug Isolated from Indian Medicinal Plants over Diabetic Neuropathy Harsha Kashyap1,*, Hagera Dilnashin2 and Mukesh Kumar3 Department of Bioscience and Biotechnology, Banasthali Vidyapith, Vanasthali-304022 (Rajasthan), India 2 Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005 (U.P.), India 3 School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong 1

Abstract: Diabetes is a hyperglycemic metabolic condition. Diabetes may lead to obesity and neuropathic changes in a patient. Damage to any neurological part or organ during diabetes causes diabetic neuropathy. Neuropathy occurs due to hypersensitivity in nerves because of abnormal epinephrine-mediated transmission of the impulse from axon to axon. In 1864, Marchal de Calvi explained that diabetes causes neurologic lesions by observing the pain in sciatic distribution and peripheral areas of anesthesia. Anti-hyperglycemic components, polypeptide-p and osmotin, can not only reduce the blood glucose level of mice but have also proven to be without any side effect or negative impact as they reduce oxidative stress level, improve the activities of endogenous antioxidants, and positively alter the activities of neurotransmitters, like cholinesterase, serotonin, and γ- aminobutyric acid (GABA).

Keywords: Anti-hyperglycemic components, Diabetes, Nerves, Osmotin, Polypeptide-p. INTRODUCTION Polypeptide-p and osmotin, as protein anti-oxidants, act as defense systems of plants and animals against free radical damage. Anti-oxidants defend cells from damage through the oxidation of free radicals by unstable molecules [1]. Oxidation is a chemical reaction that takes place in our body by producing free radicals. It transfers an electron from a reactive substance to an oxidizing agent. Anti-oxidants remove intermediates of free radicals and also inhibits other oxidCorresponding author Harsha Kashyap: Department of Bioscience and Biotechnology, Banasthali Vidyapith, Vanasthali-304022 (Rajasthan), India; E-mail: [email protected] *

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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ation reactions by oxidizing themselves, followed by terminating chain reactions. Defense of enzymes, such as superoxide dismutase (SOD), catalase (CAT), diverse peroxidases, and different types of antioxidants [glutathione (GSH), vitamin C, vitamin E], is maintained by plants and animals. In pharmacology, anti-oxidants are utilized as a medicine for stroke and neurodegenerative diseases [2 - 4]. Anti-oxidants are found in vegetables, fruits, fish, and foods, such as nuts, grains, some meats, and poultry [1, 5]. In diabetic patients, glucose may get oxidized, which may direct the generation of free radicals, reactive ketoaldehydes, or H2O2 [6]. The imbalance between endogenous anti-oxidants and free radicals can cause oxidative stress [7]. Enhancement in reactive oxygen species (ROS) and reactive nitrogen species (RNS) causes oxidative stress [8]. To overcome oxidative stress, cells have enzymatic and non-enzymatic antioxidant defenses [9]. CAT, SOD, Glutathiones-transference (GST) along with glutathione peroxidase (GPX), lipid peroxidation (LPO), reduced glutathione (GSH), and protein carbonyl content (PCC) act as non-enzymatic indicators of oxidative stress in our body. Oxidative damage generates free radicals, and PCC and thiobarbituric acid reactive substances (TBARS) are biomarkers that indicate oxidative damage [10]. Therefore, their rate of activity in the brain, heart, blood, lung, liver, kidney, and muscles is detected to analyze the overall damage index [11 - 13]. In a person suffering from diabetes, self-oxidation of glucose, declination in the concentration of anti-oxidants, and redox ions shift are the main cause of oxidative stress [8]. The tricarboxylic acid (TCA) cycle helps in the production of neurotransmitters, such as acetylcholinesterases (AChE), butyrylcholinesterase (BChE), glutamate, aspartate, and γ- aminobutyric acid (GABA), by providing the specific substrate [14]. Maintaining strict glucose levels and treating respective risk factors by medications or diet is considered as therapy for diabetic neuropathy (DN) [15]. Chronic hyperglycemia leads to abnormalities in synaptic plasticity and cognitive impairments. As compared to the standard glucose treatment, diabetic rats show a reduction in the rate of brain atrophy in rats with balanced glucose levels [16]. Lesions in sensory nerve and peripheral motor are reported in diabetic mice and rats [17]. There are various reports that medicinal plants affect the central nervous system (CNS) as anti-convulsant, sedative, anti-depressant, anxiolytic, antipsychotic, memory-enhancing, anti-Parkinson, locomotor, and also as neuroprotective moiety, and are considered as a safe and effective source of drugs [18 - 21]. TCA cycle enzymes, α-ketoglutarate dehydrogenase complex (KGDHC), succinate dehydrogenase (SDH), and fumarate hydratase or fumarase, are regulated by free radicals [22]. Downregulation of the TCA cycle reduces the

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level of neurotransmitters endorsing oxidative stress in the brain [23]. Alteration in the anti-oxidant enzymes and key respiratory enzymes of glycolysis, glucose 6 phosphate dehydrogenase (G6PDH), can generate free radicals [24]. Excess free radicals can upregulate glycolysis and pentose phosphate pathways. They also inhibit or reduce the rate of the TCA cycle in mitochondria [25, 26]. Any inequity of dehydrogenases in the TCA cycle enhances ROS and free radicals generation above antioxidant defenses, which may cause oxidative hassle [27]. Recent studies on type I diabetic models report down-regulation of the key enzyme of the TCA cycle as well as mitochondrial proteins. Diabetes leads to an increase in the amount of protein and lipid oxidation, due to which the TCA cycle and glycolytic intermediates decrease [28]. Diabetes generates ROS in the body, which leads to the enhancement of natural endogenous antioxidants [29]. Consequently, oxidative stress is reduced. It also corrects the improper regulation of glycolysis, TCA cycle enzymes as well as gene expression of the animal model (Fig. 1). The previous study shows that diabetes reduces anti-oxidant defenses and increases the level of free radicals. In severe cases, it may also change gene expression [30]. DN is a cause of nervous system lesions; therefore, it becomes necessary to study the molecular changes responsible for DN to understand its mechanisms behind causing diabetes and neurological problems. Also, it can help us in developing therapies to prevent and treat DN [31]. Nerve injuries, due to certain reasons, can interrupt the function of regulatory factors, such as nerve growth factor (NGF). NGF interruption decreases the levels of calcitonin generelated peptide (CGRP) and substance P (SP) mRNAs [32]. In the human body, free radicals are generated indigenously or inhaled from any exogenous sources, and, therefore may cause cumulative damage to protein, lipid, DNA, carbohydrates, or membrane. Aβ injections to rodents resulted in impairment of learning and memory. Also, neurodegeneration was observed in the brain areas related to cognitive function. Aβ injected mice showed declination in the expression of an apoptosis-associated protein. This protein prevents the cell from Aβ toxicity and cell death [33]. Aβ protein and insulin are the substrates of insulin-degrading enzymes (IDE).

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Fig. (1). Impact of hyperglycemic or various metabolic pathways in in vivo studies.

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DN Excess glucose in cells affects various pathways of glucose metabolism as the polyol pathway increases osmolarity and reduces NADPH level in the cell, which consequently causes oxidative stress. It also increases the rate of glycolysis and affects the electron transport chain (ETC) in mitochondria that causes ROS. Damage to neurons, vascular endothelial cells, and glial cells is termed neuropathy [34]. It can damage any part of the nervous system and can be diagnosed very early in type II diabetes, but in type I, it is diagnosed in advanced stages [35]. Hyperglycemia affects various body activities, which cause overexpression of the polyol pathway, an increase in advanced glycation end products, nerve ischemia/hypoxia, γ-linolenic acid deficiency, the inclination of protein kinase C (PKC), and declination in various growth factors. These pathways cumulatively cause oxidative stress. Oxidative stress has a serious adverse impact on nerves and neuronal cells. Therefore, diabetes can lead to DN [36]. DN occurs in approximately half of the patients suffering from diabetes, resulting in dysfunction of peripheral and automatic nerves. ROS formation is the major reason for causing DN in hyperglycemia. There are various reports that experimental DN can be treated by anti-oxidants as the scavengers of free radicals can normalize blood flow in nerves as well as electrophysiology [37]. Imbalance of Oxidative Homeostasis Polypeptide-p and osmotin increase endogenous anti-oxidants (GST, SOD, GSH, CAT, GPX) but reduce the levels of markers of oxidative stress (TBARS, PCC), including SOD, CAT, and GPX, which are the critical endogenous enzymatic anti-oxidants of the body to maintain ROS. On the other hand, GSH, albumin, vitamin C, and E are non-enzymatic antioxidants [38]. LPO in the brain increases the amount of PCC. Reactive species can be easily eliminated from our bodies by the mechanisms of enzymatic and non-enzymatic antioxidants [9]. Enzymatic anti-oxidants have a major role in protecting the cell membrane from LPO and cellular injury through their defense mechanism [25]. TCA cycle in mitochondria is inhibited due to the production of free radicals and is also responsible for the up-regulation of glycolysis and pentose phosphate pathways. SOD-CAT-GPX is a ubiquitous catalytic triad that is established in every cell of prokaryotic as well as eukaryotic aerobic organisms [39]. H2O2 can generate hydroxyl radical (OH•), which is very aggressive and can harm any cell constituent, such as lipids in membranes, proteins, sugars, and nucleic acids, thus resulting in cell death. Cytosolic CAT acts as the primary scavenger of H2O2 [7]. According to various researches, alteration in anti-oxidant enzymes and enzymes of glucose catabolism produces free radicals, which may cause oxidative hassle [24].

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The generation of free radicals may cause a disproportion among oxidants and antioxidants in the body, which leads to oxidative stress. It is a core cause of various human diseases, such as Alzheimer’s, atherosclerosis, stroke, diabetes, and cancer [40]. It is also noted that in Alzheimer’s, the level of PCC increases and that of GSH reduces in the hippocampus and midbrain of rats. Oxidative stress is the disparity between ROS production and antioxidants, leading to pathological conditions [41, 42]. Studies prove that the levels of MDA and TBARS increase in the person suffering from AD [43 - 45]. The level of GSH, GPX, and SOD decreases in brain mitochondria in diabetic conditions [46]. GSH removes excess free radicals and protects against oxidative stress [47]. Membrane fluidity is impaired due to the inclination in LPO, which hampers cell functioning and also changes the activity of membrane-bound enzymes. The products thus formed by LPO impairment are harmful to the body cells and can cause brain damage [48]. Free radical generates LPO that leads to basic cellular deteriorative changes in our body induced by oxidative stress. SOD converts O2- to H2O2 and detoxifies it into water within the lysosome by CAT and in the mitochondria by GPX. Glutathione reductase (GR) is an important enzyme that is responsible for regenerating glutathione; it eliminates H2O2 by donating hydrogen [49]. Alteration in Neurotransmitters The activity of neurotransmitters (AChE, BChE, GABA, and serotonin) was enhanced in polypeptide-p as well as osmotin-exposed groups of mice. The study reports that any disorders in GABA metabolism can lead to neurological brain diseases. Our CNS consists of less than 2% of the total serotonin. It is responsible for the functioning of the brain, such as mood control, sleep, regulation of pain perception, blood pressure, body temperature, and hormonal activity. Alteration in the level of AChE influences the level of BChE in the body as AChE has synergistic relations with BChE for maintaining the cholinergic function of the body. AChE is reduced with the reduction in αKGDHC activity [27]. GABA is present in higher concentrations in cerebral structures of the brain; it works as an inhibitory neurotransmitter. GABA is present in the SN and globus pallidus nuclei of the basal ganglia in higher concentration, followed by the hypothalamus, the hippocampus, and the periaqueductal grey matter for many types of growing neurons, and acts as a tropical signal. The study proves that in a person suffering from Alzheimer’s, the activity of AChE declines under oxidative stress conditions of the brain [50]. Animal cholinesterases are present in two forms, true cholinesterase (AChE) and pseudocholinesterase/acyl cholinesterase (BChE) in tissues, plasma, and other body fluids. BChE act as a detoxifying enzyme as it scavenges endogenous anticholinesterase compounds. It also eliminates neurotoxicity caused by depression or any compound [51]. It is mainly localized

