Glia and Inflammation in Neurodegenerative Disease [1 ed.] 9781616688745, 9781594549847

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Copyright © 2006. Nova Science Publishers, Incorporated. All rights reserved. Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

Copyright © 2006. Nova Science Publishers, Incorporated. All rights reserved. Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

Copyright © 2006. Nova Science Publishers, Incorporated. All rights reserved.

GLIA AND INFLAMMATION IN NEURODEGENERATIVE DISEASE

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Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

Copyright © 2006. Nova Science Publishers, Incorporated. All rights reserved. Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

GLIA AND INFLAMMATION IN NEURODEGENERATIVE DISEASE

M. A. YENARI AND

R. G. GIFFARD Copyright © 2006. Nova Science Publishers, Incorporated. All rights reserved.

EDITORS

Nova Science Publishers, Inc. New York

Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

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All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material.

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This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS.

Library of Congress Cataloging-in-Publication Data Glia and inflammation in neurodegenerative disease / M.A. Yenari and R.G. Giffard (editors). p. ; cm. Includes bibliographical references and index. ISBN:  (eBook) 1. Nervous system--Degeneration. 2. Inflammation. [DNLM: 1. Neurodegenerative Diseases--physiopathology. 2. Inflammation--physiopathology. 3. Neuroglia--pathology. WL 359 G559 2006] I. Yenari, M. A. II. Giffard, Rona Greenberg. QP363.2.G65 2006 616.8'0479--dc22 2005038024

Published by Nova Science Publishers, Inc. New York

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Contents PaRT 1:

BASIC MECHANISMS OF INJURY IN THE CENTRAL NERVOUS SYSTEM

1

Chapter I

Introduction M. A. Yenari and R. G. Giffard

3

Chapter II

The Central Nervous System and Inflammation: Microglia Wolfgang J. Streit, Kelly R. Miller and Kryslaine Lopes

5

Chapter III

The Central Nervous System and Inflammation: Astrocytes Valerie Chock and Rona Giffard

25

Chapter IV

Cell Death Pathways and the Immune Response Jennifer M. Pocock, Claudie Hooper, Emma East and Fleur Jones

41

Chapter V

Glial-Neuronal Cross-Talk in Neurodegeneration Michael P. Flavin

63

PART 2:

NEUROLOGICAL DISEASES AND INFLAMMATION

83

Chapter VI

Inflammation in Stroke Xian Nan Tang and Midori A. Yenari

85

Chapter VII

Interactions of Neuroinflammatory and Neurodegenerative Mechanisms in Alzheimer’s Disease Michael T. Heneka, Magdalena Sastre and Michael Hüll

Chapter VIII

Inflammation in Parkinson’s Disease R. Lee Mosley, Eric J. Benner, Irena Kadiu, Mark Thomas and Howard E. Gendelman

Chapter IX

Hypoxic Ishcemic Insults and Inflammation in the Developing Brain Zinaida S. Vexler

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197

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Contents

Chapter X

Neurotrauma and Inflammation Roberta Brambilla, John R. Bethea and Valerie Bracchi-Ricard

221

Chapter XI

Anti-Inflammatory Treatments for Neurodegeneration Masabumi Minami and Takashi Uehara

241

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Index

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259

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Part 1: Basic Mechanisms of Injury in the Central Nervous System

Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

Copyright © 2006. Nova Science Publishers, Incorporated. All rights reserved. Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 3-4 © 2006 Nova Science Publishers, Inc.

Chapter I

Introduction M. A. Yenari1 and R. G. Giffard2

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1

Dept. of Neurology, University of California, San Francisco & the San Francisco Veterans Affairs Medical Center, San Francisco 2 Dept. of Anesthesia, Stanford University, Stanford, CA

The brain has long been considered an immune privileged organ, meaning that inflammatory cells are excluded due to a relatively impenetrable blood brain barrier (BBB). However, this is not to say that the central nervous system is incapable of eliciting immune responses, as resident inflammatory cells exist within the brain parenchyma. Microglia have long been thought to be the brain’s resident immune cell with myeloid lineage similar to monocytes and macrophages [1]. More recent work in the field has shown that astrocytes, long viewed as “supportive” cells of the brain, are also capable of functions similar to that of more conventional immune cells [2]. For example, astrocytes, when exposed to traditional inflammatory stimuli, changed morphology and can present antigen and express a variety of cytokines. Even neurons in certain settings have been documented to generate immune mediators such as inflammatory cytokines. While exogenous, or blood borne inflammatory cells are known to infiltrate the brain under conditions where the BBB is disrupted, such as trauma, stroke, or multiple sclerosis, endogenous responses, presumably mediated by microglia and possibly astrocytes, have come under intense investigation in a variety of neurodegenerative diseases such Alzheimer’s and Parkinson’s diseases. Such observations have led to the study of immune modulating therapies for diseases not typically thought of as inflammatory. The immune system, while involved in protecting the organism from invading pathogens, eliminating degenerated or unnecessary material, and supporting regeneration, can also cause significant parenchymal damage. Consistent with the latter notion that inflammation in some settings can be detrimental, a number of studies suggest that preventing peripheral inflammatory cell infiltration or activation of endogenous microglia reduces the extent of neurological damage. Such has been the case in studies of experimental Alzheimer’s,

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M. A. Yenari and R. G. Giffard

Parkinson’s, stroke, trauma, and of course, multiple sclerosis. Cell death is now an extensive field of its own, but the regulation of cell death is also important in regulation of the immune response as it pertains to neurodegenerative disease. It is also possible that certain anti-inflammatory environments can limit beneficial effects of inflammation such repair and debris clearance. Recent work has shown that part of the degenerative process in Alzheimer’s is due to an impaired clearance of amyloid, and microglia in some model systems actually seem to support neuron survival. Clarification of what is meant by microglial activation is important. Regardless, it is clear that this field, though widely studied by many laboratories, is still in its infancy, and many questions remain. Is all neuroinflammation necessarily “bad”, and if not, when is it “good”? Do the trophic versus damaging functions of inflammatory cells change with the acuity or timecourse of the disease? How do various cell populations interact under disease conditions? To what extent is the brain’s inflammatory response modulated with development? In this volume, we review the current state of knowledge with regard to immune responses and cell-cell interactions as they pertain to a variety of neurodegenerative diseases. The changing role of inflammation with development is considered. We also present a summary of the various therapeutic strategies employed both in the laboratory and at the clinical level.

References [1]

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[2]

Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996;19(8):312-318. Dong Y, Benveniste EN. Immune function of astrocytes. Glia 2001;36(2):180-190.

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In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 5-23 © 2006 Nova Science Publishers, Inc.

Chapter II

The Central Nervous System and Inflammation: Microglia Wolfgang J. Streit, Kelly R. Miller and Kryslaine Lopes Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL 32610

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1. Introduction A network of microglial cells extends throughout the central nervous system (CNS) forming a ubiquitous system of endogenous immunocompetent cells (Graeber & Streit, 1990). This pervasive system ensures that every part of the CNS is under continuous surveillance and that any disturbance in homeostasis, regardless of its location, receives immediate attention for it is the role of microglia to provide a first line of defense in response to any kind of acute perturbation or injury. Inflammation is the tissue response to injury, and microglia represent the principal parenchymal cell type involved in the neuroinflammation that occurs inevitably as a result of acute CNS tissue injury. Often an injury, such as trauma or ischemia, directly causes irreversible tissue necrosis that can produce large amounts of tissue debris. Removal of tissue debris is the primary and undisputable function of microglial cells, which provide a quintessential source of endogenous CNS macrophages. This appreciation of microglia as brain macrophages has a long history dating as far back as the beginning of the 20th century (Barron, 1995), and it is probably fair to say that the macrophage identity is one of the few facts that is beyond debate when it comes to microglial cell functions. Other aspects of microglial biology have been more controversial, for example, the question of ontogeny, i.e. whether the cells derive from mesoderm or neuroectoderm, was debated for decades but appears to have been resolved in favor of mesoderm (Streit, 2001). One issue that has received much discussion in the past and continues to remain controversial is the issue of the functional significance of activated microglia, i.e. Are activated microglia harmful or beneficial? (Schenk & Yednock, 2002; Schwartz, 2003). This

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issue is of paramount importance within the context of neuroinflammation because in recent years the term neuroinflammation has come to be used more or less synonymously with reactive microgliosis and/or with microglial activation. It is therefore essential to understand and define the features that characterize microglial activation, and summarizing these will be one goal of this chapter. A second goal will be to analyze and retrace the developments that have led to the now prevalent notion that neuroinflammation is a key contributory factor in the pathogenesis of neurodegenerative diseases rather than simply a cellular response to tissue perturbation. We will point out significant caveats in this regard. We will make the point that the diversity in experimental approaches involving both in vivo and in vitro work have created a rather confusing vision of what exactly constitutes an activated microglial cell and what its function may be. While, in theory, there could be multiple states of microglial activation that span the spectrum from beneficial to harmful, there are currently no methods for identifying different functional microglial “isotypes” in situ, yet this would be critical for demonstrating supposedly dangerous, activated cells. Moreover, there is a need for distinguishing between truly activated microglia and ostensibly activated microglia because there is now growing evidence from studies in human brain that some seemingly activated cells may, in fact, be degenerating cells (Streit et al., 2004b; Wierzba-Bobrowicz et al., 2004).

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2. What is Microglial Activation? Although neuroscientists in the early decades of the 20th century, such as Nissl and Spielmeyer, and certainly del Rio-Hortega, were keenly aware that microglia undergo transformation into brain macrophages when CNS tissue is destroyed by injury or disease, research reports dealing with activated (or reactive) microglia were rare until the 1970s. Importantly, the term reactive (activated) microglia was coined and used strictly within the context of in vivo neuropathological studies investigating the tissue response to CNS injury. As we shall discuss later, “activated microglia” currently is being used in a much broader sense to include, most notably, in vitro scenarios which do not mimic the in vivo responses for which the term was intended. Thus, “activated microglia” nowadays can have a very different meaning depending on whether it is used by an in vitro or an in vivo investigator. Microglia function not only as phagocytes, but are highly dynamic cells that display exceptional morphological and functional plasticity. In the quiescent brain, microglia are described as “resting”, based primarily on their morphological characteristics. Contrary to what this classification may suggest, it has long been the working assumption that resting microglia are in fact busy monitoring their microenvironment in an attempt to maintain homeostasis within the CNS. This assumption was confirmed recently through in vivo experiments revealing extremely motile processes and protrusions on resting microglia in the living neocortex of mice (Nimmerjahn et al., 2005). Distributed along their processes and on the cell body are a plethora of surface receptors and ion channels, allowing microglia to detect and respond to myriad signals, such as neurotransmitters, neuropeptides, cytokines, chemokines, ions, growth factors and serum derived components like immunoglobulins, thrombin and complement. Upon insult or injury to the brain, microglia become “activated”

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undergoing phenotypical changes that include hypertrophy, mitosis, as well as changes in immunophenotype and in cytokine/growth factor production.

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2.1 Morphology In accordance with their highly adaptable nature, microglial morphology varies in correlation with unique functional states. Microglia in the normal, healthy brain are approximately 30-40 µm in diameter, smaller than both astrocytes and oligodendrocytes (Raivich et al., 1999). Resting microglia exhibit a stellate morphology in gray matter, while in the white matter they lie in parallel to nerve fibers. Electron microscopy performed in organotypic hippocampal slice culture reveals microglia with oval or elongated nuclei, dense cytoplasm, dense laminar bodies, homogenous droplets, lysosomes, lipofuscin and a granular endoplasmic reticulum (Skibo et al., 2000). Because of their long, highly branched processes, resting microglia are often referred to as “ramified.” Primary branches on resting, ramified microglia may extend more than 50 µm in length, with thin finger-like protrusions extending outward sometimes forming bulbous endings (Nimmerjahn et al., 2005; Stence et al., 2001). Furthermore, both Nimmerjahn et al., (2005) and Stence et al., (2001) provide evidence that microglial processes undergo cycles of formation and withdrawal that occur within minutes, thereby resulting in extensive morphological changes within an hour’s time. Upon insult or injury to the brain, microglia undergo a stereotypical, graduated response commensurate with the severity of brain damage incurred. Prior to becoming fully activated, or in the event of a mild perturbation, microglia may take on a hyper-ramified form (Streit et al., 1999). Fully reactive microglia retract their processes and develop an enlarged cell body. Shortened processes exhibit increased thickness proximally and deramification of distal branches. Additionally, experiments performed using the electron microscope describe reactive microglia as having enlarged nuclei and perikaryon, increased size and number of lysosomes and the appearance of phagosomes (Blinzinger & Hager, 1962). Ultimately, activated microglia responding to injury that does not involve frank neuronal degeneration will decrease in number and return to a resting state (Graeber et al., 1989). When brain damage leads to neuronal degeneration, microglia undergo further transformation from an activated phenotype to that of a phagocyte (Streit & Kreutzberg, 1988). In cases of neuronal cell death, microglia with a macrophage appearance can be detected as early as one to four hours post-injury (Kaur & You, 2000; Skibo et al., 2000). Microglial-derived macrophages take on a rounded, amoeboid shape similar to that of peripheral macrophages . When examined under the electron microscope, phagocytic microglia showed abundant lysosomes and phagosomes as well as copious lipid droplets and lipofuscin material (Kaur & You, 2000; Sobaniec-Lotowska, 2005). Further examination revealed oval or round nuclei with dense heterochromatin accumulated under the nuclear envelope and sparse euchromatin. Finally, microglia-derived macrophages customarily revert to a resting phenotype within a few days to weeks, but active macrophages have been found in white matter tracts up to ten years following middle cerebral artery occlusion (Kosel et al., 1997).

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2.2 Proliferation The mitotic potential of microglia in the adult brain was discovered when autoradiographic studies employing [3H] thymidine incorporation showed that microglia undergo mitosis following brain injury (Friede & Johnstone, 1967; Kreutzberg, 1966; Sjostrand, 1971) Microglial proliferation occurred to a much lesser degree in the absence of an injury, likely reflecting normal cell turnover (Dalton et al., 1968; Lawson et al., 1992; Tonchev et al., 2003). Later experiments confirmed that microglia are the only glial cell type to undergo mitosis after facial nerve axotomy in the rat (Graeber et al., 1988b). However, astrocytic proliferation has been reported in other models (Cao et al., 2003; du Bois et al., 1985; Li et al., 2005; McGinn et al., 2004) Despite the variations in experimental injury models, species and strain differences, as well as methods of detection used to assess glial proliferation, mitosis proves to be a prominent and consistent component of the microglial response to injury. Microglial proliferation has been studied most exhaustively in the facial nerve axotomy model (Cammermeyer, 1965; Fendrick et al., 2005; Graeber et al., 1988b; Kreutzberg, 1966; Streit & Kreutzberg, 1988). This well established injury paradigm is advantageous in the study of microglial activation primarily because there is no direct trauma to the CNS and the blood brain barrier remains intact, providing an opportunity to study purely endogenous glial responses. An additional advantage is that the injury is well tolerated and highly reproducible from animal to animal. Insights gained from studies employing the facial nerve axotomy and other regenerating nerve models, as well as from acute and chronic neural injury models reveal that microglial proliferation begins as early as 12 hours post-lesion (Ziaja & Janeczko, 1999), peaks at approximately three to four days after insult (Kreutzberg, 1966; Ladeby et al., 2005; Sjostrand, 1971; Streit & Kreutzberg, 1988; Stuesse et al., 2000) and declines thereafter. In contrast to the prevailing mitotic response described above, Tonchev et al. (2003) have shown that there is a differential proliferative response exhibited by microglia after ischemic insult in the macaque monkey. As expected, their study showed that microglial proliferation peaks four days after ischemia in the hippocampus, but surprisingly, mitotic activity in the superior temporal gyrus was delayed until 15 days post-injury. There was no significant increase in microglial proliferation in the parahippocampal region or olfactory bulb. This study highlights the fact that microglial responses are highly specialized and context-specific. Furthermore, there is evidence to show that after microglia have proliferated population control is implemented by apoptosis. In models of facial (Jones et al., 1997), as well as hypoglossal and sciatic nerve injuries (Gehrmann & Banati, 1995), apoptosis of microglia was measured using terminal transferase mediated d-UTP nick end labeling (TUNEL) and in situ end labeling (ISEL) and found to occur beginning four to six days after injury and continuing for up to 21 days. While the proliferative response of microglia is well-documented and characterized, little is known about mechanisms underlying its regulation. The literature abounds with reports of pharmacological agents and/or endogenous chemicals that stimulate or inhibit microglial proliferation in vitro, which is not unexpected given the high sensitivity of microglia to their surrounding milieu. However, these findings are difficult to extrapolate to the in vivo situation. Upon careful review of current data, a picture emerges of likely common

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mechanisms governing microglial mitosis in vivo. Specifically, it seems that inducers of microglial proliferation could include interleukin-6 (IL-6) (Streit et al., 2000), the neurotrophin NT-3 (Elkabes et al., 1996) and macrophage colony-stimulating factor (M-CSF) (Kloss et al., 1997). Insights into the molecular mechanisms by which these microglial mitogens exert their effects has been gained in the last few years. In vitro experiments have shown that GM-CSF activates Hck tyrosine kinase, which in turn activates the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway (Ito et al., 2005; Suh et al., 2005). Additionally, studies have shown that microglial mitosis induced by GM-CSF administration (Koguchi et al., 2003) and cerebral ischemia (Kato et al., 2003) lead to expression of the cell cycle-associated proteins cyclin D1, E, A and cyclin-dependent kinase inhibitor p21 as well as cyclin D1 and cyclin-dependent kinase-4, respectively. Given the fact that Akt is known to activate cyclins (Mirza et al., 2004) these data collectively provide a highly plausible mechanism for GM-CSF induced microglial mitosis. The macrophage colony-stimulating factors have received considerable attention for their abilities as microglial mitogens, but IL-6 has also come to be thought of as an inducer of glial proliferation. This is not completely surprising given that IL-6 was previously known as “B cell growth factor” for its stimulation of proliferation in B lymphocytes. Studies strongly suggest that IL-6 released from injured neurons serves as a signal for microglial proliferation and activation in general (Kiefer et al., 1993; Streit et al., 2000; Streit et al., 1998). It was shown that there is an early and robust upregulation of IL-6 mRNA following facial nerve injury that precedes the onset of microglial mitosis (Streit et al., 2000). Concordantly, low levels of IL-6 expression were seen in the red nucleus following rubrospinal tractotomy, as well as in the facial nucleus of neonates post-axotomy, both situations wherein microglial proliferation does not occur. Furthermore, experiments performed on IL-6 deficient mice show significantly delayed microglial responses. Specifically, impairment of microglial proliferation was reported in IL-6 -/- mice following facial nerve axotomy (Galiano et al., 2001; Klein et al., 1997) and in the substantia nigra pars compacta (SNpc) after MPTP lesions (Cardenas & Bolin, 2003). Thus, when examining the beneficial proliferative response of microglia to IL-6, we are again reminded of the highly specialized and contextspecific reaction of microglia to a molecule that is known to have multiple effects, both proand anti-inflammatory.

2.3 Cytokine/Growth Factor Production Microglial production of cytokines and growth factors is complex and occurs in a heterogeneous and escalating manner. Certain cytokines known to be constitutively expressed by microglia are thought to act in an autocrine fashion, specifically, transforming growth factor β (TGFβ) (Kiefer et al., 1993; Lehrmann et al., 1998), a pleiotropic growth factor. TGFβ has been shown to exert inhibitory effects on microglial phagocytosis (Stoll et al., 2004) and proliferation (Jones et al., 1998), as well as prevent the induction of microglial genes involved in chemotaxis and cell migration, among others (Paglinawan et al., 2003). The list of cytokines, chemokines and growth factors produced by microglia upon activation is extensive (Hanisch, 2002); however, it is important to note that many cytokines exert both

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positive and negative effects on the CNS and that it is the degree of microglial activation, or severity of neuronal damage, that determines the ensuing cytokine expression patterns. For example, microglia rapidly upregulate IL-1β, IL-6, TNF-α mRNAs following traumatic spinal cord damage (Bartholdi & Schwab, 1997; Streit et al., 1998; Yang et al., 2005), whereas in the regenerating facial nerve injury paradigm mRNAs of TNF-α and IL-1β, both prototypic proinflammatory cytokines, are only minimally elevated and there is no change in M-CSF mRNA (Raivich et al., 1999; Streit et al., 1998). Interleukin-6, which shows prolonged expression after facial axotomy, is rapidly downregulated after spiking initially in spinal cord injury (Streit et al., 1998). Finally, microglial activation resulting from infection, such as viral meningitis or bacteria-induced encephalitis, leads to production of not only those cytokines listed above, but also interferon-γ (IFN-γ) (Frei et al., 1988; Suzuki et al., 2005). IFN-γ acts to promote upregulation of surface molecules like major histocompatibility complex (MHC) class I and II molecules, complement receptors, Fc receptors and CD14, as well as induce the release of cytokines, complement and nitric oxide (NO) (Hanisch, 2002). In addition, IFN-γ acting synergistically with beta-amyloid (Aβ) peptide has been shown experimentally to induce microglial production of the chemokine monocyte chemotactic protein (MCP-1) (Meda et al., 1996). Microglia are capable of producing many additional cytokines, chemokines and neurotrophins not discussed herein and for additional information the interested reader is referred elsewhere (Hanisch, 2002; van Rossum & Hanisch, 2004).

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2.4 Immunophenotype As with all other aspects of microglial biology, surface molecule expression is highly dynamic and exhibits changes in association with various states of microglial activation. Resting microglia constitutively express type three complement receptors (Graeber et al., 1988a), and Fc and macrophage-specific antigen (Perry et al., 1985), as well as CD4 (Perry & Gordon, 1987) and leukocyte common antigen (Akiyama & McGeer, 1990). However, when microglia become activated, there are changes in surface marker expression that suggest changes in cell function. Within 24 hours of activation, microglia express many molecules important for interactions between lymphocytes and antigen-presenting cells. Specifically, they exhibit an upregulation of CR3 (OX-42) expression (Graeber et al., 1988a) accompanied by an increase in IgG-immunoreactivity, thrombospondin, and intercellular adhesion molecule 1 (Kloss et al., 1999; Moller et al., 1996; Raivich et al., 1999). Peak expression of integrin subunits α5 and α 6 occurs at day four post-injury and the αM-subunit at day 1 and again at days 14-42. Furthermore, within three days of CNS injury, proliferating microglia have been shown to express the stem cell antigen CD34 (Ladeby et al., 2005). Consistent with a role as antigen-presenting cells, reactive microglia show enhanced major histocompatibility complex type I and II (MHC I and II) expression during the first week after injury (Streit et al., 1989a, 1989b). Upregulation of MHC I can be detected in all activated microglia, while MHC II expression is restricted primarily to microglia in degenerating white matter tracts (Streit et al., 1989b; Watanabe et al., 1999). Phagocytic microglia are known to display all of the surface molecules previously discussed, as well as the macrophage surface antigens ED1 and ED3 (Graeber et al., 1990). All in all, there is great

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heterogeneity in microglial immunophenotypes, which can vary with the type and severity of a lesion, the location within the parenchyma (white versus grey matter), and perhaps also with the cells’ age, as we shall discuss below.

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3. What is Neuroinflammation? Contrary to the statement that inflammation is a “poorly defined concept” (McGeer & McGeer, 2001) general pathology defines it rather clearly and simply as the reaction of living tissues to all forms of injury (Robbins, 1981). Historically, the term “inflammation” was used primarily in the context of non-CNS injuries, but for about ten years now “neuroinflammation” has become a commonly used phrase (Streit et al., 2004a). Before neuroinflammation came into widespread use, neuroscientists used to talk about “reactive gliosis” to describe the endogenous CNS tissue response to acute injury, and it was recognized thirty years ago that microglia are the prevalent cell type associated with an inflammatory response in the brain (Oehmichen & Huber, 1976). Reactive gliosis specifically refers to the activation of microglia and astrocytes that is triggered immediately and inevitably after CNS injury has occurred. However, CNS injury can occur in many different ways and it can vary dramatically in severity. On one extreme could be a traumatic injury of the brain or the spinal cord where direct physical destruction of the tissue results in hemorrhagic necrosis. This type of lesion is accompanied by an extensive breakdown of the blood brain barrier and infiltration of the CNS parenchyma by blood borne leukocytes, primarily neutrophils (Sroga et al., 2003; Streit et al., 1998). Clearly, in this scenario the term “neuroinflammation” is appropriate because the principal features of general pathology that characterize acute inflammation apply: there are profound vascular changes, as well as a polymorphonuclear leukocytic exudate. Together with the rapid activation of glial cells, these changes represent the response of the living tissue to injury and the critical first step in the wound healing process. On the other end of the spectrum of acute CNS injuries lies a subtle, non-lethal and reversible neuronal injury that triggers glial cell activation but does not involve a breakdown of the blood brain barrier and a concomitant leukocytic exudate. This form of “pure” reactive gliosis occurs after an axotomy of motoneurons which results in chromatolysis, the classic example of reversible neuronal injury (Kreutzberg, 1996). Although reactive gliosis could also be called “neuroinflammation” in line with the general definition of inflammation, i.e. the reaction of living tissue to injury, it is more specific and accurate to talk about reactive gliosis in this situation. Most other types of acute CNS injury, including stroke and neurotoxicant-induced damage, fall in between these two extremes of axotomy and traumatic CNS injury exhibiting patterns of neuroinflammation that are blends between reactive gliosis and leukocytic infiltration. While acute inflammation comprises the immediate and early response to an injurious event and is basically an adaptive response that paves the way for repair of the damaged site, chronic inflammation results from injurious stimuli that are persistent. In the periphery, both acute and chronic inflammation are characterized by leukocytic exudates consisting primarily of polymorphonuclear cells (neutrophils) in the former and mononuclear cells (macrophages, lymphocytes, plasma cells) in the latter. However, in the CNS, due largely to the presence of

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the blood brain barrier, leukocytic exudates may not be part of chronic neuroinflammation, certainly not in the way the term is currently being used in the context of neurodegenerative diseases (see below). Chronic neuroinflammation is indeed more relevant in the context of CNS disease rather than CNS injury, since “disease” implicitly carries the notion of chronicity. The classic example of chronic neuroinflammation is the autoimmune neuroinflammation that occurs in multiple sclerosis. Although the underlying cause(s) of MS have not been elucidated, it is probably safe to say that the persistent injurious stimulus that accounts for MS neuroinflammation is a myelin-related protein that has escaped selftolerance and become an autoantigen. Consistent with the chronic persistence of this CNS autoantigen is a persistent accumulation of blood-derived mononuclear leukocytes in the CNS parenchyma, which mirrors the presence of leukocytic exudates in peripheral autoimmune diseases, such as rheumatoid arthritis or polymyositis. Most infectious diseases of the CNS, if they are not cleared, produce chronic neuroinflammation. The most important example in modern times is infection with the human immunodeficiency virus (HIV) which is known to enter and remain in the CNS via myelomonocytic cells, such as monocytes, perivascular cells, and microglia (Garden, 2002). However, HIV infection is uniquely different from most other infectious diseases affecting the CNS in that the virus targets and disables precisely those cells that are key players in neuroinflammation – microglia and T lymphocytes. It therefore comes as no surprise that prominent T cell infiltrates do not occur in HIV encephalopathy. Similarly, prion diseases, which represent another infectious CNS disease of major current interest, are atypical with regard to neuroinflammation (Eikelenboom et al., 2002; Perry et al., 2002). Microglial activation appears to be the most prominent component of the neuroinflammation associated with prion diseases, although there are a few reports describing T cell infiltration as well (Betmouni et al., 1996; Lewicki et al., 2003). As an interesting parallel to HIV infection, prions seem to infect microglial cells in addition to neurons and this may help explain the unusual patterns of neuroinflammation that becomes manifest not only in atypical cellular infiltrates but also in unusual cytokine profiles (Baker & Manuelidis, 2003). Thus, both HIV and prion infections probably produce an altered microglial physiology that is likely to translate into microglial dysfunction, which could be a contributing factor in the development of dementia that occurs in these conditions.

3.1 Reactive Microgliosis versus Chronic Neuroinflammation in Neurodegenerative Diseases Neurodegenerative diseases, particularly Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), but also Parkinson’s and Huntington’s disease lack the prominent infiltrates of blood-derived mononuclear cells that characterize autoimmune diseases and can therefore not be categorized as chronic inflammatory conditions. On the other hand, there is abundant evidence to show that many substances involved in the promotion of inflammatory processes can be detected in the CNS of patients with neurodegenerative diseases, and some of these proinflammatory mediators appear to be increased relative to non-diseased controls. By far the bulk of this body of evidence is related to studies in AD (Akiyama et al., 2000),

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and we therefore discuss the issue of reactive microgliosis versus chronic neuroinflammation within the context of AD. What distinguishes AD from other neurodegenerative diseases is the widespread presence of extracellular deposits of amyloid in senile plaques. Senile plaques are present in the AD brain in different stages of maturity ranging from diffuse to dense core or neuritic, but they all contain the amyloid beta protein (Aβ). Aβ is a pathological protein that tends to form aggregates creating insoluble extracellular deposits which attract microglial cells, as suggested by the clustering of microglia at sites of Aβ deposition (Streit, 2004). There is compelling evidence from experimental studies in animals to support the idea that microglia phagocytose and attempt to degrade amyloid (Frautschy et al., 1992; Weldon et al., 1998), but whether they do so effectively in humans with AD is questionable. In fact, a very recent report strongly suggests that they do not (Fiala et al., 2005). A key question within the current context is, Does the presence of amyloid in AD brain represent a persistent injurious stimulus that incites chronic neuroinflammation? Differently put, Does phagocytosis or attempted phagocytosis of amyloid by microglia constitute chronic neuroinflammation? The answer to this is not obvious, because it is not certain whether amyloid represents an injurious stimulus or a consequence of an injury. Direct injection of amyloid into the brain does not produce neurodegeneration or overt neuronal injury (Weldon et al., 1998), and transgenic mice that overexpress the amyloid precursor protein and develop amyloid deposits do not show neurodegenerative changes, such as neurofibrillary tangles (Irizarry et al., 1997). At the same time, there is evidence that shows increased presence of Aβ and amyloid precursor protein after traumatic head injury (Smith et al., 2003) suggesting that Aβ production is enhanced as a result of CNS injury. It is therefore conceivable that the increased presence of Aβ in the AD brain is a result of ongoing neuronal damage rather than the cause of it, but a final answer as to whether Aβ is pathogenic or merely a byproduct of the disease process must await further studies. What seems to be indisputable at this point in time is that amyloid, when deposited extracellularly, induces a reactive glial response by both astrocytes and microglia (Frautschy et al., 1998; Irizarry et al., 1997). For the time being it may therefore be most accurate and objective to speak of reactive gliosis rather than of chronic inflammation when considering the innate glial response to amyloid. This view is entirely compatible with the large body of evidence that shows enhanced presence of a wide array of proinflammatory substances in the AD brain because anytime reactive gliosis occurs, cytokines and other proinflammatory substances are produced as part of the mobilization of the endogenous defense system (Raivich et al., 1999; Streit et al., 2000; Streit et al., 1998). In conclusion, while it is reasonable and acceptable to include reactive microgliosis under the more general heading of neuroinflammation since reactive microglia are cells responding to CNS injury, it is inappropriate at this point to classify neurodegenerative diseases, particularly AD, as chronic inflammatory conditions because these disorders do not show leukocytic exudates. Moreover, there is no compelling evidence to show that the reactive gliosis that occurs in AD or other neurodegenerative diseases is causing any loss of neurons or synapses that accounts for cognitive deficits and dementia. Nonetheless, it appears that a large number of researchers has embraced the idea that microgliosis in AD is indeed contributing to neurodegeneration. In the following, we attempt to retrace the evolution of this neuroinflammation theory of AD pathogenesis hoping that in the process we are able to shed some new light on the relationship between microglia and CNS inflammation.

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3.2 Evolution of the Neuroinflammation Hypothesis In the early 1980s amidst newfound excitement over astrocytes and oligodendrocytes which stemmed in part from the availability of new methods for maintaining these glial cells in vitro (McCarthy & de Vellis, 1980), microglia had become the forgotten third element of Cajal. However, it wasn’t long before methods were published that described methods for culturing microglia (Giulian & Baker, 1986). At about the same time, advances were also being made on a different front, namely, the in vivo visualization of microglia using immunohistochemical and lectin histochemical procedures (Mannoji et al., 1986; Perry et al., 1985; Streit & Kreutzberg, 1987). Together, the simultaneous developments of both in vitro and in vivo methodologies for studying microglia gave rise to an upsurge in the numbers of papers published on microglia (Graeber, 1994), a trend that has continued to the present day . However, the take-home messages that emerged from the two different lines of investigations were quite divergent. While investigators working in vivo produced primarily descriptive data that provided details on morphological and phenotypic changes occurring on activated microglia as they were responding in situ to a variety of experimental CNS lesions, others who worked primarily in vitro were quick to report findings with perceived functional significance for the activity of microglia in vivo, namely, that activated microglia function as potentially harmful immune effector cells (Boje & Arora, 1992; Giulian, 1987). We can now state with confidence that this was a fallacy, not only because other cell culture studies have reported neurotrophic effects of in vitro activated microglia (Elkabes et al., 1996; Nagata et al., 1993), but primarily because the methods that were and are still being used for inducing microglial activation in vitro do not simulate in vivo conditions where neuronal injury or death is a trigger for microglial activation. Bacterial endotoxin (LPS) was and is the most commonly employed microglial stimulant to generate so-called activated microglia in vitro, but the LPS stimulation paradigm at best simulates a fulminant bacterial infection of the brain parenchyma, which is uncommon clinically and usually occurs only in severely immunocompromised patients. Moreover, those unstimulated microglial cells in vitro that are subjected to LPS treatment are already activated as they have already undergone transformation into macrophages following dissociation and trituration of brain tissue which is a necessary first step in the preparation of primary microglial cell cultures. Thus, unstimulated microglia in vitro are not at all like resting microglia in vivo; they are much more similar to microglia-derived macrophages that accumulate after extensive brain damage. The stimulation of these cells with LPS or other immunostimulatory agents in vitro essentially produces superactivated cells that have no known counterpart in vivo. Notwithstanding these serious shortcomings, cell culture studies gained widespread acceptance and were crucial in promoting a perception of microglia as harmful, neurotoxinproducing immune effector cells (Giulian et al., 1993). Many cell culture studies have also used amyloid as a microglial activator and although there is little doubt that amyloid exposure does indeed alter microglial functional states in vitro (Araujo & Cotman, 1992; Korotzer et al., 1993; McDonald et al., 1997; Meda et al., 1995), a causal link between amyloid-activated microglia and the development of neurofibrillary degeneration has not been established. In fact, the aforementioned in vivo studies using APP overexpressing mice

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(Irizarry et al., 1997) that fail to develop neurofibrillary degeneration provide a very strong argument against such a connection. Another issue that contributed significantly to the neuroinflammation hypothesis concerns the somewhat arbitrary identification of activated microglia in human brain. Investigators performing post-mortem histopathological studies in the late 1980s were quick to identify microglia as activated based on the fact that the cells were positive for MHC antigens (McGeer et al., 1987; Rogers et al., 1988). Although this seemed to be in concordance with experimental animal studies where reactive microgliosis was usually accompanied by an increase in MHC antigen expression, we know now that MHC expression alone is not a good method for identifying activated microglia. In human brain, MHC antigen expression is seen frequently on microglia exhibiting a resting (ramified) non-activated morphology (Streit et al., 2004b). In addition, MHC expression is virtually absent from microglia in very young humans (Streit & Sparks, 1997), as well as from young rodents and acute injury in neonatal rats produces very limited expression of these microglial markers on activated cells (Morioka & Streit, 1991). On the other hand, MHC expression clearly increases with normal, non-pathological aging on microglia in all species examined thus far, including humans (Perry et al., 1993; Rogers et al., 1988; Sheffield & Berman, 1998; Streit & Sparks, 1997). In light of these observations, it seems much more likely that MHC expression is a marker of cell maturation rather than of cell activation. Another factor that contributed significantly to the propagation of the neuroinflammation hypothesis is found in epidemiological data from arthritis patients taking anti-inflammatory drugs who seemed to have a lower incidence of AD, which in turn has led to the suggestion that anti-inflammatory drugs could be used in the treatment and/or prevention of AD (McGeer et al., 1996). Since then clinical trials have been conducted with NSAIDs, but thus far no benefits of these drugs for AD prevention have been reported (Aisen et al., 2003). A significant caveat in the epidemiological studies analyzed by McGeer et al. (1996) is that the studies reviewed were largely focused on rheumatoid arthritis, which is a truly inflammatory and autoimmune condition that has its usual onset in young adults (Robbins, 1981). This condition is to be distinguished from osteoarthritis, which is aging-related, degenerative joint disease characterized by minimal inflammation. Osteoarthritis seems like a condition that is much more analogous to AD than rheumatoid arthritis (which might be likened to multiple sclerosis), and it would therefore appear to be more relevant to ask if any treatments for osteoarthritris might be beneficial for AD.

4. Summary In closing, the idea that neuroinflammation contributes to neurodegeneration in conditions other than autoimmune diseases was borne out of misconceptions about the nature and function of activated microglia. We are inclined to maintain the original perception of activated microglia as cells that are reacting to a disturbance of tissue homeostasis. Accordingly, use of the term should be limited to in situ investigations of tissues where the identification of activated microglia can be performed reliably using a combination of morphologic and immunophenotypic criteria.

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[44] Klein, M. A., Moller, J. C., Jones, L. L., Bluethmann, H., Kreutzberg, G. W.& Raivich, G. (1997). Impaired neuroglial activation in interleukin-6 deficient mice. Glia, 19(3), 227-233. [45] Kloss, C. U., Kreutzberg, G. W.& Raivich, G. (1997). Proliferation of ramified microglia on an astrocyte monolayer: characterization of stimulatory and inhibitory cytokines. J Neurosci Res, 49(2), 248-254. [46] Kloss, C. U., Werner, A., Klein, M. A., Shen, J., Menuz, K., Probst, J. C., Kreutzberg, G. W.& Raivich, G. (1999). Integrin family of cell adhesion molecules in the injured brain: regulation and cellular localization in the normal and regenerating mouse facial motor nucleus. J Comp Neurol, 411(1), 162-178. [47] Koguchi, K., Nakatsuji, Y., Okuno, T., Sawada, M.& Sakoda, S. (2003). Microglial cell cycle-associated proteins control microglial proliferation in vivo and in vitro and are regulated by GM-CSF and density-dependent inhibition. J Neurosci Res, 74(6), 898905. [48] Korotzer, A. R., Pike, C. J.& Cotman, C. W. (1993). beta-Amyloid peptides induce degeneration of cultured rat microglia. Brain Res, 624(1-2), 121-125. [49] Kosel, S., Egensperger, R., Bise, K., Arbogast, S., Mehraein, P.& Graeber, M. B. (1997). Long-lasting perivascular accumulation of major histocompatibility complex class II-positive lipophages in the spinal cord of stroke patients: possible relevance for the immune privilege of the brain. Acta Neuropathol (Berl), 94(6), 532-538. [50] Kreutzberg, G. W. (1966). Autoradiographische Untersuchung uber die Beteiligung von Gliazellen an der axonalen Reaktion im Facialiskern der Ratte. Acta Neuropathol (Berl), 7, 149-161. [51] Kreutzberg, G. W. (1996). Microglia: a sensor for pathological events in the CNS. Trends Neurosci, 19(8), 312-318. [52] Ladeby, R., Wirenfeldt, M., Dalmau, I., Gregersen, R., Garcia-Ovejero, D., Babcock, A., Owens, T.& Finsen, B. (2005). Proliferating resident microglia express the stem cell antigen CD34 in response to acute neural injury. Glia, 50(2), 121-131. [53] Lawson, L. J., Perry, V. H.& Gordon, S. (1992). Turnover of resident microglia in the normal adult mouse brain. Neuroscience, 48(2), 405-415. [54] Lehrmann, E., Kiefer, R., Christensen, T., Toyka, K. V., Zimmer, J., Diemer, N. H., Hartung, H. P.& Finsen, B. (1998). Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats. Glia, 24(4), 437-448. [55] Lewicki, H., Tishon, A., Homann, D., Mazarguil, H., Laval, F., Asensio, V. C., Campbell, I. L., DeArmond, S., Coon, B., Teng, C., Gairin, J. E.& Oldstone, M. B. (2003). T cells infiltrate the brain in murine and human transmissible spongiform encephalopathies. J Virol, 77(6), 3799-3808. [56] Li, Y., Chen, J., Zhang, C. L., Wang, L., Lu, D., Katakowski, M., Gao, Q., Shen, L. H., Zhang, J., Lu, M.& Chopp, M. (2005). Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia, 49(3), 407-417. [57] Mannoji, H., Yeger, H.& Becker, L. E. (1986). A specific histochemical marker (lectin Ricinus communis agglutinin-1) for normal human microglia, and application to routine histopathology. Acta Neuropathol (Berl), 71(3-4), 341-343.

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[58] McCarthy, K. D.& de Vellis, J. (1980). Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol, 85(3), 890-902. [59] McDonald, D. R., Brunden, K. R.& Landreth, G. E. (1997). Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. J Neurosci, 17(7), 2284-2294. [60] McGeer, P. L., Itagaki, S., Tago, H.& McGeer, E. G. (1987). Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett, 79(1-2), 195-200. [61] McGeer, P. L.& McGeer, E. G. (2001). Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging, 22(6), 799-809. [62] McGeer, P. L., Schulzer, M.& McGeer, E. G. (1996). Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology, 47(2), 425-432. [63] McGinn, M. J., Sun, D., Schneider, S. L., Alexander, J. K.& Colello, R. J. (2004). Epidermal growth factor-induced cell proliferation in the adult rat striatum. Brain Res, 1007(1-2), 29-38. [64] Meda, L., Bernasconi, S., Bonaiuto, C., Sozzani, S., Zhou, D., Otvos, L., Jr., Mantovani, A., Rossi, F.& Cassatella, M. A. (1996). Beta-amyloid (25-35) peptide and IFN-gamma synergistically induce the production of the chemotactic cytokine MCP1/JE in monocytes and microglial cells. J Immunol, 157(3), 1213-1218. [65] Meda, L., Cassatella, M. A., Szendrei, G. I., Otvos, L., Jr., Baron, P., Villalba, M., Ferrari, D.& Rossi, F. (1995). Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature, 374(6523), 647-650. [66] Mirza, A. M., Gysin, S., Malek, N., Nakayama, K., Roberts, J. M.& McMahon, M. (2004). Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT. Mol Cell Biol, 24(24), 10868-10881. [67] Moller, J. C., Klein, M. A., Haas, S., Jones, L. L., Kreutzberg, G. W.& Raivich, G. (1996). Regulation of thrombospondin in the regenerating mouse facial motor nucleus. Glia, 17(2), 121-132. [68] Morioka, T.& Streit, W. J. (1991). Expression of immunomolecules on microglial cells following neonatal sciatic nerve axotomy. J Neuroimmunol, 35(1-3), 21-30. [69] Nagata, K., Takei, N., Nakajima, K., Saito, H.& Kohsaka, S. (1993). Microglial conditioned medium promotes survival and development of cultured mesencephalic neurons from embryonic rat brain. J Neurosci Res, 34(3), 357-363. [70] Nimmerjahn, A., Kirchhoff, F.& Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 308(5726), 13141318. [71] Oehmichen, M.& Huber, H. (1976). Reactive microglia with membrane features of mononuclear phagocytes. J Neuropathol Exp Neurol, 35(1), 30-39. [72] Paglinawan, R., Malipiero, U., Schlapbach, R., Frei, K., Reith, W.& Fontana, A. (2003). TGFbeta directs gene expression of activated microglia to an anti-inflammatory phenotype strongly focusing on chemokine genes and cell migratory genes. Glia, 44(3), 219-231.

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[73] Perry, V. H., Cunningham, C.& Boche, D. (2002). Atypical inflammation in the central nervous system in prion disease. Curr Opin Neurol, 15(3), 349-354. [74] Perry, V. H.& Gordon, S. (1987). Modulation of CD4 antigen on macrophages and microglia in rat brain. J Exp Med, 166(4), 1138-1143. [75] Perry, V. H., Hume, D. A.& Gordon, S. (1985). Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience, 15(2), 313-326. [76] Perry, V. H., Matyszak, M. K.& Fearn, S. (1993). Altered antigen expression of microglia in the aged rodent CNS. Glia, 7(1), 60-67. [77] Raivich, G., Bohatschek, M., Kloss, C. U., Werner, A., Jones, L. L.& Kreutzberg, G. W. (1999). Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res Brain Res Rev, 30(1), 77-105. [78] Robbins, S. L., Angell, M., Kumar, V. (1981). Basic Pathology (3rd ed.). Philadelphia: W.B. Saunders. [79] Rogers, J., Luber-Narod, J., Styren, S. D.& Civin, W. H. (1988). Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease. Neurobiol Aging, 9(4), 339-349. [80] Schenk, D. B.& Yednock, T. (2002). The role of microglia in Alzheimer's disease: friend or foe? Neurobiol Aging, 23(5), 677-679; discussion 683-674. [81] Schwartz, M. (2003). Macrophages and microglia in central nervous system injury: are they helpful or harmful? J Cereb Blood Flow Metab, 23(4), 385-394. [82] Sheffield, L. G.& Berman, N. E. (1998). Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol Aging, 19(1), 47-55. [83] Sjostrand, J. (1971). Neuroglial proliferation in the hypoglossal nucleus after nerve injury. Exp Neurol, 30(1), 178-189. [84] Skibo, G. G., Nikonenko, I. R., Savchenko, V. L.& McKanna, J. A. (2000). Microglia in organotypic hippocampal slice culture and effects of hypoxia: ultrastructure and lipocortin-1 immunoreactivity. Neuroscience, 96(2), 427-438. [85] Smith, D. H., Uryu, K., Saatman, K. E., Trojanowski, J. Q.& McIntosh, T. K. (2003). Protein accumulation in traumatic brain injury. Neuromolecular Med, 4(1-2), 59-72. [86] Sobaniec-Lotowska, M. E. (2005). A transmission electron microscopic study of microglia/macrophages in the hippocampal cortex and neocortex following chronic exposure to valproate. Int J Exp Pathol, 86(2), 91-96. [87] Sroga, J. M., Jones, T. B., Kigerl, K. A., McGaughy, V. M.& Popovich, P. G. (2003). Rats and mice exhibit distinct inflammatory reactions after spinal cord injury. J Comp Neurol, 462(2), 223-240. [88] Stence, N., Waite, M.& Dailey, M. E. (2001). Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia (33), 256-266. [89] Stoll, G., Schroeter, M., Jander, S., Siebert, H., Wollrath, A., Kleinschnitz, C.& Bruck, W. (2004). Lesion-associated expression of transforming growth factor-beta-2 in the rat nervous system: evidence for down-regulating the phagocytic activity of microglia and macrophages. Brain Pathol, 14(1), 51-58.

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[90] Streit, W. J. (2001). Microglia and macrophages in the developing CNS. Neurotoxicology, 22(5), 619-624. [91] Streit, W. J. (2004). Microglia and Alzheimer's disease pathogenesis. J Neurosci Res, 77(1), 1-8. [92] Streit, W. J., Graeber, M. B.& Kreutzberg, G. W. (1989a). Expression of Ia antigen on perivascular and microglial cells after sublethal and lethal motor neuron injury. Exp Neurol, 105(2), 115-126. [93] Streit, W. J., Graeber, M. B.& Kreutzberg, G. W. (1989b). Peripheral nerve lesion produces increased levels of major histocompatibility complex antigens in the central nervous system. J Neuroimmunol, 21(2-3), 117-123. [94] Streit, W. J., Hurley, S. D., McGraw, T. S.& Semple-Rowland, S. L. (2000). Comparative evaluation of cytokine profiles and reactive gliosis supports a critical role for interleukin-6 in neuron-glia signaling during regeneration. J Neurosci Res, 61(1), 10-20. [95] Streit, W. J.& Kreutzberg, G. W. (1987). Lectin binding by resting and reactive microglia. J Neurocytol, 16(2), 249-260. [96] Streit, W. J.& Kreutzberg, G. W. (1988). Response of endogenous glial cells to motor neuron degeneration induced by toxic ricin. J Comp Neurol, 268(2), 248-263. [97] Streit, W. J., Mrak, R. E.& Griffin, W. S. (2004a). Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation, 1(1), 14. [98] Streit, W. J., Sammons, N. W., Kuhns, A. J.& Sparks, D. L. (2004b). Dystrophic microglia in the aging human brain. Glia, 45(2), 208-212. [99] Streit, W. J., Semple-Rowland, S. L., Hurley, S. D., Miller, R. C., Popovich, P. G.& Stokes, B. T. (1998). Cytokine mRNA profiles in contused spinal cord and axotomized facial nucleus suggest a beneficial role for inflammation and gliosis. Exp Neurol, 152(1), 74-87. [100] Streit, W. J.& Sparks, D. L. (1997). Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits. J Mol Med, 75(2), 130-138. [101] Streit, W. J., Walter, S. A.& Pennell, N. A. (1999). Reactive microgliosis. Progress in Neurobiology, 57, 563-581. [102] Stuesse, S. L., Cruce, W. L., Lovell, J. A., McBurney, D. L.& Crisp, T. (2000). Microglial proliferation in the spinal cord of aged rats with a sciatic nerve injury. Neurosci Lett, 287(2), 121-124. [103] Suh, H. S., Kim, M. O.& Lee, S. C. (2005). Inhibition of granulocyte-macrophage colony-stimulating factor signaling and microglial proliferation by anti-CD45RO: role of Hck tyrosine kinase and phosphatidylinositol 3-kinase/Akt. J Immunol, 174(5), 2712-2719. [104] Suzuki, Y., Claflin, J., Wang, X., Lengi, A.& Kikuchi, T. (2005). Microglia and macrophages as innate producers of interferon-gamma in the brain following infection with Toxoplasma gondii. Int J Parasitol, 35(1), 83-90. [105] Tonchev, A. B., Yamashima, T., Zhao, L.& Okano, H. (2003). Differential proliferative response in the postischemic hippocampus, temporal cortex, and olfactory bulb of young adult macaque monkeys. Glia, 42(3), 209-224.

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[106] van Rossum, D.& Hanisch, U. K. (2004). Microglia. Metab Brain Dis, 19(3-4), 393411. [107] Watanabe, T., Yamamoto, T., Abe, Y., Saito, N., Kumagai, T.& Kayama, H. (1999). Differential activation of microglia after experimental spinal cord injury. J Neurotrauma, 16(3), 255-265. [108] Weldon, D. T., Rogers, S. D., Ghilardi, J. R., Finke, M. P., Cleary, J. P., O'Hare, E., Esler, W. P., Maggio, J. E.& Mantyh, P. W. (1998). Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci, 18(6), 2161-2173. [109] Wierzba-Bobrowicz, T., Lewandowska, E., Kosno-Kruszewska, E., Lechowicz, W., Pasennik, E.& Schmidt-Sidor, B. (2004). Degeneration of microglial cells in frontal and temporal lobes of chronic schizophrenics. Folia Neuropathol, 42(3), 157-165. [110] Yang, L., Jones, N. R., Blumbergs, P. C., Van Den Heuvel, C., Moore, E. J., Manavis, J., Sarvestani, G. T.& Ghabriel, M. N. (2005). Severity-dependent expression of proinflammatory cytokines in traumatic spinal cord injury in the rat. J Clin Neurosci, 12(3), 276-284. [111] Ziaja, M.& Janeczko, K. (1999). Spatiotemporal patterns of microglial proliferation in rat brain injured at the postmitotic stage of postnatal development. J Neurosci Res, 58(3), 379-386.

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In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 25-40 © 2006 Nova Science Publishers, Inc.

Chapter III

The Central Nervous System and Inflammation: Astrocytes Valerie Chock and Rona Giffard Departments of Anesthesia and Neonatology Stanford University School of Medicine Stanford, CA 94305

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1. Introduction Astrocytes have many roles in the central nervous system. In addition to their role in the establishment, maintenance and function of synapses, the production of neurotrophic factors, and the antioxidant defense of the brain, astrocytes are essential to establish and maintain the blood brain barrier and function as primary inflammatory cells. As inflammatory cells, astrocytes may be neuroprotective by promoting tissue repair and containing further injury, or they may be detrimental by contributing to delayed oxidative injury and upregulation of inflammatory processes. In this chapter, we examine astrocyte function in the context of inflammation and describe the contribution of astrocytes to several inflammatory disease processes. In particular we will consider the role of astrocytes in inflammation during neurodegeneration.

2. Inflammatory Response of Astrocytes in the CNS 2.1 Morphological Activation Astrocyte activation results in cytoplasmic hypertrophy and proliferation. A key ultrastructural change is the cytoplasmic accumulation of intermediate filaments including

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glial fibrillary acidic protein (GFAP). Reactive astrocytes, such as those seen following both global and focal ischemia, exhibit more intense GFAP-staining, thickened cellular processes and evidence of hypertophy (Figure 1, 2A). Activation also includes reexpression of nestin, characteristic of intermediate filaments in immature astrocytes but generally undetectable in adult brain (Figure 2B). In addition, astrocytes display increased nuclear size and an increased number of mitochondria, ribosomes, and Golgi complexes [12]; for review see [56]. They are poised for increased production of numerous molecules involved in inflammation including cytokines, chemokines, nitric oxide synthase, metalloproteinases, and intracellular adhesion molecules.

Figure 1. GFAP staining 72 hours following transient global ischemia reveals astrocyte activation in the hippocampus. Rats were subjected to bilateral carotid artery occlusion and hypotension for 10 minutes, followed by reperfusion (forebrain ischemia) or sham operation without ischemia. The animals was sacrificed 72 hours later and frozen sections were stained with anti-GFAP antibody and visualized with fluorescent secondary antibody (green). Red is propidium iodide to show nuclei. The dense horizontal band of nuclei visible in the upper left panel shows the level of the CA1 neuronal cell bodies. By 72 hours many of these neurons are lost, lower left panel, while the level of GFAP expression and the size of astrocytes is clearly increased.

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Figure 2. Changes in GFAP and nestin staining 72 hours following transient focal ischemia. Rats were subjected to suture occlusion of the middle cerebral artery for 2 hours followed by reperfusion (MCAO), and sacrificed at 72 hours. A. Sections were stained with anti-GFAP antibody and detected with fluorescent secondary antibody (green). Sham animals were not subjected to suture occlusion. Propidium iodide was used as a counterstain to show the nuclei. Increased GFAP staining is seen with relative thickening of astrocytic processes. B. Sections were stained with anti-nestin antibody (detected as green fluorescence) and counterstained with propidium iodide. In the sham animal no nestin immunoreactivity is detected, while after MCAO there is marked upregulation of nestin in astrocytes.

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2.2 Production of Cytokines The presence of cytokines in the CNS has been attributed not only to invading leukocytes and macrophages, but also to resident glial cells. Astrocytes have been shown to produce a variety of cytokines under pathologic conditions (see Table 1). These include IL-1α, IL-1β, IL-6, IL-10, IFN-α, IFN-β, IFN-γ, TNF-α, TGF-β, GM-CSF, M-CSF, and G-CSF as observed in both in vitro and in vivo investigations (for reviews see [18, 23]. Each cytokine in turn can cause a myriad of effects. For example, IL-1 is a potent mitogen for astrocytes and induces release of neuronal growth factor from astrocytes. IL-6 also promotes astrogliosis, modulates neurotransmitter biosynthesis, and protects neurons against ischemic injury (for review see [30]. Production of specific cytokines may be induced or inhibited by other cytokines previously released by activated microglia or other astrocytes in a paracrine feedback loop. Bacterial products alone such as lipopolysaccharide (LPS) are sufficient to stimulate astrocyte production of cytokines including IL-1β and TNFα [15, 28, 38] and IL-6 [5, 28] in cultured astrocytes. Astrocytes recognize bacterial products via their expression of toll-like receptors (TLRs), which are microbial pattern-recognition receptors. Cultured astrocytes express a number of different TLRs which increase after exposure to LPS and other bacterial ligands, resulting in activation of the transcription factor NF-κB and subsequent synthesis of pro-inflammatory cytokines like IL-6 [9].

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2.3 Production of Chemokines Similar to microglia, astrocytes also produce chemokines, a class of chemoattractant cytokines, which mediate migration of peripheral immune cells into the CNS. Astrocytes have been shown to produce RANTES, IL-8, MCP-1, and IP-10 (for reviews see [18, 23]. In response to the proinflammatory cytokines TNF-α, IFN-γ, or IL-1β, astrocytes are the major producers of the chemokine MCP-1. This chemokine, which is often identified in the perivascular space, binds the CCR2 receptor on endothelial cells [70] as well as binding receptors on peripheral blood monocytes and activated T-cells to induce migration of these leukocytes across the blood-brain barrier. [76]. MCP-1 is expressed by astrocytes during flares of experimental autoimmune encephalomyelitis (EAE) [26] whereas MCP-1 deficient mice are resistant to EAE [35]. MCP-1 expression has also been localized to astrocytes during traumatic brain injury [24]. MCP-1 acting via the CCR2 receptor has been shown to increase blood brain barrier leakiness and increase edema, an effect missing in CCR2 knockout mice [70].

2.4 Astrocytes as Antigen Presenting Cells (APCs) The ability of astrocytes to function as APCs is controversial. Typical antigen presenting cells like B-cells and macrophages normally express major histocompatibility complex (MHC) class II molecules, which allow presentation of processed antigens to CD4+ T-helper

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cells with subsequent T-cell activation and induction of an immune response. However, expression of MHC class II can be induced on astrocytes and is regulated by various cytokines and neuropeptides [18]. For example, interferon-γ is the most potent inducer of class II MHC expression on astrocytes [78], while TNF-α enhances IFN-γ-induced expression of class II MHC, but alone has no effect [55]. Inhibitors of class II MHC expression on astrocytes include TGF-β, IFN-β, IL-1, IL-4, norepinephrine, glutamate, nitric oxide, and vasoactive intestinal peptide [18]. Class II MHC expressing astrocytes have been shown to process and present antigens and activate both naïve and memory T cells [52, 68]. In contrast, other investigators have shown that class II MHC expressing astrocytes are not capable of stimulating T-cell proliferation and instead induce apoptosis or down-regulation of T cells [47, 75]. Such a response may be beneficial for astrocyte suppression of CNS autoimmunity like in multiple sclerosis. The absence of costimulatory molecule expression on astrocytes (B7 or CD40) may be responsible for the variability in astrocyte response [27, 62]. Other studies further suggest that astrocyte activation of T-cells can only occur after priming by microglia [67, 77]. Therefore, the ability of astrocytes to function as antigen presenting cells with ensuing T-cell proliferation or suppression may depend on the setting and awaits further clarification.

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2.5 Production of iNOS/ Nitric Oxide Exposure to bacterial endotoxin and various cytokines including IFN-γ results in inducible nitric oxide synthase (iNOS) production and subsequent nitric oxide (NO) release from both astrocytes and microglia [10]. Cultured astrocytes, moreover, were found to increase iNOS 96-fold after exposure to LPS and IFN-γ [7]. Generated nitric oxide can diffuse to and injure surrounding cells. Nitric oxide and its toxic metabolite, peroxynitrite, can inhibit components of the mitochondrial respiratory chain, leading to cellular energy deficiency and eventual cell death. Neuronal ATP loss [34] and mitochondrial damage [3] have been reported in cocultures of neurons and iNOS-producing astrocytes. Therefore, decreasing nitric oxide production by astrocytes is a potential neuroprotective strategy. Complicating the picture is the role of astrocytes in protecting neurons from oxidative stress, including potentially that induced by NO. Astrocytes have higher intracellular levels of the antioxidant glutathione, they are less vulnerable to oxidative injury than neurons, and have also been shown to protect neurons from NO [13]. In response to prolonged exposure to NO astrocytes can upregulate glutamate-cysteine ligase, the rate-limiting enzyme in GSH synthesis, while neurons appear unable to do this [22].

2.6 Maintenance of the Blood Brain Barrier The blood brain barrier (BBB) consists of a continuous capillary endothelium with tight junctions between cells. Astrocytes and microglia cover approximately 85% of the endothelial surface, with astrocyte foot processes in close apposition to the microvascular endothelium (for reviews see [4, 33]. At the BBB interface astrocytes and microglia interact

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with each other and with peripheral inflammatory cells via cytokines, influencing entry of inflammatory cells into the brain. Interactions between astrocytes and endothelial cells are essential to the integrity of the BBB and modulate endothelial cell function. For example, astrocytes increase electrical resistance across cultured endothelial cells and enhance their intercellular connections [40]. Ablation of astrocytes led to failure of BBB repair and vasogenic edema [11]. Selective ablation of reactive astrocytes in the setting of spinal cord injury in a transgenic mouse model also resulted in failure of BBB repair, augmented leukocyte infiltration, neuronal and oligodendrocyte death, and pronounced motor deficits [20]. Astrocytes are important in maintaining BBB integrity in disease states. Disruption of this barrier leads to edema and increased access of peripheral immune cells and humoral factors to the central nervous system. Astrocytes also can express metalloproteinases (MMPs) and intercellular adhesion molecules (ICAMs) upon activation. Specifically, MMP-9 is produced by activated astrocytes and acts as an extracellular matrix collagenase, contributing to BBB breakdown [29]. ICAM-1 is expressed by activated astrocytes in response to TNF-α, IFN-γ, and TLR ligands in vitro and in vivo and can contribute to the recruitment and further invasion of circulating immune cells [23, 42] into the CNS. As noted above, MCP-1 is also produced by astrocytes and plays a role in both blood brain barrier permeability and recruitment of peripheral monocytes [70].

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3. Regulators of Astrocyte Inflammatory Function IL-1β has been shown to play a central role in regulating the reactive response of astrocytes via Rho signaling pathways [37]. The transcription factor NF-κB is persistently activated in response to cerebral ischemia, proinflammatory stimuli, and reactive oxygen species. In astrocytes and microglia, activated NF-κB can induce expression of other inflammatory genes such as iNOS, matrix metalloproteinase-9, COX-2, leukocyte adhesion molecules, and proinflammatory cytokines, eventually leading to breakdown of the bloodbrain barrier and the generation of neurotoxic reactive oxygen species [49]. Much still remains to be learned about the regulation of gene expression during inflammatory activation of astrocytes.

3.1 Response to Cytokines/ Chemokines Not only do astrocytes produce cytokines and chemokines, their production of these factors is in itself regulated by the presence of other cytokines. In vivo injection of TNF-α into mouse brain resulted in upregulation of RANTES and MIP-1α [25]. TNF-α production by astrocytes is induced by IFN-γ, IL-1, and TNF-α, but inhibited by IL-6, IL-10, and TGF-β. Astrocytic release of IL-6 is induced by TNF-α, IFN-γ, TGF-β, and IL-1, for review see [18]. There is thus a complex interplay of autocrine and paracrine effects of cytokines between astrocytes and microglia that determine the final responses of these cells as well as their

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activity as sources of these regulatory molecules. For a partial list of some inducers and inhibitors of astrocyte cytokine expression see Table 1. Table 1. Cytokines produced by astrocytes Molecule GM-CSF IL-6 TNF-

Inducers TNF- , IL-1

Inhibitors TGF-

TNF- , IFN- , TGF- , IL-1 IFN- , IL-1, TNF-

TGF- , IL-6, IL-10

TGFMCP-1

IL-1, TGFTNF- , IFN- , IL-1, TGF- , Fas ligation, HIV-1 Tat TNF- , IL-1 TNF- , IFN- , HIV-1 Tat, Fas ligation

RANTES IP-10

GM-CSF, granulocyte/macrophage colony-stimulating factor; IL-1, -6, -10, interleukin-1, -6, -10; TNF, tumor necrosis factor- ; TGF, transforming growth factor; IFN- , interferon- ; HIV-1, human immunodeficiency virus type 1. Table from Dong and Benveniste, 2001, Glia 36:180, used with permission.

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3.2 Complement Complement also activates astrocytes. Complement receptors for C3a and C5a are expressed on astrocytes and when activated lead to increased intracellular calcium via the phospholipase C pathway as well as activation of the MAPK pathway [65]. Following exposure to C3a and C5a anaphylatoxins, human astrocytes in vitro have shown increased IL6 mRNA expression which may be neuroprotective [57, 64], and may facilitate increased IL8 expression [36]. Recent work supports a role for a novel C5a receptor isoform on astrocytes with anti-inflammatory properties [21]. Complement may also play a role in mediating excitotoxic neuronal death through astrocytes [72]. Both C1q and C3 can be made by astrocytes [69], so as with cytokines, astrocytes have a dynamic role both producing and responding to complement, which also interacts with cytokine responses.

3.3 Interaction with Microglia Microglia actively monitor the brain even while in their resting state [53]. However, recent work suggests that purinergic signaling by astrocytes may be involved in the earliest responses of microglia to injury [16]. ATP, at least in part released by astrocytes, was shown to alter microglial dynamics, including in the setting of acute injury [16]. Thus astrocytes may in some cases be the first responders which then recruit microglia. Microglia as sensors and early responders to injury, can secrete proinflammatory cytokines such as IL-1b and TNF-α that can then activate adjacent astrocytes and microglia by autocrine and paracrine pathways, thus resulting in propagation of the inflammatory response. For review see [61].

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Astrocytes in turn can stimulate microglial proliferation and activation in vitro through the production of M-CSF [31] and laminin [45]. Microglia may have a synergistic inflammatory effect with astrocytes. In an in vitro model of the blood brain barrier exposed to ischemia-like conditions, co-cultures of brain endothelial cells and astrocytes exhibited markedly greater injury when microglia were plated with the other two cell types [80]. However, others have found a more protective role for interacting microglia and astrocytes. Microglia-derived GDNF protects astrocytes in culture from ischemia-like injury [43]. Also, microglia in vitro survived ischemia-like injury better in the presence of astrocytes [74]. See chapter 2 this volume by Streit et al. for a discussion of the beneficial effects of microglia and an in depth discussion of microglia activation.

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3.4 Developmental Changes in Astrocyte Inflammatory Response Little work has been done on glial inflammatory responses in the context of development. We have found that microglia cultured for a short time are more sensitive to ischemia-like injury in vitro than those cultured for longer durations, and may contribute to worsening brain injury by increased release of the inflammatory cytokines TNF-α and IL-1β [14]. Early differentiating oligodendrocytes are also more vulnerable to free radical injury and cytokine injury compared to mature oligodendrocytes [1, 2]. However, similar exploration of astrocytic inflammatory changes with development still needs investigation. Age-specific changes occur with astrocyte expression of apoptotic mediators. Primary astrocytes cultured for short times undergo more apoptosis after serum deprivation and have higher levels of the pro-apoptotic protein bax and greater ERK kinase expression compared astrocytes cultured for longer durations [79]. Blood brain barrier breakdown after an excitotoxic lesion in juvenile rats resulted in greater leukocyte recruitment compared to adult rats [8], potentially reflecting changing astrocytic response in BBB maintenance with age. On the opposite end of the age spectrum, a model of traumatic brain injury in aged rats showed exacerbated glial activation and enhanced release of the inflammatory cytokines Il-1β, TNFα, IL-6, ICAM-1, iNOS, and MMP-9 compared to young rats [41]. Clinical studies further demonstrate developmental variation in glial responses. Pathology data from the National Collaborative Perinatal Project showed that in preterm infants, periventricular leukomalacia, a debilitating white matter injury, peaked at 32-35 weeks’ gestation while hypertrophic astrocytes peaked at 36-44 weeks’ gestation [44]. This correlation of change in astrocyte response with reduced susceptibility is suggestive. Developmental differences in astrocytic response to insult may account for some of the variation in outcomes at different gestational ages. Similarly with regards to the aged population, chronic inflammation and production of pro-inflammatory cytokines by astrocytes and microglia may in part contribute to amyloid formation and the pathogenesis of Alzheimer’s disease [32, 48].

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4. Specific Neurological Diseases and Astrocyte Activation The role of astrocytes in various disease states will be discussed more thoroughly in subsequent chapters, specifically looking at the role of inflammation in stroke, Alzheimer’s disease, Parkinson’s disease, and trauma. We briefly discuss astrocyte inflammatory involvement during the pathologic processes of ischemia and multiple sclerosis.

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4.1 Ischemia Astrocytes may serve both protective and destructive roles during cerebral ischemia. Astrocytes play a crucial role in antioxidant defenses. Astrocytes have more glutathione and are more resistant to oxidative injury [6]. Astrocytes also express the metal-binding proteins metallothionein I and II which suppress metal-catalyzed free-radical production and can scavenge reactive oxygen species [51, 63]. Neurons co-cultured with astrocytes were protected from nitric oxide-induced injury by enhanced astrocytic glutathione levels [13]. Moreover, neuronal glutathione concentration was found to double after 24 hours of coculturing with astrocytes [34]. Thus, astrocytes can upregulate neuronal antioxidant capability in addition to actively detoxifying reactive oxygen species in the brain. Furthermore, glutamate excitotoxicity after ischemia can be modulated by astrocytic clearance of glutamate. Neuronal vulnerability to glutamate was 100-fold greater in astrocytepoor cultures in comparison to cultures with abundant astrocytes [19, 60]. In addition, neuronal growth factors like BDNF, EGF, NGF, and FGF are released by reactive astrocytes and may contribute to synaptogenesis and neurogenesis after ischemia [66, 71]. Astrocytes also release neuropilin and VEGF which may promote angiogenesis after cerebral ischemia [39, 83], although VEGF is also associated with increased vascular permeability and could contribute to edema formation [58]. In contrast, astrocytes may have detrimental effects after ischemia. Increased NO production after ischemia may lead to decreased glutamine synthase activity by astrocytes, decreased glutamate uptake, and subsequent glutamate neurotoxicity [7, 50]. Activated astrocytes after ischemia also produce numerous inflammatory cytokines with pleiotropic effects including thrombosis, demyelination, and BBB disruption [18]. As noted above, MCP-1 may be another mediator released by astrocytes which could modulate BBB function and increase edema in the setting of ischemia [70]. Rat brain astrocytes were found to have increased MMP-2 activity after ischemia, which correlated with increased BBB permeability [59]. Furthermore, investigators have shown that activation of cultured astrocytes by LPS and IFN-γ led to increased induction of iNOS and production of NO. After this glial activation, increased glutamate-mediated neuronal death occurred only when combined with hypoxic conditions, illustrating the synergistic effect of inflammation with ischemia. [46].

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Valerie Chock and Rona Giffard

34 4.2 Multiple Sclerosis

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system in which glial cells play a prominent role. In murine experimental autoimmune encephalomyelitis (EAE), an established animal model of multiple sclerosis, astrocyte hypertrophy coincided with manifestation of axonal damage [73]. Astrocytes in multiple sclerosis plaques produce IL-6 [54], lack β-2 adrenergic receptors, and potentially serve as antigen-presenting cells [82], thus facilitating T-cell invasion and activation. Repeated exposure of these astrocytes to inflammatory cytokines triggers unregulated inflammatory responses and increased noradrenalin levels, leading to focal areas of myelin and axonal damage [17, 81].

5. Conclusions The role of astrocytes as primary inflammatory cells in the brain is now well-established. Recent results suggest that they are among the first cells in the brain to react to an insult and activate other cells including microglia. Future investigations are imperative to clarify the complex interactions of astrocytes with other CNS cell types in normal brain function and in pathologic conditions. New studies will identify areas in which astrocyte function can be enhanced or suppressed for neuroprotection.

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Acknowledgements We would like to thank Andrew Morrow for help preparing the manuscript, Drs. Yibing Ouyang and Grace Sun for the photomicrographs. This work was supported in part by NIH grants NS37520, NS14543, and GM49831.

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[38] Kimberlin, D.W., et al., Modulation of expression of genes involved in the inflammatory response by lipopolysaccharide and temperature in cultured human astroglial cells. Immunol Invest, 1995. 24(5): p. 775-85. [39] Krum, J.M. and A. Khaibullina, Inhibition of endogenous VEGF impedes revascularization and astroglial proliferation: roles for VEGF in brain repair. Exp Neurol, 2003. 181(2): p. 241-57. [40] Kuchler-Bopp, S., et al., Astrocytes induce several blood-brain barrier properties in non-neural endothelial cells. Neuroreport, 1999. 10(6): p. 1347-53. [41] Kyrkanides, S., et al., Enhanced glial activation and expression of specific CNS inflammation-related molecules in aged versus young rats following cortical stab injury. J Neuroimmunol, 2001. 119(2): p. 269-77. [42] Kyrkanides, S., et al., TNF alpha and IL-1beta mediate intercellular adhesion molecule1 induction via microglia-astrocyte interaction in CNS radiation injury. J Neuroimmunol, 1999. 95(1-2): p. 95-106. [43] Lee, G.A., et al., Microglia-derived glial cell line-derived neurotrophic factor could protect Sprague-Dawley rat astrocyte from in vitro ischemia-induced damage. Neurosci Lett, 2004. 356(2): p. 111-4. [44] Leviton, A. and F.H. Gilles, Acquired perinatal leukoencephalopathy. Ann Neurol, 1984. 16(1): p. 1-8. [45] Liesi, P., et al., Laminin is induced in astrocytes of adult brain by injury. Embo J, 1984. 3(3): p. 683-6. [46] Mander, P., et al., Nitric oxide from inflammatory-activated glia synergizes with hypoxia to induce neuronal death. J Neurosci Res, 2005. 79(1-2): p. 208-15. [47] Matsumoto, Y., K. Ohmori, and M. Fujiwara, Immune regulation by brain cells in the central nervous system: microglia but not astrocytes present myelin basic protein to encephalitogenic T cells under in vivo-mimicking conditions. Immunology, 1992. 76(2): p. 209-16. [48] Mattson, M.P., Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer's disease. J Neurovirol, 2002. 8(6): p. 539-50. [49] Mattson, M.P. and S. Camandola, NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest, 2001. 107(3): p. 247-54. [50] Muscoli, C., et al., The effect of inflammatory stimuli on NMDA-related activation of glutamine synthase in human cultured astroglial cells. Neurosci Lett, 2005. 373(3): p. 184-8. [51] Nakajima, K. and K. Suzuki, Immunochemical detection of metallothionein in brain. Neurochem Int, 1995. 27(1): p. 73-87. [52] Nikcevich, K.M., et al., IFN-gamma-activated primary murine astrocytes express B7 costimulatory molecules and prime naive antigen-specific T cells. J Immunol, 1997. 158(2): p. 614-21. [53] Nimmerjahn, A., F. Kirchhoff, and F. Helmchen, Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 2005. 308(5726): p. 13148. [54] Okuda, Y., et al., The development of autoimmune encephalomyelitis provoked by myelin oligodendrocyte glycoprotein is associated with an upregulation of both

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Valerie Chock and Rona Giffard proinflammatory and immunoregulatory cytokines in the central nervous system. J Interferon Cytokine Res, 1998. 18(6): p. 415-21. Panek, R.B., et al., Characterization of astrocyte nuclear proteins involved in IFNgamma- and TNF-alpha-mediated class II MHC gene expression. J Immunol, 1994. 153(10): p. 4555-64. Panickar, K.S. and M.D. Norenberg, Astrocytes in cerebral ischemic injury: morphological and general considerations. Glia, 2005. 50(4): p. 287-98. Penkowa, M., et al., Astrocyte-targeted expression of interleukin-6 protects the central nervous system during neuroglial degeneration induced by 6-aminonicotinamide. J Neurosci Res, 2003. 73(4): p. 481-96. Proescholdt, M.A., et al., Vascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brain. J Neuropathol Exp Neurol, 1999. 58(6): p. 613-27. Rosenberg, G.A., et al., Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res, 2001. 893(1-2): p. 104-12. Rosenberg, P.A. and E. Aizenman, Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci Lett, 1989. 103(2): p. 162-8. Rothwell, N.J. and S.J. Hopkins, Cytokines and the nervous system II: Actions and mechanisms of action. Trends Neurosci, 1995. 18(3): p. 130-6. Saoudi, A., et al., Prevention of experimental allergic encephalomyelitis in rats by targeting autoantigen to B cells: evidence that the protective mechanism depends on changes in the cytokine response and migratory properties of the autoantigen-specific T cells. J Exp Med, 1995. 182(2): p. 335-44. Sato, M. and I. Bremner, Oxygen free radicals and metallothionein. Free Radic Biol Med, 1993. 14(3): p. 325-37. Sayah, S., et al., Expression of cytokines by human astrocytomas following stimulation by C3a and C5a anaphylatoxins: specific increase in interleukin-6 mRNA expression. J Neurochem, 1999. 72(6): p. 2426-36. Sayah, S., et al., Two different transduction pathways are activated by C3a and C5a anaphylatoxins on astrocytes. Brain Res Mol Brain Res, 2003. 112(1-2): p. 53-60. Schwartz, J.P. and N. Nishiyama, Neurotrophic factor gene expression in astrocytes during development and following injury. Brain Res Bull, 1994. 35(5-6): p. 403-7. Sedgwick, J.D., et al., Major histocompatibility complex-expressing nonhematopoietic astroglial cells prime only CD8+ T lymphocytes: astroglial cells as perpetuators but not initiators of CD4+ T cell responses in the central nervous system. J Exp Med, 1991. 173(5): p. 1235-46. Soos, J.M., et al., Astrocytes express elements of the class II endocytic pathway and process central nervous system autoantigen for presentation to encephalitogenic T cells. J Immunol, 1998. 161(11): p. 5959-66. Speth, C., et al., Complement synthesis and activation in the brain of SIV-infected monkeys. J Neuroimmunol, 2004. 151(1-2): p. 45-54.

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[70] Stamatovic, S.M., et al., Monocyte chemoattractant protein-1 regulation of blood-brain barrier permeability. J Cereb Blood Flow Metab, 2005. 25(5): p. 593-606. [71] Strauss, S., et al., Increased levels of nerve growth factor (NGF) protein and mRNA and reactive gliosis following kainic acid injection into the rat striatum. Neurosci Lett, 1994. 168(1-2): p. 193-6. [72] van Beek, J., et al., Complement anaphylatoxin C3a is selectively protective against NMDA-induced neuronal cell death. Neuroreport, 2001. 12(2): p. 289-93. [73] Wang, D., et al., Astrocyte-associated axonal damage in pre-onset stages of experimental autoimmune encephalomyelitis. Glia, 2005. 51(3): p. 235-40. [74] Wang, J.Y., et al., Production of macrophage inflammatory protein-2 following hypoxia/reoxygenation in glial cells. Glia, 2000. 32(2): p. 155-64. [75] Weber, F., et al., Human astrocytes are only partially competent antigen presenting cells. Possible implications for lesion development in multiple sclerosis. Brain, 1994. 117 (Pt 1): p. 59-69. [76] Weiss, J.M., et al., Astrocyte-derived monocyte-chemoattractant protein-1 directs the transmigration of leukocytes across a model of the human blood-brain barrier. J Immunol, 1998. 161(12): p. 6896-903. [77] Williams, K.C., et al., Antigen presentation by human fetal astrocytes with the cooperative effect of microglia or the microglial-derived cytokine IL-1. J Neurosci, 1995. 15(3 Pt 1): p. 1869-78. [78] Wong, G.H., et al., Inducible expression of H-2 and Ia antigens on brain cells. Nature, 1984. 310(5979): p. 688-91. [79] Xu, L., et al., Susceptibility to apoptosis varies with time in culture for murine neurons and astrocytes: changes in gene expression and activity. Neurol Res, 2004. 26(6): p. 632-43. [80] Yenari, M.A., et al., Microglia Potentiate Damage to Blood-Brain Barrier Constituents. Improvement by Minocycline In Vivo and In Vitro. Stroke, 2006. 37: in press [81] Zeinstra, E., N. Wilczak, and J. De Keyser, [3H]dihydroalprenolol binding to beta adrenergic receptors in multiple sclerosis brain. Neurosci Lett, 2000. 289(1): p. 75-7. [82] Zeinstra, E., et al., Astrocytes in chronic active multiple sclerosis plaques express MHC class II molecules. Neuroreport, 2000. 11(1): p. 89-91. [83] Zhang, Z.G., et al., Up-regulation of neuropilin-1 in neovasculature after focal cerebral ischemia in the adult rat. J Cereb Blood Flow Metab, 2001. 21(5): p. 541-9.

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In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 41-62 © 2006 Nova Science Publishers, Inc.

Chapter IV

Cell Death Pathways and the Immune Response Jennifer M. Pocock1*, Claudie Hooper2, Emma East3 and Fleur Jones1

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1

Cell Signalling Laboratory, Department of Neuroinflammation, Institute of Neurology, University College London, 2 Department of Neuroscience, Institute of Psychiatry, King's College London, London, SE5 8AF, UK 3 Laboratory of Experimental Neuroinflammation, Department of Neuroinflammation, Institute of Neurology, University College London,

1. Introduction In this review, we will discuss the role of cell death in inflammatory processes within the CNS and consider this with regard to disease progression in Alzheimer’s disease (AD) and multiple sclerosis (MS) in particular. It is becoming increasingly clear that many chronic neurodegenerative diseases exhibit evidence of a highly localised (“microlocalised” – Akiyama et al., 2000), innate, neuroinflammatory process, even though the classic signs of inflammation seen in other tissues may not be present or required for neurotoxicity (Cooper et al., 2000; Raine 2000; McGeer and McGeer 2001; Eikelenboom et al., 2002). Thus in AD, early research proposed that the neuronal and glial changes associated with the fibrils in AD brains were a reaction to a foreign substance (see Eikelenboom et al., 2002). A number of inflammatory proteins including complement factors, acute-phase proteins and proinflammatory cytokines have been subsequently identified (Akiyama et al., 2000), and the

*

corresponding author: [email protected], Tel: +44 20 7679 4031, Fax: +44 20 7278 65721 Wakefield Street, London WC1N 1PJ, UK

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presence in amyloid plaques of activated complement factors and activated microglia is strongly suggestive of an inflammatory process. These findings together with the absence of immunoglobulins, T-cell subsets and recruited leukocytes supports the view that fibrillar amyloid-beta plaques are associated with a locally induced, non-immune mediated, chronic inflammatory type response (Eikelenboom et al., 2002). Other neurodegenerative diseases in which localised chronic inflammatory processes are evident include Prion disease, Parkinson’s disease, HIV-associated dementia and MS. Each of these has its own characteristics with regard to the degree of T-cell activation and leukocyte recruitment (from no evident systemically driven immune-mediated mechanisms to chronically stimulated) and cytokine repertoire (as well as an ongoing debate about whether the molecular processes observed constitute neuroinflammation given a lack in some cases of a systemic, humoral component) but all are characterised by the presence of activated microglia (Cooper et al., 2000; Raine 2000; Fassbender et al., 2000; Eikelenboom et al., 2002; Vilhardt 2005).

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2. Microglia and Neuroinflammatory Cell Death Pathways Microglia, the immune cell of the brain, are present in normal brain tissue in a downregulated ramified state, and may also function as a cerebral cleansing system, limiting the spread of diffusible neurotransmitters and removing extracellular debris (Thomas 1992). Ramified microglia also secrete a number of neuroprotective factors, such as neurotrophins and nerve growth factors, which promote neuronal survival (Kreutzberg 1996). Under pathological conditions, microglia proliferate and transform into active brain macrophages. In the activated state, microglia secrete a number of immunoregulatory factors including cytokines, glutamate, proteases and free radicals (Pocock and Liddle 2001; Vilhardt 2005). Thus, if microglia remain activated for a sustained period, the persistent secretion of toxic inflammatory mediators becomes detrimental to neuronal survival. Therefore, chronic microglial activation is likely to contribute to the pathogenesis of a number of neurological disorders where the presence of abnormal extracellular deposits and/or protein aggregates elicit a cerebral immune mediated response. The ‘end point’ of microglial activation is a field of research that has not been extensively studied. In general, activated microglia proliferate or undergo apoptosis. Proliferation under controlled conditions is a beneficial response instigated to maintain cerebral homeostasis by combating injury thereby minimising tissue damage. However, in disease states chronic microglial activation and proliferation becomes deleterious. In vitro, cultured microglia that undergo proliferation do inevitably die. However, in vivo activated microglia may proliferate then revert back to a ramified quiescent phenotype following the subsidence of the damaging event (Jordon and Thomas 1988). Alternatively, the expanded microglial population may endure activation-induced apoptosis thereby returning the microglial population to a steady-state level. Thus, activation-induced apoptosis may be an advantageous mechanism, which serves to terminate microglial inflammatory reactions thereby limiting bystander damage to neighbouring neurones.

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It could equally be argued that decreasing the microglial population via apoptosis could be detrimental since it reduces the sink of microglia producing neurotrophins and aiding regeneration (Streit, 2002). It is possible that the type and extent of a pathological insult governs whether activated microglia ultimately undergo cell death or down-regulation and conversion into a dormant state. Interestingly, activation-induced microglial apoptosis in vitro is elicited by chromogranin A (CGA) and Amyloid beta peptide (Aβ, two proteins that are up-regulated in AD (Kingham et al., 1999; Kingham and Pocock 2000). Apoptosis is also instigated in microglia by the proto-typical microglial activator lipopolysaccharide (LPS) and apoptotic microglial death has been attributed to overstimulation of these cells by LPS (Liu et al., 2001).

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2.1 Cell Death Pathways and the Immune Response in Alzheimer’s Disease AD may begin with the degeneration of neurones in the nucleus basalis of Meynert (Walace 1991; Whitehouse 1982). These cholinergic neurones play an important role in cognitive functions, especially memory and learning, and their degeneration is considered important for the initiation of sporadic AD (Coyle et al., 1983; Perry 1986). However it is the deposition of Aβ peptides into senile plaques, which is thought to be a critical factor for cell death pathways triggered in both familial and sporadic AD (Selkoe 1991). Whilst neuronal death in AD may occur as a result of microglial activation following their exposure to Aβ peptides, activated microglia are present not only around the Aβ plaques, but also in hippocampal areas devoid of amyloid deposition (Roe et al., 1996). Furthermore, whilst neuronal death in AD is higher in amyloid plaques than in the surrounding tissue, most dying neurones are not associated with amyloid plaques (Lassmann et al., 1995; Sugaya et al., 1997; Hull and Hampel 2002). Microglial activation is associated with the release of toxic inflammatory mediators and their prolonged production and exposure to neurones may result in neuronal death. Furthermore, the activation of microglia may shift their function from a neuroprotective role in which they aid repair and regeneration to a neurotoxic phenotype (Morgan et al., 2004). Cell loss in AD was originally believed to be confined to specific neuronal populations (as stated above). However, there is increasing evidence that the cell death in AD involves not only loss of neurones but also microglia, astrocytes and oligodendrocytes (Smale et al., 1995; de la Monte et al., 1997). Apoptotic microglia have been detected around senile plaques in post-mortem AD tissue (Yang et al., 1998). Furthermore, fragmented DNA has been demonstrated to co-localise with microglia and oligodendrocytes as well as neurones in the AD brain (Lassmann et al., 1995) and TUNEL-positive microglia have also been observed in AD brain (Dragunow et al., 1995). Conversely, Bcl-xL positive microglia frequently co-localise with senile plaques. High levels of this potent apoptotic inhibitor may render microglia more resistant to cytotoxic environments, such as areas of neurodegeneration (Drache et al., 1997). This suggests that microglia exhibit protective mechanisms that serve to prolong their survival under pathological conditions. It is argued that microglia may contribute to AD pathology and imaging studies show that reactive

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microglia are apparent at an early stage in AD (Cagnin et al., 2001; Banati 2003). On the other hand, microglial activation in AD may serve to curtail amyloidogenesis, consequently limiting neurodegenerative processes. Activated microglia upregulate amyloid precursor protein (APP) expression and have been reported to release Aβ in vitro, which is the main constituent of senile plaques (Biting et al., 1996).

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Nuclear condensation ****

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Mitochondrial depolarisation

Figure 1. Amyloid beta peptide induces microglial mitochondrial depolarisation and apoptosis Primary cultured rat microglia treated with Amyloid beta peptide fragment (25-35) (Aβ(25-35)) were stained with JC-1 or Hoechst 33342 to provide an estimation of mitochondrial depolarisation and apoptosis respectively. (A) Microglia were treated with increasing concentrations of Aβ(25-35) (15-55 µM) or the reverse peptide Aβ(35-25) (55 µM) for 48 hours before the cells were stained with JC-1 (grey

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bars) or Hoechst 33342 (open bars). Control microglia were left untreated for 48 hours before staining (basal). (B) Microglia were treated with Aβ(25-35) (55 µM) for 0, 16, 24, 28, 32, 40 or 48 hours before being stained with JC-1 (closed circles) or Hoechst 33342 (open circles). Cells displaying depolarised mitochondria or brightly stained pyknotic nuclei were counted and the degree of mitochondrial depolarisation or apoptosis was expressed as a percentage of the total number of cells counted. The values shown represent the mean ± SEM of data from experiments performed in triplicate. Experiments consisted of 3 coverslips per treatment, each comprising 10 fields of view and experiments were performed on three independent occasions. Statistical analysis was performed using ANOVA followed by the Tukey post test. * p < 0.05 vs control; ** p < 0.01 vs control (A: control describes basal. B: control describes 0 hours). (C) Microglia were treated Aβ(25-35) (55 µM) for 48 hours then the cells were stained with JC-1 (grey bars) or Hoechst 33342 (open bars). In addition, microglia treated with Aβ(25-35) (55 µM) in the presence of CsA (1 µM), Poly I (0.5 µg/ml), neutralising RAGE antibody (200 µg/ml), PTX (2 µg/ml), BAPTA-AM (10 µM), PP2 (50 nM) or U0126 (5 µM) were stained with JC-1 (grey bars) or Hoechst 33342 (open bars) after 48 hours in culture. Control microglia were left untreated for 48 hours before staining (basal). Cells displaying depolarised mitochondria or brightly stained pyknotic nuclei were counted and the degree of mitochondrial depolarisation or apoptosis was expressed as a percentage of the total number of cells counted. The values shown represent the mean ± SEM of data from experiments performed in triplicate. Experiments consisted of 3 coverslips per treatment, each comprising 10 fields of view and experiments were performed on three independent occasions. Statistical analysis was performed using ANOVA followed by the Tukey post test. ** p < 0.01 vs control. *** p < 0.001 vs control. (control describes Aβ treated microglia).

Aβ triggers microglial cell death in vitro. Korotzer et al., (1993) have demonstrated that process bearing microglia show signs of degeneration after exposure to Aβ(25-35). Additionally, it has been reported that Aβ(25-35) induces microglial cell rounding (Casal et al., 2002), which is a morphological transition that often precedes activation-induced death in microglia. We have found that Aβ(25-35)-induced microglial apoptosis is mediated by mitochondrial depolarisation as demonstrated using the mitochondrial permeability transition pore (PT) inhibitor cyclosporin A (Figure 1 – Hooper and Pocock, unpublished observations). Exposure of microglia to Aβ(25-35) (15-55 µM) for 48 hours induced in a dose-dependent increase in mitochondrial depolarisation and nuclear pyknosis (Figure 1B). Conversely, microglia treated with the reverse peptide, Aβ(35-25) (55 µM) for 48 hours, maintained polarised mitochondria and large healthy nuclei. This indicates that apoptosis and mitochondrial depolarisation are a specific response to Aβ(25-35) treatment. Aβ (25-35)-induced mitochondrial depolarisation preceded apoptosis temporally. Microglia displaying depolarised mitochondria were initially detectable 32 hours after the addition of Aβ(25-35) (55 µM). Consistent with these findings Aβ(25-35) has been shown to selectively decrease complex IV (cytochrome oxidase) activity in isolated mitochondria (Canevari et al., 1999). Therefore it is conceivable that internalised Aβ(25-35) triggers mitochondrial damage via this mechanism in microglia. Apoptosis is often preceded by a reduction in mitochondrial membrane potential (∆Ψ), which is caused by the opening of the PT pore (Zamzami et al., 1996). The involvement of the PT pore in Aβ induced microglial apoptosis was subsequently assessed using the pore inhibitor cyclosporin A (CsA) (Zamzami et al., 1996; Kingham and Pocock 2000; Pocock and Liddle 2001). Pre-treatment with CsA (1 µM) significantly attenuated Aβ (55 µM) induced mitochondrial depolarisation and apoptosis after 48 hours in culture (Figure 1C). This suggests that the PT pore is involved in Aβ(25-35) induced microglial cell death. Oligodendrocytes treated with Aβ(25-35) or Aβ(1-40) also undergo apoptosis accompanied by loss of mitochondrial function (Xu et al., 2001).

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The upstream signalling pathways involved in Aβ-induced mitochondrial depolarisation and apoptosis were also studied using a number of inhibitors. Pre-treatment with the scavenger receptor inhibitor, poly I (0.5 µg/ml), the Gi/0 G-protein inhibitor, pertussis toxin (PTX; 2 µg/ml) or the Src tyrosine kinase inhibitor, PP2 (100 nM) significantly attenuated Aβ(25-35) (55 µM) induced mitochondrial depolarisation and apoptosis (Figure 1C) whilst pretreatment with neutralising RAGE (receptor for glycated end products) antibody (200 µg/ml), the intracellular calcium chelator, BAPTA-AM (10 µM) or the MEK inhibitor, U0126 (5 µM) exerted no inhibitory effects. Microglial cultures treated with the inhibitors alone did not contain significantly different levels of mitochondrial depolarisation or apoptosis from control (basal). These data imply that a scavenger receptor-mediated pathway coupled intracellularly to a Gi/0 protein and a Src non-receptor tyrosine kinase is involved in the microglial response to Aβ whilst the RAGE receptor and ERK mediated signalling pathways appear to play no role. CGA is a member of the Granin family of acidic glycoproteins. CGA was originally identified in the secretory granules of chromaffin cells. However, it is now known that CGA is widely distributed in the secretory granules of nervous tissue (Volknandt et al., 1987) as well as endocrine tissue (Fischer-Colbrie et al., 1987). CGA is implicated in a number of neurodegenerative disorders including AD, stroke, Parkinson’s disease and Pick’s disease. In AD, CGA accumulates in granular deposits, which are associated with senile plaques (Rangon et al., 2003) and in the surrounding dystrophic neurites (Munoz 1991; Yasuhara et al., 1994; Rangon et al., 2003). CGA also genetically maps to a chromosomal locus associated with APP, which indicates that CGA and APP may act synergistically in pathology (Modi et al., 1989). Following a stroke, CGA is upregulated in axonal swellings located at the infarct periphery (Yasuhara et al., 1994). Furthermore, CGA accumulates in the Lewy bodies present in the substantia nigra in Parkinson’s disease (Nishimura et al., 1994) and is upregulated in the Pick bodies and swollen neuronal processes in Pick’s disease (Yasuhara et al., 1994). CGA is a potent microglial activator inducing microglia to switch from a resting ramified phenotype into a reactive neurotoxic state (Ciesielski-Treska et al., 1998; Kingham et al., 1999; Ciesielski-Treska et al., 2001). In vitro, CGA-induced microglial activation results in microglial cell death, which is predominantly mediated by a nitric oxide (NO)-dependent fall in mitochondrial membrane potential (Kingham and Pocock 2000). Increasing evidence is accumulating to suggest that NO plays a significant role in cell death pathways in neuroinflammatory diseases. NO has been reported to promote the activation of caspases and apoptosis in macrophages (Messmer et al., 1998). Furthermore, Complexes I, II and IV of the electron transport chain are readily nitrated by NO dependent mechanisms (Clementi et al., 1998; Murray et al., 2003). Oxidative damage results in mitochondrial dysfunction, which precipitates mitochondrial PT pore opening and downstream apoptosis (Hortleno et al., 1997; Heales and Bolaños 2002). Interestingly, CGA-induced apoptosis is cytochrome c independent, although microglia exhibit other signatures of apoptosis including DNA fragmentation and caspase-1 activity (Kingham et al., 1999; Kingham and Pocock 2000). CGA stimulation of microglia induces the shedding of soluble Fas ligand, (sFasL), which can promote neuronal apoptosis (Ciesielski-Treska et al., 2001).

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Microglia exposed to CGA show a prominent upregulation of the transcription factor and tumour suppressor protein, p53 (Pocock et al., 2002, Figure 3). There is evidence that the expression of p53 is increased in both neurones and glia (microglia as well as astrocytes and oligodendrocytes) in AD brain (de la Monte et al., 1997; Kitamura et al., 1997) and that this is associated with Fas (CD95/APO-1) expression. Fas is a cell surface membrane receptor of the tumour necrosis superfamily and binding of Fas ligand (FasL/CD95L) to Fas trimerizes the intracellular domain of Fas (death domain) that attaches to adaptor intracellular proteins (FADD/MORT1) and activates caspases that execute apoptosis (Webb et al., 1997). Microglia constitutively express FasL in culture (Spanaus et al., 1998; Frigerio et al., 2000; Taylor et al., 2005) and at low levels in normal human white matter (Dowling et al., 1996; Bechmann et al., 1999). Microglial activation as a result of, for example, oxidative stress and hypoxia/reoxygenation, exposure to lipopolysaccharide or cytokines such as TNF-α or IFN-γ can lead to the enhanced expression of Fas, and FasL in microglia (Spanaus et al., 1998; Vogt et al., 1998; Badie et al., 2000; Niinobu et al., 2000; Ciesielski-Treska et al., 2001; Terrazzino et al., 2002; Taylor et al., 2005). However, there have also been reports that activation can induce a reduction in FasL expression on ramified microglia exposed to IFN-γ compared with a lesser reduction in amoeboid microglia (Frigerio et al., 2000). In this instance, the authors argue that the higher expression of FasL on ramified microglia serves to eliminate potentially damaging infiltrating immune cells. Microglial activation can also enhance metalloproteinase (MMPs) and protease (eg cathepsins) release (Kingham and Pocock 2001). We find that cultured non-stimulated microglia express FasL (Taylor et al., 2005) but also Fas and p53 in “protected” locations – thus Fas is localised in the nucleus and p53 in the cytoplasm (Figure 2). In line with this is the finding that resting microglia, whilst expressing FasL, are resistant to FasL-mediated apoptosis (Spanaus et al., 1998). Furthermore microglia activated with CGA, which induces microglial apoptosis, (Kingham et al., 1999) show upregulation of p53 (Pocock et al., 2001) and activated microglia display a cytosolic but predominantly nuclear p53 location (Saito et al., 2000). Thus microglia express the Fas ligand at the cell surface but not the receptor and may therefore protect themselves from cell suicide, and the location of the p53 transcription factor in the cytosol prevents it switching the cells to an apoptotic state. In light of this, increases in Fas and FasL expression in different cells during neuroinflammatory disease must also take into account the cellular location of these proteins for any meaningful conclusions to be drawn. The expression of FasL is positively controlled by p53, which also negatively controls matrix metalloproteinase (MMP) expression (Figure 3). Furthermore, mutations in the p53 gene affect transcription of the Fas gene, resulting in lack of Fas expression on the cell membrane (Zalcenstein et al., 2003). FasL can be cleaved by metalloproteinases to soluble FasL (sFasL), which can then induce neuronal apoptosis. Furthermore microglia under oxidative stress may release the inflammatory cytokines TNF-α, IL-1 and IL-6 to name a few, and these can further increase MMP and cathepsin production. TNF-α and IFN-γ can render microglia sensitive to FasL induced apoptosis by induction of Fas expression and down regulation of Bcl-2 and Bcl-xL (Spanaus et al., 1998). Proteinases released from microglia can also lead to microglial and neuronal apoptosis (Kingham and Pocock 2001). Furthermore, we have recently shown that microglia stimulated through metabotropic glutamate receptor 2

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(mGlu2) release both sFasL and TNF-α which act in concert to trigger neuronal apoptosis (Figure 3; Taylor et al., 2005). p53

fas

p53+fas

DAPI

p53+fas+DAPI

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Figure 2. Immunofluorescence of Fas and p53 on non-stimulated cultured rat microglia. Top row, p53 is expressed in the cytosol and Fas is expressed in the nucleus (DAPI) of primary cultured non-stimulated rat microglia. Lower row, overlay of Fas and p53 staining, overlay of Fas, p53 and DAPI staining. Cells were fixed, permeabilised in methanol and stained with rabbit polyclonal anti-Fas and goat polyclonal anti-p53 followed by TRITC-tagged anti-rabbit and FITC-tagged anti-goat respectively.

Autocrine activation of metabotropic glutamate receptors (mGluRs) is also implicated in CGA-induced microglial apoptosis (Kingham et al., 1999; Taylor et al., 2002; 2003). Microglia treated with CGA release vast amounts of glutamate into the extracellular milieu. Glutamate is generated in the mitochondria from α-ketoglutarate. Thus, in response to cellular stress, microglial metabolism and subsequent glutamate synthesis may be enhanced to support the production of the anti-oxidant glutathione. The FasL-induced cell death pathway in microglia involves reactive oxygen intermediates since the antioxidants Nacetylcysteine and glutathione have been found to interfere with the induction of apoptosis by TNF-α and IFN-γ in these cells (Spanaus et al., 1998). We have previously reported that CGA-induced glutamate release is mediated in part by the Xc- transporter (Kingham et al., 1999). Other microglial activators including soluble amyloid precursor protein alpha (APPα), (Barger and Basile 2001), LPS (Piani and Fontana 1994) and the phorbol ester, phorbol myristate acetate (PMA) (Nakamura et al., 2003) trigger glutamate secretion via this transporter. Furthermore, zymosan (which stimulates microglial phagocytosis), the cytokine TNF-α and various bacterial products including protein A and tuberculin induce microglial glutamate release, although the involvement of the Xc- transporter has not yet been investigated (Piani and Fontana 1994).

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TNFR1 R

T-cell Fas

sFasL

MMPs cleave FasL from membrane

Apoptosis through TNFR1 R activation

Enhanced expression of FasL at cell surface

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Activation induced TNF-alpha release

FasL shedding

FasL

Upregulation and release of proteases including MMPs

TNFR1 R

Fas

Apoptosis via Fas receptor

Receptor activation by CGA, LPS, TNF-alpha, IFN-gamma, mGlu2 stimulation

Oligodendrocyte

TNFR1 R

Fas

49

Fas Trafficking of Fas to cell membrane

Microglia Expression of FasL and Fas enhanced Apoptosis Activation of p53 in the nucleus

Figure 3. Pathways for the triggering of apoptotic cascades following microglial activation in neuroinflammatory disease Receptor activation by chromogranin A (CGA), lipopolysaccharide (LPS), cytokines or glutamate activation of mGlu2 can lead to apoptosis of microglia and enhance the expression and release of proteases including the metalloproteinases. Activation of microglia can lead to p53 activation in the nucleus resulting in enhanced cell surface expression of FasL and the expression of Fas at the cell membrane. In addition, microglial activation can lead to the release of TNF-α which can lead directly to neuronal and oligodendrocyte apoptosis via stimulation of TNFR1 and also enhance the expression of Fas on the microglia. The released MMPs can lead directly to neuronal or glial death but can also cleave FasL from the microglial cell membrane. This can in turn lead to apoptosis of neurones, T-cells

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or oligodendrocytes and can also interact with microglial-expressed Fas causing microglial apoptosis (see Text for references).

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2.2 Cell Death Pathways and the Immune Response in Ischaemia

Research has mainly focussed on the effects of ischaemia on neuronal cell death. However, it is known that ischaemia also modulates microglial signalling and survival. In light of the close proximity of microglia to neurones and the emerging awareness of microglial-neuronal interactions this area of research warrants further investigation. Currently, it is known that microglial cultures exposed to ischaemia for 6 hours followed by reoxygenation exhibit very low levels of death (Yenari and Giffard 2001). Lyons and Kettenmann (1998) also found that microglia are extremely resistant to 6 hours of hypoxia. Conversely, the vast majority of microglia die when subjected to chemical ischaemia involving 6 hours of hypoxia in the presence of 2-deoxyglucose (a non-hydrolysable analogue of glucose) (Lyons and Kettenmann 1998). Interestingly, if microglia are subjected to hypoxia in the presence of mannitol (a non-metabolisable sugar) considerably less microglia die (Lyons and Kettenmann 1998). Mannitol acts as a free radical scavenger and therefore may protect the microglia from reactive oxygen or nitrogen species these cells produce during ischaemic episodes. Together these findings demonstrate that microglia can tolerate ischaemic conditions for a few hours, after which the cells endure death, which is probably due to saturation of survival mechanisms. Cultured astrocytes exhibit a similar susceptibility to ischaemic-like insults as microglia (Yu et al., 1989; Goldberg and Choi 1993; Smith et al., 2003), whereas, other central nervous system cell populations appear to be more vulnerable to such insults. The majority of cultured neurones (Goldberg and Choi 1993; Strasser and Fischer 1995) and oligodendrocytes (Lyons and Kettenmann 1998; Fern and Möller 2000) succumb to ischaemic insults after 25-60 minutes of exposure. The ability of microglia and also astrocytes to withstand ischaemia may reflect the fact that they possess large intracellular glycogen stores, which are depleted to fuel respiration under anaerobic conditions (Swanson and Choi 1993).

2.3 Cell Death Pathways and the Immune Response in Multiple Sclerosis MS is a relapsing and often progressive neurodegenerative disorder, which has an immune-mediated aetiology but potentially incorporates viral, bacterial and/or genetic triggers. Cell death in MS is due to damage and death of oligodendrocytes as a result of immune attack of the myelin sheath by resident and infiltrating macrophages which have been primed by recruited T- and B- cells (Van Noort and Amor 1998; Zipp et al., 2002). This results in demyelination and axon loss in the brain and spinal cord, with the degree of loss correlated to inflammation and demyelination (Trapp et al., 1998). The ultimate failure of oligodendrocytes to regenerate in chronic lesions is thought to be due to a depletion in the number of oligodendrocyte progenitors (Ludwin, 2005) or their inability to proliferate and regenerate due to a non-conducive environment within the lesion (John et al., 2002; Chang et al., 2000). However, it has recently been shown that adult oligodendrocyte progenitors can differentiate and remyelinate when transplanted into cuprizone-induced chronic lesions

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therefore indicating that remyelination failure could be the result of oligodendrocyte depletion rather than a non-conducive environment (Mason et al., 2004). Thus an understanding of the mechanisms of oligodendrocyte cell death could provide potential therapeutic strategies aimed at preventing demyelination in MS.

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2.4 Oligodendrocytes in Neuroinflammatory Cell Death Pathways Oligodendrocytes are extremely sensitive to glutamate toxicity and elevated glutamate levels in the cerebrospinal cord correlate with disease severity (Werner et al., 2001). Oligodendrocytes are also highly sensitive to oxidative stress, cytokines and other compounds released during injury, and immature oligodendrocytes appear more sensitive than mature oligodendrocytes (Back et al., 1998; Ladiwala et al., 1998; Gu et al., 1999). Thus TNF-α can cause cytotoxicity to oligodendrocytes at concentrations that do not affect other cell types such as astrocytes or neuronal populations (Selmaj and Raine 1988). Furthermore oligodendrocytes are more susceptible to cell death induced by ceramide than astrocytes or neurones (Casaccia-Bonnefil et al., 1996). Glutamate can induce excitotoxicity and oxidative stress due to membrane depolarisation and subsequent Ca2+ influx. Oligodendrocytes are sensitive to oxidative stress as a result of their high metabolic requirements. Indeed stimulation of AMPA ionotropic glutamate receptors is toxic to oligodendrocytes in vitro (Matute et al., 1997; McDonald et al., 1998) inducing rapid Ca2+ influx (Fern and Moller 2000; Yoshioka et al., 2000). Blockade of AMPA receptors prevents subsequent damage and Ca2+ influx implicating Ca2+ as the principal trigger for apoptosis through mechanisms involving depletion of glutathione and activation of JNK, calpain and caspase-3 (Liu et al., 2002). Blockade of caspase-3, however does not effectively protect against excitotoxicity induced by maximal AMPA receptor activation which suggests that oligodendrocyte death in this case can be mediated by caspasedependent and -independent mechanisms (Sanchez-Gomez et al., 2003). Glutamate-induced oligodendrocyte death can occur by non-receptor mediated inhibition of cysteine uptake and oxidative stress, which is dependent on ERK activation (Rosin et al., 2004). The antioxidant n-acetylcysteine can prevent excitotoxicity by increasing intracellular glutathione levels (Liu et al., 2002). The molecular mechanisms which protect against toxicity induced by reactive oxygen species are regulated during oligodendrocyte differentiation. Indeed, as stated above, mature oligodendrocytes are less sensitive than oligodendrocyte progenitors to H2O2 exposure, which induces caspase-3 activation suggesting apoptotic cell death mechanisms. High levels of H2O2, however, induce release of lactate dehydrogenase indicative of necrotic cell death (Fragoso et al., 2004). Members of the TNF superfamily, including TNF and Fas/FasL have been implicated in MS pathology (Dowling et al., 1996; D’Souza et al., 1996). Myelin phagocytosis by microglia occurs in vitro and induces microglial activation, leading to cytokine release and increased affinity for oligodendrocytes, inducing their death by cell contact through TNF receptors (Zajicek et al., 1992; Williams et al., 1994). Signalling through TNF receptor 1 (TNFR1) induces apoptosis; TNFR1 has been shown to be upregulated on oligodendrocytes in MS lesions as a result of chronic inflammation (Figure 3; Tchelingerian et al., 1995).

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Furthermore, TNF production by glial cells selectively induces oligodendrocyte apoptosis (Selmaj et al., 1991; Akassoglou et al., 1998) and TNFR1 knockout mice show no evidence of demyelination or oligodendrocyte pathology (Akassoglou et al., 1998). Fas/FasL interaction is an important mediator of apoptotic cell death (Figure 3). In the normal CNS, Fas is constitutively expressed at low levels on oligodendrocytes and is upregulated during the experimental animal model of MS (experimental autoimmune encephalomyelitis, EAE) and in MS (D’Souza et al., 1996; Bonetti et al., 1997). However it is the infiltrating CD4+ T-cells and parenchymal microglia which have been shown to express Fas, FasL, the pro-apoptotic protein Bax, active caspase 3, and DNA fragmentation/TUNELpositive staining (Bonetti et al., 1997; Kohji and Matsumoto 2000), all of which are strongly suggestive of an ongoing apoptotic process. The distribution of apoptotic markers suggests that neurones, astrocytes and oligodendrocytes do not appear to be undergoing apoptosis in EAE (Bonetti et al., 1997; Kohji and Matsumoto 2000). However the presence of Fas and FasL but not Bax on astrocytes, and the increased expression of FasL on microglia in MS lesions suggests that these two cell types have the capacity to regulate inflammation by inducing apoptosis of T-cells and microglia, and are likely effectors of oligodendrocyte damage in MS. Fas ligation induces a lytic response in oligodendrocytes, which could exacerbate inflammatory activity by release of myelin antigens and is suggestive of a necrotic cell death pathway. Co-localisation of Fas expression and TUNEL positivity has also been demonstrated which could indicate an apoptotic cell death pathway (Dowling et al., 1996). Contradictory to this however is the finding that oligodendrocytes did not show Bax reactivity or DNA fragmentation and maintained high expression levels of the anti-apoptotic protein Bcl-2 during the course of EAE (Bonetti et al., 1997).

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2.5 T-cells, B-cells and Neuroinflammatory Cell Death Pathways Microglia are able to process and present antigen to T-cells. A key early event in neuroinflammatory diseases such as MS is the invasion of the CNS by activated B-cells, Tcells and macrophages. Dual inflammatory responses are observed in the CNS. Innate immunity involving microglia produces a focal and limited response. The adaptive immune response produces antigen-specific T-lymphocytes to a more global and extended attack (Luchinetti et al., 2001). Inflammation in MS occurs in focal demyelinating lesions or plaques. The perivascular cuffs formed at the sites of invasion contain macrophages, lymphocytes (the majority being T-cells), B-cells and plasma cells. The T-cells can be further divided into CD4+ (helper) and CD8+ (cytotoxic) cells. The CD4+ cells may be further divided into pro-inflammatory (Th1) and anti-inflammatory (Th2) cells and the proportions and activity of these cells may control overall lesion activity (Jackson, 2004). During disease progression in EAE, the experimental animal model of MS, a large number of apoptotic T-lymphocytes are found in the CNS, having undergone a process of activation-induced cell death (AICD) a mechanism by which inflammation subsides resulting in clinical remission (Pender et al., 1991; Griffith et al., 1995; White et al., 1998; Zipp et al., 2002; Strasser and Pellegrini 2004). The phagocytosis of apoptotic T-cells is understood to lead to a down-regulation of microglial immune functions (Magnus et al., 2001). However in

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AIDS patients who have characteristically depleted T-cell populations, termination of the immune response by elimination of activated T-lymphocytes by AICD is strongly enhanced and accelerated (Gülow et al., 2005). T-cells are sensitised to Fas induced apoptosis and upregulate FasL expression. In the Lewis rat model of EAE, a typically monophasic disease with spontaneous recovery, up to 49% of T-lymphocytes in CNS lesions were found to show signs of apoptosis at the time of recovery (Schmied 1993). In a chronic relapsing EAE model, staining for proapoptotic protein expression on lymphocytes revealed that approximately 30 % of CD4+ Tcells showed expression of Fas, FasL, and the pro-apoptotic protein Bax as well as DNA fragmentation, whilst infiltrating CD3+ cells showed no Bax reactivity, DNA fragmentation but high levels of the anti-apoptotic protein Bcl-2 (Bonetti et al 1997). Suppression of T-cell apoptosis in EAE, by overexpression of the anti-apoptotic protein Bcl-2, increases the severity of the disease, but does not affect recovery from the acute phase (Okuda et al 2002). B-cells, the antibody producing cells of the immune system, are present in inflammatory infiltrates in EAE, albeit by a smaller proportion that T-cells. Their role however, is unclear; but they may act as antigen presenting cells in the CNS and locally produce anti-myelin antibodies which could exacerbate inflammatory demyelination. White et al., (2000) discovered that a high proportion of B-cells are found in EAE at the peak of disease where they contribute to 15.4 % of the total number of inflammatory infiltrates. Additionally, they found that just prior to clinical recovery, 10.8 % of these cells were apoptotic. B-cells expressing Bcl-2 were relatively protected from apoptosis, whilst B- cells expressing Fas or FasL were highly vulnerable to apoptosis. Apoptosis represents an immunologically “quiet” process as apoptotic cells do not normally contribute to or stimulate an immune response, which is important in an environment where further inflammation could be detrimental. Cells undergoing apoptosis are rapidly ingested by nearby phagocytic cells. Macrophages, microglia, astrocytes and oligodendrocytes are all capable of ingesting apoptotic cells (Nguyen and Pender, 1998), however microglia are shown to be more efficient at phagocytosis (Magnus et al., 2002). Furthermore, ingestion of apoptotic cells by microglia down-regulates their activity, resulting in a significant decrease in pro-inflammatory cytokine secretion by microglia (Magnus et al., 2002) thus contributing to clinical remission of disease. There are several putative mechanisms for lymphocyte apoptosis in the CNS (White et al 1998; for review, see Pender and Rist, 2001). However, it appears that these mechanisms are non-specific and involve both antigen-dependent and antigen-independent mechanisms (Bauer et al., 1998). Crosslinking of Fas antigen with its ligand initiates a signalling cascade that leads to apoptotic cell death. Fas is expressed on memory or previously activated T cells, and its upregulation on infiltrating lymphocytes in EAE tissue is associated with increased apoptosis (Bonetti et al., 1997). Several studies investigating the role of the Fas/FasL pathway in EAE using transgenic mice have revealed conflicting results. Mice lacking functional expression of Fas showed a reduced severity of EAE, and fewer apoptotic cells were detected in inflammatory lesions compared with wild-types (Sabelko et al., 1997). However Bachmann et al., (1999) found no significant differences in EAE histology and degree of apoptosis in mice lacking function FasL, although they did show a 50% reduction in T cell apoptosis in TNF receptor 1 knockouts.

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Other mechanisms which could affect induction of apoptosis are the balance and expression of pro- and anti-apoptotic proteins. It is postulated that impaired apoptosis contributes to disease activity in MS patients (Macchi et al 2001). The anti-apoptotic protein bcl-2 can be regulated by bax and the ratio of anti- to pro-apoptotic protein expression in inflammatory cells from MS patients has been shown to be significantly increased when compared with control samples (Sharief et al 2003), leading to suggestions that apoptosis could be impaired in MS lesions. Such impairment could lead to enhanced and prolonged inflammatory processes, resulting in increasing damage to oligodendrocytes and neurones. Thus overexpression of bcl-xL in T-cells results in an earlier onset and a more chronic form of EAE (Issazadeh et al., 2000; Zipp et al., 2002).

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References [1] Akassoglou K., Bauer J., Kassiotis G., Pasparakis M., Lassmann H., Kollias G., Probert L. (1998) Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signalling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy. Am. J. Pathol. 153, 801-813 [2] Akiyama H., Barger S., Barnum S., Bradt B. et al., (2000) Inflammation and Alzheimer’s disease. Neurobiol. Aging 21, 383-421 [3] Bachmann R., Eugster H.P., Frei K., Fontana A., Lassmann H. (1999). Impairment of TNF-receptor-1 signalling but not Fas signalling diminishes T-cell apoptosis in myelin oligodendrocyte glycoprotein peptide-induced chronic demyelinating autoimmune encephalomyelitis in mice. Am. J. Pathol. 154 (5): 1417-1422 [4] Badie B., Schartner J., Vorpahl J., Preston K. (2000) Interferon-gamma induces apoptosis and augments the expression of Fas and Fas ligand by microglia in vitro. Exp. Neurol. 162, 290-296 [5] Back S.A., Gan X., Li Y., Rosenberg P.A. Volpe J.J. (1998) Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J. Neurosci. 18, 6241-6253 [6] Banati R. (2003) Neuropathological imaging: in vivo detection of glial activation as a measure of disease and adaptive change in the brain. Brit. Med. Bul. 65, 121-131 [7] Barger S.W., Basile A.S. (2001) Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cysteine exchange and attenuates synaptic function. J. Neurochem. 76, 846-854 [8] Bauer J., Bradl M., Hickey W.F., Forss-Petter S., Breitschopf H., Linington C., Wekerle H., Lassmann H. (1998) T-cell apoptosis in inflammatory brain lesions. Destruction of T cells does not depend on antigen recognition. Am. J. Pathol. 153, 715-724 [9] Bechmann I., Mor G., Nilsen J., Eliza M., Nitsch R., Naftolin F. (1999) FasL (CD95L/Apo1L) is expressed in normal rat and human brain: evidence for the existence of an immunological brain barrier. Glia 27, 62-74

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In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 63-81 © 2006 Nova Science Publishers, Inc.