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in nerve pathways within the brain arising from the raphe nuclei, which is a cluster of nuclei at the center of the reticular formation in the midbrain, pons, and medulla. It is an organic compound synthesized from the tryptophan amino acid; it acts as a powerful vasoconstrictor that occurs in blood serum. Brain serotonin is very sensitive to dietary supplements. Serotonin-secreting neurons are serotonergic as they enhance the level of superoxide radicals in the pulmonary artery of the smooth muscles [52]. Oxidative stress has a very important role in the breakdown of the mitochondrial membrane potential and in the opening of mitochondrial membrane permeability transition pores [53, 54], which can cause oncotic necrosis due to cell death and ATP depletion [55]. The occurrence of LPO in the cell membrane can cause impaired function of the membrane, diminish membrane fluidity and structural integrity, and inactivate membrane-bound enzymes; it causes oxidative degradation of polyunsaturated fatty acids (PUFAs) [55]. ROS inactivates the enzyme protein, which depletes the substrate for the enzyme and down-regulates the transcription and translation process [56]. Oxidative stress causes modification in lipids and proteins, which play an essential role in a variety of biological activities, which is a result of enhanced oxidative stress, like cell proliferation and apoptosis [57]. The abundance of PUFAs in the blood composition makes body tissue susceptible to damage by ROS. DNA strands can cause DNA adduct due to the ROS break, which may lead to genetic defects. Moieties of sugars and bases can be degraded due to ROS production and may cause cross-linking to protein and oxidation of bases. DNA-MDA adducts can cause nucleic acid oxidation as 4-hydroxyl and 2-deoxyguanosine are believed to be the oxidative markers of DNA oxidation. It can be due to the activity of antioxidants that eliminate O2 radicals [58]. It is also stated that in humans, the inclined amount of serotonin enhances O2 radicals. MDA can devastate the structure of the cell membrane leading to apoptosis and DNA fragmentation. Elevation in oxidants may cause modification of DNA, resulting in mutagenesis, which deteriorates its function. Alteration in the level of anti-oxidants may cause several physiological changes, including excess production of ROS and modulation in DNA [59]. Inactivation of enzyme protein by ROS can reduce the activity of endogenous antioxidants in the cells that depletes the substrate for enzyme and down-regulates the transcription and translation processes [56]. ROS can straightly cause modification in proteins along with the ultimate arrangement of oxidized amino acids, such as methionine, ortho-tyrosine, and also carbonyl groups [56, 60]. Oxidative stress causes modification in lipids and proteins, which play a vital role in various biological activities; it is a result of enhanced oxidative stress, like cell

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proliferation and apoptosis [61]. The abundance of PUFAs in the blood composition makes body tissue susceptible to damage by ROS [61]. This increases the risk of damage to body tissues due to various mechanisms, such as an increase in LPO, protein, and DNA alteration, which causes cell death [57]. DNA strands can cause DNA adduct due to the ROS break, which may lead to genetic defects. Moieties of sugars and bases can be degraded due to ROS production and may cause cross-linking to protein and oxidation of bases. DNAMDA adducts can cause nucleic acid oxidation as 4-hydroxyl and 2deoxyguanosine are believed to be the oxidative markers of DNA oxidation. It can be due to the activity of antioxidants that eliminate O2 radicals [58]. It is also stated that in humans, the inclined amount of serotonin enhances O2 radicals. MDA can devastate the structure of the cell membrane, leading to apoptosis and DNA fragmentation [62]. Elevation in oxidants may cause modification of DNA, resulting in mutagenesis, which deteriorates its function. Alteration in the level of anti-oxidants may cause several physiological changes, including excess production of ROS and modulation in DNA. Inactivation of enzyme protein by ROS can reduce the activity of endogenous antioxidants in the cells that depletes the substrate for enzyme and down-regulates the transcription and translation processes [63]. ROS can straightly cause modification in proteins along with the ultimate arrangement of oxidized amino acids, such as methionine, ortho-tyrosine, and also carbonyl groups [64]. For the study of gene expression, the actin gene is selected as a housekeeping gene. Expression of actin and GAPDH remains constant and frequently used as housekeeping in many studies. AChE has an important role in cholinergic neurotransmission [65]. In all animals at cholinergic synapse, AChE is expressed. It is responsible for terminating neurotransmission as it hydrolyzes acetylcholine, which is a neurotransmitter. But overexpression of AChE can cause apoptosis as cell proliferation is inhibited due to its cholinergic activity [66]. It supports noncholinergic functions by promoting differentiation and neuronal outgrowth. It can terminate signal transmission by hydrolyzing the neurotransmitter, cholinergic synapses of the brain, and acetylcholine at neuromuscular junctions. During synaptogenesis or long-term synapse maintenance, it is responsible for cell adhesion processes due to the involvement of protein mammalian neuroligins [67]. CONCLUSION Antihyperglycemic components (polypeptide-p and osmotin) are very effective in lowering the glucose level of mice without affecting mice physiology adversely. Polypeptide-p and osmotin both act as a scavenger of free radicals. They also

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increase the activity of endogenous anti-oxidants. Both the components have a very positive impact on neurotransmitter levels (level of AChE and GABA increases whereas the level of serotonin decreases). Anti-hyperglycemic component isolated from the leaves of fenugreek can be a better choice for the medication of neurological lesions or DN. It also increases the activity of G6PDH and TCA cycle enzymes responsible for enhanced glucose metabolic rate in the diabetic state. So these components can be formulated as medicine for DN. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENT Declared none. REFERENCES [1]

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CHAPTER 14

Natural Herbs Polishing Memory: Neuroprotection against Alzheimer's Disease Manisha Thakkur1,*, Hagera Dilnashin2 and Priyanka Kumari Keshri2 Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar-125001 (Haryana), India 2 Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005 (U.P.), India 1

Abstract: Alzheimer's Disease (AD) is an irreversible and progressive neurodegenerative disorder that directly deteriorates the memory and cognitive function of the human brain in such a way that a person finds difficulties in dealing with daily life tasks. It is characterized by irregular neurofibrillary tangles (NFTs), intraneuronal accumulation, and the development of senile plaque (SP) consisting of abnormal polypeptide accumulation called βA4 amyloid. The pathophysiology can be collectively explained by five major hypotheses that are amyloid β (A β) hypothesis, the hyperphosporelated tau hypothesis, chronic inflammation, the cholinergic hypothesis, and the metal ion hypothesis. WHO estimated that a total of 40 million people worldwide are tested for the ill effects of dementia, and this is predicted to be twice as high as 114 million by around 2050. Currently, FDA-approved treatments for Alzheimer’s involve Donepezil, Rivastigmine, Galantamine, and Memantine that do not act specifically against Alzheimer's pathology and are also associated with loss of appetite, increased frequency of bowel movements, mental confusion, and dizziness as their side effects promote the approach to disease-modifying drugs. Nowadays, treatment with herbal medicines is a powerful alternative worldwide due to their high safety of margin against the side effects of allopathic drugs. Herbs are not restricted to a specific activity; they are generally enclosed with lignans, flavonoids, tannins, triterpenes, sterols, and alkaloids with wide pharmacological activities, such as antiinflammatory, anti-amyloidogenic, anti-cholinesterase, and anti-oxidant effects. Many herbal plants of India, such as Glycyrrhiza glabra, Acorus calamus, Convolvulus pluricaulis, Centella asiatica, Sesbania grandiflora, etc., have already proved their efficacies in treating dementia in various scientific studies.

Keywords: Alzheimer’s disease, Dementia, Herbal plants, Herbal medicine. Corresponding author Manisha Thakkur: Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar-125001 (Haryana), India; E-mail: [email protected]

*

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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INTRODUCTION Have you ever found that your grandparents misplaced their important things or lost their way to familiar places or even forgot the names of their family members or recalled them with the wrong names? If this is so, then it could be an early indication of dementia developing from Alzheimer’s disease (AD). There are numerous functions associated with the brain, like memory, thinking, direction, understanding, estimation, learning, language, and judgment. But dysfunctioning of all these functions can affect the capacity of an individual, particularly known as dementia. It is considered to be an overall term for a specific group of symptoms [1] More than 2500 years ago, from an unclear concept of inescapable age-related cognitive decline to a modern perception of its unique clinical and pathological highlights, the idea of dementia came into existence. In the Greco-Roman model, 'senescence itself is a disease' alluded to as a characteristic product of aging in ancient writings depicting mental decrease [2]. AD is an irreversible and progressive neurodegenerative disorder that directly deteriorates the memory and cognitive function of the human brain in such a way that a person finds difficulties in dealing with daily life tasks [3]. It is characterized by irregular neurofibrillary tangles (NFTs), intraneuronal accumulation, and the development of senile plaque (SP) consisting of abnormal polypeptide accumulation called βA4 amyloid. Generally, β-amyloid plaques and tangles are the two unexpected structures from the brain that are the fundamental drivers of AD conglomerates outside and inside the neurons, respectively, and marked as killers of nerve cells [4]. Morphologically, the decay of neurons in the hippocampus region deteriorates its functioning and expands as the brain atrophy over time. A deficiency of the enzyme choline acetyltransferase along with cholinergic markers has also been found in biochemical findings of the entire cholinergic system [5]. Currently, five well-established medications licensed by FDA for AD treatment are symptomatic only and target to overcome the neurotransmitter dysfunction in the disease. These include Donepezil (Aricept®), Rivastigmine (Exelon®), and Galantamine (Razadyne®) cholinesterase inhibitors for mild to moderate phases as well as Memantine (Namenda®) NMDA receptor antagonist and its combination with Donepezil (Namzaric®) used for moderate to severe phases of care (FDA-approved treatments for Alzheimer’s, Alzheimer’s Association, 2019) [6, 7]. These medications do not act on the pathological mechanisms driving Alzheimer's and are also associated with loss of appetite, increased frequency of bowel movements, mental confusion, and dizziness as their side effects promote the approach to disease-modifying drugs. These are the agents that sedate the development of structural damage within the brain and

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primarily focus on the reduction of production of β-and γ- secretase inhibitors (CTS-21166: phase I trials, Avagacestat: phase II trial), prevention of aggregation (Colostrinin: phase II trial (±), Scyllo-inositol: phase II trial (±)), and clearance of amyloid β protein (Bapineuzumab: phase II trial (+) Solanezumab: phase II trial IVIg: phase III trial) respectively; agents that inhibit the phosphorylation of Tau protein (Tau kinase inhibitors (lithium: phase I trial (–) in AD (+) in MCI) and prevent its agglomeration (Methylene blue: phase II trial (+)) or stimulate its disassembly are the most studied medical therapies under the clinical pipeline [6, 8 - 10] Behavioral and psychological symptoms most often observed in people with dementia are extensively treated with the help of anti-depressants, antipsychotics, anti-anxiety, and anti-convulsants [6]. Nowadays, targeting the neuroinflammation associated with Alzheimer's is emerging as an evident approach to the management of the disease. Medications like Sargramostim, Azeliragon, Etanercept, Neflamapimod, Minocycline, etc., have effectively proved their potential in arresting the inflammatory responses by working through different pathologic mechanisms [11]. Over the years, our medical care has been modernized with amazing technology, but this also paves the way for medications with more and more serious side effects. This makes the treatment with allopathic medications more costly and somewhat detrimental to the body. So, scientists and researchers are heading back to nature’s cave of Ayurveda seeking alternative therapeutics. Ayurvedic medicine is a customized form of Indian and Indian subcontinent traditional medicine coined by the eminent father of Ayurveda, “Maharshi Charaka”. It is based on a holistic approach to care that supports and promotes harmony in various facets of human life: Body, Mind, and Spirit. This chapter of the book holds the scientific evidence of Indian herbal medicines possessing the neuroprotective potential against Alzheimer's Disease and thus try to support the title of the book ‘Indopathy for Neuroprotection’. EPIDEMIOLOGY AD is meant to be one of the most widely regarded medical difficulties in our century. It is widely affecting 10% of people aged over 65 and about 50% of those over 85. WHO estimated that a total of 40 million people worldwide are tested for the ill effects of dementia, and this figure is predicted to be twice as high as 114 million by around 2050 [12]. This represents 60-80% of all cases of dementia. Alzheimer's is not a typical part of maturing — it is a reformist brain disease, which means it deteriorates over the long haul [13]. With 5.8 million Americans still surviving with AD, the American Alzheimer's Association published its 2020 facts and figures report, also highlighting the elevated mortality rate to 146 percent between the years 2000 and 2018. These statistics have cost the nation's