Chapter V

Glial-Neuronal Cross-Talk in Neurodegeneration Michael P. Flavin Departments of Pediatrics, Anatomy and Cell Biology, Queen's University, Kingston, Ontario, K7L 2V6. Canada. [email protected]

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1. Introduction There is growing awareness that molecular and physical exchanges between neurons and glia may instigate and/or actively participate in deleterious events, in acute and chronic neurodegenerative disorders [1]. Genetic and molecular techniques have enabled neuron–glia interactions to be scrutinized in relatively simple invertebrate nervous systems particularly in Drosophila where the glia-neuron ratio is about 1:1. In humans, glial cells outnumber neurons by a factor of ten [2] which suggests more important roles. Astrocytes are by far the most numerous glia and play a dynamic role in regulating neuronal function (see [3], [4], [5] for reviews). Combined neuron-glia functions enable the brain to work properly, as in neuronal plasticity which depends on both nerve impulse activity and glial input. Interdependence begins during development with significant glial input being required for brain growth and maturation. Glia provide trophic support to neurons, insulate axons, provide water, electrolyte, acid-base and glutamate homeostasis and maintain blood–brain barrier competence. Physiologic glial-neuronal interactions involve Na/K current, Ca++ waves, direct cellcell contact and communication via soluble mediators. A deleterious interaction may simply be an imbalance or disruption of day-to-day physiologic interactions or aberrant replaying of cell interactions which first took place during development [6].

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Understanding key messages in the cross-talk between neurons and glia may form a basis for understanding mechanisms which underly neurodegeneration. In this chapter the key interactions between neurons, oligodendrocytes, astrocytes and microglia will be reviewed (see Table 1). Table 1. Some key interactions between glia and neurons • • • • • • • • • • •

normal neuronal activity maintains microglia in a quiescent state stressed or injured neurons activate microglia intact neurons counter-regulate IFN- -mediated induction of MHC class II molecules on astrocytes and microglia neuronal glutamate inhibits MHC class II inducibility in astrocytes neurons release ATP and adenosine from non-synaptic regions which activates purinergic receptors on myelinating oligodendrocytes astrocyte activity signals to microglial purinergic receptors neurons cause microglia to express glutamate and GABA receptors astrocytes have receptors and transporters for many neurotransmitters astrocytes increase the number of mature functional synapses on neurons an individual protoplasmic astrocyte makes direct contact with several neurons in it’s domain neurotrophins from astrocytes inhibit MHC class II expression in isolated microglia

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2. Neuronal Participation in Cross-Talk While neurons communicate with other neurons through a serial, one-way, flow of action potentials, they have a two-way communication with glia [7]. A variety of glial interventions help fine-tune axonal conduction and synaptic transmission. These include control of ion fluxes and production of cell adhesion molecules, neurotransmitters and specialized signaling molecules, such as ATP and adenosine. [8]. Stressed neurons can bring microglia closer to them, using either chemokines or PAF. Neurons in cell culture synthesize PAF in response to glutamate application [9]. Microglia, which express functional PAF receptors, exhibit a marked chemotactic response to PAF. Normal neuronal electrical activity suppresses MHC expression in nearby microglia and astrocytes. The quiescent state of microglia is maintained, at least partly, by interaction of CD200 neuronal membrane protein with microglial CD200 receptors. Mice deficient in CD200 show morphological and molecular signs of microglial activation even in nonperturbed CNS and their response to different forms of experimental brain injury is excessive [10]. In acute insults neurons assume a state of emergency, rapidly changing their gene expression. They signal to nearby microglia and astrocytes for support (reviewed by McGeer [11]). The first step is glial activation. The intensity of this activation response depends on stimulus strength [12]. Several lines of evidence suggest that the increased expression of MHC molecules on microglia in the target area after neuronal insult or injury is due to reduced neuronal electrical

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activity. Astrocytes and microglia exhibit low MHC class II expression despite treatment with the proinflammatory cytokine IFN-γ[13], but when neuronal electrical activity is abolished by tetrodotoxin, induction of MHC molecules is promptly enhanced. Similarly, when neurons are co-cultured with glia LPS-stimulated nitrite and TNF-α production is reduced. Culturing of mixed glia with neurons reduces LPS-induced nitrite and TNF- α production compared to cultures with only glial cells. [14]. Conversely when neurons are excluded from co-cultures, LPS causes significantly greater microglial nitrite and TNF- α production. Messages from neurons to glia can be transmitted by indirect electrical coupling. Membrane excitability involves substantial changes in local extracellular ion concentration. Glia themselves also release transmitters in response to neuronal activity which can locally modulate neuronal excitability and synaptic transmission [15]. This can depolarize the cell membranes of neighboring astrocytes. Astrocytes are intimately associated with synapses and can rapidly remove neurotransmitter from the synaptic cleft, thereby limiting spillover of transmitter to neighboring sites [16]. Ionotropic and metabotropic receptors on glia can also detect neuronal activity and trigger MHC expression. Activation of glutamate receptors in rat cerebral microglia enhances TNF-α production [17] which may explain the rapid increases in TNF-α production after excitotoxic, ischemic and traumatic brain injury. Thus if we assume that microglial activation is a hallmark of neuroinflammation, the suppressive potential of healthy physiologically active neurons may be key in preventing or limiting the development of an inflammatory response and limiting bystander damage.

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3. Oligodendrocyte Participation in Cross-Talk Nerve impulses release ATP and adenosine from non-synaptic regions of neurons, which activates purinergic receptors on myelinating glia [18]. Through this receptor system, neuronal activity can regulate oligodendrocyte gene expression, mitosis, differentiation and myelination, thus helping coordinate functional activity in the developing brain. Oligodendrocyte precursors in the hippocampus have functional glutamatergic and GABAergic receptors [19]. Although probably designed for activity-dependent modulation, proliferation and differentiation of oligodendrocyte precursors, glutamate receptors may participate in death pathways [20], [21] which may occur in white matter damage in premature infants [22]. Oligodendrocytes are very sensitive to broad-based insults such as ischemia, irradiation, and heat shock (reviewed in [23]) and agents such as pro-oxidants, glutamate, TNF-α and catecholamines [24]. Mature oligodendrocytes are more susceptible to TNF- [25]. Oligodendrocyte destruction mediated by macrophages within the brain white matter, as seen in models of EAE, (see [26] for review), leads to profound axonal damage. See further discussion below on role of TNFα in neurodegeneration. Maturity of target oligodendrocytes is important. For example, bFGF elicits a proliferative response in oligodendrocyte progenitors while it kills postmitotic oligodendrocytes via apoptosis [27], [28].

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4. Astrocyte Participation in Cross-Talk Astrocytes are the major source of trophic factors such as NGF, CNTF, PDGF, IGF-1 and TGFα each of which can support neuronal and oligodendrocyte survival (see Raivich et al for review [1]). Astrocytes play a pivotal role in the type and extent of brain inflammatory response through anti-inflammatory cytokine and chemokine production [29]. They induce the ramified “resting” phenotype in microglia [30]. In cultured brain slices, the neurotrophins, NGF, BDNF and to a lesser degree NT-3, downregulate inducibility of MHC class II on microglia. NGF and NT-3 acts directly in isolated microglia culture to inhibit MHC class II expression mediated by IFN-γ [31]. In this way astrocytes suppress microglia and restrict neuroinflammation. Furthermore, after brain injury, astrocyte-derived factors downregulate expression of LFA-1, ICAM-1 and reduce phagocytosis and cytotoxicity [30]. TGF-β and IL4 inhibit phagocytic activity of macrophages. Astrocytes inhibit LPS-induced NO production by macrophages [32] and secrete TGF-1 which induces macrophage apoptosis [29]. Secretion of IL-12, p75, and p40 by IFN-γ and LPS-stimulated macrophages is decreased following coculture with astrocytes [33]. LPS stimulated astrocytes also secrete anti-inflammatory IL-10 [33]. Astrocytes can control oxidative damage by synthesizing glutathione and by scavenging extracellular NO and reactive oxygen species [34]. Astrocytes have extensive physical and chemical networks which facilitate cross-talk with neurons [35]. The anatomical connections of protoplasmic astrocytes reveal a vast territory of communication and potential interactions. They extend multiple very thin, flappy, sheet-like processes in all directions [36]. The processes intersperse themselves amongst neurons making direct contact with many synapses. These extensions of neighboring protoplasmic astrocytes are organized in non-overlapping domains, each domain extending over ~ 100,000 synapses. These processes have been shown to retract in response to receptor activation. Impaired function of protoplasmic astrocytes in an ischemic zone, will leave neurons embedded within their domains unprotected. Thus failure of gap junctions following ischemia can cause overwhelming excess of extracellular K+, glutamate or lactate, all of which may act to cause secondary injury. Astrocytes are key modulators of neuronal excitability [37]. They possess a sodium bicarbonate co-transporter which is important for extracellular pH balance (see [34] for review). During neuronal activity elevated extracellular K+ leads to glial depolarization and activation of the co-transporter [38]. This acidifies the extracellular pH, while the intracellular pH of the astrocyte is alkalinized. This transporter may play a critical role in pH regulation after insult such as ischemia [39]. Astrocytic gap junction channels allow electrical and chemical communication and are permeable to ions and substances up to about 1.2kDa allowing high concentration K+ (as high as 50-80mM) and glutamate to dissipate to areas of lower concentration. However these channels may also provide a route for pro-apoptotic signals to potentially viable cells after ischemia [40].

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Reactive astrogliosis is detected in brain following ischemia, trauma, and neurodegenerative disorders which have an inflammatory component [41] (see [42] for review). Reactive astrocytes express iNOS and produce neurotoxic levels of NO from day 3 lasting for 1 month after a brief period of global ischemia [43]. Prolonged reactive astrogliosis, a characteristic of ischemia, Alzheimer's and Parkinson's disease, may be detrimental in these disorders. In regions subject to ischemic damage astrocyte death actually precedes neuronal death [44], [45]. The hippocampus is well known for sensitivity to transient global ischemia. When separate cultures of hippocampal and cortical astrocytes are exposed to OGD the LD50 for OGD duration in hippocampal astrocytes is 2 h compared to 8 h in cortical astrocytes. This regional difference in sensitivity of astrocytes to OGD implies that this vulnerability may contribute to regional differences in predisposition to post-ischemic neuronal death through loss of astrocyte protection. Exciting recent evidence indicates that astrocytes may play a key role in regeneration whereby they instruct ependymal stem cells in adult hippocampus to give rise to neurons [46] under the guidance of genes such as nestin [47]. This process may serve to compensate for loss of function in neurodegenerative disease.

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5. Microglial Participation in Cross-Talk Microglia detect pro- and anti-inflammatory signals by expressing a variety of cytokine and chemokine receptors and expressing glutamate and GABA receptors which sense neuronal and astrocytic activity [48]. In non-perturbed brain, microglia are quiescent with long, ramified processes covering territories 30–40 µm in diameter. Upon insult to the brain, microglia become activated and rapidly transform to an amoeboid shape. There is increased size of the cell body, a thickening of proximal processes and a decrease in the ramification. In regions with injury, these cells may exhibit membrane ruffling, consistent with a motile, exploratory behavior [49] as they migrate and come into direct contact with nerve cell bodies. The intensity of microglial activation depends on the spectrum of inflammatory mediators generated by a variety of local cells [11], [50] Microglial expression of the CD40 molecule in the CNS is an important step since it promotes production of cytokines, chemokines and other mediators after interaction with it’s ligand CD154. CD40-positive microglia are implicated in AD and MS. Aberrant expression of CD40 by microglia, in conjunction with the cytokines IFN-γ and TNF-α, is directly correlated with the initiation and progression of EAE [51], [52]. The graded process in acquiring activation functions includes cell proliferation, migration, phagocytosis, upregulation of immune capabilities and secretion of multiple products [53]. Different stimuli e.g. IFN-γ or LPS or prion protein will elicit only a subset of these functions and molecular products [54]. In turn there is a gradient of cellular susceptibility to macrophage-mediated damage, with oligodendrocytes and myelin being most vulnerable, followed by axons and neurons, while astrocytes appear to be relatively resistant [50], [52].

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In HIV infection infected monocytes migrate into the brain and shed virus and infect resident microglia [55]. Infected microglia release viral proteins, cytokines, chemokines and PAF, which promote microglial activation. Cytokines and viral proteins from blood-borne macrophages in turn can also promote microglial activation. Activated and/or infected microglia release substances that promote vesicular release of glutamate from astrocytes and inhibit uptake. The combination of cytokine, chemokine and glutamate release from microglia and astrocytes results in neurotoxicity. In ischemia, microglial TNF α and IL-1β are upregulated within hours [56]. This is a measured reaction whereby glial responses in regions with selective post-ischemic neuronal death differ significantly from areas which are more resistant to ischemic insult. In AD activated microglia may contribute to neuronal damage by the production of proinflammatory cytokines (IL-1, IL-6, TNFα, MIP-1α, MCP-1) and reactive oxygen and nitrogen species [57], [58], [59]. Interestingly, microglia activated by AD plaques can produce an amine that evokes fulminant excitotoxicity [60]. Treatment with antiinflammatory drugs, particularly NSAIDs, reduces microglial activation in vivo, inhibits neurotoxin production and reduces the risk of developing AD by ~60% (for review see [61].

6. Groups of Neuronal and Glial Factors which Orchestrate Cytotoxicity Given the vast array of interacting factors, a limited number of mediators will be discussed further. Loose groupings have been derived from known interacting effects.

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6.1 Complement, Cell Adhesion Molecules (CAMs) and Chemokines The classical complement pathway has more than 20 components, many sequentially activated in an amplifying cascade. Although low levels can protect against TNF attack [62] complement may also be involved in death pathways. Glial activation produces multiple complement molecules that are potentially cytotoxic. The anaphylatoxins C3a and C5a and the opsonins C4b, C3b, and C5b provide chemotactic and activating signals to inflammatory cells bearing appropriate receptors. Microglia and astrocytes express complement receptors, including C1qRP, CR1, CR3, CR4, C3aR, and C5aR. Inhibitors of complement pathways, such as vaccinia complement control protein, inhibit macrophage chemotaxis and infiltration, reduce spinal cord destruction, and improve motor skills associated with spinal cord injury [63]. A setting of activated microglia in the presence of complement is sufficient to kill oligodendrocytes and phagocytose the oligodendrocyte-myelin complex in vitro [64]. In AD brain complement activation fragments, reactive astrocytes and activated microglia are colocalized with plaques containing aggregated Aβ suggesting a deleterious role (see [61] for review). In physiologic states CAMS are involved in neuronal sprouting and synaptogenesis and contribute to neuronal plasticity, preservation of neurons and regeneration. Expression or translocation to the cell membrane of certain CAMs such as L1 and PSA-NCAM is

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modulated by neuronal activity [65]; [66]. CAMs such as TAG-1 and glial CNP are important in glial cell migration, arranging ion channels, regulating gene expression and controlling cell survival [67], [68]. However CAMs can also re-organize the extra-cellular space to cause disturbances which drive the development of brain pathology in conditions such as AD and MS. A breakdown in the organization of key CAMs and activation of their signal transduction mechanisms may be a major source of neurodegeneration. [69]. The damping effect of neurons on glial activation discussed above is partly due to cellcell contacts via NCAM. For example the application of NCAM to microglial cultures significantly reduces LPS-stimulated nitrite production. Chemokines may also have a key role in neurodegeneration. The chemokine MCP-1 attracts microglia/macrophages to sites of injury. Deletion of the MCP-1 gene attenuates microglial activation and alters expression of cell death and survival molecules, including Bcl-2, Bax, Fas, Fas ligand [70]. Another chemokine, fractalkine, is constitutively expressed, mainly in neurons, and is up-regulated and released in pro-inflammatory states such as HIVassociated dementia [71], [72]. It induces cell adhesion, chemoattraction, and activation of microglia. The expression of fractalkine and its receptor, CX3CR1 by glial cells during neuroinflammation could be influenced by cytokine milieu [71], [72].

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6.2 IL-1, TNF-α, FAS, Fas-ligand and ROS Cytokines modulate glial-neuron cross-talk and also have direct killing potential. They participate in complex messaging which involves cytokine receptor-coupled signal transduction pathways. They exhibit their most significant effects when cell-bound, rather than as dissolved molecules [73]. The evidence implicating a key cytokine, IL-1, in neurodegeneration has recently been reviewed [74]. IL-1 enhances free radical production by macrophages. It’s expression is elevated in AD and Parkinson's disease [75], [76]. Increased IL-1, noted in rodents in ischemic, hypoxic, excitotoxic and traumatic insults, precedes neuronal death [77]. Injection of IL-1 into non-perturbed rodent brain does not cause neuronal injury. However it does worsen ischemic, excitotoxic and traumatic brain injury. Inhibition of IL-1 in vivo dramatically reduces the neuronal loss in rodents caused by ischemia, kainic acid or trauma [78], [79]. IL-1ra, the most effective and complete blocker of IL-1, not only reduces ischemic brain damage, but also attenuates glial activation, neutrophil invasion and edema and improves neurological function after injury [78], [77], [79]. In addition IL-1 appears to act at specific brain regions in the striatum to enhance or cause distant neuronal damage in the cortex [80]. These actions appear to involve complex polysynaptic pathways, which are dependent on induction and action of endogenous IL-1 in the hypothalamus [80]. It is possible that IL-1 causes increases in local brain temperature which would increase neuronal vulnerability [81]. IL-1-activated astrocytes express death protein Fas ligand which can induce apoptosis in human neurons. TNF-α may also upregulate Fas ligand on the cell surface, thus modulating early response to injury [82], [83]. TNF-α is produced by microglia and astrocytes and is active at all times in the CNS [49]. Transgenic mice which overexpress TNF-α exhibit rampant, fatal inflammation and

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encephalopathy [84]. When mGlu2 receptors located on microglia are stimulated they work in concert with microglial-derived Fas ligand to trigger TNF-α-induced neurotoxicity. [85] This exemplifies the multi-faceted input which is required for neurodegeneration to occur. Oligodendrocyte killing by TNF-α, appears to require the presence of microglia in the culture [86], [87]. In addition microglial-mediated oligodendrocyte death depends on TNF-α being bound to the surface of the microglia [64], [88]. A number of reports describe the death of rodent oligodendrocytes exposed to soluble TNF- α, either by apoptosis [89], [90], or by necrosis [91], [86]. However TNF- α has the potential to be protective in particular settings, as might be expected, since it belongs to the family of neurotrophins many of which favour survival of oligodendrocytes, e.g. NT3 and NGF. Reactive oxygen and reactive nitrogen species generated by glial activation can directly cause apoptotic death or cause mitochondrial dysfunction which further increases free radical generation. Reactive molecules include superoxide, nitric oxide, hydroxyl radical, hydrogen peroxide and peroxynitrite. These cause lipid peroxidation and protein misfolding and denaturation which lead to cell death. It is still not clear if oxidative stress is a primary inititiating event or a final common pathway in neurodegeneration (see [92] for review). However there is abundant evidence that it propogates cell injury mechanisms by participation in a series of deleterious pathways. NO from LPS-activated glia can synergize with hypoxia to induce neuronal death in vitro [92]. In cerebellar granule neuron cultures containing 22% astrocytes and 2% microglia, neither high levels of NO donor nor hypoxia exposure alone cause neuronal death. However the same exposure following LPS-induced activation causes extensive neuronal death.This death is prevented by the NMDA glutamate receptor antagonist MK-801 [93]. Activated microglia may release NO which inhibits neuronal respiration and trigger glutamate release. This has been demonstrated in culture [94].

6.3 Glutamate, Calcium and Connexins Glutamate plays a central role in astrocyte-neuronal interactions [95]. It is cleared from the neuronal synapses by astrocytes via glutamate transporters, and is converted into glutamine, which is released and in turn taken up by neurons. All metabolic processing and actions of glutamate are regulated by astrocytes - synthesis, vesicular and non-vesicular release and uptake. Neuroprotective roles of glutamate include participation in production of antioxidant glutathione by astrocytes. Transmitter glutamate is accumulated by astrocytes and returned to neurons as glutamine where it is converted to glutamate in the glutamate–glutamine cycle. Therefore excitotoxic neuronal death depends on the ability of astrocytes to synthesize glutamine (see [96] for review). Both inter- and intra-cellular Ca2+ is important for glia-neuron communication. Ca2+dependent glutamate release from the astrocytes modulates the activity of both excitatory and inhibitory synapses. In addition, activation of mGLU 2 receptor on astrocytes increases cytosolic Ca2+, which triggers a variety of responses. Cytokine and chemokine receptors expressed on microglia are linked to mobilization of Ca2+.

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Ca2+ is key to several different functions of astrocytes including responses to neurotransmitters such as glutamate and ATP [97], [98], [99] . It regulates gene expression [100] and release of signaling molecules [101]. Recent data strongly indicates that receptormediated intracellular Ca2+ increases are capable of inducing glutamate release from astrocytes in sufficient quantities to generate sizeable currents in nearby neurons [102]. Intercellular Ca2+ waves may transfer signals across astrocytes to neurons modulating their activity and potential for survival [103], [104]. Ca2+ elevations in a single astrocyte in culture can propagate to adjacent astrocytes, forming a Ca2+ wave that can extend for hundreds of micrometers [105], [106]. This long-range signaling, migrating across a group of cells, has been attributed to astrocytic gap junctions [107]. Connexin proteins form the structure of gap junction channels. Astrocytic connexins Cx43, Cx30 and Cx26 are present at inter-astrocytic and astrocyte–oligodendrocyte gap junctions [108]. Lack of astrocytic Cx43 leads to altered long-range signaling, indicating that a specific connexin isotype may control spatial buffering. This effect is likely to be compensated for by other connexins although Cx32 and Cx47 can functionally compensate for each other, deficiency of both leads to severe myelopathy. [97]. Abnormalities in glial Ca2+ regulation has been documented in AD (see [97] for review). Ca2+ responses in PS1 mutation results in the hyperactivation of microglia under proinflammatory conditions. This may contribute to the neurodegenerative process in AD patients with these mutations [109]. Cultured microglia from PS1 mutant mice exhibit increased sensitivity to LPS as indicated by superinduction of iNOS and activation of MAP kinase [110].

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6.4 Acute-Phase Proteins Secreted glial proteases contribute to cell death through both nonspecific and specific proteolysis. tPA is induced as an acute phase protein in seizures and in kindling [111] and is released by astrocytes, microglia and neurons – activated microglia being the major producers. tPA cleaves plasminogen. Plasmin, the product of cleavage, facilitates glutamate receptor-mediated neurotoxicity [112]. Significantly smaller focal ischemic infart size is found in tPA knock-out compared to wild-type mice [113] suggesting that increased endogenous tPA expression influences the fate of neurons after ischemia. In addition to direct neuronal effects, tPA has been shown to participate in the activation of microglia after kainic acid injury [114]. There is debate as to the impact of endogenous tPA on neuronal death in neurodegenerative conditions such as ischemia and MS [115], [116], [117], [118], [119]. In thrombotic ischemia, the proteolytic effect of tPA can be either protective (via thrombolysis) or neurotoxic via cleavage of the NR1 subunit of the NMDA receptor by plasmin, facilitating Ca2+ influx [112]. Demyelination and axon degeneration is delayed following induction of EAE in mice which have deletion of the tPA gene [120]. LPS-activated macrophages and microglia in culture produce conditioned medium which results in membrane damage and apoptosis in neurons [121]. Zymographic analysis of the medium shows that only the neurotoxic medium derived from activated microglia contained

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tPA. The toxicity of this conditioned medium can be attenuated in a dose-dependent fashion by PAI-1 or a neutralizing antibody to tPA [122]. Exogenous tPA exaggerates the neurotoxic effects of microglial conditioned medium. This suggests that microglial tPA may contribute to hippocampal neuronal death by triggering apoptosis. In cultures of hippocampal neurons exogenous tPA has a direct neuroprotective effect in a modest OGD injury [115]. Protection is not impeded by PAI-1, but tPA antibody abolishes the protective effect of tPA. Neuroprotection by tPA in OGD is thus mediated through a nonproteolytic action. A setting which favours enhanced plasminogen activation may negatively affect outcome of ischemia [123], [124], [125]. Thus the relative balance of tPA, plasminogen and PAI-1 in post-ischemic brain may be an important determinant of tissue viability. After transient MCA occlusion in rat brain we found an extensive ipsilateral lesion in the cerebral cortex and striatum. This was associated with progressive increases in tPA immunostaining and protein expression in lesioned tissue in the first 24h after occlusion while PAI-1 staining and expression diminished progressively i.e. reversed patterns of tPA and PAI-1 protein expression after transient focal ischemia [126]. Another immediate response gene, c-jun, produces c-Jun protein which appears to be important for late activation of microglia [127]. In vivo and in vitro experiments suggest that the expression of the c-Jun transcription factor is a prerequisite that allows other transcriptional components to exert their specific decision towards either apoptotic death or survival. This regulation of two opposing cellular programs has been described as a master switch. Expression of c-Jun alone, however, does not trigger the molecular cascades leading to apoptotic cell death. c-Jun is a component of the heterodimeric transcription factor AP-1. A straightforward link between c-Jun and neurodegeneration is complicated by the fact that other acute phase proteins are also expressed. Most notable is c-Fos expression in ischemia [128] and Alzheimer's plaques adjacent to neurons [129]. The properties of c-Jun and its interactions in non-neuronal cells support the concept that the eventual fate of neurons following c-Jun expression is a function of specific homo- or heterodimers formed by the cJun protein and the phosphorylation of these complexes by JNK enzyme [130].

7. Hormones – Modulators of Neuron-Glial Cross-Talk Hormone receptors are present both in neurons and glia. Hormones can stimulate astrocyte expression of neurotrophic factors, can potentiate antioxidant defense mechanisms, liberate Ca2+ from intracellular stores, limit stimulation of innate immunity and stimulate neuronal repair mechanisms. The expression of hormone receptors is altered by brain insult. For example, the expression and activity of aromatase, the enzyme that synthesizes estradiol, is increased in injured brain areas and its inhibition results in more extensive neurodegeneration [131]. Loss of glial GR function sharply increases the vulnerability of nigrostriatal dopaminergic neurons to the neurotoxin MPTP. This is as a result of hyper-induction of iNOS in astrocytes and

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microglia and a loss of astroglial neuroprotective functions. Upregulation of inflammatory events in the brain is natural and does not lead to neuronal cell death provided it is transient. GCs in their role as potent endogenous anti-inflammatory molecules are key modulators of this response, inhibiting pro-inflammatory gene expression via negative feedback [132] [133]. GCs regulate transcription of many pro-inflammatory molecules [134]. They inhibit production of two key enzymes mediating inflammation-induced prostaglandin synthesis: COX-2 [135] and phospholipase A2 [136]. GC treatment also reduces IL-1β and TNF-α production [137], [138]. GCs inhibit NOS induction and thus the ability to produce peroxynitrate [139]. Consistent with an anti-inflammatory action in the brain, microglial ramification, proliferation, and increased lysosomal vacuolation are all inhibited by glucocorticoids in vitro [140]. GC hormone released during an inflammatory response may directly modulate astrocyte functions [141]. The activation of astrocytes is regulated by type II GC receptors, whereas microglial activation depends more on type I receptors. Nanomolar concentrations of the potent synthetic GC dexamethasone completely blocks the generation of neurotoxic culture medium LPS and hypoxia-activated microglia, even when applied to microglial cultures during LPS and hypoxia stimulation [142]. In an in vitro model of ischemia (OGD) the application of dexamethasone to mixed neuron-glia cultures is neuroprotective if applied 24h before OGD but makes injury worse if applied after OGD [143]. This suggests that timing of GC effect is critical to glial response.

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8. Summary In conclusion, given that strategies emphasizing direct protection of neurons have not been successful, therapy aimed at glial cells and their products is worth exploring as an alternative approach to neuroprotection. In order to plan treatment of neurodegenerative diseases we need more data on sources and targets of messengers, diversity of glial functions and of the biologic switches which determine whether a protective or deleterious communication will take place occur between glia and neurons. The multi-facetted nature of interactions involved confirms that multiple strategies will be required. AP-1, activator protein-1; ATP, adenosine tri-phosphate; GABA, γ amino butyric acid; MHC, major histocompatibility class; CNS, central nervous system; GFAP, glial fibrillary acidic protein; AMPA, alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid; IFN-γ, interferon γ; TNF-α, tumor necrosis factor alpha; PAF, platelet activating factor; NGF, nerve growth factor; CNTF, ciliary neurotrophic factor; PDGF, platelet-derived growth factor; IGF1, insulin-like growth factor; TGF, transforming growth factor; LFA-1, leucocyte function is associated antigen-1; ICAM-1, intercellular adhesion molecule 1; LPS, lipopolysaccharide; NO, nitric oxide; BDNF, brain derived neurotrophic factor; GDNF, glial cell line-derived neurotrophic factor; bFGF, basic fibroblast growth factor; NGF, nerve growth factor; NT-3, neurotrophin-3; NOS, nitric oxide synthase; MCP-1, monocyte chemoattractant protein-1; EAE, experimental allergic encephalomyelitis; AD, Alzheimer’s disease; MS, multiple sclerosis; HIV, human immunodeficiency virus; IL-1, IL-4,IL-6,IL-10, interleukin1,4,6,10; NSAID, non-steroidal anti-inflammatory drug; Aβ, beta amyloid peptide; tPA, tissue

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plasminogen activator; CAM, cell adhesion molecule; NCAM, neuron cell adhesion molecule; PSA-NCAM, polysialated neuronal cell adhesion molecule; mGlu2, metabotropic glutamate receptor subunit 2; NMDA, N-methyl-D-aspartate; Ca++, calcium ion; Cx , connexins; PS1, presenilin-1; iNOS, inducible nitric oxide synthase; NR1, NMDA receptor subunit 1; PAI-, plasminogen activator inhibitor-1; OGD, oxygen glucose deprivation; GR, glucocorticoid receptor; MPTP, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; GC, glucocorticoid; MAP kinase, mitogen-activated protein kinase; JNK, Jun N-terminal kinase; OGD, oxygen glucose deprivation

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[125] Yepes, M., et al., Neuroserpin reduces cereral infarct volume and protects neurons from ischemia-induced apoptosis. Blood, 2000. 96: p. 569-576. [126] Zhao, G., J.N. Reynolds, and M.P. Flavin, Temporal profile of tissue plasminogen activator (tPA) and inhibitor expression after transient focal cerebral ischemia. NeuroReport, 2003. 14: p. 1689-1692. [127] Raivich, G., et al., The AP-1 transcription factor c-Jun is required for efficient axonal regeneration. Neuron, 2004. 43: p. 57-67. [128] Herdegen, T. and J.D. Leah, Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. Brain Res. Rev., 1998. 28: p. 370-490. [129] Marcus, D.L., et al., Quantitative neuronal c-fos and c-jun expression in Alzheimer's disease. Neurobiol. Aging, 1998. 19: p. 393-400. [130] Herdegen, T., P. Skene, and M. Bahr, The c-Jun transcription factor--bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci., 1997. 20: p. 227-231. [131] Garcia-Ovejero, D., et al., Glia-neuron crosstalk in the neuroprotective mechanisms of sex steroid hormones. Brain Res. Rev., 2005. 48: p. 273-286. [132] Rivest, S., Molecular insights on the cerebral innate immune system. Brain Behav. Immunol., 2003. 17: p. 13-19. [133] Babcock, A.A., et al., Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J. Neurosci., 2003. 23: p. 7922-7930. [134] Brattsand, R. and M. Linden, Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. Aliment. Pharmacol. Ther., 1996. 10: p. 81-90. [135] Masferrer, J.L., et al., In vivo glucocorticoids regulate cyclooxygenase-2 but not cyclooxygenase-1 in peritoneal macrophages. J. Pharmacol. Exp. Ther., 1994. 270: p. 1340-1344. [136] Masferrer, J.L. and K. Seibert, Regulation of prostaglandin synthesis by glucocorticoids. Receptor, 1994. 4: p. 25-30. [137] Buttini, M., et al., Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain: inhibition by methylprednisolone and by rolipram. Br. J. Pharmacol., 1997. 122: p. 1483-1489. [138] Schmidt, M., et al., Glucocorticoids induce apoptosis in human monocytes: potential role of IL-1 beta. J. Immunol., 1999. 163: p. 3484-3490. [139] Golde, S., et al., Decreased iNOS synthesis mediates dexamethasone-induced protection of neurons from inflammatory injury in vitro. Eur. J. Neurosci., 2003. 18: p. 2527-2537. [140] Tanaka, J., et al., Glucocorticoid- and mineralocorticoid receptors in microglial cells: the two receptors mediate differential effects of corticosteroids. Glia, 1997. 20: p. 2337. [141] Bohn, M.C., et al., In vitro studies of glucocorticoid effects on neurons and astrocytes. Ann. N.Y. Acad. Sci., 1994. 746: p. 243-258. [142] Flavin, M.P., L.T. Ho, and K. Coughlin, Neurotoxicity of soluble macrophage products in vitro - influence of dexamethasone. Exp Neurol, 1997. 145: p. 462-470.

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[143] Flavin, M.P., Influence of dexamethasone on neurotoxicity caused by oxygen and glucose deprivation in vitro. Exp Neurol, 1996. 139: p. 34-38.

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Part 2: Neurological Diseases and Inflammation

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In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 85-115 © 2006 Nova Science Publishers, Inc.

Chapter VI

Inflammation in Stroke Xian Nan Tang1,2 and Midori A. Yenari 1,* 1

Department of Neurology, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, CA 2 Department of Anesthesia, Stanford University School of Medicine, Stanford, CA

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1. Introduction The brain has long been believed to be an immunologically privileged organ since it is isolated from the systemic circulation and is able to exclude components of the immune system by its blood-brain barrier (BBB) (1). However, it is well known that stroke triggers a robust inflammatory reaction characterized by peripheral leukocyte influx into the cerebral parenchyma and activation of endogenous microglia (2-6). Following stroke, the generation of reactive oxygen species (ROS) and intracellular calcium accumulation in neurons and other brain cells trigger immune responses ultimately leading to inflammatory cell activation and infiltration. Ischemic cells, even ischemic neurons secrete inflammatory cytokines that cause, among other things, adhesion molecule upregulation in the cerebral vasculature which leads to peripheral leukocyte recruitment. Brain cells are also capable of secreting chemokines, leading to further inflammatory cell chemotaxis into the ischemic lesion. Once activated, inflammatory cells can release a variety of cytotoxic agents including cytokines, matrix metalloproteinases (MMPs), nitric oxide (NO) and more ROS (Figure 1). These substances can contribute to more cell damage as well as disruption of the BBB and extracellular matrix (7-9). BBB disruption can further potentiate brain tissue injury and contribute to secondary ischemic brain damage by permitting serum elements and blood to enter the brain (10, 11). Secondary damage develops as a consequence of brain edema, postischemic microvascular stasis and vasomotor/hemodynamic deficits leading to hypoperfusion

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and post-ischemic inflammation, thus involving activation of microglia and brain infiltration of peripheral inflammatory cells (10, 12). These processes are especially pronounced during reperfusion when previously occluded vessels are opened and lead to massive influx of ROS and leukocytes into injured brain. Blocking various aspects of the inflammatory cascade has shown to ameliorate injury from experimental stroke (9), although this has yet to be demonstrated at the clinical level (13). Brain Ischemia Cell Necrosis, ↑ROS

↑cytokines/chemokines ↑Adhesion Molecules

Microglial Activation Leukocyte Adherence

Leukocytes infiltrate brain parenchyma

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↑MMPs

↑iNOS/NO ↑cytokines

↑ROS

Extracellular Matrix Disruption

Brain Edema Hemorrhage, cell death

Figure 1. Inflammation following stroke. Brain ischemia is triggers inflammatory responses due to the presence of necrotic cells, generation of reactive oxygen species (ROS) and production of inflammatory cytokines even within neurons. These initiators lead to microglial activation which produce more cytokines causing upregulation of adhesion molecules in the cerebral vasculature. Chemokines lead to inflammatory cell chemotaxis to ischemic brain. Adhesion molecules mediate adhesion of circulating leukocytes to vascular endothelia and infiltration into the brain parenchyma. Once in the brain, activated leukocytes and microglia produce a variety of inflammatory mediators such as matrix metalloproteinases (MMPs), inducible nitric oxide synthase (iNOS) which generates nitric oxide (NO), cytokines and more ROS which lead to brain edema, hemorrhage and ultimately, cell death. MMPs are thought to mediate extracellular matrix disruption, a key event in brain edema and hemorrhage.

* Contact information: Midori A. Yenari, MDAssociate Professor, Neurology, University of California, San FranciscoNeurology (127) VAMC 4150 Clement St. San Francisco, CA 94121415 750-2011, FAX 415 750-2273, [email protected] Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

Inflammation in Stroke

87

2 Cells Involved in the Inflammatory Response after Stroke Inflammation is characterized by the accumulation of inflammatory cells and mediators in the ischemic brain. Inflammatory cells are composed mainly of invading leukocytes and activated resident microglia. Recent work has suggested that astrocytes, with their reactive properties, may behave as inflammatory cells after stroke as well.

2.1 Leukocytes

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Leukocytes accumulate in ischemic brain tissue within 4-6 h hours after ischemia onset. Neutrophils are generally the first subtype recruited to the ischemic brain, and may potentiate injury by directly secreting deleterious substances or other inflammatory mediators (4). Some mediators, while not directly cytotoxic, may be involved in the destruction of necrotic and neighboring viable tissue. Evidence that neutrophils potentiate ischemic injury include numerous studies documenting improved neurological outcome following neutrophil depletion and inhibition of adhesion molecules which facilitate neutrophil entry into injured brain (see reviews (5, 14)). While neutrophils are the earliest leukocyte subpopulation in the brain after stroke, lymphocytes have also been documented (15). Whether lymphocytes play an active role in ischemic brain pathogenesis is unclear. In a study of cultured primary neurons, isolated neutrophils, but not lymphocytes potentiated neuronal injury due to excitotoxin exposure (16). However, preventing lymphocyte trafficking into ischemic brain ameliorated injury, suggesting that like neutrophils, lymphocytes play a deleterious role (13).

2.2 Microglia/Macrophages Macrophages in ischemic brain lesions derive from distinct sources, including (1) perivascular monocytes, (2) infiltrating macrophages derived from blood monocytes and (3) parenchymal microglial cells. Microglia, often viewed as the brain’s resident inflammatory cell, play a critical role as resident immunocompetent and phagocytic cells in the CNS (17), and serve as scavenger cells in the event of infection, inflammation, trauma, ischemia, and neurodegeneration in the CNS (18, 19). Once activated, microglia can undergo morphologic transformation into phagocytes, making them virtually indistinguishable from circulating macrophages. Brain ischemia can induce microglial activation causing a release of a variety of substances many of which are cytotoxic and/or cytoprotective (20). Microglia are thought to be activated via CD14, a receptor recognized by endotoxin, followed by stimulation of tolllike receptor 4 (TLR4) (21, 22). How microglia are activated following ischemia is not completely clear, but CD14 receptors have been documented in monocytes and activated microglia in brains of stroke patients (23). Furthermore, work in neonatal mice indicated that TLR4 was necessary for microglial activation following hypoxia/ischemia (24).

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Whether microglia/macrophages are necessarily damaging following brain ischemia is unclear, but a few lines of evidence suggest that activated microglia, like neutrophils, may contribute to injury. The addition of microglia/macrophages to neuron or oligodendrocyte cultures potentiates injury from various ischemia-like insults (24-28). Minocycline, a tetracycline family antibiotic, was shown to provide significant protection against brain ischemia by inhibiting of microglial activation and proliferation (29, 30). However, other studies indicate that microglia/macrophages or their secreted factors may actually protect cells (31, 32). Administering isolated microglia intracerebroventricularly improved behavioral and histologic outcome in an experimental stroke model (33). Yet another study where investigators depleted peripheral macrophages using liposome encapsulated clodronate showed a lack of effect on infarct size (34). However, this latter study did not deplete brain macrophages and may suggest that brain, rather than circulating macrophages are important in ischemic pathogenesis.

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2.3 Astrocytes Aside from traditional inflammatory cells, astrocytes are known to express different kinds of inflammatory mediators (35-37). While astrocytes are traditionally thought to contribute to neuron homeostasis and the structure and maintenance of the BBB, it has been increasingly recognized that astrocytes also have immune modulating roles in brain. Following ischemia, brain astrocytes are activated resulting in increased glial fibrillary acidic protein (GFAP) expression and a so-called "reactive gliosis," characterized by specific structural and functional changes (38). While the function of GFAP to the brain ischemic damage is controversial, GFAP-null mice had significantly larger cortical infarct volumes than their wild-type littermates, suggesting a beneficial role of GFAP during ischemia (39). Astrocytes also participate in brain inflammation by expressing major histocompatibility complex (MHC) and costimulatory molecules, developing Th2 (anti-inflammatory) immune responses and suppressing interleukin-12 (IL-12) expression, though this has yet to be demonstrated in ischemia models (reviewed by Dong and Benveniste (40)). Astrocytes are also capable of secreting inflammatory factors such as cytokines, chemokines and inducible nitric oxide synthase (iNOS) (40, 41). Furthermore, inducible nitric oxide synthase (iNOS) has been shown to potentiate ischemia-like injury to neurons (42). Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate proinflammatory molecule production by interaction with its Fn14 receptor found on astrocytes (43). Expression of TWEAK and Fn14 has been documented in a murine model of stroke, and a soluble decoy to Fn14 markedly reduced infarct volume (44). These data may suggest that while astrocytes normally play important roles in neuron maintenance and function, activated astrocytes have the potential to pose harm to ischemic brain.

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3. Transcriptional Regulation of Inflammation It is now well recognized that cerebral ischemia upregulates gene expression. Activation of several transcription factors have been documented in experimental stroke models. Some of these transcription factors are particularly involved in the inflammatory response, and will be discussed here. (Figure 2).

IκB P

P

Ischemia/reperfusion

NFκB

IκB

↑ROS, ↑Ca++,

IKK

↑Cytokines, etc

NFκB P

UBI

P

MKKs IκB NFκB NFκB

p38 MAPK P

ATF2

SAPK/JNK c-Jun, c-Fos

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NFκB AP-1 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX Nucleus Figure 2. Transcriptional activation of inflammation following ischemia. Brain ischemia leads to the generation of a variety of substances that are capable of activating various inflammatory transcription factors (see text section 3 for details). Ischemia triggers the activation of the following inflammation relevant transcription factors: nuclear factor kappa B (NFkB), the p38 mitogen activated protein kinase (p38 MAPK), and stress activated protein kinase (SAPK/JNK). NFkB is normally contained in the cytosol by its inhibitor protein (IkB). When phosphorylated by its kinase, IKK (P), IkB is ubiquitinated (UBI) and degraded in the proteasome. Once liberated from IkB, NFkB translocates to the nucleus where it binds to consensus DNA sequences. p38 MAPK and SAPK/JNK are activated in a tiered fashion by MAPK kinase (MKK). Activated p38 MAPK phosphorylates activating transcription factor (ATF2), while SAPK/JNK leads to c-Jun and c-Fos expression. These three factors make up the transcription factor, activator protein-1 (AP-1).

3.1. Nuclear Factor κB (NF-κB) NF-κB, is a dimeric transcription factor consisting of subunits of the Rel family, and are involved in the regulation of inflammation (45, 46). The most common form of NF- κB is a

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heterodimer composed of Rel A (p65) and p50. NF-κB is normally located in the cytoplasm bound to its endogenous inhibitor protein, known as IκB. IκB is a family of proteins consisting of IκB-α, IκB-β, IκB-γ and IκB-ε. Phosphorylation of IκB-α at serines 32 and 36 by an upstream IκB kinase (IKK) leads to IκB phosphorylation, ubiquitination and degradation in the 26S proteasome. This liberates NF-κB and allows it to translocate to the nucleus. Once in the nucleus, NF-κB binds to κB sites, specific domains within the promoters of downstream genes to activate their transcription. Many genes involved in inflammation contain functional κB sites, such as tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), iNOS and interleukin-6 (IL-6). Following experimental stroke, IKK and NF-κB activation have been documented, and these processes appear to be correlated to the anti-inflammatory effect of mild hypothermia (47). However, the function of NF-κB in stroke is still controversial (48). Mice deficient in NF-κB’s p50 subunit are protected from experimental stroke (49), consistent with a death-promoting role of NF-κB in focal ischemia. However, another study demonstrated that rats given diethyldithiocarbamate (DDTC), a NF-κB inhibitor, had enhanced neuronal DNA fragmentation and larger infarct sizes compared to controls, suggesting a beneficial role (50).

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3.2. Mitogen-Activated Protein Kinase (MAPK) Mitogen-activated protein kinases play an important role in transducing stress-related signals by a cascade of intracellular kinase phosphorylation and transcription factor activation that regulate inflammatory gene production among other functions (For reviews, see (51-54)). There are three well characterized, interlinked signaling pathways which have been documented following brain ischemia: the stress-activated protein kinases/c-Jun Nterminal kinases (SAPK/JNK), the p38 MAPKs and extracellular signal-regulated kinases (ERKs) (52, 54-56). Of these, p38 MAPK appears to be the best studied in terms of promoting inflammatory signals in the ischemic brain (57). p38 MAPK promotes the stabilization and enhanced translation of mRNAs encoding proinflammatory proteins (54). It is activated by inflammatory cytokines such as IL-1 and TNF, both of which have been documented in the ischemic brain. Following activation and phosphorylation by its upstream kinase, MAPK kinase (MKK), p38 phosphorylates and activates the transcription factor, activating transcription factor (ATF2), whereas phosphorylation of JNK induces c-Jun. Following forebrain ischemia in rodents, phosphorylated p38 MAPK was detected in the hippocampus within neuron- (56) and microglia-like (58) cells, suggesting its role in the endogenous inflammatory response. Furthermore, p38 MAPK inhibitors reduced brain injury and neurological deficits in focal cerebral ischemia as well as ischemia-induced cytokine expression. SB 239063, a second generation inhibitor also reduced lipopolysaccharide (LPS)induced plasma TNF production (59). These results indicate that p38 activation occurs in brain cells and that this activation participates in the induction of inflammatory cytokines and cell death.

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3.3. Activator Protein -1 (AP-1) AP-1 is a heterodimer comprised of bZIP transcription factors (e.g., c-Jun and JunD), activating transcription factor 2 (ATF2) and c-Fos. Upstream activation of AP-1 components is mediated through the JNK/SAPK cascade. c-Fos was found to be up regulated as early as 30 minutes after stroke onset (60). The Fos protein contains a DNA binding region and a leucine zipper. The leucine zipper forms an α-helix which can align with other proteins (such as Jun) containing like structures to form dimers. These dimers bind to specific DNA regions known as the AP-1 domain, which regulates the expression of a number of target genes (collectively referred to as late response genes). Combinations of c-Fos and c-Jun family proteins form different dimers consisting of various subunits depending on the circumstances. The composition of the dimer may determine whether the late response gene is turned on or off (61). ATF2 is a member of the cAMP response element binding protein (CREB) subfamily of bZIP transcription factors. AP-1 heterodimers containing ATF transcription factors can bind both to the TPA (12-O-tetradecanoylphorbol-13-acetate) responsive element (TRE) and to the cAMP response element (CRE) (62). AP-1 is an important activator of a number of inflammatory genes including the genes for IL-1 and TNF. In addition, AP-1 participates in the transcriptional induction of cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and E-selectin which are involved in leukocyte recruitment (54, 62, 63).

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4. Adhesion Molecules Adhesion molecules play a pivotal role in the infiltration of leukocytes into the brain parenchyma after stroke and may represent important therapeutic targets (see recent review by Sughrue et al (64)). Activated leukocytes, especially neutrophils, enhance the development of ischemic lesions through reperfusion or secondary injury mechanisms (4). Several reports have shown that inhibiting leukocyte adhesion by targeting various adhesion molecules, thus preventing leukocytes from entering ischemic brain, results in reduced neurologic injury (65, 66). The interaction between leukocytes and the vascular endothelium is mediated by three main groups of cell adhesion molecules: selectins (P-selectin, E-selectin, and L-selectin), the immunoglobulin superfamily (intercellular adhesion molecules, e.g. ICAM-1, 2 and vascular cell adhesion molecule-1, or VCAM-1) and integrins (CD11a-c) (8, 67).

4.1 Selectins Selectins mediate rolling of leukocytes on the endothelium of postcapillary venules. Three kinds of selectins have been identified: E-selectin (originally described on endothelial cells), P-selectin (originally described on platelets, but has also been described on endothelial cells (68)) and L-selectin (originally described on lymphocytes, but also present on other leukocyte populations) (4, 69, 70). They are expressed on the outer cell membrane

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immediately upon cell activation by stimulants such as thrombin or histamine. P-selectin has also been observed on endothelium (68), whereas L-selectin is present on lymphocytes, neutrophils, and monocytes. While E- and P-selectin are involved in leukocyte rolling and recruitment during the early stages of activation, L-selectin acts as a guide for unstimulated leukocytes (71). In the presence of activated endothelium, rolling stops and L-selectin is shed from the cell membrane by proteolytic cleavage, followed by endothelial transmigration (7274). The expression of P- and E-selectins have been documented in different experimental stroke models (68, 75-80). P-selectin, though not necessarily E-selectin have also been documented in the serum of stroke patients (81), and P-selectin may persist in the circulating blood for up to 90 days after stroke (82). Soluable sE- and sL-selectin have also been detected in stroke patients (83), and polymorphisms in the P-selectin gene were found to be independent predictors of thrombo-embolic stroke in humans (84). E- and P-selectin upregulation appears to be involved in promoting ischemic inflammatory responses and increases injury due to ischemic stroke. Mice deficient in Pselectin had smaller infarcts and neutrophil infiltration after transient middle cerebral artery occlusion (tMCAO) compared to wildtype (WT) littermates (85). Conversely, mice overexpressing P-selectin had exacerbation of infarcts. Furthermore, treatment with antibodies or inhibitors against P- and E-selectin was similarly associated with improved neurological outcome (79, 85-88). The role of L-selectin in brain ischemia is less clear, as preventing its shedding by a blocking antibody, and presumably its ability to mediate leukocyte transmigration, does not appear to significantly influence stroke outcome (89, 90). Interestingly, recent work has shown that exposing animals to E-selectin intranasally can induce immune tolerance to brain antigens, and consequently reduce the extent of injury due to experimental stroke (91, 92) and even prevent their occurrence (93). Since E-selectin is almost exclusively upregulated in stimulated endothelium, tolerance to E-selectin could lead to suppression of immune responses and reduce trafficking of peripheral leukocytes to ischemic brain. Thus, it is conceivable that this approach could lead to the development of a vaccine against stroke.

4.2 Immunoglobulin Superfamily Firm adhesion of leukocytes to the endothelial cells as well as leukocyte activation is mediated by receptors of the immunoglobulin superfamily. These molecules cause stronger attachment of leukocytes to the endothelium than the selectins. This family includes 5 molecules that are expressed by endothelial cells: ICAM-1 and ICAM-2, VCAM-1, plateletendothelial cell adhesion molecule-1 (PECAM-1), and the mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1). These molecules are involved in leukocyte adhesion at relatively low shear forces. ICAM-1 (CD54) is constitutively present in low levels on the cell membranes found on endothelial cells, leukocytes, epithelial cells, and fibroblasts. Its expression greatly increases upon stimulation by cytokines. ICAM-2 (CD102) is an endothelial cell membrane receptor that does not increase after stimulation, whereas VCAM-

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1 (CD106) is induced by TNF-α and IL-1. PECAM-1 (CD31) is involved in the attachment of endothelial cells to each other, and leukocyte transmigration across the endothelium. Most of the work concerning immunoglobin superfamily adhesion molecules in cerebral ischemia has involved ICAM-1. Increased expression of ICAM-1 in ischemic brain occurs within hours of stroke onset, peaks at about 12-24 h, and appears to precede leukocyte infiltration (94-96). Several studies have now shown that blocking ICAM-1 with antibodies (97, 98) or inhibiting ICAM-1 mRNA with antisense oligonucleotides (99) improves outcome from experimental stroke. Similarly, mice deficient in ICAM-1 had smaller infarcts compared to wildtype mice (100-102). Furthermore, combination treatment with recombinant tissue plasminogen activator (rt-PA) anti-ICAM-1 antibodies led to reduced infarct size compared to rt-PA treatment alone (103). Whether anti-ICAM-1 treatment requires reperfusion to be effective is unclear as one report indicated that such therapy was ineffective in ischemia without reperfusion (104), yet another study in ICAM-1 deficient mice demonstrated otherwise (100). The role of VCAM-1 in stroke is less clear. While increases in VCAM-1 mRNA after cerebral ischemia have been observed by some investigators (105), others have failed to document significant changes (99). One study by Cervera et al (106) showed that unfractionated heparin lead to reduced infarct size in experimental stroke, and was associated with a reduced inflammatory response including decreased VCAM-1 expression. However, treatment with anti-VCAM-1 antibodies did not have any effect on stroke outcome (107) and would suggest that VCAM-1 may not play a significant role in ischemic brain injury. Elevated soluble intercellular and vascular cell adhesion molecules-1 (sICAM-1 and sVCAM-1) have been documented in clinical stroke (83), and VCAM-1 expression has been observed in autopsied brains of stroke victims within cerebral vessels and astrocytes (105). Furthermore, stroke patients treated with unfractionated heparin were found to have blunting of the typical rise in serum sVCAM-1 (108). However, one phase III clinical trial of antiICAM therapy for stroke was not only ineffective, it significantly worsened outcome (109). The interpretation of this study may have been confounded by the use of a murine antibody in humans, with subsequent neutrophil and complement activation (110)

4.3 Integrins Integrins are a family of adhesion molecules that are heterodimers consisting of a common β subunit and a variable α subunit (111). Of the β subunits, there are three subfamilies, denoted β1-3. Members of the β1 subfamily (or VLA, very late activation) bind collagen, laminin and fibronectin and are involved in the structure of the extracellular matrix, whereas β2 integrins (CD18) are involved in leukocyte cell adhesion. β3 integrins, also known as the cytoadhesins, include the platelet glycoprotein IIb/IIIa (αIIb/ β3) and the vitronectin receptor (αv/β3), factors involved in clot generation and stabilization. Leukocyte integrins are transmembrane cell surface proteins activated by chemokines, cytokines, and other chemoattractants. In order for leukocytes to bind to activated endothelium, integrins must be expressed on the cell surface in order to recognize endothelial cell adhesion molecules (112). Their surface expression is increased by agonists such as TNF-

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α and after adhesion to E-selectin. The β2 integrins bind to receptors of the immunoglobulin gene superfamily, and contain a common β2 chain with one of 3 distinct α chains (CD11a, CD11b, or CD11c). The CD11a/CD18 integrin is also referred to as LFA-1, whereas CD11b/CD18 is also called Mac-1. Of the α chains, CD11b has been the most studied in stroke models. Leukocytes and monocytes also express the α4ß1 (very late antigen-4,VLA-4, CD49d) integrin, which binds to VCAM-1 and ligands of the subendothelial matrix (74). Blocking CD11b (98, 113, 114), CD18 (115-119) or both (120-122) reduces injury from experimental stroke and is associated with decreased neutrophil infiltration. Similarly, neutrophils from mice that lack CD18 exhibited reduced leukocyte adhesion to endothelial cell monolayers, and when these mice were subjected to experimental stroke, they had improved cerebral blood flow and less neurological injury and neutrophil accumulation compared to the wildtype phenotype (123). Blocking integrins essential for lymphocyte and monocyte trafficking may also limit damage due to reperfusion injury. Antibodies against VLA-4 given 2 h after a 3 h period of temporary MCAO followed by reperfusion decreased infarct size (13). Importantly, a few studies have shown that anti-integrin strategies are not effective in models where there is no reperfusion (115, 118, 123, 124), and suggest that integrins play an important role in leukocyte infiltration following reperfusion. At the clinical level, two studies examined the potential of anti-integrin therapies in acute stroke patients. In one phase III trial, a humanized CD11/CD18 antibody was administered to patients within 12 h symptom onset (125). The second trial was a phase IIb dose escalation study of a non-antibody peptide, recombinant neutrophil inhibiting factor (rNIF) in stroke patients (Acute Stroke Therapy by Inhibition of Neutrophils or ASTIN) (126) administered within 6 h of symptom onset. Both studies were stopped prematurely due to a lack of effect on predetermined endpoints. Although both compounds appeared to be effective in preclinical studies (121, 122, 124), lack of an obvious effect in humans could be due to study design not in line with laboratory data (such as late treatment) or the inherent heterogeneity of clinical stroke. Another possibility is that changes in neutrophil integrins are different in acute ischemic stroke patients compared to rodents. For example, while many integrins are upregulated after stroke in humans, CD11b is actually decreased (127); therefore, some antiadhesion molecule approaches may not be appropriate. Regardless, it is clear that more work and possibly improved trial design are needed.

5. Inflammatory Mediators 5.1. Cytokines Cytokines are upregulated in the brain after a variety of insults including stroke. They are expressed not only in cells of the immune system, but also through endogenous production by resident brain cells, including glia and neurons (128-130). The most studied cytokines related to inflammation in stroke are interleukin-1 (IL-1), TNF-α, interleukin-6 (IL-6), interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) (9, 32).

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5.1.1. IL-1 IL-1 is a 17-kDa polypeptide and exists two isoforms, IL-1α and IL-1ß and its endogenous inhibitor, IL-1 receptor antagonist (IL-1ra) (131). In experimental stroke, IL-1ß mRNA elevations have been documented within 15-30 min after ischemia (130, 132), with protein detected a few hours later (133, 134). mRNA expression appeared biphasic with peaks occurring at 30 and 240 min after transient forebrain ischemia (135). Much of the data to date suggests that IL-1 potentiates brain injury in experimental stroke (136). Increased brain damage occurred when IL-1 ß was administered to rats (137), and mice deficient in IL1 have smaller infarcts compared to wildtype mice. In rat models of focal ischemia, administration of IL-1ra (138) or its overexpression by adenoviral vectors (139) has been shown to reduce neurologic deficit and infarct size. IL-1 has two receptors, IL-1R1 and IL1R2, but only the former is involved in signal transduction (131). However, IL-1ß does not appear to act through IL-1R1 to exacerbate brain injury, as IL-1ß administration increased infarct volume even in IL-1R1 deficient mice (140, 141). 5.1.2. TNF-α TNF-α is also upregulated in the brain after ischemia with similar epression patterns as IL-1ß Initial increases are seen 1-3 h after ischemia onset (128, 142, 143). TNF-α expression was initially observed in neurons (128), then later in microglia and some astrocytes (144). Expression is also biphasic with a second increase appearing at 24 and 48 h (142). TNF-α appears to have pleiotropic functions in the ischemic brain (145). Inhibition of TNF-α reduces ischemic brain injury (146), while administration of recombinant TNF-α protein after stroke onset worsens ischemic brain damage (147). However, TNF- α may also protect the brain under certain circumstances. TNF- α appears to be involved in the phenomenon of ischemic tolerance (148), and mice deficient in TNF receptors have larger infarcts (149, 150). The reasons for this disparity might be due to different pathways through which TNF-α signals. There are at least two TNF-α receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Most effects induced by TNF-α are mediated by TNFR1. TNFR1 contains a death domain (DD) that interacts directly with TNFR1 and may act as a bifurcation point for signaling related to cell death or cell survival. By reacting with Fas-associated death domain (FADD) and caspase-8, TNF- α may lead to apoptosis. Reacting with TNF-receptor associating factor 2 and receptor-interacting protein may lead to anti-inflammatory and antiapoptotic functions (reviewed by Hallenbeck (145)). Whether and how this applies in brain ischemia has yet to be clearly elucidated. 5.1.3. Other Inflammation Related Cytokines IL-6 is largely thought of as a pro-inflammatory cytokine, but whether it plays a significant role in ischemic stroke is far from clear. IL-6 deficient mice have similar sized infarcts compared to wildtype suggesting that it does not participate in ischemic pathogenesis (151). However, other studies suggest either a beneficial (152) or detrimental role (153). IL-10 is an anti-inflammatory cytokine, and acts by inhibiting IL-1 and TNF- α and also by suppressing cytokine receptor expression, and inhibiting receptor activation. It is synthesized in the central nervous system (CNS) and is upregulated following experimental

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stroke (154). Exogenous administration (155, 156) and gene transfer of IL-10 (157) in cerebral ischemia models both appear to have a protective effect. TGF-β1 is a multifunctional cytokine involved in the modulation of cell growth, differentiation, angiogenesis, immune function, extra-cellular matrix production, cell chemotaxis, apoptosis and hematopoiesis (158). Its expression has been reported in microglia and astrocytes, with low levels in neurons. Overexpression of TGF- β1 using an adenoviral vector protected mouse brains from ischemic stroke and reduced the accompanying inflammatory response (159). A recent study showed that cultured neurons may be protected from ischemia-like insults by microglia-secreted TGF-β1 (32).

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5.2. Chemokines Chemokines are members of the cytokine family that possess chemotactic properties, regulating the migration of leukocytes in inflammatory and immune responses. Production of chemokines and their receptors in the brain has been reported under conditions of brain ischemia. Expression of chemokines following focal ischemia is thought to have a deleterious role by increasing leukocyte infiltration (8). They are classified into four classes based on the positions of key cysteine residues (C): C, CC, CXC, and CX3C, and act through specific and shared receptors belonging to the superfamily of G-protein-coupled receptors (160). Chemokines are constitutively expressed by microglial cells, astrocytes, and neurons, but levels are increased by various stimuli. Chemokines mediate their biological effects by binding to cell surface receptors. Receptor binding triggers various effector enzymes, which leads not only to the activation of chemotaxis but also to a wide range of functions in different leukocytes, such as an increase in the respiratory burst, degranulation, phagocytosis, and lipid mediator synthesis (reviewed by Horuk (161, 162)). Accumulated data indicate that a variety of chemokines such as monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) are induced in the animal models of focal cerebral ischemia (163-165). Consistent with a deleterious role, their inhibition or deficiency is associated with reduced injury (166-171), whereas overexpression of at least MCP-1 exacerbated injury (165). The CX3C chemokine, fractalkine is expressed almost exclusively in neurons. Following ischemia, expression has been localized to viable neurons in the infarct periphery as well as some endothelial cells. Interestingly, expression of its receptor, CX3CR1 was observed only on microglia/macrophages (172). The significance of these observations are not entirely clear, but fractalkine deficiency is associated with reduced infarct size suggesting that fractalkine may mediate neuron-microglial interactions and cell death (171). In addition to chemotactic properties, chemokines may play other roles in ischemic injury. Microglia/macrophage-derived MCP-1 was shown not only to direct the migration of circulating monocytes across BBB, but it also down regulated tight junction proteins (173). This would suggest that MCP-1 can directly affect BBB permeability. With recent interest in the area of cell based therapy for stroke, chemokines may also play an important role in honing stem cells to regions of injury. Several chemokines such as MCP-1 and SDF-1 and/or their receptors have been observed at the interface of ischemic

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tissue and cell transplants (174-177). Inhibiting these chemokines reduced stem cell migration into ischemic tissue (174, 175).

glycerophospholipids ↑Cai2+ PLA2 , PLC AA

COX

5-LOX

5-HPETE

LTB4

PGH2

LTA4 TXA2

PGE2

PGD2

PGI2

LTC4

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LTD4 LTE4 chemoattraction

↑ Brain Edema & BBB Permeability Figure 3. Ischemic activation of the arachidonic acid cascade. In the setting of cerebral ischemia, excess intracellular calcium (Cai2+ ) activates various lipases, including phospholipase A2 (PLA2) and phospholipase C (PLC) which breakdown both intracellular and membrane phospholipids and release arachidonic acid (AA). Both the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways are activated. The COX pathway converts AA to prostaglandin H2 (PGH2), a precursor prostaglandin. PGH2 is then metabolized to various eicosanoids, including prostacyclin (PGI2), thromboxane A2 (TXA2), prostaglandin E2 and prostaglandin D2. Eicosanoid family members have been shown to exert potent effect on brain vasomotor regulation and increase microvascular and BBB permeability. In the brain, they can act as neutrophil chemoattractants. AA can be also converted to 5hydroperoxyeicosatetraenoic acid (5-HPETE) by LOX-5. 5-HPETE is then metabolized to leukotriene A4 (LTA4) and B4 (LTB4). LTA4 is a precursor of cysteinyl leukotrienes (cysLTs). cysLTs are converted sequentially to leukotriene C4 (LTC4), leukotriene D4 (LTD4), leukotriene E4 (LTE4). Leukotrienes play multiple roles to mediate events such as chemoattraction, brain edema and BBB permeability.

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5.3. Arachidonic Acid metabolites

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The arachidonic acid (AA) cascade is initiated by the activation of phospholipase A2 (PLA2) (178). Energy failure due to cessation of blood flow can result in calcium accumulation in brain cells. Calcium then activates PLA2 which hydrolyses glycerophospholipids to release AA. The cytosolic form, cPLA2 is found in reactive astrocytes and microglia following cerebral ischemia (179). It is an important enzyme in ischemia, as cPLA2 deficient mice had smaller infarcts and developed less brain edema with fewer neurological deficits than their wild type littermates (180). Arachidonic acid metabolites are potent mediators that contribute to post-ischemic brain inflammation and circulatory disorders (181). AA is metabolized through two different pathways via cyclooxygenase (COX) or lipoxygenase (LOX). (Figure 3). 5.3.1 Cyclooxygenase Pathway Arachidonic acid released from brain phospholipids during ischemia/reperfusion is converted to prostaglandin H2 (PGH2) by cyclooxygenase (COX). There are two isoforms of COX. COX-1 is constitutively expressed in many cells types, including microglia and leukocytes during brain injury (182). COX-1 deficient mice have increased vulnerability to brain ischemia, and would support a protective role possibly due to an effect on maintaining cerebral blood flow (183). COX-2 is an inducible isoform and is increased following ischemia (184, 185). PGH2 is further metabolized to a variety of prostaglandins such as prostacyclin (PGI2) and thromboxane A2.(TXA2). The roles of various COX metabolites are protean, but accumulated data suggest that those downstream of COX-2 are likely deleterious. Several studies have now shown that treatment with COX-2 inhibitors improve neurological outcome after stroke (186-189). Furthermore, COX-2 deficient mice have reduced injury after N-methyl-D-aspartate (NMDA) exposure (190), whereas COX-2 overexpression exacerbates brain injury (191). Interestingly, COX-2 mediates its toxic effect through PGE2 rather than ROS, even though COX-2 can generate both (192). 5.3.2 5-Lipoxygenase Pathway Compared to the COX pathway, less work has been done to study interventions in the lipoxygenase pathway, but like COX, modulators of lipoxygenase have the potential to improve the stroke outcome as well. AA can be converted to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) by 5-lipoxygenase (5-LOX) which is metabolized to leukotriene A4 (LTA4), a precursor of cysteinyl leukotrienes (cysLTs). cysLTs are proinflammatory lipid mediators and consist of leukotriene C4 (LTC4), D4 (LTD4) and E4 (LTE4). LTC4 synthase is found exclusively in inflammatory cells of hematopoietic origin, and converts LTA2 to LTC4 after conjugation with glutathione (193). LTC4 is a potent chemoattractant that has been implicated in the BBB dysfunction, edema and neuronal death after ischemia/reperfusion. During brain ischemia/reperfusion, biphasic AA and LTC4 elevations have been documented and appear to correspond to biphasic patterns of BBB disruption (194). Pretreatment with a 5lipoxygenase inhibitor, AA861 resulted in significant attenuation of LTC4 levels and reduction in brain edema and cell death (195). Although little work has been done to study

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interventions in the lipoxygenase pathway, but have the potential to improve the stroke outcome.

5.4. Nitric Oxide/ Nitric Oxide Synthase Nitric oxide (NO) is a small, relatively stable, free-radical gas that readily diffuses into cells and cell membranes where it reacts with molecular targets. NO synthase (NOS), which is the key enzyme that converts L-arginine to NO exists in three isoforms, of which iNOS is especially relevant to inflammatory cells. In fact, iNOS expression is thought to be restricted to cells involved in inflammatory responses such circulating leukocytes, microglia and astrocytes. In the brain, ischemia-induced upregulation of iNOS mRNA and protein is associated with increases in iNOS enzymatic activity and NO production (196, 197). NO can then further react with superoxide to produce peroxynitrite, an especially reactive species that can lead to, among other things, DNA damage. Endothelial cells generate NO via the endothelial form of NOS (eNOS). In addition to its vasodilatative properties, NO in this setting may prevent leukocyte adhesion to vascular endothelium (198). However, NO generated by iNOS is believed to be neurotoxic (199). This view is supported by observations that pharmacological inhibition of iNOS reduces the volume of the infarct by about 30% (200) and that iNOS-null mice have smaller infarcts and better neurologic outcomes than wild-type control animals (201). Consistent with a damaging role, protection by hypothermia is associated with reduced microglial generation of both NO and iNOS (202).

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5.5. Reactive Oxygen Species Once activated, the inflammatory cells in the brain generate reactive oxygen species (ROS) as a defense mechanism against microbes. Inflammatory cells generate ROS via several enzyme systems. Superoxide is generated via COX, xanthine dehydrogenase, xanthine oxidase and NADPH oxidase, whereas myeloperoxidase (MPO) and monoamine oxidase (MAO) generate hypochlorous acid and H2O2.. Superoxide anion is a major oxidant generated in the brain parenchyma after MCAO, and is well known to cause direct injury to ischemic brain as well as to react with NO to generate peroxynitrite (203). NADPH oxidase is a multicomponent enzyme that consists of two membrane bound subunits, gp91 and p22, and three cytosolic subunits, p67, p47 and p40 plus Rac, a small GTPase (204). With appropriate stimuli, the cytosolic subunits translocate to the membrane where they interact with the membrane bound subunits to transfer electrons from NADPH to oxygen to form superoxide. Prior work has shown that NADPH oxidase deficient mice have smaller infarcts than wild type mice. Furthermore, when bone marrow from NADPH oxidase deficient mice were transplanted into either wildtype or deficient mice, wildtype mice transplanted with deficient marrow suffered the same amount of injury as wildtype mice transplanted with wildtype marrow. These latter data would suggest that NADPH oxidase generated within endogenous brain cells such as microglia, rather than circulating leukocytes, are responsible for the worsened ischemic damage (205).

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MPO, found in neutrophils and monocytes but not macrophages, is thought to mediate bactericidal killing through H2O2 and hypochlorous acid. However, very little has been directly investigated regarding its role in ischemic brain pathophysiology. One study subjected MPO deficient mice to focal cerebral ischemia and found that infarct size was paradoxically increased (206). The authors subsequently found that these MPO deficient mice also had increased products of nitrosylation within the ischemic brain. Subsequent work suggested that MPO‘s protective effect may be due to its ability to scavenge nitrotyrosine (a by product of peroxynitrite reactions) in the presence of glutathione (206, 207). Related work has also shown that MPO contributes to the termination of neutrophil influx, as MPOdeficient leukocytes can exhibit a stronger and more prolonged respiratory burst (208). Therefore, it is possible that MPO may actually limit the extent of ROS-mediated tissue injury.

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5.6. Matrix Metalloproteinases Matrix metalloproteinases (MMPs) are a family of extracellular soluble or membranebound proteases that are involved in remodeling the extracellular matrix. They appear to contribute to BBB disruption, brain edema and hemorrhage (see reviews by Cunningham et al (209) and Rosenberg (210)). MMPs are normally found in the cytosol in a pro- or inactivated state, and are cleaved by proteases such as plasmin or other MMPs to their active state (210). Microglia are not only a major source of the MMPs following ischemia but are also necessary to stimulate astrocytes to generate active MMPs (211). Cells in the ischemic brain, including infiltrated neutrophils, pericytes, vascular endothelium, microglia and astrocytes have all been reported to express MMPs. MMPs appear to be responsible for the biphasic opening of the BBB. In experimental stroke models, MMP inhibition reduces infarct size, brain edema and hemorrhage (212, 213). Furthermnore, MMP-9 appears to play a more significant role in stroke compared to MMP-2, as mice deficient in MMP-9 had smaller infarcts compared to wildtype controls (214). Such an effect was not observed in MMP-2 deficient mice (215). MMP-9 has largely been observed in peripheral leukocytes (216, 217) and microglia (218), thus linking the role of MMPs to the inflammatory system. Furthermore, circulating leukocytes secrete MMP-9 in order to cross the BBB formed by the endothelial cells and the basal lamina. Peripheral inflammatory cell, rather than brain derived MMP-9 may contribute significantly to ischemic brain injury as mice transplanted with bone marrow from MMP-9 deficient mice suffer less injury and less BBB disruption than mice transplanted with marrow containing intact MMP-9 (219).

6. Summary Stroke triggers a robust inflammatory response in brain. For the time being, an overwhelming number of publications have linked post-ischemic inflammation to the progression of brain damage. Thus, inhibition of inflammation is thus thought to be a

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straightforward strategy to treat the stroke. However, inflammation is also a host defense against pathogens, and inflammation plays a role in angiogenesis, tissue remodeling and regeneration. Though the potential benefits of post-ischemic inflammation have not been well documented, at least some cytokines or other inflammatory mediators produced by inflammatory cells showed to be neuroprotective after stroke. Whether inflammation is destructive or protective may depend on how severe the ischemia is, how inflammatory cells are activated and the stage of stroke in which inflammatory responses contribute. Future work should address the optimal timing of inflammation modulating interventions as well as elucidating how the immune system moves from damaging to protective/restorative responses.

Acknowledgements This work was supported by grants from NIH NINDS R01 NS40516 (MAY), American Heart Association Established Investigator Award (MAY), and a Stanford University Dean’s Postdoctoral Fellowship Award (XT).

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In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 117-157 © 2006 Nova Science Publishers, Inc.

Chapter VII

Interactions of Neuroinflammatory and Neurodegenerative Mechanisms in Alzheimer’s Disease Michael T. Heneka*, Magdalena Sastre and Michael Hüll

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Department of Neurology, Molecular Neurology, University of Münster, Mendelstrasse 7, D-48149 Münster, Germany Deptartment of Neurology, University of Bonn, Sigmund-Freud-Str. 25, D-53127-Bonn, Germany Department of Psychiatry, University of Freiburg, Hauptstr. 5, D-79104 Freiburg, Germany

1. Alzheimer’s Disease As one of the most recognized neurodegenerative disorders, Alzheimer’s disease (AD) currently affects 20 to 30 million individuals worlwide (Selkoe, 2005). AD accounts for most cases of dementia that are diagnosed after the age of 60 years of life. While currently more than 900,000 patients in Germany suffer from dementia, about 650.000 are supposed AD cases (Bickel, 2000). In the US, the number reaches roughly 4 million patients. The prevalence of AD rises with age, affecting approximately 1% to 3% of the population in the 6th decade of life, some 3% to 12% of the population between 70 and 80 years, and up to 25 to 35% older than 85 years (Walsh and Selkoe, 2004). Because life expectancy has been constantly increasing in civilized countries, it has been predicted that the incidence of AD will increase three fold over the next 50 years.

* To whom correspondence should be addressed: Michael T. Heneka Department of Molecular Neurology, University of Münster Mendelstrasse 7 Tel. +49 251 9802810 Fax. +49 251 9802804 Email: [email protected] Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

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AD often starts with mild memory deficits, primarily affecting the short term memory and gradually progresses to severe dementia and stupor. The earliest symptoms often appear as subtle, intermittent deficits in the remembrance of minor events of everyday life, such as forgetfullness and difficulties recalling new names or recent conversations, referred to as loss of episodic memory. At later stages, a profound dementia develops affecting multiple cognitive and behavioral spheres. The patient is unaware of time and place, and, at times, cannot identify even closest family members. These symptoms are frequently accompanied by additional neurological symptoms such as extrapyramidal motor signs, slowing movements and hampering motor coordination. Death occurs, in average, 9 years after the initial clinical diagnosis and is usually caused by respiratory complications, such as aspiration or pneumonia. At autopsy, the brain of a typical AD patient reveals a macroscopically visible cerebral atrophy involving brain regions implicated in learning and memory processes, including the temporal, parietal and frontal cortex as well as the hippocampus and amygdala. This brain volume reduction is due to a profound degeneration of neurons and synapses (Mattson, 2004). Next to this, AD brains show two characteristic lesions: extracellular deposits of βamyloid peptides, so called neuritic or senile plaques, and the intracellular neurofibrillary tangles of hyperphosphorylated tau protein (Lee et al., 2001;Selkoe, 2003). Toxic β-amyloid peptides (Aβ) are being generated by the sequential action of two proteases denoted as β-secretase (BACE1) and γ-secretase, which cleave the amyloid precursor protein (APP). Aβ exists with different carboxyl endings, from which Aβ1-40 and Aβ1-42 appear to be the major subtypes deposited in the brain. Aβ peptides can also be detected in normal cerebrospinal fluid and in conditioned media from various tissue culture cell lines (Haass et al., 1992;Seubert et al., 1992;Shoji et al., 1992), suggesting that it is constantly produced and constitutively secreted. The importance of Aβ formation was instigated by dominantly inherited familial forms of AD that are linked to APP mutations in or close to the β- and γ-secretase cleavage sites (Hardy and Allsop, 1991). This made it possible to generate transgenic mouse models of cerebral amyloidosis and AD-like histopathology, i.e. amyloid plaques and cerebral amyloid angipathy (Hsiao et al., 1995;Sturchler-Pierrat et al., 1997;Lamb et al., 1999;Moechars et al., 1999;Van Dorpe et al., 2000). Neurofibrillary tangles constitue intraneuronal cytoplasmatic accumulations of nonmembrane-bound bundles of paired helicoidal filaments, whose main component is the hyperphosphorylated form of the Tau protein. Tau is found in neurofibrillary tangles and distrophic neurites. It aggregates conjugated with ubiquitin, a fact that it shares with other intraneuronal proteins, such as α-synuclein. Of importance, Aβ deposits as well as neurofibrillary tangles can also be found in other neurodegenerative diseases and even in brains of patients without any history of cognitive or other neurological deficits (Lee et al., 2001), indicating the need for other factors to fully establish the disease. The eventual deposition of Aβ and the neurofibrillary tangle formation do not account for all, and particularly not for the most early clinical symptoms present before neuronal degeneration is evident. Inflammatory changes are observed in AD brain overall, and particularly near amyloid deposits, invariably comprising activated microglia. Once stimulated by beginning neuronal degeneration, microglia release a wide variety of pro-

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inflammatory mediators including cytokines, complement components, various free radicals and nitric oxide (NO), which all contribute to further neuronal dysfunction and eventually death. These create and feed a vicious cycle that could be essential in the pathological progression of AD.

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2. Inflammation and AD Despite the “amyloid hypothesis” has been considered to play a key role for AD pathogenesis in recent years (Walsh et al., 2002b;Walsh and Selkoe, 2004), open questions remain, as to whether Aβ plaques and neurofibrillary tangles are causative for AD. These doubts are being fueled by the finding that the Aβ plaque burden only poorly correlates with the progression and severity of dementia in AD. Moreover, transgenic animals, that develop widespread Aβ plaque deposition in response to mutant APP overexpression, show only slight cognitive deficits (Braak and Braak, 1998;Davis and Laroche, 2003). Furthermore, neurofibrillary tangles may correlate better with the decline in cognitive skills, but seem to occur rather as a late event and in some cases possibly downstream of Aβ accumulation. However, some experimental evidence indicates that protofibrils and oligomers of Aβ1-40 and Aβ1-42, rather than concrete Aβ plaques, contribute to early dendritic and synaptic injury and thereby to neuronal dysfunction (Walsh et al., 2002a). In addition, a recent study implicates intraneuronal Aβ load to the onset of cognitive dysfunction (Billings et al., 2005). Next to the direct toxic effects of Aβ1-40 and Aβ1-42 peptides, Aβ may promote neurodegeneration by additional mechanisms including the activation of microglial cells and astrocytes. The induction of a microglia driven inflammatory response results in the release of various inflammatory mediators including a whole array of neurotoxic cytokines (Akiyama et al., 2000;Tan et al., 1999). Once activated, microglia cells may also recruit astrocytes to the scene of which some may actively prolong the inflammatory response to extracellular Aβ deposits (Figure 1). This neuroinflammatory component of AD is further characterised by a local cytokine-mediated acute-phase response, the 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). Several lines of evidence suggest that all of these factors can either alone and presumably more effectively in concert contribute to neuronal dysfunction and cell death (Abbas et al., 2002;Bezzi et al., 2001;Brown and Bal-Price, 2003). This chapter will discuss several aspects of neuroinflammation in AD particulary addressing the following questions: 1. Which cells contribute to the inflammatory component of AD and how do they interact ? 2. Which pro- and antiinflammatory mediators are being released in the AD brain, and what is their supposed mechanism of action? 3. Are there any known pathogenetic factors in the AD brain that may facilitate the induction and persistence of neuroinflammatory mechanisms?

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4. Is neuroinflammation just a reaction to neurodegenerative events or do they act on neurodegenerative pathomechanisms thereby establishing a vicious and selfperpetuing cycle? 5. Can antiinflammatory treatment strategies serve as a future AD therapy?

Bielschowsky

CD68

GFAP

Figure 1. Classical Alzheimer’s disease histopathology and accompanying inflammatory changes. Bielschowsky staining (to delineate amyloid containing plaques, neuritic degeneration and neurofibrillary tangles), CD68 (a macrophage/microglial marker) and GFAP (astrocyte marker) double stainings with Aβ1-42 are shown in post mortem tissue.

3. Cellular Components of Neuroinflammation in Alzheimer`s Disease

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3.1 Microglia Microglia cells constitute around 10% of all cells in the nervous system. They represent the first line of defense against invading pathogens or other types of brain tissue injury. Under pathological situations, such as neurodegenerative disease, stroke, traumatic injury and tumor invasion, these cells become activated, migrate to and surround damaged or dead cells and subsequently clear cellular debris from the area, similar to the phagocytic active macrophages of the peripherial immune system (Fetler and Amigorena, 2005). Activated microglia up-regulate a variety of surface receptors, including the major histocompatibility complex and complement receptors (Liu and Hong, 2003). They also experience dramatic morphological changes from a resting ramified phenotype to motile activated amoeboid microglia (Kreutzberg, 1996). Once immunostimulated in response to neurodegenerative events, these microglia cells release a variety of proinflammatory mediators including cytokines, reactive oxygen species, complement factors, neurotoxic secretory products, free radical species and NO, which all can contribute to neuronal dysfunction and cell death, ultimately creating a vicious cycle (Griffin et al., 1998). Several amyloid peptides and APP can act as potent glial activators (Barger and Harmon, 1997;Dickson et al., 1993;Schubert et al., 2000) and disruption of APP gene and its proteolytic products delay and decrease microglial activation (DeGiorgio et al., 2002). Microglial cells have been suggested to be preferentially associated with certain amyloid plaque types indicating that plaque development and degree of microglial reaction are

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interrelated (D'Andrea et al., 2004). The extent of astrocytosis and microglial activation has been shown to dependent on the Aβ load, and treatment with peptide β-sheet breakers reduced brain inflammation (Permanne et al., 2002). Aβ is able to stimulate a nuclear factor kappa B (NFκB)-dependent pathway that is required for cytokine gene transcription (Combs et al., 2001), and microglial and astrocyte activation. Not only Aβ, but also the last 100 aminoacids of APP, which are also present in senile plaques, can induce astrocytosis and neuronal death. CT100 exposure results in activation of the mitogen-activated protein kinase (MAPK) pathways as well as NFκB (Bach et al., 2001). Additionally, other proteins involved in APP processing have been described to be implicated in the inflammatory response. Loss of presenilin function in presenilin conditional knockout mice leads to differential upregulation of inflammatory markers in the cerebral cortex, such as strong microglial activation, and elevated levels of glial fibrillary acidic protein, complement component C1q, and cathepsin S (Beglopoulos et al., 2004). However, this effect may be unrelated to APP processing, since presenilin is also involved in a variety of other metabolic pathways including the β-catenin pathway and the cleavage of other type I transmembrane proteins, such as Notch, CD44, E-cadherin, ErbB-4, and the Notch ligands (Brunkan and Goate, 2005). It has to be noted that some aspects of microglia function may even be beneficial, since activated microglia is able to reduce Aβ accumulation by increasing its phagocytosis, clearance and degradation (Frautschy et al., 1998;Qiu et al., 1998;Yan et al., 2003). Thus, secreted Aβ1–40 and Aβ1–42 peptides are constitutively degraded by the insulin degrading enzyme (IDE), a metalloprotease released by microglia and neural cells. Next, microglia can also secrete several trophic factors, such as the glia-derived neurotrophic factor (GDNF), which exert a well documented neuroprotective function (Liu and Hong, 2003).

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3.2 Astrocytes In AD, astrocytes are known to participate in β-amyloid clearance and degradation, for providing trophic support to neurons, and for forming a protective barrier between Aβ deposits and neurons (Wyss-Coray et al., 2003). The presence of large numbers of astrocytes associated with Aβ deposits in AD suggests that these lesions generate chemotactic molecules that mediate astrocyte recruitment. It has been shown that astrocytes throughout the entorhinal cortex of AD patients gradually accumulate Aβ1-42 positive material and the amount of this material correlates positively with the extent of local AD pathology. Aβ1-42 within these astrocytes appears to be of neuronal origin, possibly accumulated by phagocytosis of locally degenerated dendrites and synapses, especially in the cortical molecular layer (Nagele et al., 2003). In line with this finding, recent evidence suggests that astroglial cells are capable of phagocytosing Aβ peptides, a process which may depend on their apolipoprotein E (ApoE) status, suggesting that ApoE polymorphisms may influence the risk to develop AD by affecting astroglial Aβ phagocytosis (Jiang et al., 1998;Niino et al., 2001). In contrast, a recent report suggests that astrocytes could also act as a source for Aβ, because they overexpress BACE1 in response to chronic stress (Rossner et al., 2005). While it remains unclear whether astrocyte activation contributes to Aβ generation or to its clearance, it seems apparent that astrocytes also play an inflammation prolonging role e.g. by

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the expression of iNOS and the L-arginine-supplying enzyme argininosuccinate synthetase and subsequently increased NO-mediated neurotoxicity (Heneka et al., 2001;Heneka and Feinstein, 2001). While under physiological conditions, astrocytes serve as a constant and important source of neurotrophic factors, in vitro and in vivo experiments suggest that activated astrocytes do not generate significant amounts of these molecules. Parenteral immunization of APP transgenic mice with synthetic Aβ in complete Freund’s adjuvant can markedly decrease the number and density of Aβ deposits in the brain, with accompanying improvements in neuritic dystrophy and gliosis (Weiner and Selkoe, 2002). However, astro- and microglial activation could be an early event in the disease, occurring even in the absence of focal Aβ deposition (Nunomura et al., 2001). In keeping with this assumption, a clinical study detected microglial activation at very early stages of AD, comparing PET and volumetric magnetic resonance imaging of the brain in patients with mild to moderate dementia to healthy individuals (Cagnin et al., 2001). In parallel, it has been recently reported that focal glial activation preceeds amyloid plaque deposition in APPV717I transgenic mice at 3 month of age (Heneka et al., 2005a). Because these animals show both, cognitive deficits and focal glial cytokine production well before Aβ plaque deposition (Moechars et al., 1999), it seems likely that senile plaques are, at least at the beginning of the disease, not the cause of glial activation, but rather a response to Aβ oligomers or protofibrils (Hu et al., 1998;Lindberg et al., 2005;White et al., 2005). Interestingly, already at this age, APPV717I transgenic mice show a significant decrease of hippocampal long-term potentiation (LTP), a mechanism essential for memory storage and consolidation. Because cytokines such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin 6 (IL-6) directly impair neuronal function and suppress hippocampal LTP (Tancredi et al., 1992;Murray and Lynch, 1998) it can be hypothesized, that early focal inflammatory events may already contribute to neuronal dysfunction well before neuronal cell death and parenchymal volume reduction become visible.

3.4 Neurons While for decades neurons have been believed to be passive bystanders in neuroinflammation, more recent evidence suggests that, neurons themselves are capable of producing inflammatory mediators. Thus, neurons have been shown to serve as source of complement, COX-2-derived prostanoids (Davis and Laroche, 2003;Pavlov and Tracey, 2005)(Natarajan and Bright, 2002), and several cytokines including IL-1β, IL-6, and TNF-α (Botchkina et al., 1997;Breder et al., 1993;Gong et al., 1998;Murphy et al., 1999;Orzylowska et al., 1999;Suzuki et al., 1999;Tchelingerian et al., 1994;Yan et al., 1995) and M-CSF (Du et al., 1997). Despite in the case of COX-2, it has been demonstrated that expression is driven by physiological synaptic activity (Yermakova and O'Banion, 2000), it is possible that neurons themselves may exacerbate inflammatory reactions in their vicinity and so contribute to their own destruction in AD. Furthermore, expression of iNOS has been described in degnerating neurons in AD brains (Vodovotz et al., 1996;Lee et al., 1999;Heneka et al., 2001), next to compelling evidence for iNOS related long-term NO release and NO dependent peroxynitrite formation (Smith et al., 1997). Glial and neuronal derived NO and

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peroxynitrite have been demonstrated to cause neuronal dysfunction and cell death in vitro and in vivo (Boje and Arora, 1992;Heneka et al., 1998). Alternatively, some of the classical pro-inflammatory mediators such as TNF-α and low concentrations of NO may actually confer neuroprotection rather than destruction in the brain and therefore constitute a defense mechanism against local inflammatory reactions.

4. Pro- and Antiinflammatory Mediators

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4.1 Complement The complement system represents a complex and tightly regulated attack system, designed to destroy invaders and to assist in the phagocytosis of waste materials. The components of this system carry out four major functions: recognition, opsonization, inflammatory stimulation and direct killing through the membrane attack complex (McGeer and McGeer, 2002). In addition to triggering the generation of a membranolytic complex, complement proteins interact with cell surface receptors to promote a local inflammatory response that contributes to the protection and healing of the host. Complement activation causes inflammation and cell damage, yet it is an essential component for eliminating cell debris and potentially toxic protein aggregates (Shen and Meri, 2003). The complement system consists of some 30 fluid-phase and cell-membrane associated proteins that can be activated by three different routes: The classical pathway (involving C1q, C1r, C1s, C4, C2, and C3 components) is activated primarily by the interaction of C1q with immune complexes (antibody-antigen), but activation can also be achieved after interaction of C1q with non-immune molecules such as DNA, RNA, C-reactive protein, serum amyloid P, bacterial lipopolysaccharides, and some fungal and virus membranes. The initiation of the alternative pathway (involving C3, factor B, factor D, and properdin) does not require the presence of immune complexes and leads to the deposition of C3 fragments on target cells. Mannose-binding lectin (MBL), a lectin homologous to C1q, can recognize carbohydrates such as mannose and N-acetylglucasamine on pathogens and initiate the complement pathway independently of both the classical and the alternative activation pathways. MBL is associated with two serine proteases, like the C1 complex in the classical pathway, that cleave C4 and C2 components, leading to the formation of the classical C3 convertase (van Beek et al., 2003). Various brain cells can produce complement proteins to recognize and kill pathogens locally. Cell lines and primary cultures of human origin were used to show that glial and neuronal cells could produce most complement proteins, particularly after stimulation with inflammatory cytokines (Gasque et al., 1995). Studies using RT-PCR have shown locally upregulated complement mRNA in AD brain, especially in the areas of primary pathology: entorhinal cortex, hippocampus, and midtemporal gyrus (Yasojima et al., 1999b). Numerous groups reported the association of complement proteins of the classical pathway in AD brains, in particular the MAC has been found to colocalize with amyloid plaques and to be associated with neurofibrillary tangles (Webster et al., 1997).

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Studies of mutant mice lacking complement proteins suggest that impaired phagocytosis can result in immune-mediated tissue damage and inflammation (Botto, 1998;Taylor et al., 2000). Wyss-Coray et al (2002) demonstrated that complement activation can protect against Aβ-induced toxicity and may reduce the accumulation or promote the clearance of senile plaques (Wyss-Coray et al., 2002). AD mice expressing a soluble form of the complement inhibitor Crry, which inhibited C3 activation, under the control of the glial fibrillary acidic protein promoter displayed higher Aβ deposition and more prominent neurodegeneration than compared to age-matched mice. However, more recently it was reported that transgenic mouse models of AD lacking C1q showed reduced pathology, consisting of decreased activated glia and improved neuronal integrity, without changes in plaque area. These data suggest that at ages when the fibrillar plaque pathology is present, C1q exerts a detrimental effect on neuronal integrity, most likely through the activation of the classical complement cascade and the enhancement of inflammation (Fonseca et al., 2004).

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4.2 Chemokines Next to cytokines, recent experiments intended to unravel the role of chemokines and their receptors for AD neuroinflammation. The chemokine family consists of over 50 different molecules that confer chemotaxis, tissue extravasation, and functional modulation of leukocyte function during inflammation (Luster, 1998;Owens et al., 2005). The importance of chemokine generation in AD brain is underlined by the fact that these molecules may represent the major class of molecules that regulate microglial migration and recruitment of astrocytes to the neuroinflammatory scence and thus, are responsible for the extent of local inflammation. The CXC subclass of chemokines, is considered one of the two major chemokine subfamilies and its members e.g. IL-8 are primarily chemotactic for neutrophils and endothelial cells. Their conserved glutamate-leucine-arginine (ELR) motif within the receptor-binding domain (Strieter et al., 1995) parts them from non-ELR CXC chemokines such as IP-10, which primarily attract activated T cells (Strieter et al., 1995). Finally the CC chemokine subfamily, which members include macrophage inflammatory protein 1 (MIP1α), Monocyte chemoattractant protein-1 (MCP-1), and Regulated on Activation, Normal T Expressed and Secreted (RANTES), do not affect neutrophils but are chemotactic for monocytes/macrophages, T lymphocytes, basophils and eosinophils. Seven transmembrane, G-protein-coupled cell-surface receptors mediate the biological activities of chemokines and these receptors are named according to their chemokine subfamily classification. At present there are five CXC receptors (CXCR1 to CXCR5) and nine CC receptors (CCR1 to CCR9). While it has been reported that chemokines exert physiological actions in healthy brain (Hesselgesser and Horuk, 1999), the majority of studies has focused on the expression pattern of chemokines and their respective receptors in neurological diseases such as multiple sclerosis, traumatic brain injury and stroke. All of these disorders share the disruption of the blood brain barrier as an important pathogenetic event subsequently allowing peripheral leukocytes to infiltrate the lesion site (Glabinski and Ransohoff, 1999). In strong contrast, there exists no convincing evidence for blood brain barrier disruption or signficant leukocyte infiltration in the AD brain. However, several chemokines and chemokine receptors have

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been found to be upregulated in the AD brain (Xia and Hyman, 1999), and chemokines may play an important role for recruiting microglia and astroglia to the site of Aβ deposition. Thus, Aβ stimulated human monocytes generate IL-8, MCP-1, MIP-1α/β in vitro and similary, microglia cultured from rapid autopsies of AD and non demented patients reveal an increased expression of IL-8, MCP-1 and MIP-1α after experimental exposure to Aβ. Neuropathological studies have found MCP-1 (Ishizuka et al., 1997), and increased expression of CCR3 and CCR5 in reactive microglia (Xia et al., 1998). Supporting the hypothesis that astrocytes actively contribute to the inflammatory disease component, MIP1α has been detected in reactive astrocytes nearby Aβ plaques.

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4.3 Inflammatory Cytokines Next to chemokines, the cytokine class of inflammatory mediators has been shown to be secreted by microglia and astrocytes surrounding β-amyloid neuritic plaques. The cytokine family includes several interleukins (ILs), TNFα and TNFβ. Their production is increased in inflammatory states and they function by regulating the intensity and duration of the immune response (Tuppo and Arias, 2005). In astrocytes, IL-1 induces IL-6 production, stimulates iNOS activity (Rossi and Bianchini, 1996), and induces the production of macrophage-colony stimulating factor (MCSF). In addition, IL-1 enhances neuronal acetylcholinesterase activity, microglial activation and additional IL-1 production, astrocyte activation, and expression of the cytokine S100β by astrocytes, thereby establishing a self propagating cycle (Griffin et al., 1998;Mrak and Griffin, 2001). IL-6 promotes astrogliosis (Selmaj et al., 1990), activates microglia (Heyser et al., 1997), and stimulates the production of acute phase proteins (Castell et al., 1989). IL-6 knockout mice exhibit a facilitation of radial maze learning over 30 days and show a faster acquisition, suggesting a possible involvement of IL-6 on memory processes (Braida et al., 2004). TNF-α is able to induce both pro-apoptotic and anti-apoptotic effects. This proinflammatory cytokine represents the majority of the neurotoxic activity secreted by monocytes and microglia (Combs et al., 2001). On the other hand, TNFα has been reported to have neuroprotective properties (Akiyama et al., 2000) in AD brain. In addition to the general role of cytokines, AD-specific interactions of certain cytokines and chemokines with Aβ may be pathophysiologically relevant. Thus, IL-1 can regulate APP processing and Aβ production in vitro (Blasko et al., 1999). In turn, fibrillar Aβ has been reported to increase neurotoxic secretory products, proinflammatory cytokines and reactive oxygen species (Eikelenboom et al., 1994;McGeer and McGeer, 1995;Eikelenboom and van Gool, 2004). Cultured rat cortical glia exhibit elevated IL-6 mRNA after exposure to the carboxy-terminal 105 amino acids of APP (Chong, 1997). IL-1, IL-6, TNF-α MIP-1α and MCP-1 increase in a dose-dependent manner after cultured microglia are incubated with Aβ. Production of IL-6 and M-CSF by human neurons is reportedly stimulated by glycation endproducts-modified tau and Aβ (Akiyama et al., 2000). Additionally, Aβ is able to stimulate a NFκB-dependent pathway that is required for cytokine production (Combs et al., 2001). The production of interleukins and other cytokines and chemokines may also lead to

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microglial activation, astrogliosis, and further secretion of proinflammatory molecules and amyloid, thus perpetuating the cascade (Ho et al., 2005). A second general category of cytokine action is manifested by inhibitory, antiinflammatory cytokines such as IL-1 receptor antagonist (IL-1Ra), IL-4, IL-10 and TGF-β. The use of anti-inflammatory cytokines such as IL-4 and TGF-β could be beneficial, because they are able to inhibit CD40 and class II MHC by restricting their expression and activity (Benveniste et al., 2001). Whereas transgenic mouse models are widely used to study in vivo consequences of APP processing, only a limited number of studies has addressed the occurrence of neuroinflammation in these animals and all but one study were using APP695 transgenic mice (Tg2576) in part demonstrating controversial results. Thus, Mehlhorn and colleagues analysed APP695 transgenic animals from 2 to 14 month of age but failed to detect mRNA levels of several cytokines including IL-1-α/β, IL-6, IL-10, IL-12 and IFN-γ using a ribonuclease protection assay (Mehlhorn et al., 2000). In the same study IL-1-β-positive astrocytes were detected in close proximity to Aβ deposition, whereas immunohistochemistry for TNF-α, IL-1-α, IL-6, and MCP-1 was negative. In contrast, Sly and colleagues detected TNF-α mRNA as early as 6 month of age (Sly et al., 2001), and Abbas and colleagues IFN-γ and IL-12 mRNA and protein levels by in situ hybridization and immunohistochemistry in 9 month old APP 695 transgenic mice (Abbas et al., 2002). Moreover, IL-1-β, TNF-α and IL10 were found by immunohistochemistry in animals of 12 and 13 month of age (Benzing et al., 1999;Apelt and Schliebs, 2001). The differences reported in the same transgenic mouse line are likely to be caused by different techniques employed and indicate the difficulty to assess inflammatory changes in these animal models. Nearly all cytokines that have been studied in AD, including IL-1α/β, IL-6, TNF-α, IL-8, TGF-β, seem to be upregulated in AD compared to control individuals (Akiyama et al., 2000;Tuppo and Arias, 2005). In addition to these primarily immunohistological evaluations, an association of AD with several polymorphisms of proinflammatory genes has been described, including IL-1 (Nicoll et al., 2000), Il-6 (Papassotiropoulos et al., 1999), TNF-α (McCusker et al., 2001;Perry et al., 2001), and α1-antichymotrypsin, an acute phase protein (Kamboh et al., 1995). However, none of the various members of the interleukin cytokine family that have been reported to be associated with AD actually map to chromosomal regions with evidence of genetic linkage (Tanzi and Bertram, 2005). Thus, although inflammation and the upregulation of inflammatory mediators like the interleukins are regularly observed in AD brain, it appears less likely that variation at the genomic level of these proteins makes a large contribution to AD risk in general.

4.4 Cyclooxygenase and Prostanoids The two isoforms of cyclooxygenases include the mainly constitutively expressed COX1 and the inducible COX-2 both catalyzing key steps of the prostanoid synthesis in mammalian cells. Downstream of both, COX-1 and COX-2, several other enzymes regulate the generation of a whole spectrum of prostanoids of which some may exert neuroproptective

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but others neurodestructive action. It should therefore be emphasized that the composition and proportion of all prostanoids together may actually determine whether the activity of COX enzymes is beneficial or detrimental. In vitro, bacterial lipopolysaccharide (LPS) activated microglial cells and IL-1βstimulated astroglial cells are capable of synthesizing COX-2 (Bauer et al., 1997;O'Banion et al., 1996). In contrast to peripheral monocytes, cultured rat microglia cells do not synthesize COX-2 in response to IL-1 or IL-6 (Bauer et al., 1997) suggesting that COX-2 regulation differs between CNS and peripheral cells. In rat microglial cell cultures, the major enzymatic product of COX-2 appears to be prostaglandin E2 (PGE2). Because PGE2 itself is able to induce COX-2 in microglial cells (Minghetti et al., 1997), some sort of autocrine or paracrine amplification of the COX-2 induction in microglial cells or a spreading of COX-2 expression between neurons and microglial cells seems therefore possible. PGE2 acts on four different receptors, namely EP1-EP4 (Narumiya et al., 1999). EP1 and EP2 receptors have been detected on cultured microglia while EP3 receptors are also present in activated microglia in vivo (Slawik et al., 2004). Microglial EP2 receptors inhibit phagocytosis and enhances neurotoxic activities of microglia (Shie et al., 2005b;Shie et al., 2005a). In cultured rat and human astrocytes EP2 and EP4 receptors are present which may potentiate glial cytokine production (Fiebich et al., 2001). PGE2 may also act on the neuronal EP2 receptor which is involved in apoptosis, although investigations of the role of neuronal EP2 activation on neuronal cell death have shown conflicting results and suggest a neuroprotective role of neuronal EP2 stimulation under several pathophysiological circumstances (Bilak et al., 2004;Lee et al., 2004;McCullough et al., 2004;Takadera et al., 2004). In conclusion, neuronal and glial secretion of PGE2 may impair phagocytotic clearance of Aβ by binding to microglia EP2 receptor and enhance microglial toxicity. However the role of PGE2 in neurodegeneration may be far more complex due to the presence of other EP receptor subtypes on microglial cells and the effects of PGE2. on other cell types. COX-2 expression may further interact with other pathogenetic mechanisms, thus, neuronal death elicited by excitotoxins is elevated in transgenic animals with high expression of COX-2 (Kelley et al., 1999). COX-2 mRNA seems to be elevated in the frontal cortex in AD. A well controlled post mortem study indicates a higher variability of COX-2 mRNA in the brains of AD patients as compared to age matched controls (Lukiw and Bazan, 1997). Furthermore, a correlation between the presence of the transcription factor NFκB in the cell nucleus and the level of COX-2 mRNA was found in brain tissues of AD patients and age matched controls suggesting that NFκB is involved in the induction of COX-2 in the human brain (Lukiw and Bazan, 1998). The activation of NFκB has previously been shown in neurons surrounding amyloid plaques in AD (Kaltschmidt et al., 1997). Interestingly, NFκB is not only involved in the induction of COX-2 but also in the induction of IL-6 and α1-antichymotrypsin (Abbas et al., 2002;Bauer et al., 1997;Lieb et al., 1996b;Lieb et al., 1996a) and the activation of microglial cells in the brains of longterm users of NSAIDs was markedly reduced as compared to age matched controls (Sairanen et al., 1998). COX-2 expression however is not restricted to microglial or astroglial cells in AD brain but has also been described in neurons of AD brains and age matched controls (O'Banion et al., 1996). Principally, COX-2 gene transcription is rapidly regulated by synaptic activity in

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neurons, however the function of COX-2 in neurons remains unclear. The enzymatic generation of oxygen radicals by COX-2 in neurons adds to the amount of free radicals which might lead to neurodegeneration. In human autopsy studies, a high rate of COX-2 mRNA degradation is found in the brain. Divergent reports about an elevated expression of COX-2 in neurons in AD exists (O'Banion et al., 1996;Ho et al., 1999;Oka and Takashima, 1997)(Oka and Takashima, 1997). In addition to the COX-2, an upregulation of mRNA and protein of the constitutive isoform COX-1 has been described in AD (Kitamura et al., 1999;Yasojima et al., 1999a).

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4.5 NO Synthase, Nitric Oxide and Free Radicals NO is a gaseous free radical, which is generated through the conversion of L-arginine to L-citrulline by enzymes of the nitric oxide synthase (NOS) family (Bredt and Snyder, 1990). Ca2+/calmodulin-dependent constitutive isoforms are present in neuronal and endothelial cells and produce NO in a highly regulated manner. The inducible isoform of NOS (iNOS) is rapidly expressed in macrophages, microglia and astrocytes upon stimulation with LPS or several cytokines (Corradin et al., 1993;Galea et al., 1992;Simmons and Murphy, 1992;Stuehr and Marletta, 1985). This isoform produces large amounts of NO in a Ca2+independent manner for prolonged periods of time. NO generated by iNOS is cytotoxic for invading microorganisms and tumor cells (Moncada et al., 1992). However, induction of iNOS may also have deleterious consequences for the host since vasodilatation, organ dysfunction and septic shock are partly mediated by an overproduction of NO (Thiemermann, 1994). The consequences of iNOS induction in glial cells, however, seem to depend on a variety of factors including the type of cell cultures used as both deleterious effects on neurons and unaffected neuronal viability after iNOS induction in mixed glial-neuronal cultures has been reported (Chao et al., 1996;Dawson et al., 1994;Demerle-Pallardy et al., 1993;Skaper et al., 1995). Importantly, iNOS expression and NO generation has been described in several brain pathologies including demyelinating diseases (Willenborg et al., 1999b;Willenborg et al., 1999a), cerebral ischemia (del Zoppo et al., 2000), AIDS dementia (Hori et al., 1999), ALS (Almer et al., 1999) and AD (Wallace et al., 1997;Weldon et al., 1998;Heneka et al., 2001;Lee et al., 1999). The potential impact of findings that neurons are capable of expressing iNOS under certain conditions is supported by the fact that this expression has been described in two human neurological disorders. Vodovotz and colleagues (Vodovotz et al., 1996) reported that neurofibrillary tangle-bearing neurons in affected brain regions of AD patients express iNOS. Aβ peptides along with various cytokines may act as potent inducers of iNOS in AD brains. In line with the hypothesis that the observed iNOS expression may participate in the inflammatory pathomechanisms involved in AD, an increased nitrotyrosine staining has been reported in AD brains indicating sustained exposure and oxidative damage by peroxynitrite, an intermediate NO reaction product (Smith et al., 1997). In addition to neurofibrillary tangles and Aβ plaque deposition, other types of neuronal inclusions such as eosinophilic rod-like inclusions (Hirano bodies) and granulovascular inclusions are observed in AD. iNOS-immunoreactivity has also been described in

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association with Hirano bodies in the pyramidal layer of the CA1 region of the hippocampus and to a lesser extent in the stratum lacunosum (Lee et al., 1999). The same study further described another type of iNOS staining, associated with Aβ deposition and neurofibrillary tangles, that was attributable to neurons in the CA1 region, the subiculum, the molecular layer of the dentate fascia and in the CA4 region. In that study, control brains showed only occassional iNOS-positive staining in association to rare Hirano bodies, while other studies, as well as our own experiments, failed to detect iNOS in control brains. To further characterize the pathway involved in neuronal iNOS expression in AD, we investigated the expression of the enzyme argininosuccinate synthetase (AS) and its possible colocalization with iNOS in AD (Heneka et al., 2001). AS is the rate limiting enzyme in the metabolic pathway that recycles the iNOS substrate L-arginine from its catalytic byproduct L-citrulline. Several brain areas of AD patients showed a marked increase in AS expression in neurons and GFAP-positive astrocytes. Occasionally, AS expression was also detected in CD 68-positive activated microglia cells. Expression of AS was colocalized with iNOS immunoreactivity in neurons and glia. These results suggest that neurons and glial cells in AD not only express iNOS but also AS. Because an adequate supply of L-arginine is indispensable for longterm NO generation by iNOS, coinduction of AS could enable cells to sustain NO generation which could damage the iNOS expressing neurons as well as surrounding cells.

5. Inflammation-Permissive Factors in AD

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5.1 Locus Ceruleus Cell Death The locus ceruleus (LC) is located in the pontine tegmentum and serves as the main subcortical site for the synthesis of noradrenaline (NA) (Freedman et al., 1975). Ascending noradrenergic axons of the dorsal portion of the LC preferentially project to the hippocampus, the frontal and entorhinal cortex and to a minor extent to various other brain regions. Neuronal cell death of aminergic brain stem nuclei such as the LC and the dorsal raphe nucleus is a well defined, very early feature of AD and has been first described by Forno (Forno, 1966) and later confirmed by a number of different groups (Mann et al., 1980;Mann et al., 1982;Wilcock et al., 1988) In AD, the central and dorsal portion of the LC show the most extensive loss of cells (Marcyniuk et al., 1986). LC loss and the subsequent degeneration of ascending nordadrenergic axons lead to decreased NA levels in the LC projection areas (Adolfsson et al., 1979;Iversen et al., 1983) whereas adrenergic receptors are upregulated in response to noradrenergic deafferentiation (Kalaria et al., 1989). Besides its role as a classical neurotransmitter, NA acts as a potent suppressor of inflammatory gene transcription within the brain (Marien et al., 2004;Feinstein et al., 2002b). LC loss and subsequently decreasing NA levels may therefore be permissive for inflammatory mechanisms which are otherwise controlled by physiologically released NA. Specifically, NA has been shown to suppress the generation and secretion of several inflammatory molecules including microglial synthesis of TNF-α and astrocytic expression of class II antigens. Studies from ourselves and others show that NA can also inhibit LPS-

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and cytokine-dependent iNOS expression in astrocytes and microglial cells, mediated by the activation of β-adrenergic receptors, and increases in cAMP (Gavrilyuk et al., 2002). Since the initial neuropathlogical description, a number of studies also demonstrated a significant correlation of LC cell death or decreased cortical NA levels with severity and duration of dementia in AD (Bondareff et al., 1987;German et al., 1992;Yates et al., 1983). Interestingly, LC loss correlates better with the clinical course of the disease and the severity of dementia as loss of the nucleus basalis of Meynert and the perturbation of the cholinergic system (Zarow et al., 2003). It has been argued that LC degeneration may occur as a consequence of primary degenerative changes in the cortical projection areas. However, even aged APP transgenic mice that do show an intense Aβ plaque load do not reveal any significant reduction of LC cell numbers or cortical NA levels, suggesting that LC cell death occurs independently of Aβ deposition and not in response to neurodegenerative events in its projection areas. Each LC neuron sustains a widely divergent axon that innervates a large terminal field and axon terminals are found in close contact to neurons, astrocytes and microglia cells thus influencing a circumscribed microenvironment with NA acting rather as a neuromodulator than a classical neurotransmitter (German et al., 1992). LC axon terminals are also found within the perivascular neural plexus of the brain parenchyma microvasculature. In AD, LC degeneration causes a denervation microangiopathy, characterized by thickened capillary walls due to inflammatory cell infiltration that compromizes normal blood brain barrier function including nutrition of the brain parenchyma (Scheibel et al., 1987). Experimentally induced noradrenergic depletion can be achieved by systemic treatment of animals with the selective noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4) (Fritschy and Grzanna, 1989). DSP4 causes widespread degeneration of LC axon terminals decreased activity and finally loss of LC neurons (Fritschy and Grzanna, 1989;Olpe et al., 1983). Moreover DSP does not only lead to morphological destruction of the noradrenergic system it also impairs electophysiological functions of remaining LC neurons (Magnuson et al., 1993) and NA depletion by DSP4 has been demonstrated to markedly increase the neurodegeneration induced by N-metyhl-4 phenyl 1,2,3,6- tetrahydropyridine (Mavridis et al., 1991) and cerebral ischemia (Nishino et al., 1991). Using a similar model we demonstrated that DSP4 treatment of rats caused degeneration of noradrenergic projections and cell death of LC neurons, whereas the same treatment did not affect substantia nigra neurons. Local application of Aβ into the rat cortex results in a greater and prolonged Il-1β expression in microglial cells in noradrenergic depleted animals as compared to controls with an intact NA system. Likewise, the expression levels of interleukin 6 (Il-6), iNOS and COX-2 were significantly increased in NA depleted cortices. Interestingly, iNOS expression was completely restricted to microglial cells in controls, whereas NA depleted animals showed widespread iNOS expression in pyramidal neurons (Heneka et al., 2002;Heneka et al., 2003), a phenomenon which has been previously reported in AD brains (Vodovotz et al., 1996;Lee et al., 1992;Heneka et al., 2001). Similar experiments using DSP4 to induce a noradrenergic depletion in APP transgenic mice confirmed these results. Additional in vitro experiments assessing microglial migration and phagocytosis found that NA, while suppressing the inflammatory gene transcription,

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increases microglial migration and phagocytic capacity at the same time. This may indicate that NA serves as an important factor which switches activated microglial cells from a cytokines releasing phenotype to a more mobile and phagocyting one. Given the fact that approximately 45.000-50000 LC NA neurons provide NA to each hemispheres in the human brain, one can calculate the brain volume which is being innervated by a single neuron. Cell death of one neuron may impair the potential of microglial cells to migrate to and to decoy debris within this volume and hence may also ease the accumulation and deposition of otherwise cleared Aβ peptides. In summary, LC loss and noradrenergic depletion of cortical and hippocampal areas, neuropathological and inflammatory changes may be members of a vicious, self maintaining and degeneration stimulating cycle in AD. Similar to the cell death observed in the locus ceruleus, the basal forebrain nucleus (nucleus basalis of Meynert) degenerates in AD. The neuronal loss observed here is thought to be the major factor for the subsequent decrease of acetylcholine (ACh) in the cortical projection regions of its neurons. The hypothesis that the loss of ACh is permissive for neuroinflammatory events in cortical projection areas has been instigated by the finding that efferent stimulation of the vagus nerve decreases the release of TNF-α and various other proinflammatory mediators by macrophages of the gastrointestinal tract (Borovikova et al., 2000;Wang et al., 2003;Pavlov and Tracey, 2005). This effect has been attributed to the presence of the α7 subunit of the ACh receptor. Interestingly, glial cells of the CNS such as astrocytes and microglia cells express the α7 subunit (Graham et al., 2003) and the expression of the α7 subunit is increased in astrocytes derived from AD patients compared to age-matched controls (Teaktong et al., 2003).

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5.2 Diabetes Mellitus Diabetes mellitus (DM) is characterized by either an impaired production of insulin due to primary islet cell death or by insulin resistence of normally insulin responsive cells. The latter form is often observed at later stages of life and termed non insulin dependent DM (NIDDM), because most of these patients can achieve control over the blood glucose level without subcutaneous insulin administration. NIDDM often becomes apparent at a similar time as AD and moreover is an established risk factor for the development of AD (Ristow, 2004). While the connecting and underlying mechanisms are yet unclear, one may hypothesize that impaired immunological defenses of NIDDM patients and frequent peripheral infections contribute to the course of AD. Specifically, frequent infections result in higher levels of circulating cytokines and bacterial cell wall components such as lipopolysaccharides. Animal experiments suggest that the peripheral administration of lipopolysaccharides can contribute and enhance existing brain inflammation especially within the hippocampus (Semmler et al., 2005), and ultimately lead to an increased rate of Aβ plaque deposition (Sheng et al., 2003). In addition, a recent work by Fishel et al. could demonstrate, that mild hyperinsulinemia in humans provokes an increase in cytokines and prostanoids in the CSF suggesting a stimulation of inflammatory brain circuits by NIDDM (Fishel et al., 2005).

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6. Cytokine Driven Feedback Mechanisms Apart from self-propagation and direct cytopathic effects on neurons, cytokines may more directly contribute to AD related neurodegeneration. Thus, studies performed in transgenic animals, suggest that cerebral amyloid deposition is increased under inflammatory conditions (Games et al., 1995;Guo et al., 2002) and these animals do not develop amyloid plaques unless inflammation is induced suggesting that inflammatory molecules either raise the susceptibility for Aβ deposition and aggregation or directly influence the APP processing pathway. Several lines of evidence suggest that cytokines may promote Aβ formation, aggregation and deposition at multiple levels. IL-1 has been implicated in the transformation of diffuse βamyloid aggregates into β-amyloid plaques (Akiyama et al., 2000). Furthermore, when the amyloid plaque associated α1-antichymotrypsin or apolipoprotein E are added to preparations of synthetic Aβ peptide in vitro, they increase the polymerization of Aβ into amyloid filaments (Ma et al., 1994). In addition, cytokines are able to transcriptionally upregulate BACE1 mRNA, protein and enzymatic activity (Sastre et al., 2003). BACE1 and presenilin-1 are key enzymes in neuronal Aβ formation since in their absence, Aβ synthesis is either abolished or considerably reduced (Walter et al., 2001). These results are in line with data concerning increased expression and activity of BACE1 in NT2 neurons exposed to oxidative stress (Tamagno et al., 2002), in experimental traumatic brain injury (Blasko et al., 2004) and in reactive astrocytes in chronic models of gliosis (Hartlage-Rubsamen et al., 2003). Another interaction between cytokines and the APP processing pathway may target APP regulation itself since prolonged cytokine treatment can also influence βAPP maturation and secretion (Blasko et al., 1999;Blasko et al., 2000). In addition, it has been reported that TGFβ treatment of human astrocytes markedly elevated APP mRNA levels, and also increased the half-life of APP message by at least five-fold (Amara et al., 1999). Rogers et al (1999) have also demonstrated that IL-1α and IL-1β increase APP synthesis by up to 6-fold in primary human astrocytes and by 15-fold in human astrocytoma cells without changing the steadystate levels of APP mRNA (Rogers et al., 1999).