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healthcare society a socio-economic burden of $360 billion and have made Alzheimer's the sixth leading cause of death in the United States [14, 15] (Alzheimer’s Disease Facts and Figures, 2020). Indian Alzheimer’s scenario is not so different from other developed or developing nations. India is known for its powerful parenting style, where elders are the family’s core pillars and are highly respected for their presence. If they decline to have it, the family cannot compel elders for medical treatment. Earlier symptoms of Alzheimer's are thus overlooked before the later extreme phases are reached. It is predicted that by 2100, there will be 1 older person to take care of every 3 working-age population [16 - 18]. The 2015-2016 National Family Health Survey depicts that India has poor awareness about AD among its diverse cultures, rendering the elderly population of our country highly vulnerable to dementia resulting in the highest growth rate (approx 330%) of AD (National Family Health Survey, 2016). The prevalence rate in India varies across regions, i.e., from 3.39-0.84% of the rural population in southern India to northern India. “Population” Government of India, 2011, showcases the highest number of cases seen in crowded metropolitan cities, like Delhi. Southern states, like Tamilnadu and Kerala, are also with more prevalence rates. The high literacy rate in the southern part of India may also play a key role in the progression of AD. From the 7% growing GDP rate, India only contributes only 2.3% of it to the healthcare facilities, which raises the disease burden on society [18]. Genetically, ApoE gene polymorphism is crucial to dementia; as stated in the Central India review, increased presenilin gene frequency (PS1, allele 1) and ApoE gene e-4 allele polymorphism increase susceptibility to degenerative dementia. Data imported from these statistics and figures draw attention to the need for improved pharmacological, psychological, and healthcare management for patients in the future [19]. PATHOPHYSIOLOGY There are 100 billion neurons present in the brain that hold information as electrical impulses and continuously relay it to other neurons via synapses, creating the cellular foundation of memories, thinking, reasoning, emotions, perceptions, movements, and abilities [20, 21]. But in AD, memory control is disrupted by the early death of the entorhinal cortex and hippocampus neurons. In later stages, Alzheimer's frequently affects regions of the cerebral cortex that are responsible for thought, language, and social behavior. As the neurodegenerative condition progresses, it becomes so lethal that it suddenly causes death [22]. Based on genetic threats, AD can be divided into various groups. These are:

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Autosomal Dominant AD (ADAD) It is associated with early-onset, Aβ deposition, which began around 10 years before apparent symptoms emerged. It varies from EOAD by mutations in the amyloid-beta precursor (APP), presenilin 1 (PS1), or PS2. Early-Onset AD (EOAD) It occurs before the age of 65 associated with recessive inheritance and is considered to be a pure plague and tangle pathological mechanism. Late-Onset AD (LOAD) It is a polygenic disorder, usually sporadic, and a popular form of AD beginning with amnesia proceeds to complex tangles and plague pathology followed by cerebrovascular disease (Jagust, 2018). Most of the older population is diagnosed with Mild Cognitive Impairment (MCI), which is a condition associated with mild memory difficulties that are noticeable to family and friends of the person. It can be a potential precursor for AD, as found in metastable studies of 32% of people who developed dementia in 5 years (Alzheimer's Association, 2016). MAJOR HYPOTHESES The 5 major hypotheses collectively explain the pathophysiology of this multifactorial disease based on their causative variables: β-amyloid Hypothesis Extracellular amyloid or senile plaques are highly soluble and proteolytic resistant proteinaceous fibrils produced after the cleavage of Amyloid Precursor Protein (APP) by α-,β-, and γ- secretase enzymes that produce a soluble 40 amino acid peptide. But in AD, a different form of γ- secretase cleaves APP at the wrong place, forming an insoluble 42 amino acid peptide, Aβ42. Spontaneously, Aβ peptides collate into soluble oligomers that clump together to give an insoluble beta-sheet conformation, fibrils, and with a greater extent of oligomerization, they get deposited as plaques between neurons. Aβ42 are the prime oligomers that enhance neurotoxicity by potentiating inflammation, oxidative damage, and promoting tau hyperphosphorylation [23 - 25].

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Hyperphosporelated Tau Hypothesis Tau proteins are a group of six highly soluble isoforms of a gene associated with a microtubule-associated protein tau (MAPT) that binds to the microtubules to promote tubulin assembly. Thus, it stabilizes the microtubules in the axonal region of neurons. These are the structures that establish contact between the interneuronal system by acting as tracks for nutrient supply and neuronal transmission propagation [12, 24]. Tau is a phosphorylated protein and contains 85 possible phosphorylation sites for serine (S), threonine (T), and tyrosine (Y). A host of kinases, including phosphokinase (PKN), a serine/threonine kinase, regulate the phosphorylation of tau. It phosphorylates tau when PKN is activated, resulting in microtubule organization disruption. As per the pathogenesis of AD, the tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into paired-helical-filament (PHF) tau and neurofibrillary tangles (NFTs). Consequently, it dissociates from microtubules, inhibits transport, and results in the disassembly of microtubules [25] (https://en.wikipedia.org/wiki/Tau_protein). Tau hyperphosphorylation works dually, i.e., tau hyperphosphorylation makes cells more resistant to acute apoptosis, while increasing intracellular tau accumulation and causing multiple cellular impairments, including endoplasmic reticulum (ER) stress, mitophagy and autophagy deficiencies, synaptic transmission deficiencies, etc. The abnormal soluble tau and/or its oligomers are neuronally toxic and contribute to neuronal death and dementia [26]. Chronic Inflammation Acute inflammation is known for its proven protection against infection, contaminants, and injury but, as seen in AD, the imbalance between antiinflammatory and pro-inflammatory signaling produces chronic inflammation (neuroinflammation). Thus, it tends to play a dual role, a neuroprotective role during an acute-phase response, but through a chronic response, it becomes detrimental. Several pro-inflammatory and toxic products are released by chronically activated microglia, including reactive oxygen species, nitric oxide, and cytokines [27, 28]. Within 3 weeks of injury, interleukin 1 (IL-1) levels are elevated, which further escalates APP production and cerebral Aβ deposition. Besides this, hiked concentrations of IL-6 induce CDK5, a kinase known for its hyperphosphorylate tau. This signifies that neuroinflammation present in AD has a significant role in exacerbating Aβ and tau hyperphosphorylation, which pop up inflammation as a connection between these two distinctive pathologies [25, 29].

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Cholinergic Hypothesis Complex physiological mechanisms, such as concentration, learning, memory, stress reaction, awakeness and sleep, and sensory information, are involved in the cholinergic system [30]. The cholinergic hypothesis claims that degeneration in the basal forebrain nuclei of cholinergic neurons causes disruptions in the hippocampus and neocortex of presynaptic cholinergic terminals, which is the reason for memory problems and other cognitive symptoms. Moreover, neurofibrillary degeneration in the basal forebrain causes the death of cholinergic neurons. Cholinergic transmission deficits can potentially affect all aspects of cognition and behavior. Potentiation of the central cholinergic pathway activity by using acetylcholinesterase inhibitors increases the concentration of acetylcholine at the synapses of neurons [29, 31, 32]. Metal Ion Hypothesis Metal ions have an important existence in our body and are necessary for life. Metalloproteins engaged in preserving cell structure, controlling genetic expression, mediating cell signals as a second messenger, and catalyzing enzyme activities, are protein-borne metal cations, such as copper (Cu2+, Cu+), iron (Fe3+, Fe2+), magnesium (Mg2+), manganese (Mn2+), calcium (Ca2+), and zinc (Zn2+). However, the brain also requires free metal ions pooled in synaptic clefts for modulation of synaptic transmission [33]. Changes in the complex balance of metal ions in the brain in AD patients are closely linked to Aβ deposition and tau hyperphosphorylation/accumulation. Fe2+ ions, which can alter Aβ and produce oxygen radicals to cause damage to the membrane surface, are bound to the Nterminal region of Aβ. Elevated Fe3+ can bind to APP mRNA and promote APP translation in the human neuroblastoma cell line (SHSY5Y), and Fe3+ can activate β-secretase and thus induce Aβ development. Cu2+-metalled APP ectodomain promotes the death of neuronal cells. Excess copper can promote hyperphosphorylation of tau and attenuate phosphorylation of tau in human neuroblastoma cells by copper chelating agents. Zinc improved the degree of APP expression and amyloidogenic cleavage that contributes to Aβ accumulation. It also inactivates protein phosphatase 2A (PP2A) and tau hyperphosphorylation through the Src-dependent pathway, resulting in hiked tau tangles. The opening of the L-type calcium channels facilitated by the accumulation of Aβ and intracellular tau also triggers the intracellular influx of calcium consecutively, which further contributes to calcium overload and triggers neurodegeneration [34, 35].

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CONCLUDING REMARKS AND SCIENTIFIC EVIDENCE FOR NEUROPROTECTIVE POTENTIAL OF INDIAN HERBS OR PHYTOCHEMICALS FOR ALZHEIMER’S DISEASE Ayurveda, the traditional Indian system of medicine, established its foundation between 2500 and 500 B.C. through the ancient schools of Hindu philosophy, Vaisheshika, and the school of logic, Nyaya. Pancha Mahabhoots (Air, Water, Earth, Fire, and Space) play an important role in the composition of Tridoshas: Vata Dosha, Pitta Dosha, and Kapha Dosha, which are essential for regulating the physiological function of the human body [36]. Three aspects of mental abilities are listed by Ayurveda, i.e., Dhi (acquisition/learning process), Dhuti (retention process), and Smriti (a process of recall). Dysfunction of all these three processes is linked with dementia (Smritibuddhihrassa). Treatment with herbal medicines is now widely adopted as a powerful alternative worldwide due to their high safety of margin against the side effects of allopathic medicine [37, 38]. Several clinical studies have been performed with herbs containing various phytoconstituent substances, such as lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids that have flared up their pharmacological activities, such as antiinflammatory, anti-amyloidogenic, anti-cholinesterase, hypolipidemic, and antioxidant effects [39 - 44]. As a result, herbal therapy for Alzheimer's is widening its possible origins in medical science exponentially to polish the incredible memories of the human race. This section of the chapter covers all research findings from medicinal plants of Indian origin that have asserted their therapeutic value for Alzheimer's disease (Table 1). Table 1. A detailed summary of the magical herbs. S. No.

Plant Biological Source

Glycyrrhiza glabra 1. (Liquorice/Mulathi)

2.

3.

Acorus calamus (Safed bach)

Withania somnifera (Ashwagandha)

Family

Origin in India Chemical Constituents

Pharmacological Activities

Leguminoceae or Fabaceae

Punjab and Himalayas

Glycyrrhizin, Hispaglabridin A, Hispaglabridin B, Glabridin, and 4′-OMethylglabridin, Formononetin.