7. Functional and Structural Consequences of Neuroinflammation in AD Over the past decade, several lines of evidence established that inflammation actively contributes to the pathogenesis of AD. Irregardless at which time point of the disease it occurrs, it seems clear that once initiated by neurodegenerative events, inflammatory pathomechanisms can affect the AD brain. Funtional and structural consequences may be differentiated to understand the various levels at which inflammation may contribute to AD. LTP represents a key function of memory formation and consolidation. Since several cytokines including TNF-α, IL-1β and IFN-γ are able to suppress hippocampal LTP, the presence of these inflammatory molecules alone may be sufficient to induce neuronal

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dysfunction withouth structurally affecting neurons (Tancredi et al., 1992;Tancredi et al., 2000;Murray and Lynch, 1998). Similar to cytokines, immunstimulated and iNOS derived NO also impairs LTP. Since iNOS expression is a longlasting event, surrounding neurons face a sustained production of high NO concentrations. Functional impairment by increased cytokine and nitric oxide production may be of special relevance for the early stages of AD, when patients present with mild cognitive decline, often at a time where brain MRI scans fail to detect significant atrophy of cortical or limbic structures. Next to neuronal dysfunction, several inflammation evoked molecules may directly exert cytotoxic effects on neurons as previously addressed in this chapter. Paradoxical protective effects of some of these mediators such as C5a (Osaka et al., 1999;Pasinetti et al., 1996;Tocco et al., 1997) or TNF-α (Barger and Harmon, 1997;Barger et al., 1995;Feuerstein et al., 1994) have been described, however, the majority of experiments suggest that cytokines can directly lead to neuronal cell death. Further support for a more cytopathic role of these molecules comes form transgenic animal experiments showing that mice that express these inflammatory proteins under brain-specific promoters invariably exhibit profound pathologic changes (Probert et al., 1995;Stalder et al., 1998;Wyss-Coray et al., 1995;WyssCoray et al., 1997). In addition to cytokine and complement generation, microglia and astrocytes may contribute by other means to neurodegeneration: While resting glia serve as an important source of various trophic factors such as GDNF, BDNF and others, inflammatory activation strongly decreases the generation and release of these factors. It has therefore been suggested that inflammatory activation also leads to a significant trophic factor withdrawal which further contributes to neurodegeneration (Nagatsu and Sawada, 2005). Excitotoxic mechanisms significantly contribute to the neuronal loss in AD. It is important to note, that the cytotoxic effects of iNOS derived NO and several proinflammatory molecules are not simply additive but do potentiate NMDA or Kainate induced excitotoxicity (Hewett et al., 1994;Morimoto et al., 2002).

7.1 NSAIDs as Preventive Treatment for AD Epidemiological studies have convincingly documented a beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in AD (Rogers et al., 1993;McGeer et al., 1996;Anthony et al., 2000;Breitner, 1996;Breitner et al., 1995;Szekely et al., 2004;Stewart et al., 1997;Beard et al., 1998;Akiyama et al., 2000;In t'Veld et al., 2001). In particlular, longterm NSAIDs therapy delayed the onset and progression of the disease, reduced symptomatic severity, and significantly slowed the rate of cognitive impairment (Rich et al., 1995). The variety of the results between different epidemiological studies can be explained by the duration of the treatment. An editorial from Breitner and Zandi suggested that there may be an association between treatment duration and response for NSAIDs in preventing AD, with at least two years of exposure necessary to obtain full benefit (Breitner and Zandi, 2001). Thus, the benefit may be greater as longer NSAIDs are being taken (Etminan et al., 2003). Studies from age controls and postmortem AD patients, both on reported NSAID medication,

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show that long-term NSAID therapy reduces the degree of plaque associated inflammation (Alafuzoff et al., 2000;Mackenzie and Munoz, 1998;Mackenzie, 2001). Some of these beneficial effects have been further investigated in animal studies using APP overexpressing mice that display both, the amyloid as well as the inflammatory component of the disease. Six-months treatment with NSAIDs in Tg2576 significantly delayed AD sympthoms, including a decrease of 40-50% in amyloid deposition (Lim et al., 2000) and improved behavioral tasks (Lim et al., 2001;Westerman et al., 2002). This effect was also observed in a short-term administration of a subset of NSAIDs to young Tg2576 APP mice, which lowered the soluble levels of Aβ1-42 (Eriksen et al., 2003;Weggen et al., 2001). However, treatment in the same mice with Meclofen, S-flurbiprofen or indomethacine reduced both Aβ1-40 and Aβ1-42 levels (Eriksen et al., 2003). Additionally, it has been shown that long-term treatment with ibuprofen and indomethacine significantly decreased Aβ1-40 and Aβ1-42 levels in both cortex and hippocampus of APP transgenic (Tg2576) mice (Yan et al., 2003;Sung et al., 2004). These observations are further supported by three recent studies which demonstrate that the NSAID ibuprofen acts to reduce astro and microglial activation and cytokine production in APP transgenic mice (Lim et al., 2000;Yan et al., 2003;Heneka et al., 2005). To date, the underlying mechanisms by which NSAIDs are able to reduce inflammation in AD are unclear, however evidence for several mechanisms has been put forward and it seems therefore more likely that not a single effect of NSAIDs but rather several interactions or inhibition at multiple levels of AD relevant pathomechanisms account for the observed beneficial effects of NSAIDs. 7.1.1 Protection against Aβ Aggregation It has been shown that certain NSAIDs may alter the β-sheet conformation of Aβ affecting the aggregation of Aβ peptides in vitro (Agdeppa et al., 2003;Thomas et al., 2001). Another report indicates that NSAIDs could induce the expression of amyloid binding proteins such as transthyretin, subsequently decreasing Aβ aggregation (Ray et al., 1998). 7.1.2 Effect on Amyloid Precursor Protein (APP) Processing The protective effect of NSAIDs has been associated to decreased secretion of Aβ peptides and soluble APP, although there the precise molecular mechanism is still being unclear (Blasko et al., 2001;Weggen et al., 2001;Sastre et al., 2003). One hypothesis claimed that a group of NSAIDs could directly affect the generation of Aβ1-42 levels, which is the most toxic form of amyloid peptides. This subset of NSAIDs has been suggested to shift the cleavage products of APP to shorter, less fibrillogenic forms (Weggen et al., 2001), indicating that NSAIDs could have an allosteric inhibitory effect on γ-secretase (Lleo et al., 2004). 7.1.3 Inhibition of an Alternate Pathway Ibuprofen has been involved in reduction of pro-amyloidogenic α1-antichymotrypsin, an effect likely to be mediated by decreasing IL-1β (Morihara et al., 2005).

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7.1.4 Inihibition of Cyclooxygenases The canonical targets of NSAIDs are COX-1 and 2. It has been shown that prostaglandin E2 levels are increased 5-fold in the CSF of probable AD patients (Montine et al., 1999). However, the effect of NSAIDs on Aβ generation has been proven to be independent of COX activity (Weggen et al., 2001), substantiating the recent failure of a clinical trial with a selective COX-2 inhibitor and suggesting another mechanism behind the protective effect of NSAIDs (Aisen et al., 2003).

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7.2 PPARγ as Target for NSAIDs Since several NSAIDs target the peroxisome proliferator activated receptor gamma (PPARγ)(Lehmann et al., 1997), a nuclear hormone receptor studied for more than a decade by endocrinologists for its ability to increase insulin sensitivity (Vamecq and Latruffe, 1999;Patsouris et al., 2004), some of the beneficial effects ascribed to NSAID medication may actually be mediated by PPARγ activation. Ibuprofen, indomethacin and naproxen are among the five most prescribed NSAIDs, which have potentially decreased the risk for AD (In t'Veld et al., 2001). Interestingly, they are all agonists of the peroxisome proliferator-activated receptor-γ (PPARγ) (Lehmann et al., 1997). PPARs represent ligand-activated transcription factors that belong to a nuclear receptor superfamily and two isoforms, i.e. PPARγ1 (Kliewer et al., 1994) and PPARγ2 (Tontonoz et al., 1994) are formed from the same gene by alternative mRNA splicing. PPARγ2 is specifically expressed in adipose tissue and differs from PPARγ1 by the presence of 30 additional N-terminal amino acids that confer a tissue-specific transactivation function. PPARγ1 is the predominant, if not the only, isoform in all other tissues, including skeletal muscle and liver (Li et al., 2000). PPARγ forms heterodimers with retinoid X receptors (RXR) (Tugwood et al., 1992) and upon ligand activation, the PPAR/RXR heterodimer recruits coactivators and binds to sequence-specific PPAR response elements (PPRE) located in the promoter region of several target genes (Tugwood et al., 1992). Alternatively, PPARγ can inhibit specific gene expression without direct binding to the gene promoter, since transrepression of several genes, i.e. iNOS and COX-2, is achieved in part by antagonizing the activities of transcription factors STAT1, NF-κB and AP-1 (Li et al., 2000). Several different transrepression mechanisms have been described: The first mechanism involves the ability of PPARs to compete successfully for limiting amounts of intranuclear co-activator proteins serving various signal transduction mechanisms, making these co-activators unavailable to other signaling pathways. The second mechanism of transrepression is known as ‘cross coupling’ or ‘mutual receptor antagonism’ and is facilitated by the ability of PPARs to associate physically with various transcription factors such as NF-κB. This sequestration prevents the transcription factor from binding to its response element and thereby inhibits its ability to induce gene transcription. Another transrepression mechanism relies on the ability of the PPAR to inhibit activation of a MAPK. This inhibits the MAPK from phosphorylating and activating downstream

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transcription factors (Daynes and Jones, 2002). Further, the PPRE may overlap with the responsive elements from other transcription factors, a mechanism described as “mutual exclosure”. As an example, PPARγ agonists can activate binding of PPARγ/RXR to a PPRE site in MMP1, which is located in the same region as the AP-1 site in the MMP1 promoter (Francois et al., 2004). Finally PPARγ activation can induce the transcription of IκB, thereby blocking the translocation of NFκB into the nucleus (Kelly et al., 2004;Heneka et al., 2003). PPARγ is involved in several cellular functions, including control of glucose homeostasis, regulation of systemic insulin sensitivity, cell differentiation and cholesterol metabolism (Vamecq and Latruffe, 1999;Patsouris et al., 2004). The PPARγ gene knockout animal is embryonic lethal, due to essential roles in adipose, kidney and placental development (Barak et al., 1999). A role in the regulation of immune and inflammatory responses was suggested by the findings that PPARγ is being expressed in macrophages and that receptor activation results in the inhibition of various inflammatory events, such as the production of Il-1ß, TNF-α, IL-6 and iNOS (Ricote et al., 1998;Jiang et al., 1998), the proliferation and the production of IL-2 by T-lymphocytes and the IFN-γ expression in murine CD4 and CD8 cells (Cunard et al., 2004). In the brain, several anti-inflammatory effects of NSAIDs may be in part mediated through the activation of this transcription factor (Landreth and Heneka, 2001), since it has been shown that PPARγ-agonists protect neurons from cytokine-mediated death (Heneka et al., 1999). Combs et al. reported that PPARγ agonists, including ibuprofen, inhibited Aβmediated microglial activation and neurotoxicity using in vitro models (Combs et al., 2000). Similar anti-inflammatory effects of PPARγ agonists and ibuprofen were also observed following infusion of immunostimulants into rodent brain (Heneka et al., 2000). In line with these findings, recent studies have documented the salutary effects of PPARγ-agonists in animal models of multiple sclerosis (Feinstein et al., 2002a;Niino et al., 2001;Diab et al., 2002;Natarajan and Bright, 2002) and Parkinson’s disease (Breidert et al., 2002;Dehmer et al., 2004). The potent anti-inflammatory effects of PPARγ-agonists suggest that they may have beneficial effects in treating other CNS diseases with an inflammatory component. PPARγ activation is achieved by binding to a specific receptor binding pocket by various endogenous and synthetic ligands (Lehmann et al., 1997;Yki-Jarvinen, 2004). Thus, PPARγ is stimulated best by hydroxyoctadeca-9Z,11E-dienoic acid (9-HODE), 13-HODE and 15deoxy-∆12,14-prostaglandin J2 (15d-PGJ2), although there is now considerable controversy as to whether 15d-PGJ2 is actually a biologically relevant PPARγ activator or the majority of its action is mediated by inhibition of IκB kinase (IKKα) and subsequently NFκB activation (Rossi et al., 2000). However, it has been reported recently that 15d-PGJ2 is produced in vivo, and in large quantities by macrophages in vitro. Synthetic PPARγ ligands are used for their potent antidiabetic effects. In the United States, two ligands of the thiazolidinedione (TZD) class, rosiglitazone and pioglitazone, have been approved for the treatment of NIDDM. Both substances bind PPARγ with high affinity and enhance insulin-mediated glucose uptake by increasing insulin sensitivity. In addition to receptor mediated effects some of these substances exert antiinflammatory effects independently of PPARγ activation (Chawla et al., 2001;Feinstein et al., 2005). As a common anti-inflammatory drug ibuprofen is a PPARγ activator that crosses the blood brain barrier (Kunsman and Rohrig, 1993). However, the mechanism by which it

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alleviates AD brain pathology is unknown. The suggestion that ibuprofen would prevent amyloid load and plaque formation is based on experiments in cell culture where ibuprofen could decrease secretion of amyloid peptides, although these findings are controversial (Blasko et al., 2001;Weggen et al., 2001;Avramovich et al., 2002;Takahashi et al., 2003). Several studies have shown that ibuprofen decreased the levels of secreted APPs and Aβ from stimulated cells, thereby reversing the effect of the pro-inflammatory cytokines IFNγ/IL-1β or IFN-γ/TNF-α (Blasko et al., 2001;Sastre et al., 2003). Secretion of Aβ from unstimulated cells was not affected by ibuprofen or pioglitazone treatments. An argument proving the role of PPARγ in mediating the action of ibuprofen, was found in the effect of antagonists GW0072 and GW5393 on N2a cells (Sastre et al., 2003). Both drugs reversed the suppressive effect of ibuprofen on Aβ generation. Furthermore, incubation with the PPARγ agonists such as pioglitazone and transfection of PPARγ cDNA mimicked the effects exerted by ibuprofen. Both drugs did not affect cleavage by γ-secretase of APP that generates CTF-γ (Sastre et al., 2003;Weggen et al., 2003) nor on the corresponding cleavage of Notch (Weggen et al., 2001). Thus PPARγ activation may exert benefical effects in the AD brain by both, direct antiinflammatory action and interference with APP processing. There is evidence that the action of ibuprofen might reside in the inhibition of the inflammatory response that increased BACE1 activity. The specificity of the effect of inflammatory cytokines and ibuprofen on BACE1 through PPARγ was proven in mouse embryonic fibroblasts (MEF) either wild-type or deficient in PPARγ and in neuronal cells transfected with siRNA for PPARγ (Sastre et al. unpublished observations). BACE1 transcription was found to be upregulated in MEF PPARγ knockout cells compared to wildtype cells. These results were confirmed by reporter gene assays, which demonstrated that a lack of endogenous PPARγ facilitates BACE1 promoter activity, suggesting that PPARγ may serve as an endogenous suppressor of BACE1 promoter activity. Moreover, incubation of N2a cells with NSAIDs that are PPARγ activators showed a decrease in BACE1 gene promoter activity and this effect was not reproduced by NSAIDs that act not as PPARγ agonists, such as sulindac sulphide and aspirin. Overexpression of PPARγ1 and PPARγ2 also significantly reduced BACE1 promoter activity. Finally, the identification of a PPRE in the BACE1 promoter supported the possibility that PPARγ ligands may downregulate BACE1 transcription, suggesting that the potential effect of NSAIDs could be through regulation of BACE1 promoter activity (Sastre et al. unpublished observations). Studies by Camacho et al. also reported reductions of Aβ levels in cells transfected with PPARγ cDNA, suggesting a distinct mechanism which does not involve the regulation of secretase expression or activity but induces a fast, cell-bound clearing responsible for the Aβ removal (Camacho et al., 2004). More recently, it has been shown that PPARγ overexpression in cultured cells dramatically reduced Aβ secretion, affecting the expression of full length APP at a post-transcriptional level. The authors claimed that APP downregulation does not involve the pathway of the secretases but correlates with an induction of APP ubiquitination (d'Abramo et al., 2005). Two in vivo investigations on the effects of PPARγ activation in APP transgenic mice have been reported. An acute 7 day oral treatment of 10-month-old APPV717I mice with the PPARγ agonist pioglitazone or the NSAID ibuprofen resulted in a reduced number of activated microglia and reactive astrocytes in the hippocampus and frontal cortex (Heneka et

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al., 2005). Drug treatment reduced the expression of the proinflammatory enzymes COX-2 and iNOS and the levels of BACE1. The same mice presented decreased Aβ1-42 levels, while a non-statistically significant reduction of about 20-25% in Aβ1-40 levels was found (Heneka et al., 2005). Furthermore, intracellular Aβ staining reduced in mice treated with ibuprofen or pioglitazone, indicating that PPARγ activation is indeed involved in the regulation of Aβ generation (Sastre et al. unpublished observations). A different study indicated that treatment of 11-month-old Tg2576 mice overexpressing human APP with the NSAID ibuprofen and PPARγ agonist pioglitazone for 16 weeks, only modestly reduced SDS-soluble Aβ levels and did not affect amyloid plaque burden (Yan et al., 2003). Since only 20% of pioglitazone crosses the blood brain barrier, and the study by Heneka et al. used twice of the concentration used by Yan and colleagues (2003) (Yan et al., 2003;Heneka et al., 2005), the observed difference may be explained by the drug concentrations applied. All PPARs have been shown to be present in the CNS and to exhibit both unique and overlapping patterns of expression in various areas and at different developmental stages. PPARγ expression in post-mortem brain sections from AD patients have been examined (Sastre et al. unpublished observations) and the immunohistochemical assessment of frontal cortex revealed that PPARγ is expressed in astrocytes and neurons. It has previously been suggested that AD brains contain increased levels of PPARγ in the cytosolic fraction compared to healthy controls (Kitamura et al., 1999). These results are in contrast with our own analysis showing a 40 % reduction of PPARγ protein levels in AD patients compared to controls. In addition, PPARγ protein levels and its binding to a PPRE in the BACE1 promoter were decreased in AD brains. Combined, these findings point to a direct role of PPARγ in the regulation of BACE1 transcription and activity in AD, ultimately facilitating Aβ generation.

8. Conclusions and Future Directions Together, increasing evidence suggests that inflammation significantly contributes to the pathogenesis of AD. The generation and secretion of proinflammatory mediators may interact at multiple levels with neurodegenerative mechanisms. Thus, several proinflammatory cytokines can not only induce neuropathic mechanisms thereby contribute to neuronal death, but are also able to influence classical neurodegenerative pathways such as APP processing. The concomitant release of antiinflammatory mediators may partly antagonize this action ultimatly contributing to the chronicity of the disease. Several AD specific mechanisms such as cell death in the locus ceruleus and nucleus basalis of Meynert may facilitate the occurrence of neuroinflammation. Additional information on how inflammatory mediators and excitoxic factors potentiate their detrimental effects are required. Additionally, more information is needed to elucidate the extent by which inflammatory mediators functionally impair cognitition and memory. Future studies need to determine the underlying pathomechanisms and modes of interaction by which the course of the disease can be influenced. Clinically, novel approaches to visualize early neuroinflammation in the human brain are needed to improve the monitoring and control of therapeutic strategies that are targeting inflammatory mechanisms.

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Xia MQ, Qin SX, Wu LJ, Mackay CR, Hyman BT (1998) Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains. American Journal of Pathology 153: 31-37. Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G (2003) Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci 23: 7504-7509. Yan SD, Yan SF, Chen X, Fu J, Chen M, Kuppusamy P, Smith MA, Perry G, Godman GC, Nawroth P, . (1995) Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med 1: 693-699. Yasojima K, Schwab C, McGeer EG, McGeer PL (1999a) Distribution of cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs. Brain Res 830: 226-236. Yasojima K, Schwab C, McGeer EG, McGeer PL (1999b) Up-regulated production and activation of the complement system in Alzheimer's disease brain. Am J Pathol 154: 927936. Yates CM, Simpson J, Gordon A, Maloney AF, Allison Y, Ritchie IM, Urquhart A (1983) Catecholamines and cholinergic enzymes in pre-senile and senile Alzheimer-type dementia and Down's syndrome. Brain Res 280: 119-126. Yermakova A, O'Banion MK (2000) Cyclooxygenases in the central nervous system: implications for treatment of neurological disorders. Curr Pharm Des 6: 1755-1776. Yki-Jarvinen H (2004) Thiazolidinediones. N Engl J Med 351: 1106-1118. Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60: 337-341.

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In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 159-195 © 2006 Nova Science Publishers, Inc.

Chapter VIII

Inflammation in Parkinson’s Disease R. Lee Mosley*, Eric J. Benner, Irena Kadiu, Mark Thomas and Howard E. Gendelman Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE

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1. Introduction Parkinson’s disease (PD) is the most common movement disorder and second, only to Alzheimer’s disease as a cause of age-linked neurodegeneration [1-3]. The primary pathological characteristics of PD are the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and reductions in their terminals within the dorsal striatum [4]. These lead to profound and irreversible striatal dopamine loss. Indeed, extrapolated cell modeling data [5] demonstrate that 100–200 SNpc neurons degenerate per day during the course of PD [6]. However, the SNpc is not the sole site for neuronal damage involving, in measure, the locus coeruleus, raphe nuclei, and the nucleus basalis of Meynert. Nonetheless, progressive degeneration of the nigrostriatal pathway is the predominant mediator for clinical manifestations of PD including rigidity, resting tremor, slowness of voluntary movement and postural instability, and in some cases, dementia [2]. In regards to disease epidemiology, the mean age of PD onset is 55. This increases dramatically with time [7]. While the cause of PD is not known, data obtained from familial disease and from animal models of PD support a pathogenic process that is closely linked to mitochondrial dysfunction and oxidative stress. Indeed, oxidative stress is an acknowledged central component of PD pathogenesis [7-9] and is strongly linked to dopaminergic neuronal * Corresponding author: R. Lee Mosley, PhD Center for Neurovirology and Neurodegenerative Disorders Department of Pharmacology and Experimental Neuroscience 985800 Nebraska Medical Center

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apoptosis. Moreover, increased risk of localized oxidative damage for dopaminergic neurons is linked to dopamine metabolism itself [8]. With the exception of rare familial forms, the majority of PD cases are sporadic and due, in part, to mitochondrial defects at complex I [7, 10]. Indeed, complex I inhibitors (for example, rotenone) recapitulate many of the pathological features of disease [7]. Moreover, the presence of ubiquitinated and misfolded proteins suggests the dysregulation of protein assembly or defects in protein degradation pathway as a critical part of disease pathogenesis. Misfolding and abnormal degradation of brain proteins are linked to dopaminergic neuronal death [11]. A key player in the pathogenesis of PD is the microglial cell, largely believed to represent the brain’s resident macrophage population. Phagocytic function is clearly only one of the roles this cell utilizes to maintain tissue homeostasis. Indeed, macrophages orchestrate other cellular processes, including but not limited to, intracellular killing of pathogenic microbes, antigen presentation, and secretion of biologically active factors, as well as mediation of pathological processes. Underlying such cellular functions is inflammation; the same type that often proves detrimental in localized and systemic diseases, including those of the brain and in PD. Inflammation is the frontline defense of multi-cellular organisms against infection and its absence is incompatible with life. Inflammation enables the host to fend off various disease-causing microbes including bacteria, viruses, and parasites. However, inflammatory responses can also prove deadly to tissue and to the host. Inflammatory responses are closely linked to a number of degenerative states including, but not limited to, cancer, arthritis, cardiovascular disease, and autoimmune diseases. With regards to the nervous system, recent data suggests that neuroinflammation perpetrated through activation of brain mononuclear phagocytes (MP; perivascular and parenchymal macrophages and microglia), other glial elements including astrocytes and to a lesser degree endothelial cells may act in concert as a central pathway in a diverse set of neurodegenerative diseases (Figure 1). These include PD as well as Alzheimer’s and Huntington’s diseases (AD and HD), HIV-1-associated dementia (HAD), and more recently, spongiform encephalopathies or prion-mediated neurodegeneration. Central nervous system (CNS) inflammatory infiltrates are complex and multifaceted. The initial responders or the MP cell elements of innate immunity set up a cascade, which later involve the activation and recruitment of the adaptive immune system and ultimately neurodegeneration. Microglia are the primary MPs in the CNS that respond to injury [12] and whose principal function is brain defense. As professional phagocytes, they scavenge microbes, serve as effectors of innate immune responses, and coordinate adaptive immune responses within the CNS. Activated microglia participate in inflammatory processes linked to neurodegeneration by producing neurotoxic factors including quinolinic acid, superoxide anions, matrix metalloproteinases (MMP), nitric oxide, arachidonic acid and its metabolites, chemokines, pro-inflammatory cytokines and excitotoxins including glutamate. On the other hand, neuroprotective functions of microglia have been suggested through their abilities to produce neurotrophins and to eliminate excitotoxins present in the extracellular spaces [13]. In particular, evidence

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indicates that under certain circumstances microglia may also promote neuronal survival after brain injury [14, 15].

Figure 1. Brain mononuclear phagocytes (MP; perivascular macrophages and microglia) in nervous system during health and disease. (A, top panel) Under steady state conditions, microglia secrete neurotrophic factors and engage other glial elements to promote tissue homeostasis. (B, bottom panel) Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

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During disease states (for example, Parkinson’s and Alzheimer’s disease), MP inflammatory responses damage the BBB, increase oxidative stress and release pro-inflammatory and pro-apoptotic cytokines and other neurotoxic factors that affect neuronal damage or dropout. The damage and stress signals enhance microglial activation, resulting in positive feedback in the release of chemokines and cytotoxic cytokines that cause further ingress of immune cells into the brain and expand inflammatory responses.

Thus, during PD-associated neurodegeneration, a spectrum of environmental cues affects glial function, serving to accelerate the tempo of neurotoxic processes. These lead to neuronal excitotoxicity, synaptic dysfunction, and cell death (apoptosis and/or necrosis). Whether the environmental cues are dysregulated or misfolded proteins or toxic/metabolic events, the inevitable amplification of primary disease processes results in the disruption of CNS homeostasis. In all, whether responding to or directly secreting toxic factors as a result of environmental cues, microglia can affect the evolving stages of neurodegeneration. This review articulates specific features of the inflammation that occur in response to or as part of the PD process.

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2. Microglial Cells: Structure and Function in Health and Disease Microglia are bone marrow-derived myeloid-lineage cells that enter the brain early during embryogenesis and develop in parallel with the maturation of the nervous system. They are the resident phagocytes of the CNS and can react promptly in response to brain insults of various natures, ranging from pathogens to aggregated proteins and to more subtle alterations in their micro-environment such as alterations in ion homeostasis that can affect pathological processes [12]. For these processes, microglia possess macrophage-like functions and remove infected or damaged cells, thus serving as a sensor in the brain. In the normal brain, microglial cells are in a resting state as shown in Figure 1A; their cell bodies barely visible and only few fine ramified processes are detectable. However, in pathological settings (Figure 1B), resting microglial cells quickly proliferate, become hypertrophic, and increase or express de novo a large number of marker molecules such as CD11b and major histocompatibility complex (MHC) antigens transforming to macrophage-like cells [12, 16, 17]. Activated microglia, now readily visible, increase their numbers at the affected site and exhibit a “spider-like” or macrophage-like appearance. Ramified microglia change appearance by means of retracted processes and enlarged cell bodies. Within the damaged area, the maximal density of activated microglia is located at the epicenter of the lesion, close to injured cells (e.g., degenerating neurons). Following activation and during tissue regeneration, microglia gradually return to a ramified morphology exhibited prior to injury or insult. While such changes are clearly implicated in neurodegenerative processes of the CNS, the innate immune system has also been tasked with alternative functions. In addition to guarding the nervous system from invading pathogens, this system is involved in many physiological functions such as tissue remodeling during development or after damage [18, 19], transportation of blood lipids [19, 20], and scavenging apoptotic cells [21]. Neuroprotective responses are elicited through elimination of the ongoing infectious agents by innate immune activities and subsequently through adaptive immune functions

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orchestrated in the CNS by microglia and other antigen presenting cells (see below). All together MP, including macrophages and microglia, are the Dr. Jekyll and Mr. Hyde of the nervous system. In health, they support critical regulatory immune and homeostatic functions, whereas in disease their roles progress from supportive, to reactive, and ultimately to destructive. The functional transformations of brain MP from neurotrophic to neurotoxic phenotypes and the common pathways of MP activation and inflammatory responses in neurodegenerative diseases are believed to underlie the pathogenesis in PD. Indeed, harnessing the protective and nourishing capabilities of brain’s MP is believed a key element towards developing novel therapeutic treatments and preventive measures in PD.

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3. Microglia and Neuroinflammatory Responses in PD As noted, the key cell element in neuroinflammatory responses is the brain MP. Supporting this idea, PD is characterized by activation of microglial cells found in and around degenerating neurons [22-26]. Evidence for a neuroinflammatory role in disease onset and progression is significant and profound from several independent lines of investigation [26-31]. First, reactive microglia are commonly seen within the SNpc of PD brains investigated at autopsy [22, 25, 26]. A six-fold increase in numbers of reactive microglia has been shown phagocytosing dopaminergic neurons [32] and correlates with the deposition of α-synuclein [22]. Such microglia are reactive and over-express a variety of inflammatory markers including, HLA-DR of the human MHC II complex [22, 26], complement receptor type 3 (CR3, Cd11b/CD18, Mac-1, Mo 1) [17, 33], CD68 (EMB11) [17, 22], CD23 (Fc receptor for IgE) [31], ferritin [33], CD11a (LFA-1) and CD54 (ICAM-1) [34]. These reactive microglia are functionally active and secrete a plethora of proinflammatory cytokines such as interferon-γ (IFN-γ) tumor necrosis factor-α (TNF-α) [30, 31], interleukin 1-β (IL1β) [31], and upregulate enzymes such as inducible nitric oxide synthase (iNOS) [31, 35], and cyclooxygenase (COX) 1 and 2 [23, 35]. Although the SN is relatively rich in microglia when compared to other brain regions [36], the total number of MHC class II positive microglia are also significantly increased in the putamen, hippocampus, transentorhinal cortex, cingulate cortex and temporal cortex of the PD brain [34]. Second, microglia activation is strongly associated with dopaminergic neuronal cell death in PD, suggesting that reactive microglia may be a sensitive biomarker for disease. Indeed, reactive microglia serve as in vivo indicators of neuroinflammatory responses and contribute significantly to progressive degenerative processes. This is supported by early-stage PD imaging tests, where PK11195 binding to benzodiazepine receptors present on reactive midbrain microglia inversely correlates with binding of 2-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane (CFT) to the dopamine transporter (DAT) in the putamen as a measure of surviving dopaminergic termini. These observations also correlate with the severity of motor impairment [22]. Third, epidemiological data demonstrates that the use of nonsteroidal antiinflammatory agents decreases the risk of PD [37]. Fourth, biochemical and histological evidence for oxidative stress in PD abounds and includes observed increased levels of carbonyl and nitrotyrosine protein modifications, lipid peroxidation, DNA damage, and

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reduction of glutathione and ferritin [38]. Indeed, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a primary producer of reactive oxygen species (ROS), is upregulated in PD and its expression coincides with activated microglia. Postmortem samples of SNpc from sporadic PD patients show elevated levels of the protein gp91phox [39], the main transmembrane component of NADPH-oxidase [40], which colocalizes with microglia. Likewise, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, large increases in gp91phox immunoreactivity also colocalize in the SNpc with activated (Mac-1 immunopositive) microglia, but not with astrocytes or neurons [39]. Thus, microglia in the vicinity of dopaminergic neurons in disease appear to have an upregulated capacity for ROS production, consistent with an activated state leading to a continuous cycle of neuronal injury and neuroimmune activation. Fifth, a robust microglial response occurs in the midbrains of MPTP-intoxicated animals [41], one of the foremost model systems for human PD. Studies of post-mortem brains from three human subjects who injected MPTP and developed a parkinsonian syndrome [42], demonstrated the accumulation of activated microglial cells around dopaminergic neurons [43]. Thus, the initial acute insult to dopaminergic neurons likely leads to a secondary and perpetuated neuroinflammatory response. This neuroinflammatory reaction, serves to alter homeostatic neural mechanisms or to exacerbate disease process by the production of proinflammatory factors.

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4. Adaptive Immunity While naïve T cells are precluded from CNS entry, neuroinflammation aggressively recruits activated components of the adaptive immune system to sites of active neurodegeneration by increasing expression of cellular adhesion molecules and inducing chemokine gradients [44]. Moreover, glial cells secrete toxic factors that disrupt blood brain barrier function. Nonetheless, much evidence indicates a far more complex relationship between the CNS and immunological systems than previously thought. For example, immune molecules such as Thy-1, interleukins, and chemokines are expressed at high levels in neurons and surrounding glia and may be involved in direct communication between the CNS and immune cells [45]. Signaling between neurons and glia during neuronal injury incite inflammatory responses and leukocyte migration [44]. Interestingly, molecules mediating specific antigen recognition by T lymphocytes, including MHC class I and CD3ζ molecules, also have a role in axonal guidance, activity-dependent remodeling, and plasticity in the developing and mature mammalian CNS [46]. Within the neuronal synapse, MHC class I molecules may participate in the refinement or elimination of synaptic connections. The cognate receptor for MHC class I peptide complexes is the αβ T cell receptor (TCR) expressed on T cells. It was recently determined that neurons, particularly in the developing neonatal CNS, express mRNA transcripts for unrearranged β subunit of the TCR [47, 48]. Functional cooperation between these two molecules in neuronal populations has yet to be determined. Interestingly, during inflammatory states, MHC class I molecules are upregulated on neuronal surfaces yet there is no direct evidence of cytotoxic T lymphocyte (CTL) mediated neuronal damage in common neurodegenerative disorders [49, 50]. However, MHC class I molecules alone are unstable and must associate with proteasome-

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derived peptides and β2-microglobulin to form stable complexes at the cell surface. Altered peptide profiles presented at the neuronal synapse during neuronal degeneration may, therefore also affect neuronal plasticity and remodeling during disease states. Further challenging this view of the “immune privileged” status of the CNS are animal model systems where immune deficiencies translate into exacerbated neuronal loss following traumatic injuries [51-54]. Such injuries are corrected in animals that receive immune reconstitution prior to experimental injury. Rodents and humans that have sustained CNS injuries also have expanded T cell repertoires against myelin-associated antigens, yet do not appear to be at increased risk for the development of CNS autoimmunity. Any functional consequence of such T cell responses against CNS antigens following injury remains to be determined. CD8+ T cells have been reported in close proximity to activated microglia and degenerating neurons within the SN of PD patients; however, those numbers are consistently low in frequency [26]. Whether these T cells are activated, antigen-specific or migrating in response to microglial inflammation has yet to be determined; however the presence of one major T cell subset in ratios exceeding those typically found in the periphery suggests a more profound function in PD than surveillance [12, 55-57]. Numerous aberrations in peripheral lymphocyte subsets have also been detected in PD patients [58-60]. In both drug-naïve and treated PD patient cohorts compared to age-matched controls, numbers of total lymphocytes were shown to be diminished by 17%, while CD19+ B cells were diminished by 35% and CD3+ T cells were diminished by 22% [58]. Among CD3+ T cells, numbers of CD4+ T cells were diminished by 31%; whereas, numbers of CD8+ T cells were not significantly changed. The frequencies of cells within CD4+ T cell subsets are differentially diminished, with a greater loss of naïve helper T cells (CD45RA+) and either unchanged or increased effector/memory helper T cell subset (CD29+ or CD45RO+) [58, 60]. Increased mutual coexpression of CD4 and CD8 by CD45RO+ T cells [59] as well as upregulation of CD25 (αchain of the IL-2 receptor) [58], TNF-α receptors [61], and significant downregulation of IFN-γ receptors [62, 63] indicate that at least some T cell subsets from PD patients are activated; however, evaluation of these parameters to assess whether activated T cell phenotypes are derived from any one T cell subset or many have yet to be incorporated into one study. Interestingly, a significantly greater number of micronuclei and unrepaired single strand DNA breaks, which have been shown to result from exposure to higher levels of ROS and inflammation [64], are detected in lymphocytes and activated T cells from PD patients compared to age-matched controls [65, 66].

5. Pathways and Mechanisms for Neuroinflammation 5.1 Cytokines As microglia and peripheral macrophages share the same cell surface markers, it is difficult to distinguish the cell types in postmortem PD brain tissues. Lipopolysaccharide (LPS) stimulated peripheral macrophages from PD patients produce less TNF-α, IL-1β, IFN-

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γ, and IL-6 than healthy controls and their levels correlate inversely with disability, thus suggesting that impaired cytokine production may progress with disease [66]. In contrast levels of several cytokines, including TNFα, IL-1β, IL-3 and IL-6 are increased in the postmortem striatum, SN and cerebral spinal fluid (CSF) of PD patients [29, 67-70] and elevated levels of TNF-α receptor R1 (TNF-R1, p55), bcl-2, soluble Fas (sFas), caspase-1 and caspase-3 [29] support the existence of a proinflammatory/apoptotic microenvironment in PD patients. However, other regulatory cytokines, including IL-4, transforming growth factor (TGF)-α, TGF-β1, and TGF-β2 are also increased [29], which may indicate an attempt to regulate the predominantly proinflammatory environment. Additionally, hippocampal tissues from PD patients bind increased levels of IL-2 compared to controls indicating that IL-2 receptors (IL-2R) on cells contained within the hippocampus are also upregulated in PD patients [71]. Although likely expressed by both neuronal and glial cells, the localization of IL-2 and IL-2R primarily to the frontal cortex, septum, striatum, hippocampal formation, hypothalamus, locus coeruleus, cerebellum, and the pituitary and fiber tracts of the corpus callosum suggests possible regulatory interactions between peripheral tissues and the CNS [72]. Most likely, IL-2 acts in an auto- and paracrine fashion in the brain as in the peripheral immune system, but exhibits characteristics of a neuroendocrine modulator under different physiological conditions. For instance, IL-2 regulates neuronal and glial growth and differentiation during development, but has pleiotropic effects in the mature brain being involved in modulation of sleep/arousal, memory and cognition, locomotion, and neuroendocrine activities [72].

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5.2 ROS and Nigrostriatal Degeneration Once microglia are activated, they can produce noxious factors including proinflammatory cytokines, chemokines, quinolinic acid, arachidonic acid and its metabolites and excitatory amino acids among others. Importantly, large amounts of ROS production, known as a respiratory burst [73, 74], may have disastrous effects on delicate neuronal networks in the CNS. Indeed, oxidative stress is implicated as a major cause of neuronal injury in a wide range of neurological diseases including PD, however whether oxidative stress is causal or consequential is unclear. Altered configuration of proteins including aggregation may trigger aberrant cellular processes such as oxidative phosphorylation resulting in the accumulation of reactive oxygen and nitrogen byproducts, which are typically produced by microglia and serve to destroy invading microorganisms. ROS include superoxide, hydrogen peroxide and hydroxyl free radicals as well as nitrogen intermediates (nitric oxide and peroxynitrite) and can cause damage to neurons if produced in excess as occurs during prolonged neuroinflammatory responses. Much of the microglial-derived ROS such as superoxide cannot efficiently traverse cellular membranes [75], making it unlikely that these extracellular ROS gain access to dopaminergic neurons and trigger intraneuronal toxic events [39]. However, superoxide can rapidly react with NO in the extracellular space to form a more stable oxidant, peroxynitrite [39], which can readily cross cell membranes and damage intracellular components in neighboring neurons. Nitrated species have been associated with the disruption of mitochondrial electron transport chain, lipid peroxidation,

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DNA damage, and the nitration of tyrosine residues in cellular proteins. This suggests that microglial-derived superoxide, by contributing to peroxynitrite formation, is a significant contributor to the pathogenesis of PD. NADPH-oxidase is a large multi-subunit complex and is the main enzyme known to produce ROS in activated macrophages and microglia. Moreover, genetic deletion of gp91, an essential subunit of NAPDH oxidase, mitigates neuronal loss in numerous models of neurodegeneration including the MPTP model of PD [39]. NO is a biological messenger molecule that has numerous physiological roles in the CNS. In addition, NO plays an important role in innate immunity and is associated with tumoricidal and bactericidal activities of macrophages [76, 77]. Three distinct forms of nitric oxide synthase (NOS) have been identified to date and are designated neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). In contrast to the physiological roles of normal NO levels, excessive NO produced under pathological settings can act as a potent neurotoxin in a number of neurodegenerative models [78-81]. For example, nNOS and iNOS are both upregulated in sporadic PD and some animal models; however, genetic ablation or pharmacological inhibition of excess NO production is neuroprotective in the MPTP model [81, 82]. Although NO may generate much of its toxicity through the formation of peroxynitrite, it also reacts with sulfur containing cysteine residues in protein (Snitrosylation), which may modify protein structural conformations or enzymatic activities [83]. Production of ROS and NO in neurons is buffered primarily by the glutathione system, which is compromised in the brain of PD patients, leading to an imbalance in redox homeostasis and consequent oxidative stress. The tripeptide glutathione (GSH; gamma-Lglutamyl-L-cysteinylglycine) is the major cellular thiol present in brain tissue, and the most important redox buffer in mammalian cells [84]. This antioxidant molecule cycles between reduced glutathione (GSH) and oxidized glutathione disulfide (GSSG) and serves as a vital sink for control of ROS levels in cells. GSH reacts directly with oxygen and nitrogen free radicals nonenzmatically and donates electrons in the enzyme-catalyzed reduction of peroxides [85, 86]. Determination of the relative levels of glutathione and glutathione-related enzymes in neuronal and glial compartments is incompletely understood and remains an active area of research in our laboratories. GSH content in the SNpc of PD patients is decreased by 40-50%, but not in other regions of the brain, nor in age-matched controls or patients with other diseases affecting dopaminergic neurons [87-89], This diminution continues with progression and severity of disease, suggesting a correlation with concomitant increases in reactive species [88-92]. GSH depletion has been suggested as the first indicator of oxidative stress during PD progression, possibly occurring prior to other hallmarks of PD including the decreased activity of mitochondrial complex I [8, 92-94]. Also, elevated GSSG/GSH ratios in PD patients [87, 95] argue strongly for a role of oxidative stress in this disease [84]. An increase in glutathione peroxidase immunoreactivity, exclusive to glial cells surrounding surviving dopaminergic neurons, has also been observed in PD brains [96]. Interestingly, the SN and striatum have lower levels of GSH relative to other regions of the brain, which include, in increasing order: SN, striatum, hippocampus, cerebellum, and cortex [97-99]. Although varying in different regions of the brain, all GSH levels diminish by about 30% in the elderly [99], suggesting a

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possible link with the age associated risk factor for PD. GSH depletion cannot be explained by increased oxidation of GSH to GSSG as levels of both are diminished in the nigra of PD patients [87, 99]. Diminished GSH levels do not appear to be caused from failure of GSH synthesis as γ-glutamylcysteine synthetase is unaltered as are glutathione peroxidase and glutathione transferase activities [95]. Other possibilities for diminished levels include increased removal of GSH from cells by γ-glutamyltranspeptidase [95] or formation of adducts of the glutamyl and cysteinyl peptides of GSH with dopamine [100-102]. Nevertheless, depletion of GSH may render cells more sensitive to toxic effects of oxidative stress and potentiate the toxic effects of reactive microglia [103, 104]. Inflammatory responses induced by reactive microglia, macrophages, and proinflammatory T cells, provide a primary source of free radicals, ROS (O2−·, H2O2, ⋅OH, HOCl, ferryl, peroxyl, and alkoxyl) and reactive nitrogen species [nitric acid (NO⋅), peroxynitrite (ONOO−) and peroxynitrous acid (ONOOH)] with the capacity to modify proteins, lipids, and nucleic acids (Figure 2). This induces a condition of oxidative stress whereby the increased production of highly reactive species and decreased scavenging of free radicals results in increased modification and damage of biomolecules, and decreased clearance of those damaged macromolecules that are potentially toxic for neurons. The highly reactive nature and short half-lives of reactive species, combined with the restrictive nature of the neuroinflammatory foci to clinical sampling, preclude the direct measurement in disease processes of these reactive species. However, modifications of proteins, lipids and nucleic acids provide surrogate biomarkers, which can be directly measured as indirect assessments of the extent of oxidative stress. Postmortem analyses of PD patients have consistently demonstrated the increased presence of these biomarkers for oxidative stress. Protein modifications are among the many biomarkers detected in the brains of PD patients. Compared to brains from control donors, elevated levels of nitrated proteins are found in brains and CSF of PD patients [105, 106]. Most notable are modifications of proteins that comprise Lewy bodies (LB), which are neuronal inclusions that consist primarily of αsynuclein, ubiquitin, and lipids, and considered hallmarks of PD. In LB cores from PD patients, increased 3-nitrotyrosine immunoreactivity, primarily due to the presence of a nitrated form of α-synuclein identifies peroxynitrite modifications of tyrosine moieties [107109] suggesting the participation of inflammatory responses; however, whether those modifications occur before or after inclusion into LB remain unclear. Also S-nitrosylated forms of parkin, an E3 ubiquitin ligase involved in protein ubiquitination have been isolated from the temporal cortex from 4 PD patients, but not from brains of Huntington’s or AD patients [110]. In vitro and in vivo, S-nitrosylation of parkin induces an initial increase in ligase activity leading to autoubiquitination of parkin [110], eventual inhibition of ubiquitin ligase activity, and decreased activity in the E3 ligase-ubiquitin-proteasome degradative pathway [83, 110]. Carbonyl modifications, which are reflective of protein oxidation, are increased by greater than 2-fold in the SN compared to the basal ganglia and prefrontal cortex of normal subjects [111]. Increases in protein carbonyls have been found in substantia nigra, basal ganglia, globus pallidus, substantia innominata, cerebellum and frontal pole, but not in patients with incidental LB disease (ILBD), a putatively presymptomatic PD disorder [112]. The involvement of the latter two brain regions are unexpected based on the restricted neuropathology of PD, but may reflect a consequence of L-DOPA treatment or a more global

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consequence of the inflammatory spread of oxidative stress in PD. Other evidence for oxidative damage to proteins in PD is the increased expression of neural heme oxygenase-1 [113] and increased immunostaining of glycosylated proteins on nigral neurons [114].

Figure 2. Neuroinflammatory pathways in PD pathogenesis. Microglial derived NO and superoxide species react in extracellular spaces to form peroxynitrite. Peroxynitrite readily crosses cell membranes where it contributes to lipid peroxidation, DNA damage and nitrotyrosine formation in α-synuclein and other cellular proteins. Damaged proteins are targeted to cellular proteosomes for degradation via the ubiquitination pathway. Excess NO produced by activated microglia can lead to S-nitrosylation of cellular proteins, including parkin. Such modifications may diminish E3 ubiquitin ligase activity necessary for efficient protein turnover by proteosomes. Excessive protein damage caused by oxidants and disruptions in the ubiquitin pathways may overload or inhibit protein degradation quality control measures leading to the accumulation of damaged proteins in cells.

5.3 Free Radicals and Nucleic Acid Modifications

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Modification of nucleic acids by free radicals and reactive species can induce chromosomal aberrations with a high efficiency [64], suggesting that chromosomal damage exhibited in neurons of PD patients might be related to an abnormally high oxidative stress. Among the most promising biomarkers of oxidative damage to nucleic acids is nucleoside 8hydroxyguanosine (8-OHG) for RNA or 8-hydroxy-2'-deoxyguanosine (8-OHdG) for DNA. 8-OHG is an oxidized base produced by free radical attack on DNA by C-8 hydroxylation of guanine and is one of the most frequent nucleic acid modifications observed under conditions of oxidative stress [115]. In PD patients, levels of 8-OHG nucleic acid modifications are commonly increased in the caudate and SN compared to age-matched controls [116-119]. Immunohistochemical characterization of these modifications indicates that the highest levels of 8-OHG modifications are found in neurons of the SN and to a lesser extent in neurons of the nucleus raphe dorsalis and oculomotor nucleus, and occasionally in glial cells [118]. That 8-OHG nucleic acid modifications are rarely detected in the nuclear area and mostly restricted to the cytoplasm, and that immunoreactivity is diminished by RNase or DNase and ablated with both enzymes [118], suggest that targets of oxidative attack include both cytoplasmic RNA and mitochondrial DNA. Of particular interest are the findings that concentrations of 8-OHG in CSF of PD patients are higher than in age-matched controls; however, serum concentrations of 8-OHG appear highly variable [120, 121].

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5.4 Lipid Peroxidation 4-Hydroxy-2-nonenal (HNE) is a reactive α,β unsaturated aldehyde that is one of the major products during the oxidation of membrane lipid polyunsaturated fatty acids, and forms stable adducts with nucleophilic groups on proteins such as thiols and amines [122, 123]. Thus, HNE modification of membrane proteins forms can be used as biomarkers of cellular damage due to oxidative stress [123]. Immunochemical staining for HNE modified proteins on melanized nigral neurons in the midbrains of PD patients show 58% of remaining nigral neurons exhibit positive HNE-modified proteins compared to only 9% in control subjects, weak or no staining on oculomotor neurons in the same midbrain sections from PD patients [124], and are detected in LB from PD and diffuse LB disease patients, but not age-matched controls [125]. HNE species are typically more stable than oxygen species, thus can spread from site of production to effect modifications at a distant site [126]. HNE modifications of DNA, RNA, and proteins have various adverse biological effects such as interference with enzymatic reactions and induction of heat shock proteins, and are considered to be largely responsible for cytotoxic effects under conditions of oxidative stress [122, 127, 128]. The cytotoxic effects of HNE modifications may be founded in part due to inhibition of complexes I and II of the mitochondrial respiratory chain [129]; induction of caspase-8, -9, and -3; cleavage of poly(ADP-ribose) polymerase (PARP) with subsequent DNA fragmentation [130]; inhibition of NF-κB mediated signaling pathways [131]; and diminution of glutathione levels [130]. Consistent with an abundance of data showing the dysregulation of proteasomal function in PD, direct binding of HNE to the proteasome also inhibits the processing of ubiquinated proteins [132]. Concentrations that induce no acute change in cell viability in vitro, initially cause a decrease in the proteasomal catalytic activity to the extent

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that it induces accumulation of ubiquinated and nitrated proteins, reductions in glutathione levels and mitochondrial activity, and increased levels of oxidative damage to DNA, RNA, proteins, and lipids [132-134]. Another reactive aldehyde species produced from the peroxidation of lipids is malonyldialdehyde (MDA), which is formed from the breakdown of endoperoxides during the last stages of the oxidation of polyunsaturated fatty acids; particularly susceptible are those containing three or more double bonds [122, 135, 136]. MDA can exist as free aldehydes or react with primary amine groups of macromolecules to form adducts with cellular structures [122, 137, 138]. Evidence of increased levels of MDA-modified proteins in the SN [139, 140] and CSF [141] of PD patients, but not in controls is indicative of increased lipid peroxidation and supports the existence of chronic inflammatory responses in those patients. F2-isoprostanes (F2-IsoP) and isofurans (IsoF) are other products of lipid peroxidation and both are well-established as specific biomarkers of in vivo oxidative stress [142-144]. Under conditions of relatively low oxygen tension, the F2-IsoP species is favored; whereas, under higher oxygen tensions, IsoF is heavily favored [142]. Increased F2-IsoP concentrations in affected tissues from patients of most neurodegenerative disorders have provided general support for the role of inflammation and oxidative stress in those disorders [143], but the failure to detect similar levels in tissues from PD patients was particularly perplexing [145]. However comparison of tissues for IsoF as well as F2-IsoP has shown that levels of IsoF, but not F2-IsoP in the SN of patients with PD and dementia with LB are significantly higher than those of controls [142]. This preferential increase in IsoF in PD patients indicates that the microenvironmental oxygen tension is typically greater in PD than other disorders, and suggests a unique mode of oxidant injury in PD, which may be indicative of an increased intracellular oxygen tension resulting from mitochondrial dysfunction or a greater intensity of inflammatory response in PD. These data certainly indicate that oxidative stress in the SNpc region is elevated in PD, but whether microglial and astroglial (i.e. innate immune) activation during the progression of PD shifts the balance towards increased protection from ROS damage or towards exacerbation of ROS damage, and whether this dynamic changes as the disease progresses remains to be determined.

5.5 Iron and Oxidative Stress Investigators using a variety of methods have provided a consensus that iron levels naturally increase with age and are significantly increased (reported from 25% - 100%) in the SN and CSF of postmortem PD patients compared to age-matched controls [90, 146-158]. Iron in its ferrous (Fe2+) form catalyzes the formation of strong oxidants and ferric iron (Fe3+). With disease progression, levels of Fe3+ increase within the SN suggesting an increased state of oxidative stress [159]. Although most of the total iron in healthy brains is stored in ferritin, and levels are typically depleted under inflammatory conditions, ferric ions are readily released after damage to neuronal tissues by yet unknown mechanisms, making those ions available for oxidative catalysis [160]. In PD, proteins such as transferrin, ferritin, and iron regulatory proteins (IRP), which control iron homeostasis, could be modified by

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ROS and lose their regulatory capacity. Indeed, in vitro and in vivo nitrosylation of IRP2 leads to rapid ubiquitination and degradation of IRP2 in the proteasome [161]. Additionally, IRP knockout mice exhibit high levels of iron and ferritin with an extensive axonopathy in the white matter tracts and reactive microglia and vacuoles SN [162]. These mice also manifest motor impairments when axonopathy is prominent, however dopaminergic cell loss is minimal.

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6. Genetics and Immunity Recent evidence has shown that genetics may contribute to the onset of neurodegenerative disorders [163]. Linkages to the age at onset (AAO) for PD have been identified on chromosomes 1 and 10. The latter is significantly associated with glutathione stransferase omega-1 (GSTO1) [164]; a provocative finding since GSTO1 is thought to be involved in the post-translation modification of IL-1, a major component in the regulation of inflammatory responses [165-167]. One factor associated with the chromosome 1p peak is the ELAVL4 gene [168], a human homologue of the Drosophila ELAV (embryonic lethal abnormal vision) [169] and essential for temporal and spatial gene expression during CNS development. Additionally, ELAVL gene products are known to bind to AU-rich response elements (ARE) in the 3’-untranslated region (3’UTR) of inflammation-associated factors [169]. Interestingly, PD patients homozygotic for allele 1 at position -511 of the IL-1β gene have an earlier onset of the disease than those homozygotic for allele 2, which produces higher amounts of IL-1. Thus, higher production of IL-1β might provide some neuroprotective effect for dopaminergic neurons [170, 171]. The generalized toxicity of these inflammatory responses provides very little insight into the selective neurodegeneration patterns observed in various disease states. However, it is tempting to speculate that the shared phenotype of multiple genetic mutations identified in familial forms of PD suggests the dysregulation of a common pathway may be involved. Consistent with aberrant protein accumulation in PD, malfunction of the ubiquitinproteasome system appears to be a common link in these familial forms of PD. Indeed, many of the genes identified are linked to protein misfolding and/or degradation pathways [11, 172]. While these genetic mutations offer insight into common pathways involved in familial forms of PD, the information they offer for sporadic forms of the disease in individuals who lack these genetic lesions are not completely understood. Interestingly, recent data suggests that some of these PD associated genes are active targets of reactive nitrogen and oxygen species both of which are generated during chronic inflammation. In keeping with this notion, three missense mutations (A53T, A30P, and E46K) have been identified in the gene encoding α-synuclein leading to an autosomal dominant inheritance of PD. Moreover, genomic triplication of the α-synuclein gene is associated with familial PD [173]. Transgenic overexpression of wild-type or mutant forms of α-synuclein in mice produces intraneuronal aggregates [174], while in Drosophila, this resulted in both aggregate formation as well as dopaminergic neuronal cell death [175]. In sporadic PD, recent studies support a role for oxidative and/or nitrative stress in α-synuclein modification and aggregation [108]. Nitrating agents such as peroxynitrite can readily nitrate α-synuclein at tyrosine residues, and generate highly stable o,o’-dityrosine oligomers (Figure 2). These

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biochemical lesions enhance fibril formation in vitro, similar to the biophysical properties of α-synuclein isolated from PD brains [176]. Aberrant protein conformations of modified αsynuclein can potentially overload cellular proteasome and by doing so, may increase cellular stress associated with the accumulation of misfolded proteins in affected neurons [177]. Parkin is another gene associated with familial PD whose protein product may be a target of nitrosative stress-associated protein modifications. Parkin is an ubiquitin E3 ligase responsible for the addition of ubiquitin to protein substrates marked for degradation by cellular proteasomes including α-synuclein and its interacting protein, synphilin-1 [178]. Over expression of parkin in α-synuclein transgenic flies rescues neurons from degeneration [179]. Mutations in parkin result in the loss of ubiquitin E3 ligase activity and are found in juvenile PD in an autosomal recessive fashion [180]. The posttranslational modification (Snitrosylation) of parkin also abolishes its E3 ligase activity and inhibits the ability to rescue cells from α-synuclein/synphilin coexpression in the presence of proteasome inhibition (Figure 2) [83, 110]. Nitrosylation modifications on parkin were found in sporadic cases of PD in affected brain regions, as well as in both MPTP and rotenone animal models. Animal studies reveal that nitrosylation of parkin is dependent on both nNOS, as well as microglialderived iNOS [83]. Thus, it is conceivable that inflammation contributes to oxidative modifications in parkin, which in turn predispose affected neurons to cytotoxic stress caused by altered protein catabolism.

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7. Experimental Models of PD: Neuroinflammation and Disease The prevalence of reactive microglia and biomarkers of inflammatory responses in PD necessitates the inclusion of an inflammatory component in most models of PD. Although reactive microglia in PD may have an initial function to scavenge dead or dying neurons after the primary etiological event, evidence of a more adverse role in neuroinflammation and neurodegeneration emerges from animal models of PD. Several models of PD exist that induce significant inflammatory responses as evidenced by reactive microglia and degeneration of dopaminergic neurons along the nigrostiatal axis, and include 1-methyl-4phenyl-1,2,5,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), rotenone, paraquat, LPS, and trisialoganglioside GT1b [81, 181-188]. Arguably, of great importance among the compounds used to model PD is MPTP, the only agent reported to have dopaminergic effects in humans. MPTP is a neurotoxin that was discovered after induction of irreversible parkinsonian syndrome in addicts following injection of MPTP as a contaminant of illicitly and poorly synthesized meperidine [42, 43]. Postmortem examination of several patients ranging from 3 to 16 years post-exposure and onset of parkinsonism, revealed not only evidence of progressive neurodegeneration, but also reactive microglial clusters surrounding nerve cells. This ongoing inflammatory reaction years after the original toxic exposure supports the notion of a self-perpetuating process of neurodegeneration mediated by localized inflammatory processes within the nigrostriatal axis. However, that many of these patients self-administered drugs both before and after

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MPTP exposure, and that only a few were affected from an estimated 300 individuals exposed to MPTP, warrants caution about extrapolating these data to extremes. Among several animal models of PD, MPTP can reproduce many characteristics of the disease when administered to mice [189] and primates [41]. MPTP is converted to 1-methyl4-phenylpyridinium (MPP+) in astrocytes, which is taken up by dopaminergic neurons where it inhibits mitochondrial electron transport complex I, resulting in decreased ATP production and cell death. This toxin has proven to be valuable for the study of PD pathology, both in murine and primate animal models and in vitro culture systems. MPTP induces peak microglia activation within 2 days after acute MPTP intoxication and produces a proinflammatory environment in the substantia nigra and striatum with predominant production of TNFα, IL-1β, and IL-6, and upregulation of iNOS, COX-2, and MMP-9 [23, 31, 190-194]. In addition to increased reactive microglia in the MPTP model, a minor, but consistent T cell infiltrate occurs soon after MPTP treatment, but before peak neuronal loss, and is comprised mostly of CD8+ T cells with fewer CD4+ T cells [181, 182]. These T cells express LFA-1 and CD44 suggesting they are an effector/memory phenotype and may be activated. However, MPTP is not the only valid model of PD. Intrastriatal injection of 6-OHDA induces increased numbers of reactive microglia in striatum and SN, as evidenced by increased expression of MHC II, Mac-1 and peripheral benzodiazepine receptors by day 1 after exposure, which peak after 6 to 10 days post injection, and gradually resolve 20-30 days thereafter [183, 195-197]. Proinflammatory cytokines are also implicated in 6-OHDAinduced neurodegeneration as levels of TNF-α are elevated in striatum and CSF of treated rats [67]. Signs of inflammation remain after one month post-intoxication as shown by significantly increased levels of mRNA for IL-1α and IL-1β in lesioned tissues, however significant amounts of those cytokine proteins have not been demonstrated [197] suggesting a role for post-transcriptional regulation in regulation of the inflammatory response. Rotenone is a lipophilic herbicide that causes a chronic, systemic defect of mitochondrial complex 1 and release of superoxide free radicals, inducing selective degeneration of nigrostriatal dopaminergic neurons along the nigrastriatal axis and leading to hypokinesia and rigidity [184, 185, 198]. However, behavioral abnormalities occur even in the absence of detectable dopaminergic neurodegeneration, suggesting that other systems may be affected by rotenone [199, 200]. Additionally, neurons from treated rats accumulate fibrillary inclusions comprised of ubiquitin and α-synuclein. Rotenone induces a prominent inflammatory response of Mac-1+ reactive microglia in the striatum and substantia nigra, even in the absence of detectable dopaminergic neurodegeneration [185, 199]. Paraquat (PQ, 1,1’-dimethyl-4,4’-bypyridinium) is a herbicide that induces selective degeneration of dopaminergic neurons along the nigrostriatal axis [201-205]; thus PQ exposure is implicated as a putative risk factor for PD [203]. PQ induces nigral astrocytosis and microgliosis; the latter showing a reactive phenotype with increased numbers of Mac-1 immunoreactive cells [203, 206]. Co-culture with microglia is necessary to induce PQmediated degeneration of dopaminergic neurons in vitro [207]. Additionally, PQ mediates the accumulation of α-synuclein inclusions and 4-HNE modifications by nigral dopaminergic neurons [204, 205], suggesting increased oxidative stress may contribute to proteasomal dysregulation.

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To assess the role of microglial inflammation on dopaminergic neurodegeneration, known inducers of inflammation have been introduced intrastriatally. Of those, LPS is a most potent activator of microglia. Injection of LPS into the nigrostiratal area induces a strong reactive microglial response that precedes a delayed and progressive dopaminergic neuronal loss along that axis [184, 186, 187, 208], whereas injection into other brain regions, such as the hippocampus or cortex, has no detectable deleterious affect on neurons in those areas [187]. Injection of LPS between the subtantia nigra and ventral tegmental area (VTA) affects only those neuronal bodies within the SN as similarly observed with dopaminergic-specific neurotoxins. Progression of neurodegeneration without an overt neurotoxin, but in the presence of LPS-induced reactive microglia suggests that reactive microglia are a primary neurodegenerative agent for dopaminergic neurons. LPS-induced neuronal death is subsequent to upregulation by nigral microglia of iNOS, TNFα, and IL-1β, and increased production of NO and superoxide [186, 187, 208-211]. While LPS does not induce any detectable adverse effects to purified dopaminergic neurons in vitro, the presence of reactive microglia, but not astrocytes, is essential for LPS-induced neurodegeneration [186, 212, 213]. Inhibition of LPS binding to its cognate receptor inhibits activation of microglia, subsequent production and release of all proinflammatory factors and protection of dopaminergic neurons in culture [209]. Interestingly, inhibition of proinflammatory cytokines by neutralizing antibodies is also neuroprotective [211]. Thus, the salient features of these models are that prominent inflammatory responses precede a progressive dopaminergic neuronal degeneration, and a critical role for microglia and the products of inflammation in dopaminergic neurodegeneration exists.

8. Inhibition of Inflammation in PD and Experimental Models Various sources of evidence suggest that long-known inflammatory changes in the parkinsonian brain, rather than mere secondary scavenging affects, may participate more actively in the neurodegenerative processes. Of greatest interest is the finding in a large cohort of health care professionals, that daily administration of nonsteroidal antiinflammatory drugs (NSAIDs) reduces the risk for PD by 45% compared to those that did not routinely take NSAIDS [37]. Additionally, evidence for the role of neuroinflammation is provided in several intoxicant models of neuroinflammation; whereby, attenuation of the inflammatory component protects subsequent dopaminergic neurodegeneration along the nigrostriatal axis. As an inducible proinflammatory enzyme, iNOS is thought to play a major role in dopaminergic neurodegeneration. Ablation by genetic manipulation or inhibition with specific pharmaceutical agents protects nigral neurodegeneration induced by MPTP [81, 214, 215], LPS [208] or 6-OHDA [183], but is less active at protecting striatal termini [81, 214]. Interesting, not all microglia express iNOS and inhibition of iNOS does not attenuate all reactive microglia suggesting that only a subpopulation of reactive microglia may participate in neurodegeneration [81, 214].

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Minocycline is a long-acting second generation tetracycline shown to have a high capability to penetrate the brain parenchyma and CSF. Minocycline acts on activated microglia to prevent upregulation of iNOS, inhibit phosphorylation of p38 mitogen-activated protein (MAP) kinase, and reduce IL-1β converting enzyme (ICE) and IL-1β production [216-222]. In the MPTP model, the effects of minocycline have a combined effect to reduce reactive microglia and inhibit neurodegeneration of the dopaminergic neuronal bodies of the nigra as well as the termini in the striatum in a dose-dependent fashion, but does not effect the conversion of MPTP by astrocyes [183, 219, 220]. Similarly, in 6-OHDA treated animals, minocycline reduces the number of reactive microglia and protects dopaminergic neurons in the SN [183]. Similarly ablation or inhibition of COX-2, the rate-limiting enzyme in prostaglandin E2 synthesis markedly diminishes dopaminergic neurodegeneration along the nigrostriatal axis after treatment with MPTP [23, 223-227], or 6-OHDA [228]. In vitro data shows that inhibition of COX-2 is more efficacious in 6-OHDA-induced toxicity compared to that induced with MPP+ suggesting that MPTP-induced dopaminergic neurodegeneration may be COX independent [229]. Indeed, in MPTP/MPP+ induced toxicity, COX-2 inhibition does not entirely attenuate microglia activation, but rather prevents the formation of reactive oxygen/nitrogen species [23, 230]. On a more general level, MMPs are a class of extracellular soluble or membrane bound cysteine proteases involved in remodeling of the extracellular matrix and are regulated by tissue inhibitors of metalloproteinases (TIMPs). Both classes of proteins have been implicated in a range of neurodegenerative diseases including HAD, AD, PD and stoke. Indeed, consistent with the possibility that alterations in MMPs/TIMPs may contribute to disease pathogenesis, samples from PD patients show levels of MMP-2, expressed primarily by microglia and astrocytes that are significantly reduced in the SN compared to age-matched controls, but remain unchanged in cortex and hippocampus [231]. Gu and colleagues reported that S-nitrosylation of N-terminal cysteine residues within proMMP-9 leads to the subsequent activation of MMP-9 protease activity, which identifies an extracellular proteolysis mechanism putatively involved in neuronal cell death in which S-nitrosylation activates MMPs [232]. Additionally, an increase in MMP-9 expression has been determined in the MPTP model and pharmacological inhibition of MMP-9 was neuroprotective [193].

9. Therapeutic Immunoregulation To establish a disease diagnosis at earlier stages, as well as designing rational therapeutic modalities for this disease, efforts have been made in recent years to identify the neuropathological, biochemical, and genetic biomarkers of PD. α-Synuclein-containing LB and altered DAT imaging for PD are the most eminent biomarkers. Several potential markers of oxidative stress such as malondialdehyde, superoxide radicals, the coenzyme Q10 redox ratio, and 8-OHdG from RNA oxidation have been measured in blood and the levels of these markers tend to be higher in PD compared with control groups [233]. Thus, therapeutic approaches to PD may target a number of factors that play a role in disease onset, inflammation and neurodegenerative progression

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Studies involving pro-apoptotic proteins in PD animal models indicate that their suppression may lead to decreased rates of neuronal loss. Fas, a member of the TNF receptor family, shows pro-apoptotic and inflammatory functions, and is upregulated in the SNpc of both PD patients and MPTP mouse models [234]. However, Fas blockage with dominantnegative c-Jun adenovirus indicates that Fas deficiency does not significantly prevent the reduction of dopaminergic terminal fibers within the striatum or attenuate the activation of striatal microglia [234]. Numerous studies have demonstrated that Bax is a pro-apoptotic factor required for the programmed death of several types of neurons in the peripheral and central nervous systems [235]. Bax is upregulated in the SNpc of MPTP mice, and its ablation alleviates SNpc neuronal apoptosis, indicating that targeting Bax may provide a protective benefit in PD [236]. The role of neurotrophins in reducing neurodegeneration and promotion of neuroregenerative processes presents an exciting possibility for therapeutic benefit to PD. A study of lentiviral delivery of glial cell line-derived neurotrophic factor (GDNF) showed trophic effects on degenerating nigrostriatal neurons in a primate model of PD [237]. Results indicated augmented dopaminergic function in aged monkeys and reversal of functional deficits with complete prevention of nigrostriatal degeneration in MPTP-treated monkeys. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and potentially induce regeneration in primate models of PD, showing the potential for a viable therapeutic strategy for PD patients. However, recent clinical trials of intraputamenally infused GDNF in PD patients are controversial with one 2year phase I trial showing improved activity scores and no untoward effects in a limited cohort [238], while phase II trials were halted after six months due to lack of efficacy and adverse effects in patients and nonhuman primates . Immune suppression through receptor modulation has been another approach attempting to alleviate or reverse PD progression. For example, agonists of peroxisome proliferatoractivated receptor-γ (PPAR-γ), a nuclear receptor involved in carbohydrate and lipid metabolism, have been shown to inhibit inflammatory responses in a variety of cell lines, including monocyte/macrophages and microglial cells [239]. In vivo administration of PPARγ agonists modulate inflammatory responses in the brain. Pioglitazone, a PPAR-γ agonist used currently as an anti-diabetic agent, has been shown to have anti-inflammatory effects in animal models of autoimmune disease, attenuate glial activation, and inhibit dopaminergic cell loss in the SN of MPTP treated mice [239]. However, pioglitazone treatment had little effect on MPTP-induced changes in the striatum. This result seems to indicate that in the MPTP mouse model of PD, mechanisms regulating glial activation in the dopaminergic terminals compared with the dopaminergic cell bodies are PPAR-γ independent [239]. Another potential therapeutic avenue for PD may involve T cell mediated immune responses. Activation of T cells directed against antigens expressed at the injured areas of the CNS has been shown to be neuroprotective under acute and chronic neurodegenerative conditions [240-242]. However, immunization with such antigens might lead to development of an autoimmune disease. Immunization with Copolymer-1 (Cop-1, glatiramer acetate) or passive transfer of Cop-1 specific T cells has been shown to be beneficial for protecting neurons from secondary degeneration after injurious conditions [243]. Cop-1 reactive T cells have partial cross-reactivity with myelin basic protein (MBP) and other self-antigens

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expressed in the brain [244]. Therefore, immunization with Cop-1 leads to increased accumulation of T lymphocytes in areas of injury within the brain and spinal cord and is neuroprotective without causing any adverse effects; however, the molecular mechanism of this response is not fully understood. T cells reactive to Cop-1 could be a source of brainderived neurotrophic factor (BDNF) and other neurotrophic factors [243] or can induce production of neurotrophins by microglial or astroglial cells. Recently, the neuroprotective effect of immunization with Cop-1 was tested in the MPTP model of PD and demonstrated that adoptive transfer of Cop-1-specific T cells, but not ovalbumin-specifc T cells, into MPTP-intoxicated mice attenuates reactive microglia neuroinflammation and inhibits dopaminergic neurodegeneration in both the SNpc and the striatum [245]. Additionally, by determination with quantitative proton magnetic resonance spectroscopic imaging (1H MRSI), adoptive transfer of those T cells protect the loss of nigral N-acetylaspartate (NAA) levels associated with MPTP-induced neurodegeneration [246], Additionally, suppression of microglial-associated inflammation was associated with T cell accumulation within the SNpc, induction of a TH2 phenotypic T cell response with production of anti-inflammatory cytokines (IL-4, IL-10), and increased expression of GDNF by astrocytes, but not by infiltrating T cells or microglia [245]. These data suggest a putative mechanism for which regulatory T cells, induced by vaccination with cross-reactive epitopes, extravasate in response to neuroinflammation from neurodegenerative processes; secrete antiinflammatory cytokines in response to cross-reactive self-epitopes (e.g. myelin basic protein) to attenuate reactive microglia; suppress the inflammatory response; induce a neurotrophic response by T cells and/or other glia, which can interdict ensuing neurodegenerative processes (Figure 3). This therapeutic vaccine approach using Cop-1 represents a potential interdictory modality for slowing or halting the progression of neuroinflammation and secondary neurodegeneration, and could be considered in strategies with other antiinflammatory or anti-oxidant therapies for a combinatorial modality to protect against neuroinflammation and consequent neurodegeneration in PD.

10. Summary Evidence for the role of inflammatory processes in the pathogenesis of Parkinson’s disease (PD) is significant. Epidemiologic, animal, human autopsy studies, and immunebased therapeutics all support the presence of an inflammatory cascade, whereby microglial cells play center stage affecting disease processes through secretory neurotoxic and antigen presentation activities. In steady state, microglia, a cell type with a diverse functional repertoire, protect the nervous system acting as debris scavengers, killers of microbial pathogens, and regulators of immune responses. In neurodegenerative diseases, activated microglia can mediate cell injury and death through production of reactive oxygen species, mobilization of adaptive immunity, and cell chemotaxis. This induces tissue remodeling and blood-brain barrier dysfunction. As the disease progresses, inflammatory secretions engage neighboring cells including the recruitment of the adaptive immune system in a vicious cycle of autocrine and paracrine amplification of inflammation, leading to tissue injury and ultimately destruction. Such pathogenic processes contribute to neurodegeneration in PD.

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Research from others and our own laboratories seek to develop therapeutic interventions that harness inflammatory processes and block disease processes.

Figure 3. Cop-1 induced, T cell-mediated neuroprotection in a PD model. In MPTP-intoxicated mice, regulatory T cells infiltrate the inflamed nigrostriatal pathway where they encounter cross-reactive selfantigens (myelin basic protein) presented in the context of MHC by resident microglial cells. Activated T cells secrete anti-inflammatory cytokines such as IL-4, IL-10, and TGF-β that suppress toxic microglial activities. Neurotrophin expression may occur directly from T cells or T cell derived IL-4 and IL-10 may induce neurotrophin production in neighboring glia. These activities lead to neuroprotection indirectly by suppression of microglial responses and directly through the local delivery of neurotrophins.

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Acknowledgments The authors wish to thank Ms. Robin Taylor for excellent graphic and administrative assistance. The National Institutes of Health (NIH) grants that supported this work included R21 NS049264 (to R.L.M.) and P01 NS31492, R01 NS34239, P01 NS043985, and R37 NS36136 and P01 MH64570-03 (to H.E.G.).

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[221] Lin S, Zhang Y, Dodel R, Farlow MR, Paul SM, Du Y. Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons. Neurosci Lett 2001;315:61-4. [222] Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 2001;48:1393-9. [223] Teismann P, Ferger B. Inhibition of the cyclooxygenase isoenzymes COX-1 and COX2 provide neuroprotection in the MPTP-mouse model of Parkinson's disease. Synapse 2001;39:167-74. [224] Feng ZH, Wang TG, Li DD, Fung P, Wilson BC, Liu B, et al. Cyclooxygenase-2deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra. Neurosci Lett 2002;329:3548. [225] Feng Z, Li D, Fung PC, Pei Z, Ramsden DB, Ho SL. COX-2-deficient mice are less prone to MPTP-neurotoxicity than wild-type mice. Neuroreport 2003;14:1927-9. [226] Klivenyi P, Gardian G, Calingasan NY, Yang L, Beal MF. Additive neuroprotective effects of creatine and a cyclooxygenase 2 inhibitor against dopamine depletion in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. J Mol Neurosci 2003;21:191-8. [227] Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, et al. JNKmediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A 2004;101:665-70. [228] Sanchez-Pernaute R, Ferree A, Cooper O, Yu M, Brownell AL, Isacson O. Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease. J Neuroinflammation 2004;1:6. [229] Carrasco E, Casper D, Werner P. Dopaminergic neurotoxicity by 6-OHDA and MPP+: differential requirement for neuronal cyclooxygenase activity. J Neurosci Res 2005;81:121-31. [230] Wang T, Pei Z, Zhang W, Liu B, Langenbach R, Lee C, et al. MPP+-induced COX-2 activation and subsequent dopaminergic neurodegeneration. Faseb J 2005;19:1134-6. [231] Lorenzl S, Albers DS, Narr S, Chirichigno J, Beal MF. Expression of MMP-2, MMP-9, and MMP-1 and their endogenous counterregulators TIMP-1 and TIMP-2 in postmortem brain tissue of Parkinson's disease. Exp Neurol 2002;178:13-20. [232] Gu Z, Kaul M, Yan B, Kridel SJ, Cui J, Strongin A, et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 2002;297:118690. [233] Rachakonda V, Pan TH, Le WD. Biomarkers of neurodegenerative disorders: how good are they? Cell Res 2004;14:347-58. [234] Hayley S, Crocker SJ, Smith PD, Shree T, Jackson-Lewis V, Przedborski S, et al. Regulation of dopaminergic loss by Fas in a 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine model of Parkinson's disease. J Neurosci 2004;24:2045-53. [235] Martin LJ. Neuronal cell death in nervous system development, disease, and injury (Review). Int J Mol Med 2001;7:455-78.

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[236] Vila M, Jackson-Lewis V, Vukosavic S, Djaldetti R, Liberatore G, Offen D, et al. Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6tetrahydropyridine mouse model of Parkinson's disease. Proc Natl Acad Sci U S A 2001;98:2837-42. [237] Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 2000;290:767-73. [238] Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol 2005;57:298-302. [239] Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC. Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease. J Neurochem 2002;82:615-24. [240] Angelov DN, Waibel S, Guntinas-Lichius O, Lenzen M, Neiss WF, Tomov TL, et al. Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2003;100:4790-5. [241] Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E, Schwartz M. Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc Natl Acad Sci U S A 2002;99:15620-5. [242] Bakalash S, Kipnis J, Yoles E, Schwartz M. Resistance of retinal ganglion cells to an increase in intraocular pressure is immune-dependent. Invest Ophthalmol Vis Sci 2002;43:2648-53. [243] Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M, et al. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci U S A 2000;97:7446-51. [244] Arnon R, Sela M. Immunomodulation by the copolymer glatiramer acetate. J Mol Recognit 2003;16:412-21. [245] Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, et al. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A 2004;101:9435-40. [246] Boska MD, Lewis TB, Destache CJ, Benner EJ, Nelson JA, Uberti M, et al. Quantitative 1H magnetic resonance spectroscopic imaging determines therapeutic immunization efficacy in an animal model of Parkinson's disease. J Neurosci 2005;25:1691-700.

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In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 197-220 © 2006 Nova Science Publishers, Inc.

Chapter IX

Hypoxic Ishcemic Insults and Inflammation in the Developing Brain Zinaida S. Vexler* Department of Neurology, University of California San Francisco, San Francisco, California 94143

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1. Introduction Despite the traditional view that neonates compared to adults, have greater resistance to CNS injury, it has become clear that at specific early stages of brain maturation susceptibility to hypoxic and ischemic insults may be increased. In fact, the incidence of arterial stroke in newborns, about 1/4,000 term babies [39], is similar to that in the elderly. Emerging evidence suggests that although basic mechanisms of neurodegeneration are shared across all age groups, immaturity in general as well as specific stages of brain development critically affect the susceptibility of different cell types to ischemic insults (reviewed in [8,95,139,141]). For example, the immature brain is susceptible to excitotoxic, oxidative and inflammatory injury during the prenatal [7,12] and early postnatal period [79,107,124] and the modes of neuronal death differ compared to those in adult animals [30,76,149]. Another example of age-related differences is the vulnerability of cell populations such as immature oligodendrocytes and subplate neurons during specific stages of development [8,95]. Here we review current information on the contribution of inflammation in the initiation and evolution of ischemic and hypoxic brain injury in fetal and neonatal animals, discuss the involvement of inflammatory mechanisms in the preferential susceptibility of different brain regions depending on age with the emphasis on the role of individual components of the

*

Corresponding Author: Zinaida S. Vexler, Ph.D. University California San Francisco, Department of Neurology, box 0663 521 Parnassus Ave. San Francisco, CA 94143-0663 Tel (415) 502-2282 Fax (415) 502-5821 E-mail: [email protected]

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inflammatory cascade, and examine progress made in protecting the immature brain against cerebral ischemia by anti-inflammatory agents.

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2. The Dynamic State of the Developing Brain Affects the Response to Brain Injury Cerebrovascular autoregulation is vastly different between the immature and adult brain. The presence of a “pressure passive” cerebral circulation has been demonstrated in preterm babies and in sick term infants [6], and the effect of increasing maturity on functional cerebrovascular autoregulation has been shown in animals [134,140]. Energy metabolism undergoes major changes at birth and in the early postnatal period. In adults and in the newborn, glucose is the cerebral energy substrate, the use of ketone bodies as a cerebral energy substrate is unique for neonates [137]. The transition from consuming ketones as a brain substrate to glucose occurs gradually and, in rodents, is seen in the second postnatal week [137] and parallels the increase in activity of many energy-requiring pumps, such as Na+,K+-ATPase. Along with these changes, the expression of glucose transporter proteins in the brain increases, as does a glial and endothelial transporter, GLUT1, and a neuronal transporter GLUT3 [138]. The developing brain is very susceptible to oxidative stress [55,124] due to imbalanced brain antioxidative defense mechanisms, high concentrations of unsaturated fatty acids [109], high rates of oxygen consumption, low concentrations of antioxidants, and availability of unbound iron, all of which contribute to the vulnerability of the immature brain to oxidative damage (reviewed in [141]). Maturational differences in expression and activity of antioxidative enzymes, including catalase, CuZn- superoxide dismutase (SOD), mitochondrial SOD and glutathione peroxidase [5,22,36,47], impact the rate of utilization of reactive oxygen species produced in brain tissue. The status of the BBB in the immature brain remains controversial. The integrity of the BBB is controlled by a number of different and partially independent mechanisms, including the presence of extracellular matrix, tight junctions, and endothelial cells. The accumulating data indicates that the long-standing idea that the BBB is immature (permeable) not only at prenatal but also at postnatal stages, may be inaccurate. Mechanisms of BBB function in the fetus are different than those in adult [122]. Tight junctions, which limit passive permeability of the BBB, are present early in embryonic development [84], restricting entrance of proteins into the brain in a controllable fashion. Comparison of BBB disruption in response to intrastriatum injections of interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNFα) between newborn, juvenile (P21) or adult rats has shown that juvenile rather than newborn BBB is the most prone to disruption [2,3,17,123], demonstrating that there is no linear relationship between brain maturation and integrity of the BBB. The developing brain is prone to excitotoxic damage. Glutamate, the major excitatory amino acid (EAA) in mammalian brain, activates a variety of EAA receptors including Nmethyl-D-aspartate (NMDA) and AMPA receptors [25,33,105]. While the NMDA receptor is an important excitatory mechanism in both the immature and mature brain, expression and the relative composition of the four subunits of the NMDA receptor are unsynchronized

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during early postnatal development with a consequent de-regulation of the receptor [15,79,80,93]. This deregulation makes neonatal neurons vulnerable to a massive influx of calcium and the neonatal brain vulnerable to a broad range of pharmaceutical agents [107,108] and ischemia [79,80]. Programmed cell death is a part of normal brain development, as neurons are overproduced during embryonic development and, according to some estimates, more than half of the neurons are lost in several regions [79,101]. Compared to adult, expression of many of the key components of apoptosis is high in the normal immature brain, including caspase-3 [18,71,72,76,118], Bcl-2 [48,146], Bax [48,106], Apaf-1 [19,146], and apoptosisinducing factor, AIF [118]. At the same time, while activation of the executional caspase, caspase-3, in the brain is maximal during the first postnatal week [76,142,146] and declines rapidly during the second week of rodent life, expression of cytochrome c, cytochrome oxidase [118] and possibly, caspase-9 [149], changes reciprocally with age. The presence of a readily available machinery for apoptotic cell death is considered one of the factors that makes the immature CNS prone to hypoxia-ischemia (H-I) and ischemia insults. While neuronal function during development has been the focus of research for many years, relatively little is known about the function of resident inflammatory cells in the brain, microglia or astrocytes, during CNS maturation. Microglia, which are derived from mesodermal precursor cells of hemapoietic lineage, populate the brain before birth [27], forming resident brain macrophages which are distinct from circulating monocytes [26,34]. Compared to adults, the status of differentiation and activation of neonatal microglia is reportedly different in the neonate [26,120]. This may be in part due to on-going stimulation of microglial cells by neuronal programmed cell death during this developmental stage [76]. Consistent with this notion, ramification of microglial cells during early postnatal rat development [88] coincides with the decrease in physiological cell death.

3. Brain Injury and Inflammation in the Very Immature Brain 3.1 Prenatal Hypoxia-Ischemia White matter injury is the most frequently observed type of brain lesion in preterm infants. Immaturity of the cerebral blood supply, a predisposition to impaired cerebral autoregulation, hypoxia, genetic factors, growth factor deficiency, materno-fetal inflammatory processes, and subsequent cytokine production are major factors related to the susceptibility of the periventricular cerebral white matter to ischemia (clinical data are reviewed in [35,49]). While the causal relationship between inflammation (and infection) and H-I induced white matter injury in very immature infants is still debated [35], there is firm evidence for a contributory role of inflammation to injury. The contribution of white matter injury to H-I brain damage is maturation-dependent and temporally associated with the appearance of oligodendrocyte progenitors [6,7]. Oxidative stress and excitotoxicity are two mechanisms that predispose oligodendrocyte progenitors to ischemic death. This has been demonstrated in vitro by glutathione depletion and exposure to

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exogenous free radicals [6,52] and in vivo in P5 rats following activation of NMDA and nonNMDA receptors [41,53,66,70]. In contrast to early oligodendrocyte progenitors and more mature oligodendrocytes that are highly resistant to oxidative stress, late oligodendrocyte progenitors are susceptible to apoptosis resultant from oxidative stress [6,7,87]. Another cell type susceptible to an H-I insult is the subplate neuron. These cells are a transient population that are located in the developing neocortex and are involved in the formation of area-specific thalamocortical connections [94]. During normal development, subplate neurons undergo programmed cell death in the first postnatal week in mice [94]. H-I induced death of this cell population is believed to contribute to white matter damage in the very immature brain [95]. Mechanisms of selective vulnerability of subplate neurons are not well understood, but expression of NMDA-R1, AMPA and kainite receptors [28,56] may predispose these cells to death. Factors contributing to the death of immature oligodendrocytes and subplate neurons resulting from an ischemic insult occurring during gestation have been reviewed previously [8,95]. Prolonged prenatal exposure to hypoxia has been modeled by subjecting pregnant rats to hypoxia from embryonic day 5 (E5) to E20 [12]. White matter cysts, disrupted extra-cellular matrix, increased lipid peroxidation, increased numbers of activated macrophages and delayed myelination occur in pups exposed to hypoxia as fetuses [12].

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3.2 Infection Models involving lipopolysaccharide (LPS) injection, with or without hypoxia or H-I, have been used to better understand the role of inflammation on damage in the very immature brain. LPS is the active component of E. coli endotoxin which is commonly used for mimicking the induced inflammation associated with infection. Intrauterine LPS injection in rats [45,46], rabbits [37] and sheep [90] results in cystic lesions in periventricular white matter of different severity, but not in cortex-specific injury [45,46]. Injection of LPS in pregnant rats through another route, intraperitoneally, leads to upregulation of the inflammatory cytokines IL-1β and TNFα, but downregulation of the oligodendrocyte marker myelin basic protein, MBP [23]. The timing of injection may, however, affect the outcome [135]. Comparing of the effects of systemic asphyxia or endotoxemia induced by LPS in fetal sheep at midgestation has shown that while microglia activation, damage to astrocytes and to oligodendrocytes are observed in both scenarios, LPS-induced damage is restricted to the white matter and is associated with inflammatory infiltrates surrounded by microglia activation, which is not the case in global asphyxia [90]. A direct LPS injection into rodent brain at P5 results in white matter swelling, ventricle enlargement, and subsequent white matter necrosis within two weeks [24]. LPS administration activates astrocytes and microglia/macrophages and production of multiple cytokines [24]. The injurious but particular role for inflammatory cytokines has been established by demonstrating that while co-administration of LPS with the IL-1 receptor antagonist (IL-1ra) attenuates LPS-induced injury, a neutralizing TNFα antibody has no effect on white matter injury [24]. The multiple mechanisms of brain injury by LPS are discussed in a review article by Hagberg and Mallard [69].

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The timing of LPS administration prior to H-I exposure is critical for its role in H-I injury [46]. LPS administration 24 hr before H-I protects the neonatal brain (induces a preconditioning effect), whereas its administration 4 hours or 1-3 days before H-I exacerbates brain injury in P7 rats. The mechanisms leading to the opposite effects of LPS, sensitization at one point and exacerbation of injury at other time points, are presently unclear. The differences may be related to the effect on CBF or energy metabolism [45], on activation of resident inflammatory cells and initiation of inflammation locally in the brain [90], or on systemic effects that ultimately lead to neuroinflammation [69].

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4. Brain Injury and Inflammation in the Neonatal Brain The disrupted cerebral blood flow following H-I or focal ischemia initiates disturbances of energy metabolism which, when persistent, result in irreversible cellular damage. Restoration of oxygen or blood flow does not necessarily compensate for disturbed cerebral metabolism and may initiate secondary changes that contribute to injury. The role of energy metabolism in the pathophysiology of H-I has been reviewed in detail by Vannucci and Hagberg [139]. Excitotoxicity and oxidative stress also contribute to H-I and focal ischemic injury of neonatal brain. When energy metabolism is compromised, extracellular glutamate increases to levels causing excitotoxicity. As noted above, neonatal brain is susceptible to excitatory injury in part due to the immaturity of the NMDA receptor [15,79,80,93] and NMDA receptor dependent activation of neuronal nitric oxide synthase (nNOS) [16,50,104]. The limited ability of the developing brain to metabolize high levels of reactive oxygen species (ROS), including H2O2 [55], makes it prone to H-I, and the relative activities of glutathione peroxidase and Cu-ZnSOD are critical to H-I outcome [65]. We will not review excitotoxic or oxidative aspects of injury in detail, as we [141] and others [139] have previously reviewed them. The remainder of this review will focus on the role of individual inflammatory components to H-I and focal ischemic injury in the neonatal brain. As outlined in a cartoon format in Figure 1, inflammation is ongoing during both initiation and propagation of ischemic injury in the neonatal brain and may play critical role in injury outcome. According to estimates from a microarray analysis 2 - 72 hours following H-I in P7 rats, about 30% of all genes that are differentially expressed after H-I [74] belong to the immune/inflammatory system [75].

4.1 Leukocytes and the Blood-Brain Barrier Following ischemia-reperfusion in adult rodents, leukocytes are thought to cause a 'noreflow' phenomenon, priming endothelial cells and facilitating disruption of the BBB [60], and releasing free radicals, proteinases, and other cytotoxic substances after extravasation into injured tissue (reviewed in [51,82,119]). Infiltrating neutrophils appear in adult

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ischemic-reperfused tissue within hours [11,60,92], while macrophages and lymphocytes are seen in injured tissue later [11,60].

Hours 2

I S C H E M I A

Days 24

3

Weeks/Months 7

30

Metabolic Disturbances

Necrosis

Apoptosis

Inflammation Remodeling Plasticity/ Recovery

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Figure 1. Inflammation is ongoing during both initiation and evolution of ischemic and hypoxic-ischemic injury in the neonatal brain. This schematic diagram illustrates that first signs of inflammation are seen hours after ischemia-related insults and various features of inflammation last for weeks and months.

The timing and anatomic distribution of neutrophil accumulation in the immature brain is reportedly different compared to adult. While neutrophils accumulate within vessels following H-I in P7 rat, these cells either do not extravasate into the injured brain within 42 hours [77] or are present in the parenchyma only briefly [21]. Neutrophil accumulation is minimal 24 hours and 7 days following ischemia-reperfusion induced by transiently occluding the middle cerebral artery (MCA) in P7 rats. Accumulation of lipid peroxides that would have been consistent with free radical released from infiltrating leukocytes, does not increase within 24 hr after transient MCA occlusion [91]. In contrast to models with reperfusion, following permanent ligation of the MCA combined with CCA occlusion, neutrophils accumulate beginning at 24 hours and peak at 72 to 96 hours [14]. However, neutrophils can contribute to H-I injury either during the insult or within hours of recovery, because cerebral atrophy is reduced and adenine nucleotides are better preserved at the end of H-I in neutropenic pups [111]. Neuropenia initiated after the H-I insult [111] does not protect, suggesting a role for these cells during initial rather than in late injury stages. While reasons for the restricted access of leukocytes into the injured neonatal brain are unknown, studies using injections of the pro-inflammatory cytokines IL-1β and TNFα have demonstrated that leukocyte recruitment in the immature brain may be critically dependent on the pattern of cytokine expression [19], as injection of IL-1β is associated with neutrophil recruitment, whereas injection of TNFα is associated with mononuclear cell recruitment [19]. So far, there have only been a few studies looking at the status of the BBB following ischemic insults in the neonatal brain. T1-weighted MRI in conjunction with the magnetic

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susceptibility contrast agent Gd-DTPA was used to non-invasively determine leakage of the BBB following H-I [9,116] or focal transient MCA occlusion [143] in P7 rats. While based on T2-weighted MRI, vasogenic edema is present in H-I by 24 hr after the insult, no significant T1-weighted MRI enhancement is observed in the injured hemisphere, suggesting a relative integrity of the barrier at that time point [9]. Parallel experiments using the contrast agent Gd-DTPA-sLe(x)A, which is designed to bind to the activated endothelium, have demonstrated that activation of the endothelium within the hypoxic-ischemic hemisphere does not necessarily result in opening of the BBB. We performed comparative analysis of the BBB integrity/leakage at 24 hr post focal transient MCA occlusion in adult and P7 rats using MRI and Evans Blue, a technique which measures endogenous albumin extravasation. While Evans Blue leakage through the barrier was evident in adult rats, it was minimal in neonatal rats [143]. These data are not surprising in view of the differences between the normal immature and mature BBB [122] and the age-dependent “window of susceptibility” of the BBB to cytokines [3].

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4.2 Microglial Cells Microglia - resident macrophages - are the main cell type that provide immunosurveillance in the brain. These cells undergo a graded process of activation response to injury [117], which features morphological transformation, increased migratory activity, proliferation, secretion of cytokines, proteases, etc, and antigen presentation [20,26,117]. Microglia populate the developing brain by birth [27]. In contrast to the normal adult brain where microglia are fully ramified, at birth microglia retain an activated morphologic phenotype [88]. They gradually ramify during the first two weeks of life, in parallel to a decline of on-going programmed cell death [76]. Microarray analysis performed 2-72 hr post H-I has shown a rapid (within 8 hours) upregulation of structural proteins specific for cells of the monocyte lineage or products of microglial activation, including cytokines, chemokines and matrix metalloproteinases [75]. Activated microglia/macrophages readily accumulate in injured tissue following H-I [21,32,81,97]; and these cells are seen as early as 24 hr postinsult following focal stroke [14,38,54] and excitotoxic injury[42], a much more rapid response compared to that in adult stroke models. Figure 2 shows that accumulation of ED-1 immunoreactive cells is rapid in the penumbra and, to a lesser extent, in the ischemic core 24 hr following transient MCA occlusion in P7 rat. The range of morphologies of ED1-IR cells seen in Figure 2B&2C is consistent with the notion of gradual morphologic transformation of microglia under neurodegenerative conditions [117]. Activation of microglial cells is often associated with proliferation of these cells [61,64,85]. In our focal ischemia model, doublelabeling with ED-1 and BrdU following a BrdU pulse (Figure 2C) or with ED-1 and Ki67 (Figure 2D) has also revealed that up to 30% of ED-1 immunoreactive cells are proliferating cells [40]. Importantly, activation of microglial cells continues for weeks following focal ischemia [14] and excitotoxic injury [42].

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Figure 2. Glial cells are activated 24 hr following a 3 hr transient MCA occlusion in P7 rats. A. Nisslstained coronal section. B-F show higher magnification images obtained in the tissue outlined by the box in A. B. Accumulation of ED1-immunoreactive cells occurs in the penumbra (arrow) and, to a lesser extent, in the ischemic core. C-D. BrdU/ED1 double-immunolabeled cells (C) and Ki67/ED1double-immunolabeled cells (D) are seen in the injured tissue, demonstrating proliferation of microglial cells in the penumbra region. E. Caspase-3/ED1 double-labeling shows that while caspase-3 activation is abundant in the injured tissue, no caspase-3 activation is seen in activated microglial cells. F. GFAP – immunoreactive astrocytes are seen in penumbra but not in the ischemic core (not shown).

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In vivo data from several neonatal models also show that a more severe ischemic brain injury is generally associated with higher macrophage densities. Following H-I and focal ischemia models in neonatal rodents these cells produce many molecules, such as inflammatory cytokines and chemokines [32,54,68,73,125], FAS receptor [65,106] and high levels of NO [132] that can further activate microglia. Pharmacological inhibition of cytokine accumulation, such as IL- receptor antagonist [68], or deficiency of inflammatory cytokines, such as IL-18, IL-6, or deletion of the FAS receptor, reduce injury and diminish various signs of inflammation, including microglial activation [65,68,73]. Complement activation, which is seen within hours after H-I in P7 rats [31,127,128], represents another aspect of microglial involvement in injury evolution. Reduction of injury associated with microglial activation/monocyte infiltration is diminished [4,42] as oppose to unaffected injury if microglial activation is unchanged [54], supports the idea that microglia contribute to ischemic and excitotoxic injury in the immature brain. Microglial cells can affect not only the acute injury stage but can impact the repair process. For example, microglial activation and IL-6 produced by these cells have been shown to adversely affect repair and neurogenesis after adult stoke [100]. While neurogenesis is rapid in the neonatal brain following both neonatal H-I [115] and focal stroke [29], newborn neurons are not long lasting [115]. It is yet to be determined whether rapidly activated microglia affect neurogenesis in the developing brain. It is also important to realize that while activation of microglia after a brain insult is frequently referred to as a harmful process, which exacerbates injury, these cells have a dual role in the brain, by protecting the CNS by phagocytosing tissue debris and supplying growth factors. A better understanding of how to selectively enhance these functions is needed.

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4.3 Astrocytes Astrocytes play an important role within the neurovascular unit, and death of astrocytes shortly following cerebral ischemia, which is frequently underestimated, may have important implications for excitotoxicity, anti-oxidative defenses and the status of the BBB in immature animals. GFAP immunoreactive astrocytes are rarely seen within the ischemic core but are in abundance in penumbra regions at 24 hr after transient focal ischemia in P7 [38] (Figure 2F). While mechanisms of astrocytic death in the immature post-ischemic brain are not well understood, at least a subpopulation of these cells die via caspase-3 dependent pathways [13,14]. As an example, caspase-3-dependent death of GFAP –immunoreactive astrocytes is seen starting at 48 hours after permanent MCA occlusion and transient CCA occlusion results in P7 rats [13,14] and is associated with increased BAX expression [14], cytochrome c release from mitochondria, DNA fragmentation and PARP cleavage [43,83]. Astrocyte fate has been shown to be affected by microglial activation after H-I [96].

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4.4 Other Inflammatory Cells While in adult rodents after focal ischemia T and B cells are seen days after injury, infiltration of these cells following neonatal H-I and focal stroke may be less profound [21,106] or transient in neonates [14]. There is, however, increasing evidence for the role of mast cells after neonatal H-I and excitotoxic injury [98,113]. The injurious effects of mast cells has been shown to depend on TGF-β and IL-9 [75]. Agents that inhibit histamine release or degranulate mast cell have been shown to diminish excitotoxic brain injury in P5 rats [98,113]. Consistent with these findings, mast cell-deficient mice have smaller injury size [98].

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4.5 Cytokines Cytokines are polypeptides that exert a variety of biological functions affecting longterm developmental events such as proliferation, differentiation and cell survival, as well as short-term events such as modulation of synaptic activity and inflammatory responses. Circulating leukocytes, endothelial cells, and tissue macrophages are the main sources of proinflammatory cytokines. IL-1β, IL-6, and TNFα are the most extensively studied cytokines in neonatal models of H-I [73,125], excitotoxicity [41] [67] and focal ischemia [54]. They can exacerbate local inflammation by activating astrocytes and microglia to induce a number of other cytokines and chemokines, or by direct neurotoxicity [10]. IL-1β and IL-6 appear transiently several hours after the insult [73,125], and blocking their actions protects the neonatal brain [68]. A less well studied pro-inflammatory cytokine, IL-18, has been shown to play a deleterious role of in the pathophysiology of H-I [73]. This cytokine becomes bioactive upon cleavage by caspase-1 in a way similar to that for IL-1β, which occurs predominantly in activated microglia. While the exact mechanism of the IL-18 action is not known, IL-18 deficiency significantly reduces H-I injury [73]. Pre-treatment with recombinant cytokines prior to an excitotoxic stimulus in P5 rats has demonstrated that pro-inflammatory Th1 cytokines IL-1β, IL-6, or TNFα [41] or the proinflammatory Th2 cytokine IL-9 [41,113], significantly exacerbate the severity of ibotenate induced injury to cortical plate and white matter. These cytokines also significantly increase the density of activated microglia while leaving the density of astrocyte unaffected [41]. A pleotrophic Th2 cytokine IL-10, which can act on both hematopoietic and nonhematopoietic cells, in turn, can revert injury caused by IL-1β and IL-6 [99]. Importantly, protection is seen only when IL-10 is administered post-insult, whereas treatment prior to or at the time of insult is ineffective [99]. Reduction of macrophage accumulation in the injured brain is considered to be one of the mechanisms of IL-10 [99], while its counteraction of the metabolic and microcirculatory effects of H-I is another possibility. Taken together these data show that balance between different cytokines affects injury outcome.

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Figure 3. IL-1β is rapidly and transiently elevated in circulation and in the injured cortex following transient MCA occlusion in P7 rats. A. Occlusion triggers an increase in systemic IL-1β levels (3hr) and a continued increase over the 1-8 hr of reperfusion. B. Elevated IL-1β levels are seen in the injured but not in the matching contralateral tissue. * - p < 0.05, ** - p < 0.001.

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Using a multi-plex technology, we have simultaneously determined levels of 14 cytokines in the systemic circulation and in the brain following transient MCA occlusion in P7 rats. Our data show transiently increased levels of IL-1β, IL-6, IL-18, MCP-1 and CINC-1 first in the circulation and, later, in the injured brain. As an example, Figure 3 shows that IL1β is transiently elevated in circulation and in the injured cortex. Using the broad-spectra anti-inflammatory drug minocycline, we have also that attenuation of circulating levels of aforementioned cytokines is not associated with the ability of this drug to reduce levels of these inflammatory molecules locally in the injured tissue and results only in modest shortterm protection [54].

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4.6 Chemokines Chemoattractant cytokines, chemokines, and their receptors exert a variety of physiological functions, including control of cell migration, proliferation, differentiation and angiogenesis under normal and disease states [62]. An important role for β (CC), α (CXC) and δ (CXC3) classes of chemokines has been documented in many animal models of neurodegeneration, including stroke [147]. The break-down of inflammatory genes by functional category in a microarray analysis has shown that chemokines are the first family of molecules to increase (by 2 hr) following H-I in P7 rats [74]. Accumulation of multiple chemokines, including the CC chemokine MCP-1, is rapid following H-I in P7 rats [58,59,144]. The role of MCP-1 as a mediator of acute excitotoxic brain injury has become apparent from exacerbation of NMDA- induced excitotoxic injury by direct co-administration of recombinant MCP-1 together with NMDA [59] and the reversal of the injury by co-administration of a neutralizing anti-MCP-1 antibody [58]. The rapidity of an H-I induced inflammatory response is also evident from accumulation of another CC chemokine, macrophage inflammatory protein-1α (MIP-1α) [32] as well as from complement activation hours after injury [31,127,128]. The rapid induction of CINC-1, a CXC chemokine that contains an ELR+domain and exhibits potent chemoattractant activities towards neutrophils, occurs following the intracerebral administration of IL-1β in juvenile (P21) rats [2]. Increased CINC1 levels are associated with a substantial neutrophil extravasation which can be blocked by inhibiting the CXC chemokine activity [2]. The rapidly induced IL-1β and CINC-1 brain levels in P7 rats following transient MCA occlusion [54], however, is not associated with neutrophil extravasation. These differences may reflect the age-component of injury as well as are likely to depend on the balance between chemokines and the presence of the chemokine receptors. While exertion of chemokine-induced effects depends on the presence of the corresponding receptors, there have been very few studies [57] looking at expression or regulation of chemokine receptors in the developing brain.

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5. Therapeutic Strategies and Future Directions The use of neutralizing antibodies and mice lacking individual components of the inflammatory cascade has laid a foundation for establishing the role of inflammation in neonatal ischemia. Further, multiple pathways linking excitotoxicity, oxidative stress, and inflammation in the acutely injured brain have been described, and a broad range of compounds that can directly or indirectly affect the inflammatory component of injury has been tested in immature animals following ischemia-related insults. Antioxidants have been used to maintain glutathione (GSH) levels, prevent ROS accumulation and activation of glial cells. Antioxidants tested in the ischemic developing brain include allopurinol, mannitol, methionine and deferoxamine [109,121]. A mixture of mannitol, methionine and magnesium given after H-I injury resulted in a shift to less severe injury, presumably by anti-oxidative effects [103]. Allopurinol, a xanthine oxidase inhibitor is protective after HI in piglets [114,148] and neonatal rats [109,112]. Deferoxamine, an iron chelator, affords protection after HI in mice[121] and rats [110], presumably through a reduction in low molecular weight iron, and hence a decrease in the conversion of H2O2 to OH. through the Fenton reaction as well as by stimulation of hypoxia-dependent genes [102]. Induction of iNOS and the consequent NO generation, which can be damaging through ROS accumulation and activation of glial cells as well as by directly damaging proteins and DNA, has been targeted through selective iNOS inhibition. Aminoguanidine administration protected against H-I [132] but not against transient MCA occlusion in P7 rats (Dingma and Vexler, unpublished). Interestingly, combined inhibition of nNOS and iNOS following H-I improved long-term outcome but without influencing the inflammatory response in the neonatal rat brain [136]. Attenuation of microglial activation could be an attractive strategy but there are no agents that exclusively affect microglial cells. A number of agents that affect microglial activation, including chloroquine, chloroquine+colchicine, and minocycline, reduce microglial density and attenuate excitotoxic brain injury [42]. However, in neonatal models of H-I and focal stroke results of minocycline administration are mixed [4,54,133]. While study by Arvin et al [4] in P7 rat has shown remarkable protection from H-I by minocycline, and Tsuji et al [133] has shown a more modest protection in the same rat model, the latter study has also shown increased injury associated with minocycline treatment in the developing mouse [133]. Following focal stroke in animals of the same age we observed early (at 24 hr) but transient protection which did not last till 7 days after surgery [54]. The beneficial effect of minocycline acutely after reperfusion was not associated with reduction in accumulation of activated microglia. While minocycline reduced accumulation of IL-1β and CINC-1 in the systemic circulation, it failed to affect the increased levels of IL-1β, IL-18, MCP-1 or CINC-1 in the injured brain tissue. Another anti-inflammatory drug, a synthetic corticosteroid dexamethasone, can protect neonatal rats against combined LPS and H-I injury [78]. So far, the most successful and consistent anti-stroke intervention that works in all age groups is hypothermia (cooling). Several studies have shown that controlled cooling in immature animals [1,86,126,129-131] and human babies [44,63] can provide significant protection, whereas hyperthermia can exacerbate injury [145]. Reduction of the signs of

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inflammation associated with cooling may largely be secondarily to slowing the brain metabolism, but may have a direct role as well. Importantly, combining hypothermia with drug administration (such as studies with topiramate [89]) have provided a powerful message that hypothermia can extend the “therapeutic window”. To summarize, the inflammatory component of ischemia-related injury is complex in the prenatal and perinatal brain. It is important to realize that while inflammation propagates injury and its disruption can protect the developing brain by mechanisms yet to be better understood, studies are also needed to determine whether anti-inflammatory agents have adverse effects on long-term brain development, whether anti-inflammatory drugs can disrupt specific endogenous repair mechanisms, and whether the effect of such agents is affected by genetic background or gender.

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[97] McRae, A., Gilland, E., Bona, E. and Hagberg, H., Microglia activation after neonatal hypoxic-ischemia, Brain Res Dev Brain Res, 84 (1995) 245-52. [98] Mesples, B., Fontaine, R.H., Lelievre, V., Launay, J.M. and Gressens, P., Neuronal TGF-beta1 mediates IL-9/mast cell interaction and exacerbates excitotoxicity in newborn mice, Neurobiol Dis, 18 (2005) 193-205. [99] Mesples, B., Plaisant, F. and Gressens, P., Effects of interleukin-10 on neonatal excitotoxic brain lesions in mice, Brain Res Dev Brain Res, 141 (2003) 25-32. [100] Monje, M.L., Toda, H. and Palmer, T.D., Inflammatory blockade restores adult hippocampal neurogenesis, Science, 302 (2003) 1760-5. [101] Motoyama, N., Wang, F., Roth, K.A., Sawa, H., Nakayama, K., Negishi, I., Senju, S., Zhang, Q., Fujii, S. and et al., Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice, Science, 267 (1995) 1506-10. [102] Mu, D., Sheldon, R.A., Vexler, Z.S. and Ferriero, D.M., DFO, sumitted (2004). [103] Mujsce, D.J., Towfighi, J., Stern, D. and Vannucci, R.C., Mannitol therapy in perinatal hypoxic-ischemic brain damage in rats, Stroke, 21 (1990) 1210-4. [104] Muramatsu, K., Sheldon, A., Black, S., Tauber, M. and Ferriero, D., Nitric oxide activity and inhibition after neonatal hypoxia ischemia in the mouse brain, Developmental Brain Research, 123 (2000) 119-127. [105] Nicoll, R.A. and Malenka, R.C., Contrasting properties of two forms of long-term potentiation in the hippocampus, Nature, 377 (1995) 115-8. [106] Northington, F.J., Ferriero, D.M., Flock, D.L. and Martin, L.J., Delayed neurodegeneration in neonatal rat thalamus after hypoxia-ischemia is apoptosis, J Neurosci, 21 (2001) 1931-1938. [107] Olney, J.W., Wozniak, D.F., Jevtovic-Todorovic, V., Farber, N.B., Bittigau, P. and Ikonomidou, C., Drug-induced apoptotic neurodegeneration in the developing brain, Brain Pathol, 12 (2002) 488-98. [108] Olney, J.W., Young, C., Wozniak, D.F., Ikonomidou, C. and Jevtovic-Todorovic, V., Anesthesia-induced developmental neuroapoptosis. Does it happen in humans?, Anesthesiology, 101 (2004) 273-5. [109] Palmer, C., Hypoxic-ischemic encephalopathy. Therapeutic approaches against microvascular injury, and role of neutrophils, PAF, and free radicals, Clin Perinatol, 22 (1995) 481-517. [110] Palmer, C., Roberts, R.L. and Bero, C., Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats, Stroke, 25 (1994) 1039-45. [111] Palmer, C., Roberts, R.L. and Young, P.I., Timing of neutrophil depletion influences long-term neuroprotection in neonatal rat hypoxic-ischemic brain injury, Pediatr Res, 55 (2004) 549-56. [112] Palmer, C., Towfighi, J., Roberts, R.L. and Heitjan, D.F., Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats, Pediatric Research, 33 (1993) 405-11. [113] Patkai, J., Mesples, B., Dommergues, M.A., Fromont, G., Thornton, E.M., Renauld, J.C., Evrard, P. and Gressens, P., Deleterious effects of IL-9-activated mast cells and neuroprotection by antihistamine drugs in the developing mouse brain, Pediatr Res, 50 (2001) 222-30.

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[114] Peeters-Scholte, C., Koster, J., Veldhuis, W., van den Tweel, E., Zhu, C., Kops, N., Blomgren, K., Bar, D., van Buul-Offers, S., Hagberg, H., Nicolay, K., van Bel, F. and Groenendaal, F., Neuroprotection by selective nitric oxide synthase inhibition at 24 hours after perinatal hypoxia-ischemia, Stroke, 33 (2002) 2304-10. [115] Plane, J.M., Liu, R., Wang, T.W., Silverstein, F.S. and Parent, J.M., Neonatal hypoxicischemic injury increases forebrain subventricular zone neurogenesis in the mouse, Neurobiol Dis, 16 (2004) 585-95. [116] Qiao, M., Latta, P., Meng, S., Tomanek, B. and Tuor, U.I., Development of acute edema following cerebral hypoxia-ischemia in neonatal compared with juvenile rats using magnetic resonance imaging, Pediatr Res, 55 (2004) 101-6. [117] Raivich, G., Bohatschek, M., Kloss, C.U., Werner, A., Jones, L.L. and Kreutzberg, G.W., Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function, Brain Res Brain Res Rev, 30 (1999) 77-105. [118] Raivich, G., Bohatschek, M., Werner, A., Jones, L.L., Galiano, M., Kloss, C.U., Zhu, X.Z., Pfeffer, K. and Liu, Z.Q., Lymphocyte infiltration in the injured brain: role of proinflammatory cytokines, J Neurosci Res, 72 (2003) 726-33. [119] Rosenberg, G.A., Matrix metalloproteinases in neuroinflammation, Glia, 39 (2002) 279-91. [120] Santambrogio, L., Belyanskaya, S.L., Fischer, F.R., Cipriani, B., Brosnan, C.F., Ricciardi-Castagnoli, P., Stern, L.J., Strominger, J.L. and Riese, R., Developmental plasticity of CNS microglia, Proc Natl Acad Sci U S A, 98 (2001) 6295-300. [121] Sarco, D.P., Becker, J., Palmer, C., Sheldon, R.A. and Ferriero, D.M., The neuroprotective effect of deferoxamine in the hypoxic-ischemic immature mouse brain, Neurosci Lett, 282 (2000) 113-6. [122] Saunders, N.R., Habgood, M.D. and Dziegielewska, K.M., Barrier mechanisms in the brain, II. Immature brain, Clin Exp Pharmacol Physiol, 26 (1999) 85-91. [123] Schnell, L., Fearn, S., Schwab, M.E., Perry, V.H. and Anthony, D.C., Cytokine-induced acute inflammation in the brain and spinal cord, J Neuropathol Exp Neurol, 58 (1999) 245-54. [124] Sheldon, R.A., Jiang, X., Francisco, C., Christen, S., Vexler, Z.S., Tauber, M.G. and Ferriero, D.M., Manipulation of antioxidant pathways in neonatal murine brain, Pediatr Res, 56 (2004) 656-62. [125] Szaflarski, J., Burtrum, D. and Silverstein, F.S., Cerebral hypoxia-ischemia stimulates cytokine gene expression in perinatal rats, Stroke, 26 (1995) 1093-100. [126] Taylor, D.L., Mehmet, H., Cady, E.B. and Edwards, A.D., Improved neuroprotection with hypothermia delayed by 6 hours following cerebral hypoxia-ischemia in the 14day-old rat, Pediatr Res, 51 (2002) 13-9. [127] Ten, V.S., Bradley-Moore, M., Gingrich, J.A., Stark, R.I. and Pinsky, D.J., Brain injury and neurofunctional deficit in neonatal mice with hypoxic-ischemic encephalopathy, Behav Brain Res, 145 (2003) 209-19. [128] Ten, V.S., Wu, E.X., Tang, H., Bradley-Moore, M., Fedarau, M.V., Ratner, V.I., Stark, R.I., Gingrich, J.A. and Pinsky, D.J., Late measures of brain injury after neonatal hypoxia-ischemia in mice, Stroke, 35 (2004) 2183-8.

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[129] Thoresen, M., Haaland, K., Loberg, E.M., Whitelaw, A., Apricena, F., Hanko, E. and Steen, P.A., A piglet survival model of posthypoxic encephalopathy, Pediatr Res, 40 (1996) 738-48. [130] Thoresen, M., Penrice, J., Lorek, A., Cady, E.B., Wylezinska, M., Kirkbride, V., Cooper, C.E., Brown, G.C., Edwards, A.D., Wyatt, J.S. and et al., Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet, Pediatr Res, 37 (1995) 667-70. [131] Tooley, J.R., Satas, S., Porter, H., Silver, I.A. and Thoresen, M., Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective, Ann Neurol, 53 (2003) 65-72. [132] Tsuji, M., Higuchi, Y., Shiraishi, K., Kume, T., Akaike, A. and Hattori, H., Protective effect of aminoguanidine on hypoxic-ischemic brain damage and temporal profile of brain nitric oxide in neonatal rat [In Process Citation], Pediatr Res, 47 (2000) 79-83. [133] Tsuji, M., Wilson, M.A., Lange, M.S. and Johnston, M.V., Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model, Exp Neurol, 189 (2004) 5865. [134] Tuor, U.I. and Grewal, D., Autoregulation of cerebral blood flow: influence of local brain development and postnatal age, Am J Physiol, 267 (1994) H2220-8. [135] Urakubo, A., Jarskog, L.F., Lieberman, J.A. and Gilmore, J.H., Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain, Schizophr Res, 47 (2001) 27-36. [136] van den Tweel, E.R., Peeters-Scholte, C.M., van Bel, F., Heijnen, C.J. and Groenendaal, F., Inhibition of nNOS and iNOS following hypoxia-ischaemia improves long-term outcome but does not influence the inflammatory response in the neonatal rat brain, Dev Neurosci, 24 (2002) 389-95. [137] Vannucci, R.C. and Vannucci, S.J., Glucose metabolism in the developing brain, Semin Perinatol, 24 (2000) 107-15. [138] Vannucci, S.J., Clark, R.R., Koehler-Stec, E., Li, K., Smith, C.B., Davies, P., Maher, F. and Simpson, I.A., Glucose transporter expression in brain: relationship to cerebral glucose utilization, Dev Neurosci, 20 (1998) 369-79. [139] Vannucci, S.J. and Hagberg, H., Hypoxia-ischemia in the immature brain, J Exp Biol, 207 (2004) 3149-54. [140] Verma, P.K., Panerai, R.B., Rennie, J.M. and Evans, D.H., Grading of cerebral autoregulation in preterm and term neonates, Pediatr Neurol, 23 (2000) 236-42. [141] Vexler, Z.S. and Ferriero, D.M., Molecular and biochemical mechanisms of perinatal brain injury, Semin Neonatol, 6 (2001) 99-108. [142] Wang, X., Karlsson, J.O., Zhu, C., Bahr, B.A., Hagberg, H. and Blomgren, K., Caspase-3 activation after neonatal rat cerebral hypoxia-ischemia, Biol Neonate, 79 (2001) 172-9. [143] Wendland, M., Derugin, N., Manabat, C., Fox, C.K., Ferriero, D.M. and Vexler, Z.S., The blood-brain barrier is more preserved in neonatal versus adult rats following transient focal cerebral ischemia, Journal of Cerebral Blood Flow & Metabolism, 23 (2003) 169.