Anti-inflammatory and antioxidant

Araceae

Indian Himalayan Regions (IHR): the southern part of Shiwaliks, Trans-Himalaya, Jammu & Kashmir, and Himachal Pradesh

α- and β-asarone

Anti-oxidative, antiinflammatory, and neuroprotective properties and sedative effects

Madhya Pradesh, Rajasthan, Gujarat, Haryana, Maharashtra, Punjab, and Uttar Pradesh

Withaferin A (WL-A) and Withanolide A

Experimental Studies

Refs.

Improved cognition in mild cognitive impairment in adults; Glycyrrhizin alleviates neuroinflammation and memory deficit induced by systemic LPS treatment in mice; anti-cholinesterase activity of Glycyrrhizin; pharmacological inhibitor of HMGB1; [45 51] improved memory in Wistar albino rats evaluated through elevated plus maze and Morris water test; Glycyrrhizic acid reduces neuroinflammation and cognitive impairment in C57 mice via. TLR-4 signaling pathway

Prevent memory deficits and stress in LPS-induced neuroinflammation rat models; AChE inhibitory activity; improve cognition in restraint stressed Wistar rats; nootropic activity against scopolamine-induced Alzheimer

[44, 52 54]

Improved hippocampal neurodegeneration and hypobaric hypoxia-mediated memory impairment by reducing NO, corticosterone, and AChE activity in SD rats; amelioration of the level of Bisphenol A (BPA)-intoxicated oxidative stress; Neurite promoter, antioxidant, [37, anti-inflammatory,anti-apoptotic, attenuation of streptozotocin-induced cognitive impairment in a 55 and anxiolytic activities rat model; recovers memory through targeting muscarinic 60] receptors; glycowithanolides, withaferin-A, and sitoindosides were significantly reversed ibotenic acid-induced cognitive defects in AD model.

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(Table ) cont..... S. No.

4.

5.

6.

7.

8.

9.

Plant Biological Source

Family

Origin in India Chemical Constituents

Delhi, Jammu, Bacopa monniera Kerala, Udaipur, Scrophulariaceae (Brahmi) Jodhpur, Gauhati, Sikkim

Curcuma longa (Turmeric)

Convolvulus pluricaulis (Shankhpushpi)

Commiphora wightii, Commiphora mukul (Guggulu)

Centella asiatica (Gotu kola, centella, mandukparni)

Caesalpinia crista (kat-takaranja)

Zingiberaceae

Convolvulaceae

Burseraceae

Apiaceae

Caesalpiniaceae

Bacosides A and B

Andhra Pradesh, Tamil Nadu, Orissa, curcumin, Karnataka, West curcuminoid,tumerone, Bengal, Gujarat, atlantone, and Meghalaya, zingiberone. Maharashtra, Assam

Bihar

Pharmacological Activities

Nootropic, anti-oxidant, antiinflammatory, anti-amyloid activity

Refs.

Bisdemethoxy curcumin-enriched turmeric extract REVERC3 via dual inhibition of cholinesterases can be potentially used in Alzheimer's treatment; chronic CUR supplementation attenuated Aβ1-42 induced cognitive impairments and increased BDNF levels in the hippocampus in amyloid-β1-42 (Aβ1-42) treated rats; aerosol delivery of curcumin reduced Aβ deposition and improved cognitive performance in a transgenic model of AD; dual brain-targeting curcumin- loaded polymersomes Anti-oxidant, anti-inflammatory, functionalized by transferrin and Tet-1 peptide (Tf/Tet-1-POs) [30, ameliorated cognitive dysfunction in intrahippocampal and cancer chemopreventive 65 amyloid-β1–42-injected mice; Curcuma treatment prevents properties 71] cognitive deficit and alteration of neuronal morphology in the limbic system of aging rats; four-week treatment improved working memory and reduced fatigue. curcumin ameliorated the impaired insulin signaling and improved the glucose regulation in AD rats; downregulation in total and LDL cholesterol in a healthy older population; theracurmin® improved memory and attention performance and prevented neuropathological deposition in amygdala and hypothalamus in non-demented adults.

Shankhapushpine, convolamine, convoline, Scopoletin, β-sitosterol, Anti-oxidant, anti-inflammatory, ceryl alcohols, 20anxiolytic, anti-depressant, and oxodotriacontanol, nootropic activities tetratriacontanoic acids, flavonoid-kaempferol, steroids-phytosterols

Commiphoric acids, commiphorinic acid, and the heerabomyrrhols. terpenes, sesquiterpenoids, Rajasthan, cuminic aldehyde, Gujrat, Madhya eugenol, and the ketone Pradesh, steroids Z and E Karnataka guggulsterone, and guggulsterols I, II, and III. Guggulu also contains ferulic acids, phenols, and other nonphenolic aromatic acids”

Experimental Studies

It prevents cognitive impairment, oxidative damage, and morphological changes in the intracerebroventricularstreptozotocin infused rats; B. monniera extract lessened both the NaNO2 and d-Galactose levels, which improved the body weight, memory, and learning skills, and also normalized the ATPase system in AD-induced mice. B. monniera extracts [55, significantly reduced neurotoxicity of oxidized low-density 61 lipoprotein (LDL) as well as suppressed the elevation of 64] cellular AChE activity in SH-SY5Y cells. Bacoside X, Bacoside A, 3-beta-D-glucosylstigmasterol, and daucosterol could be good inhibitors of AChE and BuChE activities.; BME ameliorates learning and memory impairments through synaptic protein, neurogranin, pro-and mature BDNF signaling, and HPA axis in prenatally stressed rat offspring

Antirheumatic, anti-fertility, anti-inflammatory, hypolipidemic, anti-cancer activity, and hypocholesterolemic activity

C. pluricaulis (CP) attenuated scopolamine-induced increased protein and mRNA levels of tau, APP, Aβ levels, and histopathological changes in rat cerebral cortex; CP reversed the effect of aluminum in rat brain by decreasing the elevated enzymatic activity of AchE. Enhanced the memory of aged mice more prominently than young mice; C. pluricaulis ameliorates human microtubule-associated protein tau (hMAPτ) induced neurotoxicity in AD Drosophila model; scopoletin and scopolin, significantly and dose-dependently attenuated the scopolamine-induced amnesic effect and also exhibited significant AChE inhibitory activity.”

[72 76]

The anti-oxidant and anti-AChE activity of guggulipid against streptozotocin-induced memory deficits in mice; Zguggulsterone attenuates the scopolamine-induced memory impairments through activation of the CREB-BDNF signaling pathway in C57BL6 mice.

[77, 78]

Caffeoylquinic Acids in C. asiatica reverse cognitive deficits in male 5XFAD AD Model mice; raw-extract C. asiatica (RECA) inhibited AChE, inflammations, and oxidative stress activities Assam, Bihar, via. in vitro and in vivo; the water extract of C. asiatica (CAW) siatic acid, madecassic Kerala, Madhya improves cognitive and mitochondrial function and activates acid, asiaticoside, stimulatory-nervine tonic, Pradesh, the nuclear factor erythroid 2-related factor 2 (NRF2) regulated madecassoside, and rejuvenate, sedative, anxiolytic, Manipur, anti-oxidant response pathway in aged mice; orally [78 madasiatic acid, and intelligence promoting Odisha, administered GKW attenuated β-amyloid-associated behavioral 85] betulinic acid, thankunic property, Wound Healing, Rajasthan, abnormalities in Tg2576 mice; C. asiatica extract protects acid, and isothankunic Cardioprotective, anti-depressant against amyloid β1–40-induced neurotoxicity in neuronal cells Tamil Nadu, acid Sikkim by activating the anti-oxidative defense system; CA could alleviate d-gal/AlCl3 induced AD-like pathologies in rats via. inhibition of hyperphosphorylated tau (P-tau) bio-synthetic proteins, anti-apoptosis, and maintenance of cytoarchitecture

Kerala

Methanolic extracts of C. crista (MECC) dose-dependently bonducin, sitosterol, ameliorated the aluminum-dependent cognitive impairment by hepatsane, Nootropic / Memory Enhancer, diminution of neuron loss and pyknosis in the CA1 and CA3 furanoditerpenes- άanthelmintic activity, antiregions of the hippocampus, AChE hyperactivity, caesalpin, ß-caesalpin, γamyloidogenic activity, [86 neuroinflammation, and oxidative stress in the hippocampus caesalpin, δimmunomodulatory, analgesic, 88] and the frontal cortex in rats brain; C. crista aqueous extract caesalpin, εantipyretic, anti-inflammatory, could able to inhibit the A(42) aggregation from monomers and caesalpin,and Fanti-tumor, anti-oxidant activity oligomers and also able to dis-aggregate the pre-formed fibrils caesalpin which proved anti-amyloidogenic property.

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(Table ) cont..... S. No.

10.

11.

12.

13.

Plant Biological Source

Ginkgo biloba (Ginkgo)

Asparagus racemosus (Shatavari)

Terminalia chebula (Harad)

Celastrus paniculatus Wild (Jyotishmati/ Malkangani)

Sesbania 14. grandiflora (Agati)

Family

Ginkgoaceae

Asparagaceae

Origin in India Chemical Constituents

Kashmir

Assam, Kashmir, Maharastra, Odisha, Kerala

Pharmacological Activities

Experimental Studies

Refs.

G. biloba extract inhibited neuroinflammation, reduced cognitive deficits and synaptic impairment, enhanced autophagy and degraded NLRP3 in microglia, inhibited Aβinduced microglial inflammatory activation in APP-transgenic mice; G. biloba preparation prevented and treated senile dementia by inhibiting neuroinflammatory responses; G. biloba leaf extract (EGB) attenuated memory impairment and cell apoptosis in galactose-induced dementia model rats by anti-inflammatory, anti-oxidant, activating protein kinase B (PKB) activity in hippocampal cerebral glucose utilization, neuronal cells; EGB increased the activity of motor coquercetin, kaempferol, reduced platelet aggregation, [34, ordination (muscle relaxation) and increased the spatial isorhamnetin, neurotransmitter regulation, and 89 memory and cognitive behavior in dementia induced Wistar Ginkgolides A, B, C, and vasomotor effects, anti95] rats; Co-administration of EGb 761 and donepezil exerted J and bilobalide amyloidogenic anti - Aβ better anti-amnestic effect via. further enhanced pro-cholinergic aggregation activity and anti-oxidative effects of EGb 761 or donepezil in scopolamine-induced cognitive impairment rat without alteration in their systemic/brain exposure; G. biloba extract decreases scopolamine-induced congophilic amyloid plaques accumulation in male rat's brain; Ginkgo extracts protected against Aβ42-induced electrophysiological alterations; EGb761 attenuates hyperhomocysteinemia-induced AD-like tau hyperphosphorylation and cognitive impairment in rats. steroidal saponinssarsasapogenin, asparagine, arginine, tyrosine, flavonoids (kaempferol, quercetin, and rutin), resin, and tanninsteroidal glycosides (asparagosides), bitter glycosides, asparagines, shatavarins I

Phytoestrogenic activity, Antioxidant, Anti-inflammatory, Anticancer, Cardioprotective, Immunoadjuvant, antiamyloidogenic activity

Sarsasapogenin significantly inhibits key enzymes involved in the pathogenesis of AD which are acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE1, and MAO-B in a concentration-dependent manner; neuroprotective activity of A. racemosus against ethanol-induced cognitive impairment and [96 oxidative stress in rats brain indicated by improved learning 99] and memory behavior and decreased AChE activity; antiamnesic effect of A. racemosus root extract in scopolamine-induced amnesic mice by reducing and improving the transfer latency in elevated plus maze and passive avoidance model respectively.