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[144] Xu, H., Barks, J.D., Schielke, G.P. and Silverstein, F.S., Attenuation of hypoxiaischemia-induced monocyte chemoattractant protein-1 expression in brain of neonatal mice deficient in interleukin-1 converting enzyme, Brain Res Mol Brain Res, 90 (2001) 57-67. [145] Yager, J.Y., Armstrong, E.A., Jaharus, C., Saucier, D.M. and Wirrell, E.C., Preventing hyperthermia decreases brain damage following neonatal hypoxic-ischemic seizures, Brain Res, 1011 (2004) 48-57. [146] Yakovlev, A.G., Ota, K., Wang, G., Movsesyan, V., Bao, W.L., Yoshihara, K. and Faden, A.I., Differential expression of apoptotic protease-activating factor-1 and caspase-3 genes and susceptibility to apoptosis during brain development and after traumatic brain injury, J Neurosci, 21 (2001) 7439-46. [147] Yamasaki, Y., Matsuo, Y., Matsuura, N., Onodera, H., Itoyama, Y. and Kogure, K., Transient increase of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, in ischemic brain areas after focal ischemia in rats, Stroke, 26 (1995) 318-22; discussion 322-3. [148] Zhu, C., Wang, X., Qiu, L., Peeters-Scholte, C., Hagberg, H. and Blomgren, K., Nitrosylation precedes caspase-3 activation and translocation of apoptosis-inducing factor in neonatal rat cerebral hypoxia-ischaemia, J Neurochem, 90 (2004) 462-71. [149] Zhu, C., Wang, X., Xu, F., Bahr, B.A., Shibata, M., Uchiyama, Y., Hagberg, H. and Blomgren, K., The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia-ischemia, Cell Death Differ, 12 (2005) 162-76.

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In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 221-240 © 2006 Nova Science Publishers, Inc.

Chapter X

Neurotrauma and Inflammation Roberta Brambilla, John R. Bethea and Valerie Bracchi-Ricard The Miami Project To Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

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1. Introduction Both traumatic brain injury (TBI) and spinal cord injury (SCI) are devastating conditions and leading causes of death and severe disability among young individuals. During the acute phase of injury, the primary mechanical impact to the brain or spinal cord induces an immediate tissue disruption causing focal hemorrhage, edema, release of excitatory amino acids and oxygen radicals. As a consequence of these initial events, a phase of secondary damage is initiated, during which neurochemical and metabolic alterations take place at the cellular level, ultimately leading to diffuse cell death and, often, tissue cavitation (in the spinal cord particularly, Hausmann, 2003). The inflammatory response is activated and the initial lesion expands as the injury progresses into a chronic phase. This inflammatory response is sustained by the concerted action of both peripheral cells (neutrophils, macrophages and lymphocytes) infiltrating the central nervous system (CNS) through a compromised blood brain barrier (BBB), and resident cells, particularly astrocytes and microglia. In these cell populations, which can be considered the resident inflammatory cells of the CNS, proinflammatory signal transduction cascades, such as the NF-κB pathway, are promptly activated following injury. This leads to the synthesis and release of cytokines, chemokines, extracellular matrix molecules, prostanoids, nitric oxide (NO), etc., which sustain and amplify the inflammatory reaction resulting in additional tissue loss. The aim of this review is to discuss the contribution of glial cells to the inflammatory response of the CNS to neurotrauma, based on the vast body of data accumulated from in vivo models of TBI as well as SCI.

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2. Post-Traumatic Inflammation in the Brain and Spinal Cord

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2.1 Differences between Spinal Cord and Brain Post-traumatic inflammation is a common feature of both TBI and SCI and contributes to the pathophysiology of these traumas. The initial mechanical injury to the brain or spinal cord initiates in both cases a complex cascade of events with common features like membrane disruption, hemorrhage, ischemia, vascular damage and both immediate (mostly necrotic) and delayed (apoptotic and necrotic) cell death. The secondary phase is characterized by a robust immune response with synthesis of cytokines and chemokines, coordinated infiltration of the injury site by peripheral leukocytes, activation of resident immune cells (microglia) resulting acutely in the clearance of cell debris but chronically in bystander cell damage and progressive tissue loss. The final lesion site is far greater than that observed few hours postinjury. Schnell and colleagues provided evidence that the acute inflammatory response to traumatic injury is significantly greater in the spinal cord than the cerebral cortex using the same mouse strain with similar incision lesions performed in the frontal cortex and spinal cord (Schnell et al., 1999). The number of neutrophils recruited at the lesion 1 day following injury was much greater in the spinal cord than in the brain. This was correlated with a greater upregulation of intercellular adhesion molecules, in particular the platelet-endothelial cell adhesion molecule (PECAM) in the spinal cord. In addition, whereas neutrophils were closely lining the lesion sites in the cortex, the distribution in the spinal cord was more widespread. Similarly, the macrophages/microglia reaction was also considerably greater in the spinal cord. Lymphocytes were recruited at a relatively low number in these paradigms, but again in contrast with the brain, they could be found as far as 3-4 mm from the lesion. The astrocytic response to trauma, as measured by GFAP upregulation, was more pronounced in the spinal cord at 1 day post-injury, and doubled that of the forebrain at 2 days. Correlating with the neutrophil recruitment profile, the area of BBB breakdown, as revealed by horseradish peroxidase extravasation, was two to three times larger in the spinal cord and lasted up to 14 days (last time point studied) whereas in the brain the BBB was reestablished after 10 days.

2.2 Differences between Mouse and Rat The study by Schnell and colleagues was carried out in a mouse model. Although mice are very useful especially to study gene-specific function (knockout and transgenic mice models) they also display a unique pathology following spinal cord contusion, which is the result of a distinct inflammatory response (Sroga et al., 2003). One major difference between mice and other mammals (rats, cats, monkeys, humans) is the absence of fluid-filled cystic cavities in mice after SCI. Instead, the lesion site is filled with dense fibrous connective tissue. Sroga and colleagues reported differences in the distribution, magnitude, and composition of the inflammatory response to SCI between Lewis rats and C57BL/6 mice (Sroga et al., 2003). A major difference was the significant infiltration of T-cells and

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dendritic cells in the rat contused spinal cord. The time-course of macrophages/microglia activation was similar between rat and mouse. The role of microglia/macrophages remains controversial as they can produce a number of inflammatory cytokines, chemokines, but also growth-promoting factors. Differences in the mediators released by mouse or rat macrophages/microglia could result in a species-specific post-injury cellular environment (Sroga et al., 2003).

2.3 Strain Differences Differences have also been reported between strains of rats following SCI, where contused Lewis rats had an elevated microglia/macrophages response and an early infiltration of T-cells compared to Sprague-Dawley rats (Popovich et al., 1997). Mice also exhibit differences, some strains being excitotoxic-resistant and others sensitive. Enhanced cellular repair and axonal growth was observed in 129X1/SvJ mice, which have diminished chronic inflammatory response compared to C57Bl/6 mice receiving identical contusion to the spinal cord (Ma et al., 2004).

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2.4 Gender The inflammatory response to brain trauma may be affected by hormone levels. This issue is not well addressed and most in vivo SCI and TBI studies are conducted in male rats (to avoid hormonal issues) or female mice (because of frequent urinary tract infections in male mice after SCI). However, evidence is accumulating that the response to trauma, and particularly the inflammatory response, may be affected by the gender. Less inflammatory cells infiltrating the lesion were observed in female C57Bl/6 mice compared to males after SCI (Farooque et al., 2005). Similarly, in rats after head injury females displayed a higher survival rate and smaller lesion size than males (Roof and Hall, 2000; Bramlett and Dietrich, 2001). In contrast, in a controlled-cortical impact model no differences were observed between genders (Hall et al., 2005).

2.5 Age Enhanced glial activation was observed in aged (36 months) compared to young (3 months) rats following cortical stab injury (Kyrkanides et al., 2001). This was correlated with a greater increase in tumor necrosis factor (TNF), interleukin-6 (IL-6), interleukin-1β (IL-1β) in aged rats at 6 hours post-injury, decreasing at 72 hours to levels similar to young rats. In addition, significant increase in inducible nitric oxide synthase (iNOS), intercellular adhesion molecule (ICAM) and matrix metalloproteinase-9 (MMP-9) was observed in aged rats and still remained sustained at 72 hours, whereas in young rats the levels had returned to that of sham controls. Clinical studies have established that the outcome following TBI is worsened by age.

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3. NF-κB Activation Following Trauma The transcription factor nuclear factor kappa-B (NF-κB) regulates the expression of many genes encoding cytokines, chemokines, inflammatory enzymes (cyclooxygenase and nitric oxide synthase), and mediating the inflammatory responses in the CNS. Following TBI and SCI NF-κB is rapidly activated in the brain (Yang et al., 1995; Nonaka et al., 1999; Nomoto et al., 2001; Sanz et al., 2002; Lotocki et al., 2004) and spinal cord (Bethea et al., 1998; Kim et al., 2001; Conti et al., 2003; La Rosa et al., 2004; Brambilla et al., 2005; Genovese et al., 2005). NF-κB activation has been reported to occur in various cell types including neurons, astrocytes, microglia/macrophages, and oligodendrocytes (Bethea et al., 1998; Nonaka et al., 1999; Nomoto et al., 2001; Sanz et al., 2002; Yune et al., 2004), using coimmunolocalization of an activated form of p65 with cell-specific markers. The spatio-temporal activation of NFκB varies with the type of injury, the animal model and the CNS compartment. In a parasagittal fluid percussion model of TBI in the rat, NF-κB was first found to be activated mostly in injured axons of the cerebral cortex, within 24 hours in microglia/macrophages and within 48 hours in astrocytes (Nonaka et al., 1999). Interestingly, NF-κB activation persisted in microglia/macrophages and astrocytes up to 1 year following trauma at the margin of the progressively enlarging necrotic cavities, which correspond also to the regions undergoing persistent tissue loss. These observations suggest a role for astrocytes and microglia/macrophages in the prolonged inflammatory process through sustained activation of NF-κB. In a different model of brain injury consisting in the thermal ablation of a portion of the cortex in mice, a delayed activation of NF-κB was observed (Nomoto et al., 2001). Indeed, the first weak p65 nuclear immunoreactivity was observed 2 days after injury in mononuclear cells surrounding the lesion. Later, at 4 and 8 days, a strong p65 immunostaining was found in astrocytes and macrophage/microglia around the lesion. This NF-κB activation faded by 14 days and was absent at 28 days. Different patterns of activation were also observed in the lesioned immature rat brain, which is more plastic than the adult brain with ameboid microglia present under physiological conditions (Sanz et al., 2002). In this model of cortical aspiration the glial response was very rapid with microglia reactivity observed at 4 hours post-lesion within the neurodegenerative area bordering the cavity, and reactive hypertrophic astrocyte response evident at 10 hours in the damaged cortex. NF-κB activation was observed not only in hypertrophic reactive astrocytes surrounding the lesion and forming the glial scar, but also in white matter astrocytes located at deeper levels into the brain parenchyma (e.g., corpus callosum) (Sanz et al., 2002). In contrast to the long-lasting microglial NF-κB activation reported in adult brain (Nonaka et al., 1999), the injury to the post-natal rat brain induced a pulse-like activation of microglial NF-κB. In this study by Sanz and colleagues the latest time point was 7 days post-injury. In summary, those studies agree on an initial activation of NF-κB in microglial cells followed by activation in astrocytes in areas of progressive tissue damage, strongly suggesting a role for glial cells and the NF-κB pathway in the secondary injury process. In a model of spinal cord contusion in the adult rat, Bethea and colleagues reported the presence of activated NF-κB in macrophages/microglia and endothelial cells starting 30 minutes post-injury and lasting for 72 hours, which was the last time point studied. Activated

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NF-κB appeared in neurons at 24 hours post-injury. Although no p65 immunostaining was observed in astrocytes up to 72 hours post-injury, it is possible that delayed astroglial reactivity would have been observed at later time points. In fact, a more recent study using a transgenic mouse model where NF-κB was selectively blocked in astrocytes clearly implicated astroglial cells and the NF-κB pathway in the pathophysiology of SCI (Brambilla et al., 2005). Immediately after injury (1 hour), NF-κB was primarily activated in astrocytes and the events initiated thereafter lead to the loss of locomotor function, as transgenic mice with inactive NF-κB in astrocytes recovered from contusion-induced hindlimb paralysis significantly better than wild type mice. This appeared to be due to the reduced expression of NF-κB-dependent proinflammatory chemokines interferon-inducible protein-10 (IP10) and monocyte chemoattractant protein-1 (MCP-1) in astrocytes, as well as of the proteoglycans neurocan and phosphacan, which are synthesized by astrocytes and take part in the formation of the glial scar. The chronic activation of NF-κB in astrocytes and/or microglia/macrophages indicates the importance of these cells in the maintenance of the inflammatory response after injury, which appears to be associated with the progressive loss of nervous tissue and concomitant loss of neurological functions. In support of these observations is the use of various pharmacological strategies aimed at reducing the inflammatory response that improve the functional outcome after trauma and inhibit NF-κB activation (Xu et al., 1998; La Rosa et al., 2004; Ravikumar et al., 2004; Genovese et al., 2005). Although it is tempting to view NF-κB as a foe, we need to keep in mind that NF-κB does regulate not only the expression of proinflammatory molecules but also of anti-apoptotic factors like cIAP2 (Kim et al., 2001) and antioxidative enzymes like manganese superoxide dismutase (MnSOD) (Yune et al., 2004). Furthermore, other transcription factors may be playing important roles either on their own or in concert with NF-κB.

4. Cytokine Production Following trauma to the CNS cytokine levels rapidly increase at the site of lesion. Although several members of the cytokine family have well demonstrated anti-inflammatory properties, overall these molecules are considered amongst the principal mediators of the inflammatory response (see for review Brambilla et al., 2005). Cytokines are produced at high concentrations not only by infiltrating immune cells, but also by resident microglia and astrocytes in the CNS parenchyma, particularly during the early phase of injury. A correlation between the severity of the injury and the levels of proinflammatory cytokines was established (Yang et al., 2005).

4.1 TNFα Reactive astrocytes at the lesion site begin synthesizing TNFα within minutes (Kita et al., 2000; Lee et al., 2000) and appear to keep up the production for a relatively narrow window of time (Bartholdi and Schwab, 1997; Streit et al., 1998; Yan et al., 1999; Yan et al., 2001).

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At later times the astrocytic production of TNFα is sustained by cells surrounding the lesion (glial scar) or at even farther distances from the site of damage (Kita et al., 2000). This initial burst of TNFα is believed to be a further signal for the production of more proinflammatory cytokines from the glial cells (not only astrocytes, but also microglia) and from infiltrating leukocytes entering the CNS, therefore acting as a major player in the amplification of the inflammatory response (Pan et al., 2002). The early inhibition of TNFα and TNFα signaling after trauma, in fact, has generally proven to be neuroprotective and is paralleled by the reduction in the expression of other proinflammatory molecules. As an example, the topical application of TNF antiserum at the site of injury significantly attenuated swelling, edema, disturbances of the microvascular permeability and cell injury induced by SCI (Sharma et al., 2003). TNF antiserum also diminished the SCI-induced upregulation of neuronal nitric oxide synthase (nNOS), indicating a possible beneficial role in preventing NO-mediated oxidative damage following injury. Two other members of the TNF superfamily of cytokines, Fas and FasL (also called CD95 and CD95L, or APO-1 and APO-1L), have also been implicated in the inflammatory response triggered following CNS trauma. Both molecules are upregulated at various degrees in neurons, astrocytes, oligodendrocytes and microglia following TBI and SCI (Beer et al., 2000; Casha et al., 2001; Zurita et al., 2001; Qiu et al., 2002; Demjen et al., 2004) and act as proinflammatory and proapoptotic signals by activating the NF-κB pathway (see for review Wajant et al., 2003; Dosreis et al., 2004). In astrocytes Fas ligation (permanent death receptor activation) induces the upregulation of cytokines and chemokines such as IL-6, MCP-1 and IL-8 (Saas et al., 1999; Lee et al., 2000), which can propagate the inflammatory response by stimulating blood cell chemotaxis into the injured CNS, potentially preventing functional recovery. On the other hand, neutralization of FasL by administration of a FasL-specific antibody lead to increased oligodendrocyte and neuronal survival, axonal regeneration and improved functional outcome following SCI (Demjen et al., 2004).

4.2 IL-6 In the CNS IL-6 production, which originates largely from astrocytes and microglial cells, is upregulated following injury. Although a number of neuroprotective effects are attributed to this molecule (Morganti-Kossmann et al., 2002), a great body of evidence demonstrates the proinflammatory properties of IL-6, implicating it in the development of secondary tissue damage after trauma (see for review John et al., 2003; Brambilla et al., 2005). The destructive potential of deregulated IL-6 is evident from studies by Campbell and colleagues (Campbell et al., 1993; Barnum et al., 1996) showing that transgenic mice overexpressing IL-6 in astrocytes display extensive brain damage (neurodegeneration, BBB disruption, learning deficit) caused by a persistent state of inflammation. This is supported by studies in IL-6 knockout mice, which exhibit reduced inflammation and depressed astrogliosis after focal cryo-injury compared to wild type mice (Penkowa et al., 1999). Furthermore, in models of SCI, blocking the IL-6 receptor or IL-6 bioactivity with specific neutralizing antibodies suppressed reactive astrogliosis, decreased scar tissue formation, immune cell infiltration, iNOS activity and secondary damage, leading to significant

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improvement of functional recovery (Tuna et al., 2001; Okada et al., 2004). Along the same line, administration of a bioactive IL-6/soluble IL-6 receptor fusion protein (H-IL-6), secreted by genetically engineered fibroblasts grafted at the site of lesion, induced amplification of the inflammatory response resulting in increased neutrophil infiltration and consequent elevation in reactive oxygen species (Lacroix et al., 2002). Like IL-6, leukemia inhibitory factor (LIF) plays a key role in inflammation and can act in both a pro- and anti-inflammatory fashion (see for review Gadient and Patterson, 1999). While LIF has been extensively studied in a number of inflammatory conditions (e.g., rheumatoid arthritis), few studies have investigated the role of LIF in traumatic injury to the CNS. As indicated in a stab wound injury model of CNS trauma, LIF expression is rapidly upregulated predominantly in astrocytes in the lesion penumbra (Banner et al., 1997). In this context, LIF appears to operate as a proinflammatory signal by recruiting peripheral monocytes and inducing reactive gliosis (Sugiura et al., 2000).

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4.3 IL-1β IL-1β is expressed at low levels by neurons and glial cells under physiological conditions and like TNF is quickly upregulated within the CNS parenchyma following trauma. Studies agree on a robust and transient increase in IL-1β mRNA as early as 1 hour post-injury in both TBI (Fan et al., 1995; Rostworowski et al., 1997; Herx et al., 2000) and SCI models (Bartholdi and Schwab, 1997; Wang et al., 1997; Streit et al., 1998; Pan et al., 2002). Increase in IL-1β protein levels (measured by ELISA) is detected as soon as 1 to 4 hours following injury to the spinal cord or brain (Wang et al., 1997; Knoblach and Faden, 2000; Ciallella et al., 2002; Kinoshita et al., 2002). In a rat spinal cord contusion model, IL1β protein levels were sustained until 72 hours post-injury and remained elevated for 1 week (Wang et al., 1997), whereas in the brain IL-1β levels returned to baseline by 24-72 hours following trauma (Knoblach and Faden, 2000; Ciallella et al., 2002; Kinoshita et al., 2002). This would suggest a stronger inflammation in the spinal cord. IL-1β, which is mainly produced by microglia in the injured CNS (Woodroofe et al., 1991; Bartholdi and Schwab, 1997) contributes to the disruption of the BBB, stimulates astrogliosis and glial scar formation, and is involved in neuronal damage. In fact, intracerebral microinjection of IL-1β in rats induced a transient inflammatory reaction accompanied by apoptotic cell death (Holmin and Mathiesen, 2000). In a spinal cord contusion model in rats, IL-1β was implicated in the induction of apoptosis in neurons and oligodendrocytes through caspase-3 activation (Nesic et al., 2001). Recently the p38/mitogen-activated protein kinase (p38/MAPK) pathway was involved in mediating IL-1β-induced neuronal apoptosis (Wang et al., 2005). Furthermore, infusion of IL-1 receptor antagonist (IL-1ra) for 72 hours in the injured spinal cord using an osmotic minipump completely abolished the increase in contusion-induced apoptosis as well as the caspase activity (Nesic et al., 2001). Similarly, injections of IL-1ra in the contused brain starting at 15 minutes and up to 48 hours following injury resulted in reduced damage 3 and 7 days later (Toulmond and Rothwell, 1995). Likewise, transgenic mice overexpressing IL-1ra in astrocytes also displayed a higher neurological recovery following closed head injury compared to wild type mice (Tehranian et

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al., 2002). In contrast, in a rat brain contusion model, intracerebroventricular administration of IL-1ra or soluble IL-1 receptor type I starting at 15 minutes and until 8 hours after injury, did not significantly improve neurological outcome as assessed by a series of motor tasks performed at 1, 7 and 14 days post-injury (Knoblach and Faden, 2000). The discrepancies between the studies may be explained by the different times of treatment. IL-1β like other proinflammatory cytokines does not have only deleterious effects. It also promotes angiogenesis, wound healing and plasticity. Injecting recombinant IL-1β into the dorsal column of the spinal cord undergoing Wallerian degeneration triggered rapid macrophage/microglial activation and myelin clearance (Perrin et al., 2005). Increased IL-1β levels following brain injury were linked to increased levels of ciliary neurotrophic factor (CNTF), an important survival factor for neurons and maturation factor for oligodendrocytes (Herx et al., 2000). Upregulation of IL-1β following TBI was also temporally followed by an increase in nerve growth factor (NGF), which was suppressed by IL-1ra (DeKosky et al., 1996). Similarly, hypothermia decreased IL-1β and NGF expression (Goss et al., 1995).

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4.4 TGFβ Various members of the transforming growth factor beta (TGFβ) family of cytokines have been implicated in the pathophysiology of CNS injury. As many other cytokines, TGFβ has both anti-inflammatory and proinflammatory/profibrotic properties that can lead to either beneficial (e.g., reduction of cytokine production) or detrimental (scar formation) effects following injury (Chin et al., 2004). As a fibrotic molecule (Ihn, 2002), TGFβ is mainly produced by astrocytes, where it induces the synthesis of extracellular matrix molecules and proteoglycans (Westergren-Thorsson et al., 1992; Lagord et al., 2002), which are major constituents of the glial scar and inhibitory to axon regeneration. Following SCI, both TGFβ1 and TGFβ2 are upregulated (Lagord et al., 2002; Brambilla et al., 2005), but it is the expression of TGFβ2, rather than TGFβ1, that apparently correlates with the deposition of the glial scar (Lagord et al., 2002). Treatments aimed at inhibiting TGFβ biological activity (e.g. neutralizing antibodies) have been successful at reducing the deposition of scar tissue (Logan et al., 1994; Moon and Fawcett, 2001) establishing an environment more suitable for axonal regeneration. Interestingly, a recent work from our group has indicated that the early expression of TGFβ2 induced by SCI is significantly reduced in transgenic mice where NFκB is selectively inhibited in astrocytes, and so is the expression of the scar forming proteoglycans neurocan and phosphacan. This demonstrates that TGFβ2 production occurs primarily in astrocytes following SCI and is transcriptionally dependent on NF-κB. The inhibition of this very important proinflammatory pathway in this cells type prevents TGFβ2 expression and results in reduced scar formation and improved functional outcome (Brambilla et al., 2005).

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4.5 EMAPII The endothelial monocyte-activating polypeptide II (EMAPII) is an antiangiogenic and proinflammatory cytokine expressed by microglia/macrophages (Schluesener et al., 1997). In both a rat spinal cord transection model (Mueller et al., 2003a) and a rat cortical stab wound injury model (Mueller et al., 2003b), a significant increase in the number of EMAPII+ microglia/macrophages was observed at the lesion site peaking at 3 and 5 days following SCI and TBI, respectively. In both injury paradigms the EMAPII immunoreactivity declined gradually over several weeks, but still remained elevated compared to sham-operated animals, especially in the SCI model. Clusters of EMAPII+ macrophages/microglia were observed in Virchow-Robin spaces in both the brain and spinal cord. EMAPII might contribute to the formation of edema by compromising the blood flow through its ability to activate P- and E-selectin-mediated platelet and leukocyte rolling on endothelium. The prolonged accumulation of EMAPII+ macrophages/microglia in regions of neuronal death at the lesion site suggests a role for this proinflammatory cytokine in the secondary damage following TBI and SCI.

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5. Chemokines Chemokines are small pleiotropic molecules that act as signals not only for the recruitment of inflammatory leukocytes to the CNS but also for the activation of resident cells of the CNS (e.g., microglia and astrocytes) which, as well as leukocytes, express chemokine receptors (Cartier et al., 2005). In addition, members of the CXC group of chemokines are regulators of angiogenesis, acting either as angiogenic or angiostatic factors (Bernardini et al., 2003). In CNS trauma and other neurodegenerative disorders chemokines (e.g., CXCL10/IP10, CCL2/MCP1, CCL3/MIP1α, CCL5/RANTES), which are produced primarily in astrocytes and, in some cases, in microglial cells, are highly upregulated (Ransohoff et al., 1993; Lee et al., 2000; Otto et al., 2001; Babcock et al., 2003; Baron et al., 2005; Brambilla et al., 2005). CXCL10/IP10, CCL2/MCP1 and CCL5/RANTES expression peaks within 1 day after SCI (Lee et al., 2000; Ravikumar et al., 2004; Brambilla et al., 2005) and treatments resulting in reduction of their production have proven to be neuroprotective. Infusion of the broad spectrum chemokine antagonist vMIPII after SCI diminished hematogenous infiltration and axonal degeneration (Ghirnikar et al., 2001). Similarly, inhibition of astroglial NF-κB in a transgenic mouse model resulted in reduced CXCL10/IP10 and CCL2/MCP1 expression following SCI and improved functional outcome (Brambilla et al., 2005). Antibody neutralization of CXCL10/IP10 beginning 1 day prior to hemisection injury significantly reduced the infiltration of T-lymphocytes into the spinal cord parenchyma, limiting tissue loss and functional deficit (Gonzalez et al., 2003). In a separate study, Glaser and colleagues demonstrated that anti-CXCL10/IP10 treatment of SCI improved blood flow and oxygen supply to the injury by counteracting the angiostatic properties of CXCL10/IP10, hence promoting angiogenesis and ultimately ameliorating the functional outcome (Glaser et al., 2004).

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In an entorhinal cortex brain injury model, CXCL10 was expressed by lesioned neurons (Rappert et al., 2004). In this model of anterograde (Wallerian) axonal degeneration, microglial cells expressing the receptor for CXCL10, namely CXCR3, were attracted to the damaged axons expressing the chemokine. Conversely, in the CXCR3 knockout mice there was a lack of recruitment of microglial cells and maintenance of denervated dendrites. Whether this preservation of dendrites is functionally relevant or not remains to be determined.

6. Oxy-Radical Generating Enzymes

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6.1 Nitric Oxide Synthase Nitric oxide (NO) and reactive oxygen species exert multiple modulating effects on inflammation and regulation of immune responses. Low concentrations of NO produced by constitutive and neuronal nitric oxide synthases (cNOS, nNOS) inhibit adhesion molecule expression, cytokine and chemokine synthesis and leukocyte adhesion and transmigration. Conversely, large amounts of NO, generated primarily by inducible nitric oxide synthase (iNOS/NOS-2), can be cytotoxic and proinflammatory. NO produced after injury by iNOS in activated glia (both astroglia and microglia/macrophages) has been associated with neuronal cell death and functional impairment following CNS injury. Indeed, in many studies, treatments with various iNOS inhibitors (aminoguanidines, 1400W, antisense oligonucleotides) resulted in reduced apoptotic and necrotic cell death of neurons and improved functional outcome following TBI (Chatzipanteli et al., 1999; Jafarian-Tehrani et al., 2005) and SCI (Chatzipanteli et al., 2002; Pearse et al., 2003; Kwak et al., 2005). On the other hand, the prolonged treatment with aminoguanidine was also shown to have deleterious effects in a rat model of TBI with a significant decrease in the number of surviving hippocampal neurons 21 days after injury, suggesting that iNOS may have some protective functions (Sinz et al., 1999). The proinflammatory and deleterious role of NO generated through iNOS was demonstrated in recent studies conducted in iNOS knockout mice. In both a SCI (extradural compression of the thoracic spinal cord, Isaksson et al., 2005) and a TBI (severe aseptic cryogenic cerebral injury, Jones et al., 2004) model, iNOS knockout mice showed significantly improved functional outcome accompanied by reduced lesion volume compared to wild type littermates. In contrast, a recent study by Bayir and colleagues reported an enhanced oxidative stress in iNOS-deficient mice after controlled cortical impact, which would imply a neuroprotective role for iNOS (Bayir et al., 2005). However, in this study the authors did not provide any behavioral outcome measures.

6.2 Cyclooxygenases The production of pronociceptive and proinflammatory prostaglandins is dependent on the activity of cyclooxygenases (COXs). Two COX enzymes have been identified: a constitutively expressed COX-1 and an inducible highly regulated COX-2 (Minghetti and

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Levi, 1998; Vanegas and Schaible, 2001). Interestingly, while COX-2 is hardly expressed in most tissues under physiological conditions, it is detected at significant levels in the brain (Seibert et al., 1994). By immnunohistochemistry, COX-2 was found in both brain and spinal cord neurons, and in spinal cord white matter astrocytes (Beiche et al., 1998). The difference between brain and spinal cord astrocytes was also observed in vitro where spinal cord but not cortical astrocytes released prostaglandins when stimulated with substance P (Marriott et al., 1991). COX-2 mRNA and protein are quickly upregulated within hours following both TBI (Dash et al., 2000; Strauss et al., 2000; Cernak et al., 2001; Kunz et al., 2002) and SCI (Resnick et al., 1998; Adachi et al., 2005). The temporal expression profiles vary depending on the model and the severity of the injury but all studies concur that COX-2 protein levels are sustained for several days following injury. In a lateral cortical impact model, COX-2 protein levels peaked 1-3 days post-injury and returned to sham levels by 7 days (Strauss et al., 2000). In contrast, in an impact acceleration model, which has diffuse axonal injury as a major component, COX-2 remained elevated at least for 12 days post-injury (Cernak et al., 2001). The cell type which expresses COX-2 after trauma is controversial. Following TBI, COX-2 immunoreactivity was found in neurons (Dash et al., 2000; Strauss et al., 2000) and glial cells around the injury (Strauss et al., 2000). Following SCI, COX-2 was localized to endothelial cells lining blood vessels but was not observed in neurons, astrocytes, or macrophage/microglia (Adachi et al., 2005). However, following intraparenchymal injection of IL-1β in the spinal cord, Tonai and colleagues could detect COX-2 in glial cells, leukocytes and vascular endothelial cells (Tonai et al., 1999). Similar intraparenchymal administration of IL-1β in the brain induced COX-2 expression (Moore et al., 2004). COX-1, which has been less studied than COX-2, appears to be predominantly expressed by macrophages/microglia after both TBI and SCI (Mueller et al., 2003a, b). Pharmacological treatments with non steroidal anti-inflammatory drugs aimed at inhibiting COX-2 activity have proven efficacious in reducing the inflammatory response following trauma and improving the functional outcome both in SCI and TBI models (Resnick et al., 1998; Cernak et al., 2001; Hains et al., 2001; Hurley et al., 2002; Gopez et al., 2005).

7. Conclusion Inflammation contributes significantly to the secondary injury mechanisms that follow both traumatic brain and spinal cord injuries, with resident astrocytes and microglia as major players by releasing proinflammatory cytokines, chemokines, NO, prostaglandins, etc. If inflammation is a common factor to traumatic injury, its development varies depending on a number of factors including CNS compartment (brain or spinal cord), type of injury (focal or diffuse), age, gender, and genetic background. Interestingly, many of these factors can be associated with differences in astrocyte and microglia reactivity. These differences are crucial as they may affect the window during which an anti-inflammatory treatment strategy would be the most beneficial. As reported in many studies, the same cytokines that are proinflammatory early following injury also play beneficial roles later during regeneration.

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Acknowledgements This work was supported by National Insitute of Health grants NS37130 and NS051709 (both to JR Bethea) and by the Miami Project to Cure Paralysis.

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[70] Nomoto Y, Yamamoto M, Fukushima T, Kimura H, Ohshima K, Tomonaga M (2001) Expression of nuclear factor kappaB and tumor necrosis factor alpha in the mouse brain after experimental thermal ablation injury. Neurosurgery 48:158-166. [71] Nonaka M, Chen XH, Pierce JE, Leoni MJ, McIntosh TK, Wolf JA, Smith DH (1999) Prolonged activation of NF-kappaB following traumatic brain injury in rats. J Neurotrauma 16:1023-1034. [72] Okada S, Nakamura M, Mikami Y, Shimazaki T, Mihara M, Ohsugi Y, Iwamoto Y, Yoshizaki K, Kishimoto T, Toyama Y, Okano H (2004) Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury. J Neurosci Res 76:265-276. [73] Otto VI, Stahel PF, Rancan M, Kariya K, Shohami E, Yatsiv I, Eugster HP, Kossmann T, Trentz O, Morganti-Kossmann MC (2001) Regulation of chemokines and chemokine receptors after experimental closed head injury. Neuroreport 12:2059-2064. [74] Pan JZ, Ni L, Sodhi A, Aguanno A, Young W, Hart RP (2002) Cytokine activity contributes to induction of inflammatory cytokine mRNAs in spinal cord following contusion. J Neurosci Res 68:315-322. [75] Pearse DD, Chatzipanteli K, Marcillo AE, Bunge MB, Dietrich WD (2003) Comparison of iNOS inhibition by antisense and pharmacological inhibitors after spinal cord injury. J Neuropathol Exp Neurol 62:1096-1107. [76] Penkowa M, Moos T, Carrasco J, Hadberg H, Molinero A, Bluethmann H, Hidalgo J (1999) Strongly compromised inflammatory response to brain injury in interleukin-6deficient mice. Glia 25:343-357. [77] Perrin FE, Lacroix S, Aviles-Trigueros M, David S (2005) Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and interleukin1beta in Wallerian degeneration. Brain 128:854-866. [78] Popovich PG, Wei P, Stokes BT (1997) Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J Comp Neurol 377:443-464. [79] Qiu J, Whalen MJ, Lowenstein P, Fiskum G, Fahy B, Darwish R, Aarabi B, Yuan J, Moskowitz MA (2002) Upregulation of the Fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans. J Neurosci 22:3504-3511. [80] Ransohoff RM, Hamilton TA, Tani M, Stoler MH, Shick HE, Major JA, Estes ML, Thomas DM, Tuohy VK (1993) Astrocyte expression of mRNA encoding cytokines IP10 and JE/MCP-1 in experimental autoimmune encephalomyelitis. FASEB J 7:592-600. [81] Rappert A, Bechmann I, Pivneva T, Mahlo J, Biber K, Nolte C, Kovac AD, Gerard C, Boddeke HW, Nitsch R, Kettenmann H (2004) CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J Neurosci 24:8500-8509. [82] Ravikumar R, Flora G, Geddes JW, Hennig B, Toborek M (2004) Nicotine attenuates oxidative stress, activation of redox-regulated transcription factors and induction of proinflammatory genes in compressive spinal cord trauma. Brain Res Mol Brain Res 124:188-198. [83] Resnick DK, Graham SH, Dixon CE, Marion DW (1998) Role of cyclooxygenase 2 in acute spinal cord injury. J Neurotrauma 15:1005-1013.

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the peripheral and central nervous systems in vivo and is chemotactic for macrophages in vitro. Eur J Neurosci 12:457-466. [97] Tehranian R, Andell-Jonsson S, Beni SM, Yatsiv I, Shohami E, Bartfai T, Lundkvist J, Iverfeldt K (2002) Improved recovery and delayed cytokine induction after closed head injury in mice with central overexpression of the secreted isoform of the interleukin-1 receptor antagonist. J Neurotrauma 19:939-951. [98] Tonai T, Taketani Y, Ueda N, Nishisho T, Ohmoto Y, Sakata Y, Muraguchi M, Wada K, Yamamoto S (1999) Possible involvement of interleukin-1 in cyclooxygenase-2 induction after spinal cord injury in rats. J Neurochem 72:302-309. [99] Toulmond S, Rothwell NJ (1995) Interleukin-1 receptor antagonist inhibits neuronal damage caused by fluid percussion injury in the rat. Brain Res 671:261-266. [100] Tuna M, Polat S, Erman T, Ildan F, Gocer AI, Tuna N, Tamer L, Kaya M, Cetinalp E (2001) Effect of anti-rat interleukin-6 antibody after spinal cord injury in the rat: inducible nitric oxide synthase expression, sodium- and potassium-activated, magnesium-dependent adenosine-5'-triphosphatase and superoxide dismutase activation, and ultrastructural changes. J Neurosurg 95:64-73. [101] Vanegas H, Schaible HG (2001) Prostaglandins and cyclooxygenases [correction of cycloxygenases] in the spinal cord. Prog Neurobiol 64:327-363. [102] Wajant H, Pfizenmaier K, Scheurich P (2003) Non-apoptotic Fas signaling. Cytokine Growth Factor Rev 14:53-66. [103] Wang CX, Olschowka JA, Wrathall JR (1997) Increase of interleukin-1beta mRNA and protein in the spinal cord following experimental traumatic injury in the rat. Brain Res 759:190-196. [104] Wang XJ, Kong KM, Qi WL, Ye WL, Song PS (2005) Interleukin-1 beta induction of neuron apoptosis depends on p38 mitogen-activated protein kinase activity after spinal cord injury. Acta Pharmacol Sin 26:934-942. [105] Westergren-Thorsson G, Schmidtchen A, Sarnstrand B, Fransson LA, Malmstrom A (1992) Transforming growth factor-beta induces selective increase of proteoglycan production and changes in the copolymeric structure of dermatan sulphate in human skin fibroblasts. Eur J Biochem 205:277-286. [106] Woodroofe MN, Sarna GS, Wadhwa M, Hayes GM, Loughlin AJ, Tinker A, Cuzner ML (1991) Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production. J Neuroimmunol 33:227-236. [107] Xu J, Fan G, Chen S, Wu Y, Xu XM, Hsu CY (1998) Methylprednisolone inhibition of TNF-alpha expression and NF-kB activation after spinal cord injury in rats. Brain Res Mol Brain Res 59:135-142. [108] Yan P, Li Q, Kim GM, Xu J, Hsu CY, Xu XM (2001) Cellular localization of tumor necrosis factor-alpha following acute spinal cord injury in adult rats. J Neurotrauma 18:563-568. [109] Yan P, Xu J, Li Q, Chen S, Kim GM, Hsu CY, Xu XM (1999) Glucocorticoid receptor expression in the spinal cord after traumatic injury in adult rats. J Neurosci 19:93559363.

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[110] Yang K, Mu XS, Hayes RL (1995) Increased cortical nuclear factor-kappa B (NFkappa B) DNA binding activity after traumatic brain injury in rats. Neurosci Lett 197:101-104. [111] Yang L, Jones NR, Blumbergs PC, Van Den Heuvel C, Moore EJ, Manavis J, Sarvestani GT, Ghabriel MN (2005) Severity-dependent expression of proinflammatory cytokines in traumatic spinal cord injury in the rat. J Clin Neurosci 12:276-284. [112] Yune TY, Lee SM, Kim SJ, Park HK, Oh YJ, Kim YC, Markelonis GJ, Oh TH (2004) Manganese superoxide dismutase induced by TNF-beta is regulated transcriptionally by NF-kappaB after spinal cord injury in rats. J Neurotrauma 21:1778-1794. [113] Zurita M, Vaquero J, Zurita I (2001) Presence and significance of CD-95 (Fas/APO1) expression after spinal cord injury. J Neurosurg 94:257-264.

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In: Glia and Inflammation in Neurodegenerative Disease ISBN 1-59454-984-2 Editors: M. Yenari and R. Giffard, pp. 241-257 © 2006 Nova Science Publishers, Inc.

Chapter XI

Anti-Inflammatory Treatments for Neurodegeneration Masabumi Minami* and Takashi Uehara Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

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Abstract There is accumulating evidence that inflammatory responses play crucial roles in the pathology of stroke and various neurodegenerative diseases including multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Cytokines and chemokines have been drawing the attention of researchers as the key molecules of brain inflammation and potential targets for anti-inflammatory therapy. Here, the anti-inflammatory treatments for neurodegeneration in animal models are reviewed with special attention to brain cytokines/chemokines.

1. Cytokines Cytokines are chemical mediators that have been originally identified and play important roles in the immune system. There is accumulating evidence that cytokines are produced in the central nervous system and exert various effects on neural cells.

* Corresponding author: Masabumi Minami, Ph.D. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan Phone: +81-11-706-3246, Fax: +81-11-706-4987 E-mail: [email protected] Glia and Inflammation in Neurodegenerative Disease, Nova Science Publishers, Incorporated, 2006. ProQuest Ebook Central,

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1.1 Stroke Expression of interleukin-1β (IL-1β) mRNA was reported to be induced after ischemia in the rat four vessel occlusion (Minami et al., 1992) and middle cerebral artery occlusion (Liu et al., 1993) models. Intracerebroventricular injection of IL-1β exacerbated the brain infarction after the focal cerebral ischemia (Yamasaki et al., 1995). In addition, neutralizing antibody against IL-1β (Yamasaki et al., 1995) and IL-1 receptor antagonist (Mulcahy et al., 2003) attenuated brain infarction, suggesting the possibility of anti-IL-1 therapy for stroke. It has been reported that tumor necrosis factor α (TNFα) mRNA is induced after focal cerebral ischemia (Liu et al., 1994). Pathological role of TNFα in the ischemic brain injury is controversial. Intracerebroventricular injection of neutralizing antibody against TNFα or soluble form of TNF receptor type 1 reduced the infarct size (Barone et al., 1997). On the other hand, Bruce et al. (1996) reported that damage to neurons caused by focal cerebral ischemia was exacerbated in TNF receptor knock out mice, indicating that endogenous TNF serves a neuroprotective function. Sharp et al. (2000) proposed the idea that TNF derived from neutrophils or endothelial cells is neurodegenerative, while that from neuronal cells is neuroprotective. Both intracerebroventricular and systemic injection of an anti-inflammatory cytokine IL10 decreased the infarct volume (Spera et al., 1998), suggesting that an anti-inflammatory therapeutic approach using IL-10 can provide neuroprotection in ischemic stroke. It has been reported that granulocyte colony-stimulating factor is induced after focal cerebral ischemia (Kleinschnitz et al., 2004), and exhibits a significant neuroprotective effect in the rat transient MCAO model (Schabitz et al., 2003). Erythropoietin (EPO) (Sadamoto et al., 1998) and its derivatives (Leist et al., 2004) are reported to have a neuroprotective effect against ischemic injury. A double-blind randomized proof-of-concept trial including 40 patients, who were received either recombinant human EPO or saline was conducted to assess the efficacy of EPO for treatment of ischemic stroke in man (Ehrenreich et al., 2002). A strong trend for reduction in infarct size in EPO-treated patients as compared to controls was observed by MRI, and EPO treatment was associated with an improvement in follow-up and outcome scales at 1 month.

1.2 Multiple Sclerosis Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS), in which progressive neurological disability is observed. It is believed that demyelination in the brain and spinal cord of MS patients is caused by an inflammatory response, and that infiltration of autoreactive T cells and monocytes through the blood-brain barrier is important for the inflammatory process. Interferon beta (IFNβ) has been approved by the FDA for the treatment of patients with relapsing MS. The postulated mechanism of action of IFNβ as an immunomodulator is alteration of the balance between Th1 and Th2 cytokines. MS is caused by disruption of self-tolerance for myelin antigens. This disruption results in the cell-mediated autoimmunity where relatively high-level production of Th1 cytokines such as IL-2 and IFNγ and relatively low-level production of Th2 cytokines such as

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IL-4 and IL-10 are observed. IFNβ exerts its action, at least in part, by rectifying this unbalanced production.

1.3 Alzheimer’s Disease Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by extracellular deposition of amyloid-beta peptides (Aβ) in plaques, intracellular accumulation of the abnormally phosphorylated tau protein in neurofibrillary tangles, and neuronal cell loss in specific cortical and subcortical regions. Neuroinflammation occurs in pathologically vulnerable regions of AD brains. However, unlike other neurological disorders such as stroke and MS, in which infiltration of inflammatory blood cells into brain parenchyma occurs, only accumulation of reactive microglia and astrocytes can be observed in AD brain. Overexpression of IL-1 in AD brains was first demonstrated by Griffin et al. (1989). This cytokine has been shown to promote the synthesis (Forloni et al., 1992) and processing (Buxbaum et al., 1992) of Aβ precursor protein, and to enhance the phosphorylation of tau (Li et al., 2003). Although these findings strongly suggest the involvement of IL-1 in AD pathology, more studies, especially in vivo, are needed to evaluate the efficacy of anti-IL-1 treatment for AD.

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2. Chemokines Chemokines, which were originally identified as chemotactic factors for leukocytes, constitute a large family of structurally related cytokines that include more than forty members, and the family has been divided into four subfamilies; CXC, CC, C and CX3C (Murphy et al., 2000).

2.1 Stroke Enhanced expression of mRNAs for several chemokines including monocyte chemoattractant protein-1 (MCP-1, CCL2) (Kim et al., 1995; Wang et al., 1995, Minami and Satoh, 2003), macrophage inflammatory protein-1αMIP-1αCCL3) (Kim et al., 1995; Takami et al., 1997) and cytokine-induced neutrophil chemoattractant (CINC) (Liu et al., 1993) has been demonstrated in the ischemic brain using a rat middle cerebral artery occlusion model. Increase in the peptide contents of MCP-1/CCL2 and CINC-1 has also been reported in the brain after the ischemic insult (Yamagami et al., 1999). Cell species expressing the chemokine mRNAs were examined by a double in situ hybridization technique (Takami et al., 1997; Minami and Satoh, 2003). MCP-1/CCL2 mRNA was expressed in the GFAP mRNA-positive cells as well as in the Mac-1α mRNA-positive cells, suggesting that both astrocytes and microglia/macrophages expressed MCP-1/CCL2 mRNA. On the other hand, MIP-1α/CCL3 mRNA was expressed in the Mac-1α mRNA-positive cells, but not in the

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GFAP mRNA-positive cells, indicating that MIP-1α/CCL3 mRNA was expressed in microglia/macrophages rather than in astrocytes. The role of chemokines in ischemic brain injury has been examined by using gene manipulation techniques, chemokine receptor antagonists and neutralizing antibodies. Deletion of the MCP-1/CCL2 gene by homologous recombination afforded brain protection against focal cerebral ischemia (Hughes et al., 2002). On the other hand, overexpression of MCP-1/CCL2 under control of the myelin basic protein promoter exacerbated ischemic brain injury (Chen et al., 2003). Broad-spectrum chemokine antagonists have been reported to decrease the infarct volume in rat and mice MCAO models (Beech et al., 2001; Takami et al., 2001). A neuroprotective effect of a small molecule antagonist against CCR2 and CCR5 chemokine receptors has also been reported (Takami et al., 2002). Intravenous administration of neutralizing antibodies against interleukin-8 (Matsumoto et al., 1997) or CINC (Yamasaki et al., 1997) has been shown to attenuate brain infarction resulting from focal cerebral ischemia. Although macromolecules such as antibodies are usually unable to pass through the blood-brain barrier (BBB), it is possible that a dysfunction of the BBB due to ischemia enables such macromolecules to pass through it. Alternatively, those antibodies might act on the chemokine receptors presented on the luminal surface of the brain blood vessels to suppress the invasion of leukocytes into the brain parenchyma. These findings suggest that chemokines play a crucial role in ischemic brain injury, and therefore their receptors are likely potential targets for anti-inflammatory treatment for stroke. The mechanism underlying the harmful effect of brain chemokines in the ischemic brain remains to be elucidated. One possible site for the action of brain chemokines is microglia/macrophages, which express several types of chemokine receptors. Activated microglia and macrophages are observed in the ischemic brain, and they produce neurotoxic substances including nitric oxide (Love, 1999), free radicals and inflammatory cytokines (Mabuchi et al., 2000; Gregersen et al., 2000). Chemokines were originally identified as mediators regulating the activation and migration of leukocytes in the peripheral inflammatory and immune responses, thus it is likely that these peptides are also involved in the activation and/or recruitment of microglia/macrophages in the injured brain. In this context, it is noteworthy that a chemokine receptor antagonist (Takami et al., 2002) and MCP-1/CCL2 gene deletion (Hughes et al., 2002) reduce not only the infarct volume, but also the activation and/or recruitment of microglia/macrophages in the mouse stroke model. Another possible action site for chemokines is the brain vascular endothelium. In order to recruit the leukocytes from blood flow, chemokines produced at the abluminal surface have to be transcytosed through the endothelial cells and presented at their luminal surface, where chemokines stimulate their receptors expressed on the leukocytes to induce the activation of integrins (Worthylake et al., 2001; Middleton et al., 2002). Permeability of the blood brain barrier might be also affected by chemokines. The binding sites for MCP-1/CCL2 and MIP-1α/CCL3 have been demonstrated on the abluminal surface of the isolated brain microvessels (Andjelkovic et al., 1999). The binding of MCP1/CCL2 to the CCR2 receptors expressed on brain endothelial cells induces reorganization of actin cytoskeleton and redistribution of tight junction proteins such as Zo-1, occludin and claudin-5, and these morphological changes are associated with an increase in vascular permeability (Stamatovic et al., 2003). The increased vascular permeability leads to brain

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edema formation and parenchymal hemorrhage, which are the major cause of death in patients with severe infarctions. The roles of chemokine/cytokine/NO in neuro-glio-vascular interaction in the ischemic brain and potential anti-inflammatory treatment are schematically illustrated in Fig. 1.

Ischemic stress

Astrocyte

Edema Hemorrhage

Blood vessel

Neuron NOS inhibitors

Nitric oxide Free radicals Cytokines

Chemokine Chemokine receptor antagonists

Cytokine receptor antagonists

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Chemokine receptor

Macrophage

Microglia

Figure 1. Schematic illustration of neuro-glio-vasucular interaction in the ischemic brain. Ischemic stress induces neuronal injury and thereby chemokine production in astrocytes via neuro-glial interaction. One possible site for the action of brain chemokines is microglia/macrophages expressing several types of chemokine receptors. Activated microglia and macrophages produce neurotoxic substances including nitric oxide, free radicals and inflammatory cytokines such as IL-1 and TNFα. Another possible target for chemokines is the vascular endothelium. Chemokines, such as MCP-1, act on the endothelial cells to induce the extravasation of macrophages into the brain parenchyma. Permeability of the BBB is also affected by chemokines. Increased permeability of the BBB leads to brain edema formation and parenchymal hemorrhage. Potential targets for anti-inflammatory treatment are shown by gray arrows.

2.2 Multiple Sclerosis Production of chemokines, such as MCP-1/CCL2, MIP-1α/CCL3, RANTES/CCL5, MIG/CXCL9 and IP10/CXCL10, were observed in the brain tissue of MS patients (Van Der Voorn et al., 1999; Simpson et al., 1998). These chemokines were associated with reactive astrocytes and/or microglia/macrophages. CC chemokine receptors, CCR2, CCR3 and CCR5 were detected on microglia/macrophages and lymphocytes within MS lesions (Simpson et al.,

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2000a), while a CXC chemokine receptor, CXCR3 was on T cells and astrocytes within the plaque (Simpson et al., 2000b). Experimental autoimmune encephalitis (EAE) is a murine model for MS, which widely used to study the mechanisms underlying the pathology of MS. To clarify the significance of chemokine production in the pathogenesis of MS, the effect of anti-chemokine antibodies were examined in this model animal. Anti-MIP-1α/CCL3 and anti-MCP-1/CCL2, but not anti-RANTES, antibodies were shown to suppress the disease onset and/or relapses (Karpus and Kennedy, 1997; Kennedy et al., 1998). Administration of anti-IP10/CXCL10 antibodies decreased the incidence and severity of the disease with reduction of mononuclear cell infiltration (Fife et al., 2001). Chemokine receptor gene knockout mice were employed to study the role of individual chemokine receptor in the pathology of EAE. Deletion of CCR1 gene resulted in the reduction of disease incidence and severity (Rottman et al., 2000). In the earlier studies (Fife et al., 2000; Izikson et al., 2000), CCR2 knockout mice showed resistance to EAE. However, a recent study demonstrated the susceptibility of CCR2 knockout mice to EAE (Gaupp et al., 2003). In the latter study, a higher dose of antigen was used for immunization, and much higher levels of neutrophils with relatively few monocytes were observed in MS lesions compared to the case of the wild type mice, suggesting the compensation for the absence of CCR2 by other chemokine-chemokine receptor system. CCR5 knockout mice showed the same level of disease severity compared to wild-type animals, indicating no or little role in the development of EAE (Tran et al., 2000). On the other hand, CCR8 knockout mice showed delayed onset and less severity of the disease (Murphy et al., 2002). These findings suggest that chemokine receptors are promising targets of antiinflammatory therapy for MS. Actually, an increasing number of small-molecule antagonists for chemokine receptors have been developed by pharmaceutical companies (Schwarz and Wells, 2002; Onuffer and Horuk, 2002). Among them, BX471, a small-molecule antagonist for CCR1 decreased the severity of EAE (Liang et al., 2000).

2.3 Alzheimer’s Disease Immunohistochemical analysis has demonstrated the expression of a CXCR2 receptor on neurons in both AD and control brain, and it is upregulated in a subpopulation of neuritic plaques in the AD brain (Xia et al., 1997). Interestingly, recent report has revealed that one of the CXCR2 ligands GROα/KC is a potent trigger for tau hyperphosphorylation in the mouse primary cortical neurons (Xia and Hyman, 2002), suggesting the potent pathophysiological role of CXCR2-ligand system in Alzheimer’s disease. Immunoreactivity of CCR3 and CCR5 chemokine receptors and their ligands MIP-1α/CCL3 and MIP-1β/CCL4 was detected in normal and AD brain with increased expression in AD (Xia, et al., 1998). Immunoreactivity of MCP-1/CCL2 was reported in mature senile plaques and reactive microglia in the AD brains (Ishizuka et al., 1997). In vitro study has shown that Aβ induces the production of MCP-1/CCL2 in human astrocyte cell line (Prat et al., 2000). Recent study demonstrated that MCP-1/CCL2 level was elevated in CSF from almost all AD patients (Galimberti et al., 2003). These findings suggest the possibility that the level of MCP-1/CCL2 in CSF can be

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used as a useful marker for early diagnosis and monitoring of the disease progression of AD. Pathological role of MCP-1/CCL2 in the AD remains to be elucidated. MCP-1/CCL2 is known to attract activated microglia/macrophages, which release nitric oxide, free radicals and proinflammatory cytokines, thus it could be involved in the neurodegeneration in the AD brain. On the other hand, recent study revealed that cultured adult mouse astrocytes migrate in response to MCP-1/CCL2, and bind and degrade Aβ. In this case, MCP-1/CCL2 might contribute to the degradation of Aβ and thereby reduce the neurodegeneration associated with AD (Wyss-Coray et al., 2003).

3. Nitric Oxide

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3.1 Mechanism of Nitric Oxide-Induced Neuronal Death Nitric oxide (NO) is a free radical and short-lived gas synthesized from L-arginine by NO synthase (NOS). Appropriate amounts of NO through NOS contribute to cellular communication. On the other hand, excessive amounts of NO could be involved in neurotoxicity; however the detailed mechanism of NO-induced neuronal death is still unclear. To date, the several possible pathways for NO-induced neuronal death have been proposed (Fig. 2). NO causes mitochondrial respiratory chain inhibition and following damage (Bolanos et al., 1997). Especially, NO is known to reversibly interacts with cytochrome c oxidase (complex IV) in mitochondrial respiration chain (Lizasoain et al., 1996). In addition, it has been demonstrated that NO also triggers the mitochondrial permeability transition (Hortelano et al., 1997). Disruption of the mitochondrial transmembrane potential is believed to evoke the release of cytochrome c (an inducer of apoptosis) into cytosol via specific mitochondrial channel, and cause apoptotic cell death through the activation of caspases (Liu et al., 1996). NO activates poly ADP-ribose polymerase (PARP) in association with damage to DNA (Zhang et al., 1994). Activation of this enzyme results in the addition of a large number of ADP-ribose groups to substrates, leading to the depletion of β-nicotinamide adenine dinucleotide and subsequently ATP, which cause cell death due to energy failure. S-nitrosylation is emerging as an important form of post-translational modification of various sorts of proteins including enzymes, receptors and ion channels. A growing body of research shows that S-nitrosylation regulates cellular mechanisms underling neuronal cell death, and is implicated in several pathological conditions, such as Parkinson’s disease (PD), MS, pulmonary hypertension and asthma (for review, Hess et al., 2005). 3.1.1 Stroke It has been reported that inducible type of NOS (iNOS) is induced after brain ischemia. Generally, NO produced by the neuronal type of NOS (nNOS) or iNOS is thought to be detrimental, whereas that derived from the endothelial type (eNOS) is considered beneficial. However, experimental studies using NOS inhibitors have given contradictory results. Recently, Willmot et al. (2005) systematically analyzed the data on the effects of NOS inhibition on lesion volume from 73 studies. When assessed by type of inhibitor, total lesion

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volume was reduced in permanent models by nNOS and iNOS inhibitors, but not by nonselective inhibitors, and all types of NOS inhibitors reduced infarct volume in transient models. These findings suggest that selective nNOS and iNOS inhibitors are candidate treatments for stroke.

Nitric Oxide

DNA damage

8-Nitroguanosine PARS activation

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p53

Mitochondria damage

Protein S-nitrosylation

Membrane potential

Parkin

Permeability transition

GAPDH

Respiration chain Cytochrome c release

ERK/JNK/p38

Apoptosis (cell death) Figure 2. Possible mechanisms of nitric oxide-induced cell death in neurons.

Pharmacological studies in animal models of cerebral ischemia have demonstrated that eNOS and vascular NO plays a crucial role in regulating cerebral blood flow and preventing neuronal injury (for review, see Iadecola, 1997; Samdani et al., 1997). A genetic approach using eNOS knockout mice also indicated the beneficial role of eNOS (Huang et al., 1996). These findings suggest that the compounds which upregulate and/or activate eNOS are promising candidates of therapeutics for stroke. There is a accumulating evidence that statins, the cholesterol-lowering inhibitors of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, upregulate and activate eNOS through several mechanisms (for review, see Laufs, 2003; Endres et al., 2004). Chronic pretreatment with statins protects the brain from ischemic injury (Endres et al., 1998). Interestingly, this protective effect was abolished in eNOS knockout mice, indicating the eNOS upregulation and/or activation as the main mechanism of protection. In humans, retrospective analyses suggest that statin treatment might improve stroke outcome (Jonsson and Asplund, 2001).