Combretaceae

Ethyl acetate extract of T. chebula (TCEA) contained methyl N-(N-benzyloxycarbonyl-beta-l-aspartyl)-beta-d-glucosaminide showed potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities; 7- Methyl Andhra Pradesh, immunosuppressive, gallic acid (7-MG) enhanced cholinergic deficit through Bihar, Himachal antidiabetic, neuroprotective, anticholinesterase activity and blocked aggregation of Aβ Pradesh, gallic acid, ellagic acid, anti-inflammatory, peptides, disaggregated preformed fibrils; prevented Karnataka, tannic acid, ethyl gallate, antimutagenic, cardioprotective, scopolamine-induced amnesia via. cholinergic modulation and [100 Kerala, Madhya chebulic acid, chebulagic antioxidant, anticancer, anti-oxidative effects in mice; exhibited significant Pradesh, acid, corilagin, mannitol antimicrobial, 106] improvement in learning and memory activity in ethanolMaharashtra, immunosuppressive, improved induced cognitive impairment and diazepam induced amnesia Odisha cognition and modulate the oxidative stress; the T. chebula water extract (TWE) delayed the paralysis induced by Aβ in transgenic and/or RNA interference C. elegans, reduced the production of Aβ oligomers and also had the anti-AchE effect that exhibited the physiological function of cognitive improvement.

Celastraceae

C. paniculatus increases cholinergic activity that contributes to its ability to improve memory performance; the protective effect of C. paniculatus against 3-NP induced neurotoxicity could be due to its strong antioxidant effect and its role against Himachal glutamate toxicity by inhibiting NMDA receptors; C. Pradesh, Punjab, Saponin, β-sitosterol, paniculatus has cholinesterase inhibitory and antioxidant Haryana, Uttar Pristimerin, Zeylasteral, activity; cognitive enhancement and neuroprotective effects; C. Pradesh, Bihar, Terpenes, Zeylasterone, anti-arthritic, hypolipidemic and paniculatus seed oil has a memory-enhancing effect on spatial CelastrolAlkaloids like antioxidant, central nervous West Bengal, and fear memory using scopolamine-induced amnesia in mice; [107 Celastrine and system, antifertility, analgesic, Sikkim, Assam, CPPME showed nootropic activity in rats probably by Paniculatin, Fatty acids, and anti-inflammatory and Arunachal inhibiting brain AChE activity and also improved in learning 111] Acetic acids, Benzoic cardiovascular Pradesh, and memory of rats, as indicated by the decline in transfer Nagaland, acids, Sterol and latency using elevated plus maze and also decrease in escape Meghalaya, tetracasanol latency during training and retrieval using morris water maze; Maharashtra C. paniculatus oil was observed to have remarkable effects in raising the levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the brain. Significant improvement was also observed in the retention ability of the phenytoin-induced cognitive impairment in mice.

Fabaceae

Kerala, Tamil Nadu, Karnataka, Anti-tuberculosis, Anti-diabetic, tanins, isovestitol, Andhra Pradesh, Hepatoprotective, Antioxidant medicarpin, and sativan, Maharastra, and Cardioprotective, Antibetulinic acid, Madhya cancer, Anti-inflammatory, coumarins, steroids and Pradesh, immunomodulatory triterpenes Chhattisgarh, activity West Bengal, Assam, Punjab

Acetone ethanol extract of S. grandiflora fruits inhibited the rise in brain AChE and cholesterol level in high-fat dietinduced dementia in rats; cognition-enhancing potential of S. grandiflora fruit extract in scopolamine-induced amnesia in mice proved through an increase in transfer latency, AChE inhibition, decreased MDA level and increased GSH level

[112 115]

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(Table ) cont..... S. No.

15.

Plant Biological Source

Lycopodium serratum (Club moss)

Family

Lycopodiaceae

Origin in India Chemical Constituents

Karnataka, Maharastra, Madhya Pradesh, West Bengal

Pharmacological Activities

Experimental Studies

Refs.

serratidine and oxolycoclavinol, Lycosquarosine A derived from L. serratum (LS) has a potent oxoserratenetriol, AchE inhibitor activity; LS showed AChE inhibitory activity tohogeninol, and anti-inflammatory, anti-oxidant, and antioxidant effects; huperzine (Hup): the neuroprotective [116 tohogenol. huperzine A, and anti-microbial actions and effect of Hup a is attributed to resisting N-methyl-d-aspartate lycopodine, lycoflexine, inhibits AChE activity receptors and regulating nerve growth factor. Moreover, Hup a 120] Alpha-onocerin, and has effects on reducing iron in the brain for treating AD. sporopollenin, lycosquarosine A

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CHAPTER 15

Neuroprotective Effect of Natural Products in Attenuation of Aging-associated Neurodegeneration Abhai Kumar1 and Rameshwar Nath Chaurasia1,* Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi221005 (U.P.), India 1

Abstract: Age-associated neurodegenerative disorders are a growing cause of mortality and morbidity in the elderly population globally. The patients suffering from neurodegenerative disorders pose medical, economic, and social issues. The agingassociated neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), have different clinical and neuropathological signatures, but they share a pattern of neurodegeneration in anatomical and functionally related regions. Natural products offer great potential in the prevention and therapy of neurodegenerative diseases. Plant-derived products protect neurons by targeting oxidative stress, mitochondrial dysfunction, neurotrophic factor deficit, and abnormal protein accumulation. The current chapter discusses the neuroprotective effect of natural products in the prevention of aging-associated neurodegenerative disorders.

Keywords: Alzheimer’s disease, Cognition, Cytokines, Oxidative stress, Parkinson’s disease. INTRODUCTION The life span of the elderly population is increasing globally. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the main age-associated neurodegenerative disorders, predominantly found in the elderly population [1 - 3]. The etiology of these disorders is unknown, but the pathological hallmark for these disorders includes degeneration of a specific population of neurons and deposition of disease-specific inclusion bodies. The genetic and environmental factors regulate various pathogenic factors, including inflammation, accumulation of modified proteins, impaired homeostasis of energy, transition metals (iron, copper), hormones (insulin, estrogen for women), deficits of neurotrophic factors (NTFs), Corresponding author Rameshwar Nath Chaurasia: Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India; E-mail: [email protected] *

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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oxidative stress, mitochondrial dysfunction, and activation of programmed cell death in age-associated neurodegeneration [4, 5]. The changes in memory, cognition, and behavior are manifested due to neurodegeneration in Alzheimer’s disease. The accumulation of intracellular hyperphosphorylated tau proteins known as neurofibrillary tangles and the deposition of extracellular amyloid-beta (Aβ) plaques are the main pathological hallmark of the disease [1, 6]. Parkinson’s disease is caused by the accumulation of Lewy bodies, Lewy neurites, and misfolded protein aggregate of presynaptic protein alpha-synuclein, resulting in the loss of dopaminergic nigrostriatal neurons [7]. The loss of motor function, muscular rigidity, bradykinesia, and postural imbalance are visible symptoms of Parkinson’s disease [7]. Neuroprotection prevents and delays the process of neurodegeneration by targeting changes occurring at the pathophysiological level. Natural products have been known for their therapeutic properties since ancient times. Research on nutritional values, biological activities, and therapeutic potential of natural products has been done in recent years. Studies have reported the therapeutic and preventive potential of natural products and their bioactive compounds against lifestyle diseases, including cancer and neurodegenerative disease [8 - 10]. Natural products and their bioactive component induce neuroprotection by modifying various factors leading to neuronal death, regenerating neuronal networks, and inducing growth factors as a diseasemodifying therapy in age-associated neurodegenerative disorders [8, 11, 12]. Plant-derived phytochemicals and herbal preparations have been proposed as effective against the treatment of AD and PD [13 - 16]. The cognitive functions were improved by the consumption of fruits, tea, vegetables, and red wine due to the presence of flavonoids during clinical trials, but their efficacy has not been fully established [17 - 19]. The natural products and their therapeutic potential in the pathological process of age-associated neurodegenerative diseases will be discussed in detail. NATURAL PRODUCTS AND NEUROPROTECTION The natural products and their active biological constituents having specific targets on pathological processes of neurodegenerative disease to exhibit neuroprotection will be discussed in this section. Honey Honey is a natural sweetener and is used as medicine in traditional therapy. Antioxidants, such as polyphenols and bioactive compounds, are abundantly present in honey. There are more than 200 compounds present in honey, consisting mainly

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of proteins, carbohydrates, vitamins, minerals, volatile substances, and phenolic compounds [20 - 23]. The neuronal damage in the pyriform cortex of the brain induced by kainic acid in the rat model was lowered by pretreatment of honey, which attenuates neuroinflammation, oxidative stress, and apoptosis in the cerebral cortex, cerebellum, and brainstem. The anti-apoptotic and antiinflammatory properties of honey against kainic acid-induced neurodegeneration in an animal model have been well established [24, 25]. Studies report that honey reduces morphological impairment of the hippocampus, medial prefrontal cortex, and oxidative stress in stressed rats [26 - 28]. The honey attenuated cognitive impairment caused by chronic cerebral hypoperfusion-induced neurodegeneration [29]. The repeated paraquat exposure in rat midbrain produces oxidative stress, which decreases with the treatment of honey [30]. The spatial memory performance and morphological impairment of the hippocampus in adult male rats improved by consumption of honey, and these findings were clinically supported by studies done in postmenopausal women who received honey for 16 weeks, which improved total learning and immediate memory [31, 32]. The honey contains various compounds, such as phenolic acids (benzoic, ferulic, syringic, chlorogenic, cinnamic, caffeic, gallic, and coumaric acids), flavonoids (catechin, naringenin, kaempferol, pinobanksin-3-O-propionate, pinobanksin-3-O-butyrate, and quercetin), minerals (potassium, calcium, sodium, and magnesium), amino acids (aspartic acid, serine, glutamic acid, glycine, threonine, alanine, proline, tyrosine, valine, methionine, lysine, isoleucine, and leucine) and vitamins (vitamin B3 and vitamin C) [33 - 36]. At different stages of neurodegeneration, honey exerts its neuroprotective effect, mainly at early events. The attenuation of oxidative stress, inflammation, and apoptosis by honey and its bioactive compound makes it a potential candidate for improving cognitive and spatial memory performance. The bioactive compounds, mainly phenolic acids and flavonoids, present in honey exert a synergistic effect on neuroprotection against neurodegeneration. Polyphenols, which are one of the main constituents of honey, reduce oxidative stress, neuroinflammation, improve memory, learning, cognitive function, and protect against neuronal injury and neurodegeneration [37, 38]. Propolis It is a resinous mixture produced by bees and is used as a defense against intruders and the reconstruction of beehives. Propolis is composed of resins, balms, wax, amino acid, essential oils, pollen, micronutrients, vitamins, and other organic compounds [39, 40]. The organic compounds found in propolis include phenolic compounds, flavonoids, terpenes, aromatic aldehydes, and alcohols [41]. The plant source, geographical origin, and season of collection determine the chemical composition and properties of propolis [40]. Propolis possesses various

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biological and pharmacological properties, such as antifungal, anticancer, antidiabetic, anti-inflammatory, and antioxidant activities [41, 42]. The beneficial effect of propolis is attributed to its bioactive compound and its combined effect. Studies suggest that in kainic acid-induced excitotoxicity rat model, propolis attenuated nitric oxide level, glutamine synthetase activity, oxidative stress, tumor necrosis factor-alpha (TNF-α), and caspase-3 activity, resulting in prevention of seizures and neuronal loss [43, 44]. The hydrogen peroxide leading to mitochondrial dysfunction and oxidative damage in human neuroblastoma (SHSY5Y) was reduced by Brazilian green propolis, indicating that propolis attenuates oxidative stress in neuronal cells [45]. The propolis induces brainderived neurotrophic factor (BDNF) by reversing the impairment caused by interleukin-1β and fibrillar Aβ at the synapse, thereby increasing the expression of critical factors of synapse efficacy, ameliorating cognitive impairment, and preventing neurodegeneration through its antioxidant properties [46]. Studies support that Brazilian propolis and its component (caffeoylquinic acid derivatives, tefillin C, and p-coumaric acid) prevent oxygen-glucose deprivation/reoxygenation-induced neuronal damage and retinal damage in vitro [46, 47]. The treatments of ethanolic extract of Indian propolis in an animal model of Alzheimer’s disease reversed cognitive impairment, inhibited acetylcholinesterase activity, increased monoamine level, and improved memory level by increasing brain-derived neurotrophic factor (BDNF) level in plasma of Aβ-induced rats [48]. The study indicated that Indian propolis acts through multiple mechanisms of action, providing neuroprotection against Aβ-induced neurodegeneration [48]. The water-extracted brown propolis restored the antioxidant enzyme level, decreased LPO, and reduced infarct volume in cerebral ischemia-induced oxidative injury stroke in a mouse model [49]. The sensorymotor impairment and neurological deficits were improved by water extract of brown propolis. These findings indicate that propolis activates the endogenous antioxidant enzyme system and prevents neuronal damage resulting from oxidative damage following stroke [49]. Withania somnifera Indian Ginseng is another name for W. somnifera, which is a very popular medicinal plant in Ayurveda, belonging to the family Solanaceae. It is a perennial herb covered with hairs; each part of the plant is used for medicinal purposes due to the presence of different phytochemicals. The chemical constituents extracted and isolated from different parts of the plant include steroidal lactones, alkaloids, flavonoids, tannin, withanolides, and several sitoindosides [50]. The pretreatment with ethanolic extract of W. somnifera reduced oxidative stress in an animal model of PD and increased catecholamine content in 6-hydroxydopamine- (6-

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OHDA) induced rats [50]. The administration of root extract of Withania somnifera in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model of PD improved behavioral alterations of mice in the rotarod test, hanging test, stride length measurement, and increased anti-oxidant enzymes, striatal catecholamine level and reduced LPO [51, 52]. The extract of W. somnifera in a rotenone-induced mouse model of PD reduced nitric oxide (NO) levels, LPO, and increased the level of anti-oxidant enzymes [53]. The extract of W. somnifera reduces oxidative stress and restores mitochondrial dysfunction through its antioxidant properties. Further, studies report that extract of W. somnifera attenuated the increase in acetylcholinesterase (AChE) activity and restored dopamine levels [54]. The randomized clinical trial of W. somnifera in a double-blind, placebo-controlled study showed very promising results in terms of the improvement of cognitive functions in mild cognitively impaired subjects and amelioration of cognition in adults suffering from bipolar syndrome [55, 56]. The cognitive and psychomotor performance of healthy individuals improved after intake of W. somnifera [57]. Studies suggest that components, like withanoside IV, withanone, withaferin A, withanolide A, and other compounds present in Withania somnifera have a synergistic beneficial neuroprotective effect against the pathogenesis of the neurodegenerative disease [58 - 60]. Ginseng Traditional medicine is widely used in China, Korea, and Japan, and is frequently studied as Panax ginseng. The perennial herb belongs to the Panax genus of the Araliaceae family. Ginseng and its chemical constituents have exhibited various antioxidant, anti-inflammatory, anti-apoptotic, anti-cancer, anti-fatigue, antidiabetic, and anti-aging properties [61]. The ginseng and its active constituent ginsenosides, and derivatives ginsenosides Rb1, Rd, Re, and Rg1 have a beneficial effect on the central nervous system [61, 62]. The MPTP-induced PD mice model exhibited improvement in behavioral impairment, inhibited dopaminergic neuronal death, decreased cyclin-dependent kinase5 (Cdk5) expression, p25 expression, and increased p35 expression in substantia nigra (SN) and striatum (ST) [63]. Further, MPTP-induced proteomic changes in ST were restored by the usage of Korean red ginseng [63]. The protein expression was alleviated by Korean red ginseng in SN, which involved neurodevelopment and energy metabolism for neuronal survival and neuroprotection [64]. The Korean red ginseng treatment inhibited cell death, apoptosis, and expression of caspase-3 and caspase-9 in rat pheochromocytoma (PC12) cells following 1-methyl4-phenylpyridinium ion (MPP+) exposure [65]. Further, MPTP-induced mice treated with Korean red ginseng have enhanced differentiation and proliferation of neural stem cells in the subventricular zone and improvement in behavioral

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dysfunction [66]. Studies reported that Korean red ginseng extract suppressed proinflammatory modulator expression, inhibited microglial and astrocyte activation in SN and ST of MPTP-induced mice [66]. Studies also revealed that pretreatment with Korean red ginseng extract decreased phosphorylation of extracellular signal-related kinase (ERK), Jun-N-terminal kinase (JNK), and p38 protein, and inhibited blood-brain barrier disruption [54]. The increase in nuclear factor erythroid 2-related factor2 (nrf2) protein expression, heme oxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), quinine oxidoreductase-1 (NQO1), and gamma-glutamate cysteine ligase regulatory subunit (GLC) after Korean ginseng treatment in PD animal models was reported [67]. The pretreatment of Korean red ginseng in MPTP-induced mice restores motor functions by alleviating dopaminergic (DAergic) neurons through activation of nuclear factor erythroid 2-related factor (Nfr2) pathway and inhibition of mitogen-activated protein kinase (MAPKs), nuclear factor kappa light chain enhancer of activated B cell (NF-κB) induces activation of antioxidant, anti-apoptotic, anti-inflammatory activity in DAergic neurons, and maintain the integrity of blood-brain barrier (BBB), by inhibiting the cleavage of p35 to p25 through suppression of overexpression of Cdk5 [67]. The study done on MPP+-induced cytotoxicity in SH-SY5Y cells with water extract of Panax ginseng prevented cellular morphological deterioration, DNA fragmentation, and percentage of apoptotic cell, and attenuated the ratio of Bax/Bcl-2 ratio, cytosolic cytochrome-c, and cleaved caspase 3, indicating neuroprotective effect [68]. The extract also attenuated the accumulation of intracellular calcium Ca+2 and the release of intracellular reactive oxygen species (ROS) in MPP+-induced cytotoxicity in SH-SY5Y cells [68]. The water extract of Panax ginseng enhanced the learning and memory ability in the rat model of Alzheimer’s disease; it further reduced oxidative damage and inhibited the receptor for the advanced glycation end product, RAGE and NF-κB, expression in the cortex and hippocampus of advanced glycation end (AGE) product-induced rats [69]. The amelioration of memory impairment in scopolamine-induced amnesic mice and reduction of Aβ42 accumulation in transgenic mice by treatment of fermented ginseng and fermented Panax ginseng signify that these natural products have the potential to mitigate AD-like pathophysiological changes through downregulating RAGE and inhibiting NF-κB activation [70]. The clinical efficacy of Panax ginseng in enhancing cognitive performance in AD patients has been found in an open-label study [71]. The bioactive compound ginsenoside Rd found in ginseng has favorable pharmacokinetic and safety profile in healthy adults [72]. Further, the efficacy of the bioactive compound ginsenoside Rd was found to improve neurological deficits in acute ischemic stroke patients and did not promote severe adverse health outcomes [73].

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Curcumin Curcumin is the phytochemical derived from the rhizome of Curcuma longa and is present in Indian turmeric. Curcumin has been used for a long time in traditional Indian and Chinese medicines as a wound-healing agent and for treating a variety of diseases. The anti-inflammatory and anti-proliferative properties of curcumin that induce signaling pathways leading to the death of cancer cells through various modes have been well established [74]. Furthermore, curcumin’s role in the prevention of various diseases involving inflammation as a major causative factor has attracted research interest worldwide [75]. The role of curcumin as a potential remedy against aging-associated neurodegenerative disorders was supported by encouraging results from pilot clinical trials in AD patients [76]. Curcumin can cross BBB because of its lipophilic characteristics; its bioavailability is very low due to rapid metabolization, although it reaches the brain in sufficient quantity, activating the signal transduction pathway and inhibiting Aβ aggregation [77]. Epidemiological evidence suggests that the prevalence of AD in the Indian population is 4.4 times lower than in the United States because curcumin is one of the most prevalent nutritional and medical compounds used by the Indian population [78]. Further, studies report that elderly Singaporeans who ate curry with turmeric had higher Mini-Mental State Examination scores as compared to individuals whose diets were without turmeric [79]. The neuroprotective effect of curcumin is due to its antioxidant effect, which can prevent degeneration of SN neurons and increase striatal dopamine counts, chelating Fe2+ in the 6-OHDA-intoxicated rat model of PD [80]. Several studies have shown that curcumin exerts mitochondrial protection in various PD models; thus, the dietary consumption of curcumin offers neuroprotection against PD [81]. Similarly, the striatal dopamine (DA) and 3,4-Dihydroxyphenylacetic acid (DOPAC) levels increase following curcumin injection in MPTP (1-methyl4-phenyl-1,2,3,6 tetrahydropyridine) injected mice [82]. The beneficial effect of curcumin on PD patients has not been tested clinically; however, the promising therapeutic potential observed in animal models of PD will provide new strategies for neuroprotection in PD. Uncaria rhynchophylla U. rhynchophylla is a medicinal herb belonging to the family Rubiaceae used in traditional Chinese medicine. The main active components found in U. rhynchophylla are hirsutine, hirsuteine, coronatine, corynoxine, isorhynchophylline, rhynchophylline, and dihydrocorynantheine. The neuroprotective efficacy of the alkaloid rhynchophylline and isorhynchophylline has been widely studied [83]. The U. rhynchophylla extract suppressed free

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radical generation and LPO in the kainic acid-induced excitotoxicity rat model [84]. The reduction in microglial activation, attenuation of inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), and apoptosis by extract of U. rhynchophylla in the prevention of neuronal damage in a kainic acidinduced animal model has been reported [85]. The inhibition of expression of S100 calcium-binding protein B (S100B), reduced epileptiform discharge, and increase neuronal survival in the hippocampus was observed by pretreatment of U. rhynchophylla extract before kainic acid administration [86]. The methanolic extract of U. rhynchophylla in an experimental model of global ischemia inhibited COX-2 mRNA and protein levels in the hippocampus of rats and inhibited TNFalpha, NO levels in BV-2 microglial cells [87]. U. rhynchophylla disassembled the preformed fibril of Aβ formed in Aβ [1 - 40] and Aβ [1 - 42] and inhibited the formation of Aβ fibril in the AD model [75]. The neuroprotective effect of U. rhynchophylla in the PD experimental model has been reported; Shim and coworkers found that U. rhynchophylla treatment reduced neuronal cell death and free radical generation, restored reduced glutathione level, and prevented caspase3 activity in 6-OHDA induced toxicity in PC12 cells, and also reduced neuronal loss in DAergic neurons in SN in 6-OHDA-induced rats [88]. The MPTP-treated PD mouse model and MPP+-induced SH-SY5Y cells after treatment with extract of U. rhynchophylla increased the cell viability, attenuated DAergic neuronal loss in SN, and inhibited heat shock protein 90, thereby inducing autophagy through MAPKs and P13K-serine/threonine-protein kinase (Akt) pathways [89, 90]. The U. rhynchophylla exhibits neuroprotection through the activation of multiple pathways in the presence of bioactive compounds or their synergistic action, preventing neuronal damage. Cyanobacteria The cyanobacteria are also called blue-green algae; these are autotrophic, photosynthetic organisms that possess potential pharmacological and therapeutic potential against various medical conditions [91, 92]. S. platensis is planktonic multicellular filamentous cyanobacteria that belong to the family Oscillatoriaceae. The nutritive value of S. platensis is very high, it contains protein, polysaccharides, carotenoids, polyunsaturated fatty acids (PUFAs), minerals, and vitamins [93]. The polysaccharide derived from S. platensis increases glutathione peroxidase (GPX), superoxide dismutase (SOD), anti-oxidant enzymes in the serum and attenuates mRNA expression of tyrosine hydrolase (TH), dopamine transporter (DAT) and decreases DA level by increasing DA metabolism in SN of PD (PD) mice model-induced by MPTP treatment [94]. The activity of monoamine oxidase B (MAO-B) in serum and midbrain was unaltered in MPTPinduced PD mice [34]. The anti-oxidant enzyme system induced by S. platensis

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provides neuroprotection to DA neurons and increases DA levels without altering the expression of MAO-B. The other cyanobacterium S. maxima that belongs to the family of Oscillatoriaceae includes chlorophylls, carotenoids, vitamins, polysaccharides, and C-phycocyanin [95]. S. maxima decreased the expression of Aβ [1 - 42] in the hippocampus and impairment in memory was ameliorated by an increase in learning and memory performance in passive avoidance and the Morris maze water test in an AD mouse model [96]. These findings indicate that S. maxima prevents cognitive decline by inhibiting the acetylcholinesterase activity and accumulation of Aβ. The anti-oxidant glutathione reduced (GSH) level was found to be increased and a decrease in glutathione reductase (GSSH), glutathione peroxidase (GPX), and the expression level in the hippocampus of Aβ [1 - 42] induced mice by treatment of S. maxima was also reported [96]. This suggests that S. maxima inhibits oxidative stress and thereby decreases acetylcholinesterase (AChE) activity and Aβ accumulation. Further, studies report that S. maxima extract increased Brain-derived neurotrophic factor (BDNF) level, suppressed phosphorylated glycogen synthase kinase-3β (GSK3β), upregulated the phosphorylated P13K and phosphorylated Akt in the hippocampus of Aβ [1 - 42] mice [96]. This finding suggests that different species of cyanobacteria have the potential to prevent age-associated neurodegenerative disorders. CHALLENGES AND FUTURE PERSPECTIVE Natural products and their bioactive compounds have shown very promising results in the prevention and development of therapeutic drug discovery for neurodegenerative diseases; however, the translation of neuroprotective effects in a preclinical setting has not provided any promising result in clinical therapies for neurodegenerative diseases. The major challenges that underlie natural products and their isolated natural compounds are their low bioavailability, physiochemical instability, rapid metabolism, limited water solubility, and blood-brain barrier permeation capacity [96]. Several compounds, like curcumin, phytochemicals, and alkaloids have low bioavailability at the cellular level and active biotransformation at the physiological level, which converts them to inactive metabolites, thereby limiting their effectiveness. Moreover, the majority of the natural compounds could not access the specific site of action in the brain due to their limitation to cross the blood-brain barrier. Nowadays, the use of nanoparticles and their conjugation with bioactive natural products have increased their accessibility to the site of action and therapeutic response in various neurodegenerative diseases. The most widely used nanoparticles are solid lipid nanoparticles, nanogels, polymeric nanoparticles, complexes with dendrimers,

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liposomes, micelles, and crystal nanoparticles. The promising results of natural products like epigallocatechin-3-gallate and curcumin for the treatment of AD and other neurodegenerative diseases have been reported [97]. The natural products due to their efficacy and bioavailability and their compounds in conjugation with nanoparticles can develop new therapeutic drugs for neuroprotection in ageassociated neurodegenerative disorders. CONCLUSION The potential of natural products and their bioactive metabolites in the prevention and treatment of neurodegenerative diseases has been successfully tested in experimental studies. The findings from preclinical experiments have also been tested in clinical studies, which have provided promising results, although low bioavailability, physiochemical instability, rapid metabolism, and membrane permeability limit their usage in transforming therapeutic drugs for neurodegenerative diseases. The pathological process in age-associated neurodegenerative disorders involves multifactorial pathways, which are specifically targeted by natural products and their bioactive metabolites. The natural products and their bioactive metabolites have no harmful side effects in the treatment of neurodegenerative disorders, although their bioavailability and stability in physiological conditions can be increased by using nanotechnology approaches. The clinical trials for natural products and their bioactive compounds are required in the context of neurodegenerative disorders to develop efficient therapeutic approaches for neuroprotection. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS The authors acknowledge the Cognitive Science Research Initiative program of the Department of Science and Technology, Govt. of India, for grant support (CSRI/PDF-2018/63) to Abhai Kumar. REFERENCES [1]

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301

SUBJECT INDEX A Abnormalities 146, 181, 193, 198, 200, 253 inhibiting emotional 200 mitochondrial 146 neurobiological 193 Acetylcholinesterase 84, 90, 105, 271, 292 activity 84, 105, 292 inhibitors 90, 271 Acid 3, 8, 55, 58, 89, 106, 108, 111, 113, 114, 116, 117, 171, 194, 195, 196, 220, 252, 253, 272, 273, 274, 286 aminobutyric 252, 253 aspartic 286 betulic 171 betulinic 8, 273, 274 Brahmic 171 brahminic 8 caffeic 111, 196 chebulic 274 cinnamic 195 commiphorinic 273 gallic 3, 89, 274 gamma-aminobutyric 55, 194 glutamic 286 glycyrrhetinic 113, 114 glycyrrhizic 113, 114, 117, 272 hydroxycinnamic 195 isobrahmic 8, 171 madasiatic 273 madecassic 108, 116, 273 protocatechuic 111 quinolic 106 quinolinic 220 retinoic 58 Agents 7, 53, 85, 166, 168, 170, 192, 222, 266, 267 anti-epileptic 168 anti-inflammatory 192 effective anti-neoplastic 85 neurodegenerative 53 neuroprotective 7, 166, 222

therapeutic 170 Allium sativum 103, 105 Alzheimer’s treatment 273 Ameliorating lipid peroxidation 132 AMP-activated protein kinase 40, 68, 234 Amyloidosis 111 Amyloid precursor protein (APP) 59, 60, 106, 107, 235, 269, 273 Amyotrophic sclerosis 243 Angiogenesis 27 Anthelmintic activity 273 Anti-amyloidogenic activity 106, 273, 274 Antibacterial activity 86 Anti-cancer activities 130, 273 Anti-cholinesterase activities 82, 114, 117, 272 Anti-depressant 92, 137, 153, 198, 199, 200, 202, 203 activity 92, 137, 153, 200, 203 effect 198, 202 properties 153, 198, 199, 200 Anti-diabetic activity 151 Antifungal activity 86 Anti-inflammatory 13, 15, 26, 65, 88, 89, 112, 116, 136, 152, 155, 183, 203, 289 activities 88, 89, 136, 152, 183, 289 cytokines 26 effects 15, 26, 89, 112, 116, 136, 155, 203 functions 13, 65, 152 Anti-neuroinflammatory 82, 88, 89, 135, 136 activity 88, 89, 135, 136 properties 88 Anti-oxidant action 111 Anxiolytic 109, 168, 196, 197, 198, 200, 201, 213, 222, 272 action 109 activities 168, 272 effect 196, 197, 198, 200, 201, 213, 222 Apoptosis 47, 48, 66, 112, 114, 116, 117, 136, 215, 216, 217, 219, 258, 259, 286 inducing factor (AIF) 114 Aromatic aldehydes 286

Surya Pratap Singh, Hareram Birla & Chetan Keswani (Eds.) All rights reserved-© 2023 Bentham Science Publishers

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Artoindonesianin 115, 116, 117 Aspergillus niger 86 Atherosclerosis 202, 257 Autism spectrum disorders (ASDs) 184 Autoimmune disease 58

B Bacillus subtilis 86 Bipolar syndrome 288 Blood-brain barrier dysfunction 30 Bradykinesia 4, 7, 14, 15, 28, 104, 115, 181, 285 Brain 26, 27, 30, 48, 52, 53, 54, 56, 57, 67, 88, 90, 92, 104, 105, 107, 108, 111, 112, 113, 130, 137, 155, 161, 162, 164, 165, 166, 182, 191, 193, 194, 198, 200, 201, 203, 218, 219, 220, 238, 253, 257, 266, 287 atrophy 253, 266 cancers 130, 137 deposition 105 derived neurotrophic factor (BDNF) 27, 30, 56, 182, 191, 194, 198, 200, 201, 203, 220, 238, 287 diseased 166 functions 48, 52, 53, 56, 57, 130, 164, 165 healthy 130 imaging techniques 92 injuries 88, 112 ischemia 218 neurotransmitters 193 protein 26 Brain damage 66, 114, 233, 236, 238 reduced 114 stroke-induced 233 Brain diseases 130, 257 neurological 257

C Calcitonin gene-related peptide (CGRP) 254 Cancer 65, 85, 164, 170, 202, 214, 231, 233, 257, 273, 285 breast 85 cell proliferation 231 lung 85 ovarian 85 prostate 85

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Candida albicans 85 Cardiovascular diseases 86, 202 Cerebral ischemia 115, 218 Cerebrovascular diseases 130, 269 Chicken infectious anemia virus (CIAV) 131 Chinese medicines 231, 290 Cholinergic 259, 265, 271 hypothesis 265, 271 neurotransmission 259 Cholinesterase 200, 274 activity 200 inhibitory 274 Chromatographic techniques 85 Chronic unpredictable stress (CUS) 199 CNS 11, 26, 84 and peripheral nervous system 84 diseases 11 homeostasis 26 Communicative disorders 245 Complementary therapy 170 Concentration-dependent inhibition 237 Conditions 29, 38, 40, 47, 113, 145, 146, 155, 161, 162, 214, 215, 222, 257 amyloidogenic 113 diabetic 257 neuroinflammatory 40 Coronary heart disease 231 Corticosterone injection 220 Curcuma longa 1, 4, 177, 179, 273, 290

D Defects 242, 258, 259 genetic 258, 259 reducing mitochondrial 242 Degeneration 65, 133, 271 neurofibrillary 271 neuron 65 oxidative 133 Degenerative nervous system diseases 145 Dehydrogenases 254 Demalonylase activity 51 Dementia 29, 104, 130, 265, 266, 267, 268, 270, 272, 274 degenerative 268 Depression disorder 57 Diabetes mellitus 67

Subject Index

Diseases 28, 58, 59, 63, 83, 103, 130, 145, 154, 160, 161, 162, 166, 178, 202, 266, 290 degenerative 160 ischemic 166 memory-related 178 neural 166 viral 202 Disorders 4, 58, 63, 130, 131, 136, 146, 155, 160, 162, 163, 169, 170, 173, 284 aging-related neural degenerative 173 genetic 162 hepatic 4 immune-mediated 163 sleep 130, 146 Dizziness 90, 192, 265, 266 DNA 52, 113, 132, 153, 215, 258, 259, 289 fragmentation 113, 258, 259, 289 nuclear 132 oxidation 153, 258, 259 polymerase 52 topoisomerase 215 Drosophila melanogaster 47 Drugs 3, 29, 59, 70, 71, 85, 86, 90, 103, 144, 145, 155, 156, 160, 163, 166, 168, 178, 194 anti-Alzheimer’s 168 anti-cancer 85 neuroprotective 3 nootropic 156, 160 plant-derived 168 release proinflammatory cytokine 29 Dysfunction 194, 266 neurotransmitter 266 sexual 194 Dyskinesias 4, 14, 150 drug-induced 150

E Embryonic stem cells (ESC) 54 Enzymes, secretase 269 Epileptic syndromes 185 ERK pathway 114 Extracellular regulated kinase (ERK) 110, 114, 199, 289

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F Factors 24, 26, 29, 32, 53, 56, 58, 112, 114, 147, 152, 154, 178, 192, 193, 220, 230, 234 anti-aging 230 apoptosis-inducing 114 apoptotic 178 colony-stimulating 24 crucial 53, 56 dietary 154, 178 eukaryotic elongation 234 genetic 154 glial-derived neurotrophic 32 glia maturation 24, 26 neuroprotective 58 neurotoxic 152 pro-inflammatory cytokine transcription 220 release cytotoxic 29 serum response 112 tumor necrosis 26, 29, 147, 192, 193 Fatty acids 5, 91, 151, 245, 258, 274, 291 polyunsaturated 91, 151, 258, 291 Fibrillogenesis 112 Functions 30, 31, 48, 49, 59, 65, 66, 67, 68, 162, 166, 167, 168, 231, 257, 258, 259, 266 anti-apoptotic 68 cholinergic 257 memory-related 168 neurobiological 59

G GABA 110, 197, 257 metabolism 110, 257 transaminase enzyme 197 Gas chromatography-mass spectrometry 88 Gastrointestinal diseases 4 Gene expression 9, 49, 146, 193, 254, 259 inflammatory 146 neurogenic 9 Glial 24, 26, 32, 238 derived neurotrophic factor (GDNF) 32, 238 maturation factor (GMF) 24, 26 Glucocorticoids 70 Glutamatecysteine ligase 237

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Glutamate 30, 48, 50, 105, 237 cytotoxicity 237 decarboxylase 105 dehydrogenase 48, 50 dysregulation 30 Glutathione 7, 110, 133, 146, 154, 253, 257, 291, 292 peroxidase 7, 110, 133, 146, 253, 291, 292 reductase (GR) 154, 257, 292

H High 85, 88, 152 performance thin-layer chromatography (HPTLC) 152 pressure liquid chromatography (HPLC) 85, 88 Hippocampal neurons 56, 57, 137 Homeostasis 25, 29, 193, 230 Huntington's disease (HD) 24, 25, 31, 32, 83, 84, 103, 104, 108, 161, 162, 181, 218, 242, 243

I Immune intolerance 30 Immunomodulatory 6, 84, 129, 131, 215, 273, 274 activity 84, 131, 274 protein 131 Immunosuppressive activity 86 Infections 5, 28, 35, 85, 88, 130, 134, 135, 149, 155, 163, 187, 230, 270 microbial 130 viral 28, 85, 134 Inflammatory 34, 35, 214, 236 bowel disease 214 processes 236 reactions 34, 35 Inhibiting 6, 13, 67, 109, 181, 237 DNA synthesis 237 enzymes 109 microglia activation 13, 67 mitochondrial dysfunction 6 monoamine oxidase 181 Insulin-degrading enzymes (IDE) 254 Intermittent fasting-dietary restriction (IFDR) 136

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L Lateral hypothalamic (LH) 55, 56 Lipooxygenase 107, 111

M Magnetic resonance imaging (MRI) 25, 178 MAPK phosphatase 201 Mechanisms 32, 39, 40, 106, 116, 117, 132, 173, 192, 198, 199, 216, 218, 233, 235, 236, 237, 254, 256 anti-oxidative 192 neuroprotective 32, 173, 198 Mediators 13, 16, 26, 27, 29, 35, 39, 134, 147, 180, 191 inflammatory 13, 16, 27, 39, 134, 147, 180, 191 neuroinflammatory 26, 29 neuroprotective 35 Medicinal 83, 114 plants, neuroprotective 114 properties 83 Melissa officinalis 195 Memory 56, 59, 104, 105, 169 function 56 loss 59, 104, 105, 169 Mental diseases 130 Metabolic syndrome 233 Metabolism 49, 51, 56, 59, 84, 138, 150, 181, 215, 232, 291 glutamine 51 iron 84 Microbial endophytes 83 Microglial 26, 28, 35, 84, 134, 135, 219, 291 activation 26, 28, 35, 84, 134, 135, 219, 291 mediated apoptosis 28 Microgliosis 136 Microtubule-associated protein tau (MAPT) 270 Mild cognitive impairment (MCI) 267, 269 Mitochondria dysfunction 26, 66 Mitochondrial 2, 24, 25, 28, 30, 35, 39, 40, 48, 50, 62, 132, 133, 136, 185, 273, 284, 285, 287, 288 apoptosis 185 derived vesicles (MDVs) 40

Subject Index

dysfunction 2, 24, 25, 28, 30, 39, 40, 132, 133, 136, 284, 285, 287, 288 functions 35, 48, 50, 62, 273 quality control (MQC) 40 Mitochondrion integrity 40 Mitogen-activated protein kinase (MAPK) 15, 30, 67, 114, 180, 199, 289, 291 Modulating signaling pathways 170 Monoamine oxidase inhibitors 194 Motor neuron function 63 MPTP 6, 7, 9, 14, 15, 107, 113, 115, 181, 288, 290 MPTP-induced 133, 135 activation 135 Parkinsonism 133 Multiple sclerosis (MS) 24, 25, 30, 31, 32, 33, 36, 58, 59, 88, 103, 104, 163, 182, 183

N Nausea 90, 193, 245 Necroptosis 117 Necrosis factor 180 Nerve growth factor (NGF) 16, 109, 186, 220, 254, 275 Neural 48, 53, 54, 288 precursor cells (NPCs) 48, 53, 54 stem cells (NSCs) 54, 288 Neuroblastoma cells 110 Neurodegeneration 25, 28, 38, 39, 41, 104 age-related 104 microglia-mediated 38 mitigates 39 neuroinflammation-mediated 25, 28, 41 Neurodegenerative diseases (NDs) 8, 24, 26, 27, 33, 35, 39, 84, 91, 129, 132, 161, 162, 213, 230, 285, 292, 293 age-associated 285 Neurodegenerative disorders 24, 25, 32, 35, 36, 47, 48, 58, 59, 70, 71, 82, 83, 90, 117, 284, 285, 292, 293 age-associated 284, 285, 292, 293 Neurogenerative disease 26 Neuro-hormonal deficiency 148 Neuroinflammation 39, 136 aging-induced 136 and mitochondrial dysfunction 39 Neuroleptic activity 84 Neurological 161, 177, 178, 183, 184, 230, 245

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and communicative disorders 245 diseases 161, 177, 178, 183, 184, 230 Neuromuscular junctions 162, 259 Neuronal 6, 8, 13, 29, 30, 32, 106, 114, 178, 230, 240, 242, 258, 270, 273, 287, 291 activity 8 apoptosis 29, 106 degeneration 6, 32, 242 function 30, 114, 230 health in nerve pathways 258 loss 13, 178, 240, 287, 291 transmission propagation 270 loss 273 Neurons 2, 24, 27, 32, 47, 55, 58, 59, 65, 106, 115, 116, 146, 161, 163, 215, 235, 238, 266, 268, 284 apoptosis of 55, 116 degenerating 32 embryonic 235 Neuroobstructive diathesis 154 Neuroprotective 12, 17, 18, 38, 39, 58, 59, 60, 62, 63, 64, 70, 82, 83, 86, 106, 110, 111, 112, 113, 114, 115, 117, 151, 160, 168, 169, 170, 183, 272 effects 17, 18, 38, 39, 58, 59, 60, 82, 83, 86, 106, 111, 112, 113, 115 function 12, 60, 62, 63, 64, 70, 117, 168, 169 properties 110, 114, 151, 160, 170, 183, 272 Neurotoxin 106, 110, 115, 181 fungal-derived 110 Neurotransmitters 10, 15, 162, 165, 166, 198, 202, 220, 222, 252, 253, 254, 257, 259 inhibitory 162, 257 modulating serotonergic 198, 202 Neurotrophic factors 30, 56, 213, 220, 238, 284 Neurotropic viruses 135 Neutral sphingomyelinase 112 Nitric oxide synthase 31, 220, 291 endothelial 220 inhibition 220 neuronal 291 Nuclear magnetic resonance (NMR) 85, 88

O Obsessive-compulsive disorder (OCD) 31, 221

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Oils 6, 10, 155, 286 medicated 155 soybean 6 Osteoporosis 202 Oxidation 50, 51, 108, 146, 173, 232, 252, 254, 258, 259 enzymatic 232 fatty acid 50, 51 lipid 108, 146, 254 nucleic acid 258, 259 Oxidative damage 63, 68, 91, 106, 109, 117, 132, 133, 253, 269, 273, 287 mitochondrial 63 Oxidative 236, 256 homeostasis 256 stress and inflammatory processes 236 Oxidative stress 16, 39, 109, 110, 116, 129, 132, 133, 134, 151, 166, 217, 234, 253, 254, 256, 257, 258, 274, 286, 287 glutamate-induced 116, 133 immune-mediated 39 Oxygen 2, 67, 91, 133, 165, 166, 218, 234, 238 glucose deprivation 133 intracellular reactive 234

P Paired-helical-filament (PHF) 270 Pathways 203, 215, 216 neurodegenerative 216 neuroendocrine 203 neurological 215 Peripheral nervous systems 47, 82, 84, 162 Phosphate dehydrogenase 254 Poly ADP-ribose polymerases (PARPs) 70 Polymerase chain reaction (PCR) 85 Polyphenol(s) 37, 92, 107, 108, 154, 155, 160, 181, 182, 198, 202, 232, 285, 286 catechin-derived 107 oxidation 232 turmeric-derived 181 Positron emission tomography (PET) 25, 92, 178 Prion’s disease 84 Processes 2, 12, 29, 55, 64, 103, 114, 116, 165, 173, 182, 238, 240, 272, 285 dendritic 55 neuronal 55, 64 oxidative 173

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pathogenetic 238, 240 protein oxidation 116 Proinflammatory cytokines 15, 33, 35, 37, 38, 65, 104, 152 Protein(s) 2, 25, 51, 55, 132, 146, 153, 196, 238, 258, 259, 270, 273 dysfunction 146 enzyme 258, 259 growth-associated 196 misfolding 2, 25, 132 mutant 238 oxidation 153 phosphorylated 270 synaptic 273 tumor suppressor 51, 55 Protein kinase 107, 237, 256, 274 B (PKB) 274 C (PKC) 107, 237, 256 Proteomics techniques 166 Psychiatric disorders 57, 165, 192, 196, 202

R Reactive 24, 26, 28, 30, 35, 39, 84, 114, 132, 146, 151, 178, 180, 233, 235, 253, 256, 258, 259 nitrogen species (RNS) 24, 28, 30, 35, 253 oxygen species (ROS) 24, 26, 35, 39, 84, 114, 132, 146, 151, 178, 180, 233, 235, 253, 256, 258, 259 Resveratrol 233, 235, 237, 239, 241 and neurodegenerative disorders 239 and Parkinson’s disease 241 glycosylated 233 induced protein kinase 237 neuroprotective effects of 233, 235 RNA polymerase 48, 52

S Saccharomyces cerevisiae 47 Scopolamine-induced amnesia 274 Secretion, cytokine 131 Serotonergic 193, 198 neuronal 198 transmission 193 Serotonin 105, 150, 153, 193, 199, 201, 213, 219, 222, 252, 257, 258, 259, 260 neurotransmitter 105

Subject Index

Signal 25, 57, 92, 237, 290 transduction pathway 290 nucleotide polymorphisms (SNPs) 57, 237 photon emission computed tomography (SPECT) 25 positron emission tomography (SPET) 92 Sleep deprivation 133, 136 Sleeplessness 193 Spinal cord injury (SCI) 65, 66 Streptococcus aureus 86 Stress 32, 133, 200 heavy metal-induced 133 neuronal 32 traumatic 200 Stroke 67, 68, 185, 245, 287 Alzheimer’s disease 245 cerebral ischemia-induced oxidative injury 287 hemorrhagic 67 ischemic 67, 68, 185 Systems 62, 132, 153, 198 neurological 132 neuron 62 noradrenergic 198 serotonergic 153

T Tail suspension test (TST) 153, 198, 200, 201, 202, 219 Thin-layer chromatography, high-performance 152 Toxicity, neuronal 32 Traditional medicine systems 6, 214 Transcription activator-like effector nucleases 95 Transcription factors 37, 49, 53, 183 nuclear 53 pro-inflammatory 37 Traumatic brain injury (TBI) 66, 67, 182, 187, 219 Tumor 7, 24, 26, 29, 51, 147, 180, 181, 185, 192, 193, 203 necrosis factor (TNF) 7, 24, 26, 29, 51, 147, 180, 181, 192, 193, 203

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