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3.1.2 Multiple Sclerosis Induction of iNOS mRNA was shown in the brains of EAE model rats (Koprowski et al., 1993). Hooper et al. (1995) demonstrated the enhanced production of NO in the rat brains suffering from EAE by using spin trapping of NO and electron paramagnetic resonance spectroscopy. An in vitro study showed that a NO-releasing chemical significantly injured oligodendrocytes (Mitrovic et al., 1994). These findings suggest the harmful role of NO in the brain with EAE. However, the studies investigating the effects of NOS inhibitors in EAE led to contradictory results. Aminoguanidine, an iNOS inhibitor, was reported to ameliorate EAE in the mouse model (Cross et al., 1994). On the other hand, Aminoguanidine and some other NOS inhibitors exacerbated EAE in the rat model (Zielasek et al., 1995; Ruuls et al., 1996). Further studies are needed to clarify the roles of NO in the pathology of EAE and MS.

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3.1.3 Parkinson’s Disease Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in PD. In the case of autosomal recessivejuvenile Parkinsonism, mutation in parkin is linked to death of dopaminergic neurons. Recently, it has been reported that nitrosative stress leads to S-nitrosylation of wild-type parkin (Chung et al., 2004; Yao et al., 2004). S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. Interestingly, S-nitrosylation of parkin is observed in the brains of patients with PD. The inhibition of parkin's ubiquitin E3 ligase activity by Snitrosylation could contribute to the degenerative process in PD by impairing the ubiquitination of parkin substrates. Dysfunction of proteins by S-nitrosylation might be also involved in the pathology of other neurodegenerative diseases, such as AD, MS and amyotrophic lateral sclerosis (ALS), and is a potential target for intervention of slowly progressing neural diseases.

4. Activated Glial Cells The major source of cytokines/chemokines and NO in the brain is activated glial cells, so they are the potential targets for anti-inflammatory treatment. Immunosuppressants FK506 (Sharkey and Butcher, 1994) and cyclosporin A (Shiga et al, 1992) have been shown to exert a neuroprotective effect following cerebral ischemia. FK506 also significantly decreased microglial activation after focal cerebral ischemia (Furuichi et al., 2004). In addition, in vitro study has revealed that FK506 suppresses the expression of IL-1β and TNFα mRNAs in cultured astrocytes and microglia (Zawadzka and Kaminska, 2005). These findings suggest that protective effects of immunosuppressants against ischemic injury are, at least in part, due to their anti-inflammatory action on activated glial cells. Minocycline is a member of the tetracycline class of antibiotics. One of the unique properties of which is the ability to diffuse into the CNS at clinically effective levels. Aside from its antimicrobial action, minocycline has been shown to have anti-inflammatory effects. It has been reported that minocycline suppresses hypoxia- and lipopolysaccharide-induced microglia activation (Suk, 2004; Tomas-Camardiel et al., 2004). Concordantly, minocycline has been found to have neuroprotective effects in animal models of various neural diseases

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including stroke (Yrjanheikki et al., 1999), MS (Giuliani et al., 2005), PD (Wu et al., 2002) and ALS (Zhu et al., 2002). Recently, another class of antibiotics has been found to have beneficial effects against neurodegenerative diseases (Rothstein et al., 2005). Ceftriaxone, a member of the β-lactam class of antibiotics, increases the expression of glutamate transporter GLT-1 in astrocytes, and exerts protective effect in an animal model of ALS. Any benefit from increased glutamate clearance can be extended to other types of neuronal damage with an excitotoxic component. The proven safety of these drugs over decades of use as an antibiotic suggests that they have potential for development into an effective treatment of neurodegenerative diseases

5. Conclusion Activated glial cells, astrocytes and microglia, play crucial roles in “brain inflammation” by producing various kinds of inflammatory substances including cytokines, chemokines and NO. Although it is well known that glial cells are activated in the brain under the various pathological conditions, little is known about the molecular mechanisms allowing glial cells to sense and response to brain tissue damages. A better understanding of the cellular and molecular mechanisms of glial cell activation possibly leads to a promising anti-inflammatory treatment for neurodegeneration.

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Index

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A acceptance, 14 access, 30, 166, 202 accumulation, 12, 19, 21, 25, 75, 85, 87, 94, 98, 105, 113, 119, 121, 124, 131, 140, 153, 164, 166, 169, 171, 172, 173, 174, 178, 202, 203, 205, 206, 208, 209, 229, 243, 251 acetylcholine, 131, 145, 154, 155 acetylcholinesterase, 125 acid, 39, 59, 63, 69, 71, 73, 75, 76, 97, 98, 99, 100, 113, 136, 160, 166, 168, 170, 188, 198, 213 action potential, 64 activation, 3, 4, 6, 8, 9, 10, 11, 12, 14, 15, 16, 17, 19, 21, 23, 25, 26, 28, 29, 30, 31, 32, 33, 34, 37, 38, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 54, 55, 56, 57, 58, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 77, 78, 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 96, 97, 98, 103, 104, 105, 108, 109, 114, 119, 120, 121, 122, 123, 124, 125, 126, 127, 130, 133, 134, 135, 136, 137, 140, 143, 146, 147, 148, 149, 152, 153, 154, 157, 160, 162, 163, 171, 174, 175, 176, 177, 188, 191, 192, 193, 194, 199, 200, 201, 203, 204, 205, 208, 209, 210, 211, 212, 213, 215, 217, 218, 219, 220, 222, 223, 224, 225, 226, 227, 229, 232, 235, 236, 237, 239, 244, 247, 248, 249, 250, 255, 256, 257 adenine, 164, 202, 247 adenosine, 64, 65, 73, 239 adenovirus, 177 adhesion, 19, 26, 30, 64, 69, 74, 76, 77, 85, 86, 87, 91, 92, 93, 94, 99, 105, 106, 107, 108, 143, 164, 222, 230 adipocyte, 155

adipose, 135, 136, 140 adipose tissue, 135, 140 ADP, 58, 170, 213, 216, 234, 247, 257 adults, 197, 198, 199 aetiology, 50, 145 affect, 47, 51, 53, 54, 60, 72, 96, 124, 130, 132, 134, 137, 138, 162, 165, 175, 197, 200, 205, 209, 231 age, 11, 16, 18, 32, 117, 122, 124, 126, 127, 131, 133, 150, 151, 159, 165, 167, 170, 171, 172, 176, 190, 197, 199, 203, 208, 209, 210, 219, 220, 223, 231 ageing, 189 agent, 173, 175, 177, 203 age-related, 18, 197, 210 aggregates, 13, 42, 118, 123, 132, 172, 188 aggregation, 55, 132, 134, 155, 166, 172 aging, 15, 22, 74, 147, 148, 149, 185, 212 agonist, 137, 141, 143, 146, 150, 177, 195 AIDS, 53, 128, 143 albumin, 203 aldehydes, 171, 187 allele, 172, 190 ALS, 12, 128, 249, 250 alternative, 73, 123, 135, 162 alters, 69, 78, 107, 154, 157, 185, 219 aluminum, 189 Alzheimer's disease, 16, 17, 20, 21, 22, 37, 77, 78, 79, 80, 81, 102, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 181, 183, 188, 189, 190, 251, 252, 256 American Heart Association, 101 amines, 170 amino acids, 79, 125, 135, 166, 216, 221 aminoacids, 121

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Index

amoeboid, 7, 18, 47, 67, 120, 211 amygdala, 118 amyotrophic lateral sclerosis, 12, 139, 140, 195, 232, 249, 257 angiogenesis, 33, 96, 101, 153, 208, 228, 229, 232, 234 animals, 13, 26, 27, 92, 99, 119, 122, 126, 127, 130, 132, 164, 165, 176, 197, 198, 205, 209, 229, 246 ANOVA, 45 antibiotic, 88, 250 antibody, 26, 27, 45, 46, 53, 55, 72, 92, 93, 94, 106, 107, 108, 109, 123, 200, 208, 226, 239, 242, 254 antigen, 3, 10, 15, 19, 21, 22, 28, 29, 34, 36, 37, 39, 52, 53, 54, 73, 94, 115, 123, 160, 163, 164, 165, 178, 203, 212, 216, 246 antigen-presenting cell, 10, 34, 212 anti-inflammatory agents, 20, 149, 163, 210 anti-inflammatory drugs, 15, 68, 104, 140, 148, 152, 154, 156, 175, 182, 210, 231 antioxidant, 25, 29, 33, 51, 70, 72, 105, 167, 189, 210, 218 antisense oligonucleotides, 93, 107, 230 apoptosis, 8, 18, 29, 32, 36, 39, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 65, 66, 69, 70, 71, 75, 77, 79, 80, 81, 88, 95, 96, 102, 103, 107, 127, 142, 145, 152, 154, 160, 162, 177, 199, 200, 211, 217, 220, 227, 233, 234, 235, 236, 239, 247, 252, 253 arginine, 99, 124, 128, 129, 247 argument, 15, 137 arousal, 166 artery, 7, 19, 26, 27, 92, 101, 104, 105, 106, 107, 108, 109, 115, 202, 212, 216, 242, 243, 252, 255 arthritis, 15 ascorbic acid, 185 aseptic, 230 ash, 231 asphyxia, 200, 216 aspiration, 118, 224 assessment, 138, 140, 188 assignment, 58 association, 10, 110, 112, 123, 126, 129, 133, 147, 151, 184, 247 asthma, 247 astrocytoma, 132, 148, 254 astrogliosis, 28, 67, 125, 126, 226, 227, 237 ATP, 29, 31, 35, 64, 65, 71, 73, 79, 174, 247 atrophy, 118, 133, 202 attachment, 92 attention, 5, 9, 241

autoimmunity, 29, 165, 180, 195, 242 autopsy, 128, 163, 178 autosomal dominant, 172 autosomal recessive, 173, 191 availability, 14, 198 avoidance, 146 awareness, 50, 63 axon, 50, 71, 77, 130, 144, 228, 236 axon terminals, 130 axonal degeneration, 229, 230

B bacteria, 10, 147, 160 bacterial infection, 14 basal forebrain, 61, 131 basal ganglia, 168, 185, 186, 189 basal lamina, 100 BBB, 3, 29, 32, 33, 85, 88, 96, 98, 99, 100, 162, 198, 201, 202, 205, 221, 222, 226, 227, 244, 245 B-cell apoptosis, 61 behavior, 67 beneficial effect, 4, 32, 133, 134, 135, 136, 209, 250 benzodiazepine, 163, 174 bicarbonate, 66, 76 binding, 22, 28, 33, 39, 47, 91, 96, 123, 124, 127, 134, 135, 136, 138, 139, 140, 148, 163, 170, 175, 183, 190, 240, 244, 250 biological activity, 228 biomarkers, 168, 170, 171, 173, 176 biosynthesis, 28, 61, 153 birth, 198, 199, 203 blends, 11 blocks, 73, 194, 215 blood, 3, 8, 11, 12, 25, 28, 29, 30, 32, 34, 35, 36, 37, 39, 63, 68, 85, 87, 92, 98, 106, 108, 112, 114, 115, 124, 130, 131, 136, 138, 162, 164, 176, 178, 199, 201, 210, 211, 216, 219, 221, 226, 229, 231, 238, 242, 243, 244, 256 blood flow, 98, 201, 229, 238, 244 blood monocytes, 87 blood supply, 199 blood vessels, 231, 244 blood-brain barrier, 28, 30, 34, 35, 36, 37, 39, 85, 112, 114, 115, 178, 210, 211, 216, 219, 242, 244, 256 body, 12, 111, 186, 188, 190, 221, 226, 247 bone marrow, 100, 112, 162 brain, 3, 5, 6, 7, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 28, 29, 30, 31, 32, 33, 34,

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Index 35, 36, 37, 38, 39, 42, 43, 47, 50, 54, 55, 56, 57, 60, 61, 63, 64, 65, 66, 67, 68, 69, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 85, 86, 87, 88, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 109, 110, 111, 112, 113, 114, 115, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 136, 138, 139, 141, 142, 143, 144, 145, 146, 149, 150, 151, 152, 153, 155, 157, 160, 162, 163, 164, 165, 167, 168, 173, 175, 176, 177, 178, 181, 182, 183, 184, 185, 186, 187, 189, 191, 192, 194, 197, 198, 199, 200, 201, 202, 203, 205, 206, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 226, 227, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 254, 255, 256, 257 brain contusion, 228 brain growth, 63 brain stem, 129 brainstem, 187 breakdown, 11, 30, 32, 35, 69, 97, 115, 171, 210, 222

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C calcium, 31, 37, 46, 56, 74, 79, 80, 85, 97, 98, 144, 185, 199, 211 Canada, 63 cancer, 160 candidates, 248 capillary, 29, 36, 130 carbohydrate, 177 carcinogen, 187 carcinoma, 187 cardiac arrest, 210 cardiovascular disease, 160 catalytic activity, 170 catecholamines, 65, 75, 139, 186 causal relationship, 199 CCR, 252 CD8+, 38, 52, 165, 174 cDNA, 137, 191 cell, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 26, 29, 30, 32, 34, 36, 37, 38, 39, 41, 42, 43, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 59, 60, 61, 62, 63, 64, 65, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 85, 86, 87, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 104, 105, 107, 108, 112, 114, 118, 119, 120, 122, 123, 124, 127, 128, 129, 130, 131, 133, 136, 137, 138, 139, 142, 144,

261

145, 146, 147, 148, 149, 150, 159, 160, 162, 163, 164, 165, 166, 169, 170, 172, 174, 176, 177, 178, 179, 180, 181, 182, 187, 188, 192, 193, 194, 195, 197, 199, 200, 202, 203, 206, 208, 211, 212, 214, 215, 216, 217, 220, 221, 222, 224, 226, 227, 230, 231, 234, 235, 238, 242, 243, 246, 247, 248, 250, 253, 254, 255 cell body, 6, 7, 67 cell culture, 14, 20, 38, 56, 62, 64, 114, 127, 128, 137 cell cycle, 9, 19 cell death, 4, 7, 16, 29, 36, 39, 41, 43, 45, 46, 48, 50, 51, 52, 53, 55, 56, 57, 59, 60, 69, 70, 71, 72, 73, 75, 78, 79, 87, 91, 95, 96, 99, 104, 119, 120, 122, 123, 127, 129, 130, 131, 133, 138, 142, 145, 162, 163, 172, 174, 176, 180, 181, 188, 194, 199, 200, 203, 212, 215, 216, 217, 220, 221, 222, 227, 230, 247, 248 cell line, 37, 55, 73, 118, 139, 144, 148, 177, 181, 195, 246, 254 cell membranes, 65, 93, 99, 166, 169, 211 cell signaling, 146, 234 cell surface, 47, 49, 69, 94, 96, 123, 165 central nervous system, 3, 5, 16, 17, 18, 21, 22, 25, 30, 34, 36, 37, 38, 50, 54, 57, 58, 59, 61, 62, 73, 77, 78, 80, 96, 103, 105, 108, 111, 141, 146, 151, 155, 156, 157, 177, 182, 183, 192, 195, 215, 216, 221, 233, 236, 239, 241, 242, 251, 252, 254, 255 cerebellum, 168 cerebral amyloid angiopathy, 155 cerebral amyloidosis, 118 cerebral blood flow, 94, 98, 201, 219, 248, 256 cerebral cortex, 61, 72, 139, 211, 213, 222 cerebrospinal fluid, 118, 183, 184, 187, 251 cerebrovascular disease, 105 Chad, 59 channels, 66, 71 chemokine receptor, 36, 67, 70, 111, 112, 124, 145, 146, 156, 157, 208, 214, 229, 237, 244, 245, 246, 251, 252, 253, 254, 255, 256 chemokines, 6, 9, 26, 28, 30, 36, 64, 67, 68, 85, 88, 94, 96, 97, 124, 125, 160, 162, 164, 166, 203, 205, 206, 208, 221, 222, 223, 224, 225, 226, 229, 231, 232, 237, 241, 243, 244, 245, 249, 250, 252, 254, 255 chemotaxis, 9, 68, 85, 86, 96, 124, 178, 226 children, 212 cholesterol, 136, 248 chondrocyte, 144 chromosome, 58, 147, 172

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Index

circulation, 85, 198, 207, 208, 209 classes, 96, 176, 208 classification, 6, 124 cleavage, 58, 71, 92, 118, 121, 134, 137, 170, 205, 206 clinical diagnosis, 118 clinical trials, 15, 177 clustering, 13 clusters, 173 CNS, 4, 5, 6, 8, 10, 11, 12, 14, 17, 18, 19, 21, 22, 23, 25, 28, 29, 30, 34, 37, 41, 52, 53, 57, 60, 64, 67, 69, 73, 75, 77, 81, 87, 96, 101, 102, 127, 131, 136, 138, 145, 146, 147, 149, 151, 156, 160, 162, 164, 165, 166, 167, 172, 177, 180, 182, 183, 187, 197, 199, 205, 212, 218, 221, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 235, 236, 238, 242, 249 coenzyme, 176, 248 cognition, 166 cognitive deficit, 13, 119, 122, 140 cognitive dysfunction, 119, 233 cognitive function, 43 cognitive impairment, 133 cohort, 175, 177 collagen, 93 combined effect, 176 communication, 63, 64, 66, 70, 73, 74, 79, 164, 247 compensation, 246 competence, 63 complement, 6, 10, 18, 31, 35, 41, 62, 68, 77, 93, 106, 119, 120, 121, 122, 123, 124, 133, 141, 149, 151, 153, 154, 155, 156, 157, 163, 181, 208, 232 complex interactions, 34 complexity, 216 complications, 118 components, 6, 29, 68, 72, 85, 91, 119, 123, 131, 144, 156, 164, 166, 197, 199, 201, 209 composition, 91, 127, 198, 222 compounds, 51, 94, 173, 209, 248 concentration, 33, 65, 66, 108, 138 concordance, 15 concrete, 119 conditioning, 103 conduction, 64 confidence, 14 configuration, 166 conjugation, 99 connective tissue, 222 consensus, 89, 171 consolidation, 122, 132

contaminant, 173 context, 6, 8, 9, 11, 12, 13, 25, 32, 79, 179, 227, 244 control, 8, 18, 19, 45, 46, 52, 54, 59, 60, 64, 66, 68, 71, 74, 77, 78, 79, 81, 99, 110, 124, 126, 129, 131, 136, 138, 140, 149, 152, 156, 167, 168, 170, 171, 176, 208, 244, 246, 251 contusion, 223, 224, 227, 234, 236 conversion, 43, 128, 176, 209 cooling, 209, 214, 219 corpus callosum, 166, 224 correlation, 7, 32, 127, 130, 167, 225, 236 cortex, 21, 22, 38, 69, 103, 107, 112, 121, 130, 134, 163, 167, 168, 175, 176, 200, 207, 208, 212, 216, 222, 224, 253, 256 cortical neurons, 35, 246, 253 costimulatory molecules, 37, 88 coupling, 105 covering, 67 creatine, 194 CSF, 9, 10, 19, 28, 31, 32, 36, 122, 125, 131, 135, 150, 166, 168, 170, 171, 174, 176, 246 cues, 21, 74, 162, 218 culture, 7, 14, 21, 32, 35, 39, 45, 47, 66, 70, 71, 73, 103, 112, 118, 174, 175, 193, 210, 255 CXC, 96, 124, 153, 208, 210, 229, 243, 246 CXC chemokines, 124, 210 cycles, 7, 167 cyclins, 9 cyclooxygenase, 81, 90, 97, 98, 113, 119, 140, 146, 147, 148, 149, 151, 155, 156, 157, 163, 194, 224, 232, 233, 234, 236, 237, 238, 239 cyclopentenone prostaglandins, 152 cystine, 59 cytochrome, 45, 46, 57, 199, 205, 247, 253, 257 cytokines, 9, 13, 23, 28, 29, 30, 31, 32, 33, 34, 36, 38, 41, 47, 49, 51, 67, 68, 78, 85, 86, 90, 91, 94, 101, 119, 122, 123, 125, 126, 128, 131, 132, 133, 137, 138, 139, 142, 143, 148, 149, 152, 160, 162, 163, 174, 175, 178, 179, 181, 200, 202, 203, 205, 206, 208, 213, 222, 225, 226, 228, 231, 234, 237, 238, 240, 241, 242, 243, 244, 245 cytometry, 102 cytoplasm, 7, 47, 90, 170 cytotoxicity, 51, 59, 60, 66, 79

D damage, 3, 7, 10, 11, 13, 14, 29, 34, 37, 39, 42, 45, 46, 50, 51, 52, 54, 58, 60, 61, 65, 67, 68, 69, 71, 74, 78, 79, 80, 85, 88, 94, 95, 99, 100, 101, 103,

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Index 105, 107, 108, 110, 113, 114, 123, 124, 129, 142, 146, 150, 151, 153, 159, 162, 163, 164, 166, 168, 169, 170, 171, 184, 186, 187, 188, 193, 194, 198, 199, 200, 201, 211, 212, 213, 215, 217, 219, 220, 221, 222, 224, 226, 227, 229, 234, 236, 239, 242, 247, 250, 251, 256, 257 damping, 69 dating, 5 death, 4, 14, 30, 31, 33, 34, 37, 43, 45, 46, 47, 49, 50, 51, 52, 54, 55, 57, 60, 65, 67, 68, 69, 70, 71, 72, 76, 77, 78, 79, 81, 90, 95, 99, 103, 119, 121, 127, 130, 131, 136, 138, 146, 160, 175, 177, 178, 183, 197, 199, 200, 205, 210, 214, 221, 226, 229, 230, 237, 245, 247, 249 defects, 160 defense, 5, 13, 25, 72, 99, 101, 120, 123, 160, 198, 212 defense mechanisms, 72, 198 deficiency, 29, 71, 80, 96, 112, 141, 177, 193, 199, 205, 206, 252 deficit, 95, 218, 226, 229, 234 definition, 11 degenerate, 159 degenerative joint disease, 15 degradation, 90, 121, 128, 151, 160, 169, 172, 173, 247 delivery, 177, 179, 195, 213 dementia, 12, 13, 42, 55, 61, 69, 78, 117, 118, 119, 122, 128, 130, 139, 142, 149, 151, 152, 157, 159, 160, 171, 188 demyelinating disease, 34, 78, 128, 151, 242 demyelination, 33, 50, 52, 54, 55, 57, 75, 242, 254 denaturation, 70 dendrite, 237 dendritic cell, 223 density, 19, 122, 162, 206, 209 depolarization, 66 deposition, 13, 17, 43, 80, 118, 119, 122, 123, 124, 125, 126, 128, 130, 131, 132, 134, 145, 146, 147, 157, 163, 181, 228, 236, 243 deposits, 13, 18, 42, 46, 118, 119, 121, 122 depression, 253 deprivation, 32, 56, 60, 62, 74, 76, 80, 82, 103 deregulation, 199 derivatives, 242 destruction, 11, 65, 68, 87, 122, 130, 178 detection, 8, 37, 54, 139, 187 developing brain, 65, 198, 201, 203, 205, 208, 209, 210, 215, 217, 219 diabetes, 152

263

diaphragm, 61 differentiation, 51, 65, 96, 136, 150, 166, 181, 199, 206, 208, 252 diffusion, 211 direct measure, 168 disability, 166, 221, 255 disease activity, 54, 60 disease progression, 16, 41, 52, 139, 145, 171, 247 disorder, 146, 159, 168 dissociation, 14 distribution, 52, 109, 146, 147, 182, 185, 202, 222, 233 diversity, 6, 73 division, 20 DNA, 17, 43, 46, 52, 53, 56, 57, 60, 79, 89, 90, 91, 99, 123, 148, 163, 165, 167, 169, 170, 187, 188, 205, 209, 240, 247 DNase, 170 domain, 47, 64, 66, 80, 91, 95, 124, 208 donors, 168 dopamine, 146, 149, 159, 160, 163, 168, 186, 192, 193, 194, 249 dosing, 114 double bonds, 171 Down syndrome, 252 down-regulation, 29, 43, 52, 58, 60, 139 Drosophila, 63, 172, 190, 191 drug therapy, 157 drug use, 140, 149 drugs, 15, 56, 137, 141, 146, 173, 190, 217, 250 duration, 67, 125, 130, 133, 153

E EAE, 28, 34, 52, 53, 54, 65, 67, 71, 73, 246, 249, 251, 255 edema, 28, 30, 33, 69, 85, 87, 98, 99, 100, 102, 113, 203, 218, 221, 226, 229, 234, 238, 245, 254 elderly, 167, 197 electrical resistance, 30 electron microscopy, 76, 189 electron paramagnetic resonance, 249 electrons, 99, 167 ELISA, 227 embolism, 107 embryogenesis, 162 enantiomers, 143 encephalitis, 246 encephalomyelitis, 37, 38, 54, 57, 59, 73, 80, 150, 156, 251, 252, 254, 255

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264

Index

encephalopathy, 70, 153, 183 encoding, 90, 149, 172, 224, 237 endocrine, 46 endothelial cells, 28, 30, 32, 36, 37, 92, 96, 100, 105, 107, 124, 128, 160, 198, 201, 206, 224, 231, 242, 244, 245 endothelium, 29, 91, 92, 94, 99, 100, 112, 113, 203, 229, 236, 244, 245, 254 endotoxemia, 200, 216 enlargement, 200 entorhinal cortex, 121, 123, 129, 230 environment, 50, 53, 162, 166, 174, 223, 228 enzymatic activity, 99, 132 enzymes, 73, 96, 126, 128, 132, 138, 157, 163, 167, 170, 185, 198, 210, 224, 225, 230, 247 eosinophils, 124 ependymal cell, 78 epidemiology, 159 episodic memory, 118 epithelial cells, 93 erythropoietin, 253 ESR, 188 ester, 48 euchromatin, 7 everyday life, 118 evidence, 6, 7, 8, 12, 21, 26, 38, 41, 43, 46, 47, 52, 54, 56, 64, 67, 69, 70, 78, 88, 119, 121, 122, 124, 126, 132, 134, 137, 138, 140, 160, 163, 164, 169, 172, 173, 175, 184, 189, 197, 199, 206, 222, 223, 226, 239, 241, 248 evolution, 13, 197, 202, 205 excitability, 65, 66 excitotoxicity, 33, 34, 35, 51, 58, 68, 79, 133, 147, 150, 162, 193, 199, 201, 205, 206, 209, 217 excitotoxins, 127, 160 exertion, 208 experimental autoimmune encephalomyelitis, 28, 34, 36, 39, 52, 56, 58, 59, 60, 61, 77, 143, 150, 237, 238, 251, 252, 256, 257 exposure, 14, 18, 21, 28, 29, 31, 34, 43, 45, 47, 50, 51, 70, 87, 98, 121, 125, 128, 133, 165, 173, 174, 182, 192, 193, 199, 200, 201, 219 expression, 9, 10, 15, 18, 21, 23, 26, 28, 29, 30, 31, 32, 36, 37, 38, 39, 44, 47, 49, 52, 53, 54, 57, 60, 61, 64, 66, 67, 69, 71, 72, 76, 77, 78, 81, 88, 91, 92, 93, 94, 95, 96, 99, 102, 105, 106, 107, 109, 110, 111, 113, 114, 115, 122, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 136, 137, 138, 139, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 156, 164, 165, 169, 173, 174, 176,

178, 179, 181, 182, 183, 185, 186, 192, 198, 199, 200, 202, 205, 208, 212, 213, 214, 219, 220, 224, 225, 226, 227, 228, 229, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 243, 246, 249, 250, 252, 253, 256, 257 extravasation, 124, 201, 203, 208, 222, 245, 254

F facial nerve, 8, 9, 10, 17, 18, 183 failure, 30, 50, 66, 98, 135, 155, 168, 171, 219, 247 family, 19, 46, 60, 70, 76, 79, 88, 90, 91, 92, 93, 96, 98, 100, 118, 124, 125, 126, 128, 147, 177, 190, 208, 220, 225, 228, 243 family members, 98, 118 FAS, 69, 205, 233 fascia, 129 fatty acids, 170, 171, 198 FDA, 242 feedback, 28, 56, 59, 73 females, 223, 233 ferric ion, 171 ferritin, 163, 171, 185, 189 fetus, 198 fibers, 177 fibrin, 80 fibroblast growth factor, 73 fibroblasts, 93, 137, 153, 227, 239 fluid, 123, 166, 219, 222, 224, 235, 239 fluorescence, 27 focusing, 20 forebrain, 26, 58, 90, 95, 104, 109, 110, 154, 218, 222, 254 free radicals, 38, 42, 119, 128, 166, 167, 168, 170, 174, 189, 200, 201, 217, 244, 245, 247 frontal cortex, 118, 127, 137, 138, 166, 222 fuel, 50 functional changes, 88

G ganglion, 195 gastrointestinal tract, 131 gelatinase A, 36 gender, 210, 223, 231, 234, 238 gene, 20, 30, 35, 38, 39, 47, 58, 62, 64, 65, 69, 71, 72, 73, 79, 80, 81, 89, 90, 91, 92, 94, 96, 102, 105, 106, 111, 112, 113, 114, 115, 120, 127, 129, 130, 135, 136, 137, 142, 143, 148, 149, 150, 154,

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Index 155, 157, 172, 173, 182, 190, 191, 193, 215, 218, 222, 232, 244, 246, 252 gene expression, 20, 30, 35, 38, 39, 62, 64, 65, 69, 71, 73, 79, 81, 89, 102, 105, 113, 114, 135, 142, 143, 154, 157, 172, 193, 215, 218, 232, 252 gene promoter, 135, 137 gene therapy, 112 gene transfer, 96, 111 generation, 30, 57, 70, 73, 85, 86, 89, 93, 99, 104, 121, 123, 124, 126, 128, 129, 133, 134, 135, 137, 138, 154, 184, 193, 209 genes, 9, 20, 30, 37, 67, 90, 91, 106, 126, 135, 148, 151, 172, 190, 201, 208, 209, 212, 220, 224, 237 genetic factors, 199 genetic linkage, 126 genetic mutations, 172 genetics, 172 Germany, 117, 140 gestation, 32, 200 glatiramer acetate, 177, 195 glia, 22, 34, 35, 37, 47, 59, 61, 63, 64, 65, 70, 72, 73, 74, 75, 76, 77, 79, 94, 104, 112, 121, 124, 125, 129, 133, 152, 164, 178, 179, 230, 238, 255 glial cells, 11, 14, 16, 22, 28, 34, 39, 52, 58, 63, 65, 69, 73, 74, 76, 79, 81, 128, 129, 131, 142, 143, 144, 149, 153, 164, 166, 167, 170, 181, 182, 185, 191, 209, 221, 224, 226, 227, 231, 232, 249, 250, 251, 254, 255, 257 globus, 168 glucocorticoid receptor, 74, 78 glucose, 56, 60, 62, 74, 76, 80, 82, 103, 131, 136, 198, 213, 219 glutamate, 29, 33, 34, 35, 36, 38, 42, 47, 48, 49, 51, 54, 56, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 70, 71, 74, 75, 78, 79, 103, 124, 140, 142, 151, 160, 180, 183, 184, 201, 211, 214, 250, 253, 254 glutamate receptor antagonists, 60 glutathione, 29, 33, 34, 35, 36, 48, 51, 54, 55, 56, 66, 70, 99, 100, 164, 167, 170, 172, 185, 186, 198, 199, 201, 209, 210 glycogen, 50, 60 glycoproteins, 46 grants, 34, 101, 180, 232 granules, 46 gray matter, 7, 17 groups, 91, 123, 129, 170, 171, 176, 197, 209, 247 growth, 6, 9, 16, 18, 20, 28, 33, 38, 73, 96, 111, 166, 184, 199, 205, 216, 223, 236, 239 growth factor, 6, 9, 16, 18, 20, 28, 33, 38, 73, 111, 184, 199, 205, 239

265

guanine, 170 guidance, 67, 164 gut, 147

H half-life, 132 harm, 88 HE, 187, 237 head injury, 13, 223, 227, 238, 239 healing, 123 health, 161, 163, 175 health care, 175 health care professionals, 175 heart disease, 22 heat, 65, 170 heat shock protein, 170 heme, 169, 186 heme oxygenase, 169, 186 hemisphere, 203 hemorrhage, 87, 100, 115 hemorrhagic stroke, 107 herbicide, 174, 192 heterochromatin, 7 heterogeneity, 11, 94 hippocampus, 8, 22, 26, 60, 65, 67, 75, 78, 90, 104, 110, 111, 118, 123, 129, 131, 134, 137, 145, 147, 150, 151, 154, 163, 166, 167, 175, 176, 217 histamine, 92, 141, 206 histidine, 187 histology, 53 HIV, 12, 31, 42, 56, 68, 69, 73, 78, 160 HIV infection, 12, 68 HIV-1, 31, 56, 78, 160 HLA, 20, 163, 181, 183 homeostasis, 5, 6, 37, 42, 61, 63, 79, 80, 88, 136, 162, 167, 171 hormone, 72, 73, 135, 223 host, 101, 123, 128, 160 human brain, 6, 55, 113, 127, 138, 157, 250 human immunodeficiency virus, 12, 17, 31, 73, 77 human subjects, 164 hydrocephalus, 156 hydrogen, 56, 70, 166, 214 hydrogen peroxide, 56, 70, 166, 214 hydroperoxides, 188 hydroxyl, 70, 73, 166 hyperinsulinemia, 131 hyperthermia, 209, 220 hypertrophy, 25, 34

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hypoglycemia, 58 hypokinesia, 174 hypotension, 26 hypothalamus, 69, 166 hypothermia, 90, 99, 104, 111, 114, 115, 209, 213, 214, 216, 218, 219, 228, 233 hypothesis, 15, 59, 119, 125, 128, 131, 134, 154 hypoxia, 21, 37, 39, 47, 50, 58, 61, 70, 73, 79, 88, 199, 200, 209, 210, 211, 213, 214, 215, 216, 217, 218, 219, 220, 249

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I ibuprofen, 134, 136, 137, 139, 146, 147 ICAM, 30, 32, 66, 73, 90, 91, 92, 93, 107, 108, 110, 163, 223 identification, 15, 58, 106, 137 identity, 5, 80 idiopathic, 186, 190 IFN, 10, 20, 28, 29, 30, 31, 33, 35, 37, 38, 47, 48, 60, 64, 65, 66, 67, 73, 102, 126, 132, 136, 137, 139, 142, 156, 163, 165, 190, 242, 251 IL-6, 9, 10, 16, 28, 30, 31, 32, 34, 36, 47, 68, 73, 76, 90, 95, 110, 122, 125, 126, 127, 136, 166, 174, 205, 206, 208, 215, 223, 226, 227 IL-8, 28, 31, 112, 124, 125, 126, 226 immune activation, 58 immune function, 52, 96, 162 immune response, 3, 4, 29, 36, 52, 53, 60, 85, 88, 92, 96, 101, 104, 125, 160, 177, 178, 183, 212, 222, 230, 244 immune system, 3, 21, 53, 81, 85, 94, 101, 104, 120, 160, 162, 164, 166, 178, 184, 241 immunity, 52, 195 immunization, 122, 177, 178, 195, 246 immunocompetent cells, 5, 60 immunocompromised, 14 immunodeficiency, 146 immunoglobulin, 91, 92, 94 immunoglobulin superfamily, 91, 92 immunohistochemistry, 115, 126, 192 immunomodulation, 107 immunomodulator, 242 immunoreactivity, 10, 21, 27, 59, 106, 128, 129, 141, 147, 151, 154, 164, 167, 168, 170, 212, 224, 229, 231, 252, 256 immunostimulatory, 14 in situ hybridization, 16, 109, 126, 232, 243 in vitro, 6, 8, 14, 16, 19, 28, 30, 31, 32, 35, 36, 37, 43, 44, 45, 51, 54, 56, 58, 59, 60, 61, 68, 70, 72,

73, 75, 76, 78, 79, 80, 81, 82, 103, 122, 123, 125, 130, 132, 134, 136, 152, 156, 170, 172, 173, 174, 175, 181, 189, 199, 231, 239, 249, 254, 256 incidence, 15, 117, 140, 197, 246 inclusion, 168, 173, 190 indicators, 163, 188 inducer, 9, 29, 88, 247 inducible protein, 225, 251 induction, 9, 29, 33, 37, 47, 48, 54, 60, 64, 65, 69, 71, 72, 73, 91, 102, 103, 119, 127, 128, 137, 143, 146, 148, 150, 151, 152, 155, 170, 173, 178, 194, 208, 211, 212, 227, 234, 237, 238, 239, 251 infancy, 4 infants, 65, 198, 199 infarction, 103, 107, 242, 244, 254, 255 infection, 10, 12, 17, 22, 78, 87, 101, 160, 199, 200, 212, 219 infectious disease, 12 inflammation, 3, 4, 11, 13, 15, 17, 21, 22, 25, 26, 32, 33, 37, 38, 41, 50, 51, 52, 53, 55, 60, 69, 73, 77, 78, 86, 87, 88, 89, 90, 95, 98, 101, 102, 103, 104, 105, 111, 112, 114, 121, 123, 124, 126, 131, 132, 133, 134, 138, 140, 142, 143, 144, 145, 146, 147, 148, 152, 155, 156, 160, 162, 165, 171, 172, 173, 174, 175, 176, 178, 181, 182, 193, 197, 199, 200, 201, 202, 205, 206, 209, 210, 213, 215, 216, 218, 222, 226, 227, 230, 231, 232, 233, 234, 235, 238, 241, 250, 254, 257 inflammatory cells, 3, 4, 25, 30, 34, 54, 59, 68, 85, 87, 88, 98, 99, 101, 102, 111, 199, 201, 221, 223, 251, 255 inflammatory demyelination, 53 inflammatory disease, 25, 56, 125 inflammatory mediators, 42, 43, 67, 87, 88, 101, 119, 122, 125, 126, 138 inflammatory responses, 32, 34, 52, 86, 92, 99, 101, 136, 140, 145, 153, 160, 162, 163, 164, 168, 171, 172, 173, 175, 177, 206, 224, 238, 241 influence, 81, 92, 105, 121, 132, 138, 186, 192, 219, 220 ingestion, 53 inheritance, 172 inhibition, 19, 35, 51, 55, 72, 77, 81, 87, 96, 99, 100, 101, 106, 114, 115, 134, 136, 137, 142, 145, 150, 154, 155, 167, 168, 170, 173, 175, 176, 188, 191, 193, 194, 205, 209, 213, 217, 218, 226, 228, 229, 235, 237, 239, 247, 249 inhibitor, 9, 43, 45, 46, 74, 81, 89, 90, 95, 99, 104, 112, 113, 115, 124, 135, 154, 194, 209, 212, 215, 234, 235, 247, 249, 250, 251

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Index initiation, 43, 67, 123, 197, 201, 202, 254 injections, 198, 202, 227 injury, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 21, 22, 23, 25, 28, 29, 31, 32, 33, 35, 36, 37, 38, 42, 51, 56, 58, 60, 62, 64, 66, 67, 69, 70, 71, 72, 73, 75, 76, 77, 78, 80, 81, 85, 87, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 119, 120, 144, 146, 160, 162, 164, 165, 166, 171, 178, 182, 194, 195, 197, 199, 200, 201, 202, 203, 205, 206, 208, 209, 210, 212, 213, 214, 215, 216, 217, 218, 219, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 242, 244, 245, 248, 249, 250, 251, 252, 254, 255 innate immunity, 72, 102, 160, 167 input, 63, 70 insight, 172 instability, 159 insulin, 121, 131, 135, 136, 151 insulin sensitivity, 135, 136 integrin, 10, 94, 102, 109 integrity, 30, 124, 198, 203 intensity, 64, 67, 125, 171 interaction, 37, 52, 63, 64, 67, 74, 77, 88, 91, 123, 132, 138, 143, 154, 217, 245 interactions, 4, 10, 50, 63, 64, 70, 72, 73, 77, 96, 125, 134, 145, 166, 216 intercellular adhesion molecule, 10, 30, 37, 73, 90, 91, 105, 106, 107, 108, 222, 223 interest, 12, 97, 170, 175 interface, 29, 97, 112 interference, 137, 170 interferon, 10, 17, 20, 22, 29, 31, 34, 73, 141, 163, 183, 190, 225, 238, 252, 255 interferon gamma, 17 interferon-γ, 10 interleukin-8, 220, 244, 254 interleukine, 192 interleukins, 125, 126, 164, 184 internalised, 45 internalization, 181 interneurons, 75 interpretation, 93 intervention, 148, 209, 249 intoxication, 174, 191 intraocular, 195 intraocular pressure, 195 invertebrate, 63 ion channels, 6, 69, 247

267

ions, 6, 66, 171, 189 IP-10, 28, 31, 124, 237, 255 ipsilateral, 72 iron, 171, 185, 189, 190, 191, 198, 209 irradiation, 65 ischemia, 8, 9, 16, 18, 26, 33, 39, 66, 67, 71, 72, 73, 80, 86, 87, 88, 89, 90, 92, 93, 95, 96, 98, 100, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 128, 130, 145, 154, 193, 198, 199, 201, 203, 205, 206, 211, 213, 215, 216, 217, 218, 219, 220, 242, 244, 248, 249, 251, 253, 254, 255, 256, 257

J Japan, 190, 241 Jordan, 190

K ketones, 198 kidney, 136 kinase activity, 239 knowledge, 4

L labeling, 8, 17, 203, 204 lactate dehydrogenase, 51 laminar, 7 lead, 9, 31, 33, 47, 49, 52, 54, 70, 73, 86, 92, 93, 95, 99, 125, 128, 129, 130, 131, 133, 159, 162, 169, 177, 179, 201, 225, 226, 228 leakage, 203 learning, 43, 118, 146, 212, 215, 226 lesions, 9, 35, 50, 51, 52, 53, 61, 62, 87, 91, 121, 149, 153, 172, 173, 200, 213, 217, 222, 238, 245, 246 leucine, 91 leucocyte, 35, 73 leukemia, 227 leukotrienes, 98 LFA, 66, 73, 94, 163, 174 life expectancy, 117 ligands, 28, 30, 94, 121, 136, 137, 145, 151, 157, 246, 256 limitation, 75 links, 78 lipases, 97

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lipid metabolism, 142, 177 lipid peroxidation, 70, 163, 166, 169, 171, 187, 188, 189, 200, 212 lipid peroxides, 202 lipids, 162, 168, 171 liquid chromatography, 188 listening, 79 liver, 135 localization, 19, 21, 76, 145, 151, 166, 239 location, 5, 11, 47 locus, 46, 129, 131, 138, 141, 144, 145, 146, 149, 151, 157, 159, 166, 182, 184, 190 LTB4, 98 lung disease, 234 lymphocytes, 9, 10, 11, 52, 53, 58, 87, 92, 136, 165, 183, 202, 221, 229, 245

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M machinery, 199, 256 macromolecules, 168, 171, 244 macrophage inflammatory protein, 39, 96, 124, 208, 212, 237, 243, 252, 253, 255, 256 macrophages, 3, 5, 6, 7, 11, 14, 17, 18, 19, 21, 22, 28, 42, 46, 50, 52, 57, 59, 61, 65, 66, 68, 69, 71, 81, 87, 88, 96, 100, 102, 113, 120, 124, 128, 131, 136, 146, 153, 160, 161, 163, 165, 167, 168, 177, 180, 181, 199, 200, 202, 203, 206, 221, 222, 223, 224, 225, 229, 230, 231, 236, 239, 243, 244, 245, 247, 252, 254 magnesium, 209, 239 magnetic resonance, 57, 122, 178, 195, 211, 218 magnetic resonance imaging, 57, 122, 218 major histocompatibility complex, 10, 19, 22, 28, 75, 88, 120, 162, 182 males, 223, 233 mammalian brain, 16, 17, 198 manganese, 186, 225 manipulation, 175, 244 mannitol, 50, 209 marrow, 19, 100 Marx, 141 mass, 58 mass spectrometry, 58 mast cells, 206, 217 matrix, 30, 36, 38, 47, 85, 87, 93, 94, 96, 100, 114, 115, 144, 156, 160, 176, 194, 198, 200, 203, 221, 223, 228 matrix metalloproteinase, 30, 36, 38, 47, 85, 87, 114, 115, 144, 160, 194, 203, 223

maturation, 15, 57, 63, 132, 162, 197, 198, 199, 215, 228 maze learning, 125 MBP, 177, 200 MCP, 10, 20, 28, 30, 31, 33, 68, 69, 73, 96, 97, 111, 112, 124, 125, 126, 208, 209, 225, 226, 237, 243, 244, 245, 246, 252, 254, 255, 256 MCP-1, 10, 20, 28, 30, 31, 33, 68, 69, 73, 96, 97, 111, 112, 124, 125, 126, 208, 209, 225, 226, 237, 243, 244, 245, 246, 252, 255, 256 measurement, 55, 142, 188 measures, 163, 169, 203, 218, 230 media, 118 mediation, 160 medication, 133, 135 MEK, 46 membranes, 123, 166, 185 memory, 29, 43, 53, 118, 122, 125, 132, 138, 155, 156, 165, 166, 174 memory formation, 132 memory processes, 118, 125 mesoderm, 5 messenger ribonucleic acid, 235 messenger RNA, 215, 256 metabolism, 36, 48, 136, 145, 154, 160, 181, 185, 190, 198, 201, 210, 219, 235, 236 metabolites, 98, 160, 166 metalloproteinase, 47, 115, 192 metals, 185 methanol, 48 MHC, 10, 15, 21, 28, 29, 38, 39, 64, 65, 66, 73, 74, 88, 126, 147, 162, 163, 164, 174, 179, 182, 183, 191 MHC class II molecules, 39, 64 Miami, 221, 232 mice, 6, 9, 13, 14, 16, 17, 18, 19, 21, 28, 35, 36, 52, 53, 54, 59, 69, 71, 78, 80, 88, 92, 93, 94, 95, 98, 99, 100, 102, 103, 106, 107, 108, 110, 111, 112, 113, 114, 121, 122, 124, 125, 126, 130, 133, 134, 137, 139, 140, 141, 144, 145, 146, 147, 148, 149, 150, 151, 153, 155, 156, 164, 172, 174, 177, 178, 179, 183, 185, 190, 192, 194, 200, 206, 209, 213, 214, 217, 218, 220, 222, 223, 224, 225, 226, 227, 228, 230, 232, 233, 234, 235, 237, 238, 239, 242, 244, 246, 248, 250, 251, 252, 255, 256, 257 microinjection, 36, 227 microscope, 7, 16 midbrain, 163, 170, 193 migration, 9, 28, 67, 69, 96, 97, 112, 124, 130, 164, 183, 208, 244, 256

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Index migratory properties, 38 mineralocorticoid, 81 MIP, 30, 68, 96, 111, 112, 124, 125, 208, 243, 244, 245, 246, 252, 255 misconceptions, 15 mitochondria, 45, 48, 187 mitochondrial DNA, 170 mitogen, 28, 56, 74, 89, 104, 121, 144, 154, 176, 227, 239 mitosis, 7, 8, 9, 18, 65 MMP, 30, 32, 33, 38, 47, 100, 114, 160, 174, 176, 194, 223 MMP-2, 33, 100, 176, 194 MMP-9, 30, 32, 38, 100, 114, 174, 176, 194, 223 MMPs, 30, 47, 49, 85, 87, 100, 114, 115, 176 mode, 171, 185 model system, 4, 164, 165 modeling, 159 models, 8, 54, 57, 65, 88, 89, 92, 94, 95, 96, 100, 106, 118, 124, 126, 132, 136, 142, 144, 150, 154, 159, 167, 173, 174, 175, 177, 180, 182, 183, 184, 192, 195, 202, 203, 205, 206, 208, 209, 221, 222, 226, 227, 231, 241, 242, 244, 248, 249, 255 molecular pathology, 60 molecular weight, 209 molecules, 10, 19, 26, 28, 30, 31, 37, 64, 68, 69, 70, 71, 73, 76, 77, 78, 86, 87, 91, 92, 93, 94, 105, 106, 107, 108, 121, 123, 124, 126, 129, 132, 133, 143, 162, 164, 188, 205, 208, 221, 225, 226, 228, 229, 235, 241 monitoring, 6, 138, 247 monoclonal antibody, 106, 108 monocyte chemoattractant protein, 36, 73, 78, 96, 111, 112, 146, 214, 220, 225, 232, 237, 243, 251, 252, 253, 255 monolayer, 18, 19, 75 morbidity, 140 morphology, 3, 7, 15, 35, 162, 182 mortality, 114 motor neurons, 140 motor skills, 68 movement, 159 MRI, 133, 202, 242 mRNA, 9, 10, 16, 22, 31, 38, 39, 93, 95, 99, 107, 109, 123, 125, 126, 127, 128, 132, 135, 139, 150, 152, 153, 164, 174, 182, 185, 212, 227, 231, 232, 234, 237, 238, 239, 242, 243, 249, 253, 254, 255 multi-infarct dementia, 149 multiple sclerosis, 34, 35, 39, 41, 54, 55, 136, 255, 256

269

mutant, 71, 119, 124, 147, 155, 172, 191 mutation, 71, 80, 249 myelin, 12, 34, 37, 50, 52, 53, 54, 60, 61, 67, 68, 78, 79, 165, 177, 178, 179, 200, 228, 242, 244 myelin basic protein, 37, 177, 178, 179, 200, 244 myelin oligodendrocyte glycoprotein, 37, 54

N National Institutes of Health, 180 necrosis, 5, 35, 47, 60, 62, 70, 77, 79, 81, 88, 109, 110, 140, 149, 154, 184, 200, 211, 235, 236, 250, 253 needs, 32 neocortex, 6, 21, 148, 189, 200 neonates, 9, 197, 198, 206, 214, 219 nerve, 7, 8, 9, 17, 20, 21, 22, 39, 42, 61, 63, 67, 73, 77, 110, 141, 173, 182, 228, 234 nerve fibers, 7, 110 nerve growth factor, 39, 42, 73, 228, 234 nervous system, 21, 38, 57, 59, 63, 74, 77, 81, 105, 120, 160, 161, 162, 178, 194, 234 network, 5, 18 networking, 76 neuritis, 238, 257 neurobiology, 79 neuroblastoma, 62 neurodegeneration, 13, 15, 17, 25, 34, 35, 36, 43, 64, 65, 69, 70, 72, 77, 78, 79, 80, 87, 102, 110, 112, 119, 124, 127, 128, 130, 132, 133, 142, 146, 155, 156, 159, 160, 162, 164, 167, 172, 173, 174, 175, 176, 177, 178, 180, 181, 182, 184, 185, 186, 188, 190, 191, 192, 193, 194, 195, 197, 208, 215, 217, 226, 234, 241, 247, 250 neurodegenerative disorders, 37, 46, 63, 67, 117, 164, 171, 172, 185, 189, 190, 194, 229 neurofibrillary tangles, 13, 118, 119, 120, 123, 128, 148, 243 neuroinflammation, 4, 5, 6, 11, 12, 13, 15, 22, 42, 62, 65, 66, 69, 114, 119, 120, 122, 124, 126, 138, 150, 153, 160, 164, 173, 175, 178, 201, 218 neurological disability, 242 neurological disease, 124, 143, 166 neurons, 3, 9, 12, 13, 20, 23, 26, 28, 29, 35, 39, 60, 61, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 77, 79, 80, 81, 85, 86, 87, 88, 94, 95, 96, 102, 103, 109, 113, 118, 121, 122, 125, 127, 128, 129, 130, 131, 132, 133, 136, 138, 140, 142, 145, 147, 149, 150, 151, 154, 155, 156, 159, 160, 162, 163, 164, 165, 166, 167, 168, 170, 172, 173, 174, 175,

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Index

176, 177, 181, 182, 186, 187, 188, 189, 191, 192, 193, 194, 195, 197, 199, 200, 205, 217, 224, 225, 226, 227, 230, 231, 238, 242, 246, 248, 249, 253 neuropeptides, 6, 29 neuroprotection, 34, 36, 73, 111, 113, 123, 147, 155, 179, 180, 191, 193, 194, 195, 210, 212, 213, 216, 217, 218, 234, 242, 254, 257 neuroprotective agents, 105 neurotoxicity, 33, 41, 60, 61, 71, 78, 82, 113, 122, 136, 142, 153, 191, 193, 194, 206 neurotransmitter, 28, 65, 130 neurotransmitters, 6, 42, 64, 71 neurotrophic factors, 25, 72, 122, 161, 178 neutrophils, 11, 87, 88, 91, 92, 94, 100, 105, 108, 124, 201, 202, 208, 215, 216, 217, 221, 222, 242, 246 nicotinamide, 164, 247 nitric oxide, 10, 16, 23, 26, 29, 33, 34, 35, 36, 46, 55, 58, 70, 73, 74, 76, 79, 80, 85, 87, 88, 102, 113, 114, 119, 128, 133, 139, 141, 142, 144, 145, 146, 147, 148, 152, 153, 154, 155, 156, 160, 163, 166, 167, 180, 181, 184, 186, 193, 194, 201, 211, 213, 218, 219, 221, 223, 224, 226, 230, 233, 235, 236, 238, 239, 244, 245, 247, 248, 251, 252, 253, 255, 257 nitric oxide synthase, 23, 26, 29, 73, 76, 87, 88, 113, 114, 119, 128, 139, 142, 144, 145, 146, 147, 148, 153, 155, 156, 163, 167, 184, 193, 201, 211, 213, 218, 223, 224, 226, 230, 233, 235, 238, 239, 251, 252, 253, 257 nitrogen, 16, 36, 50, 56, 68, 70, 114, 166, 167, 168, 172, 176 nitrogen oxides, 16 NMDA receptors, 78, 200, 212, 215 nodes, 77 non-steroidal anti-inflammatory drugs, 133, 143, 148, 149, 155 norepinephrine, 29 normal aging, 21 normal development, 200 NSAIDs, 15, 68, 127, 133, 134, 135, 136, 137, 139, 143, 156, 175 nuclei, 7, 17, 26, 27, 45, 129, 159 nucleic acid, 168, 170, 187 nucleotides, 202 nucleus, 9, 16, 17, 18, 19, 20, 21, 22, 43, 47, 48, 49, 61, 76, 89, 90, 127, 129, 130, 131, 136, 138, 144, 157, 159, 170, 214, 238

O observations, 3, 15, 45, 96, 99, 134, 137, 138, 163, 224, 225 occlusion, 7, 19, 26, 27, 72, 92, 101, 104, 105, 107, 108, 109, 202, 203, 204, 205, 207, 208, 209, 212, 216, 242, 243, 252, 255 oculomotor, 170 oligomers, 119, 122, 155, 172, 191 optic nerve, 58, 195 organ, 3, 85, 128 organism, 3 organization, 69 organizations, 77 ovarian cancer, 103 overload, 169, 173 overproduction, 128 oxidation, 168, 170, 171, 176, 186 oxidative damage, 66, 128, 160, 169, 170, 171, 187, 198, 226 oxidative stress, 29, 34, 47, 51, 54, 70, 79, 112, 132, 159, 162, 163, 166, 167, 168, 170, 171, 174, 176, 182, 185, 186, 188, 192, 198, 200, 201, 209, 210, 230, 232, 235, 237 oxygen, 30, 33, 56, 60, 62, 70, 74, 76, 80, 82, 99, 103, 114, 128, 167, 170, 171, 172, 198, 201, 221, 229 oxygen consumption, 198

P p53, 47, 48, 49, 55, 57, 60, 62 pain, 238 paralysis, 225 parenchyma, 3, 11, 12, 14, 20, 37, 85, 86, 91, 99, 130, 176, 202, 224, 225, 227, 229, 243, 244, 245 parenchymal cell, 5 Parkinson’s disease, 3, 33, 42, 46, 136, 159, 178, 187, 241, 247, 257 parkinsonism, 173, 181, 183, 189, 191, 192 particles, 193 passive, 56, 122, 177, 198 pathogenesis, 6, 13, 32, 42, 59, 87, 95, 102, 107, 109, 119, 132, 138, 159, 160, 163, 167, 178, 180, 246 pathogens, 3, 101, 120, 123, 162, 178 pathological aging, 15 pathology, 11, 21, 43, 46, 51, 69, 77, 78, 109, 121, 123, 124, 137, 139, 145, 148, 149, 150, 154, 174, 181, 222, 235, 241, 243, 246, 249

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Index pathophysiology, 100, 180, 201, 206, 222, 225, 228 pathways, 31, 38, 43, 46, 57, 65, 68, 69, 70, 95, 97, 98, 104, 121, 123, 138, 163, 169, 172, 180, 186, 190, 205, 209, 215, 218, 234, 247, 256 PCR, 123 peptides, 18, 19, 43, 57, 62, 118, 119, 120, 121, 128, 131, 134, 137, 141, 147, 165, 168, 243, 244 perinatal, 37, 75, 210, 214, 215, 216, 217, 218, 219 peripheral blood, 28, 183 permeability, 30, 33, 38, 39, 45, 56, 57, 62, 96, 98, 112, 198, 210, 211, 226, 238, 244, 245, 247, 252 peroxidation, 171, 188, 211 peroxide, 140 peroxynitrite, 29, 35, 58, 70, 99, 100, 122, 128, 153, 166, 167, 168, 169, 172, 186, 253, 256 perspective, 22, 114, 154 pertussis, 46 pesticide, 192 PET, 122, 192 pH, 66 phagocyte, 7, 61, 76 phagocytosis, 9, 13, 17, 23, 48, 51, 52, 53, 58, 61, 66, 67, 96, 121, 123, 124, 127, 130, 153, 156, 181, 193 pharmacology, 75, 254 phenotype, 7, 20, 36, 42, 43, 46, 55, 66, 94, 120, 131, 172, 174, 203 phospholipids, 97, 98 phosphorylation, 72, 90, 166, 176, 243, 253 photomicrographs, 34 physiology, 12 pioglitazone, 136, 137, 141, 143, 146, 177, 195 placebo, 16, 106, 139 placenta, 219 plasma, 11, 52, 90, 108, 111, 112 plasminogen, 71, 72, 74, 80 plasticity, 6, 37, 63, 68, 77, 164, 182, 212, 218, 228 platelet activating factor, 73 platelets, 214 plexus, 130 PM, 112, 150, 154, 193, 232, 233, 234, 238 polymerase, 58, 170, 234, 247 polymerization, 132 polymorphism, 147, 149, 190 polypeptide, 36, 95, 229, 238 poor, 33, 38 population, 8, 23, 32, 42, 43, 106, 117, 156, 160, 200 positive feedback, 162 positron, 139 positron emission tomography, 139

271

potassium, 239 precursor cells, 75, 199 predictors, 92 prefrontal cortex, 147, 168, 186 preparation, 14 pressure, 198 preterm infants, 32, 199 prevention, 15, 75, 154, 177 primate, 106, 174, 177, 195 priming, 29, 201 prions, 12 probe, 139 producers, 22, 28, 71 production, 7, 9, 13, 20, 25, 26, 28, 29, 30, 32, 33, 35, 43, 47, 48, 52, 58, 64, 65, 66, 67, 68, 69, 70, 73, 74, 86, 88, 90, 94, 96, 99, 102, 109, 114, 122, 125, 127, 131, 133, 134, 136, 140, 141, 146, 147, 150, 155, 156, 157, 164, 166, 167, 168, 170, 172, 174, 175, 176, 178, 179, 181, 190, 199, 200, 214, 215, 216, 225, 226, 228, 229, 230, 234, 236, 239, 242, 245, 246, 249, 252, 256 program, 253 progressive neurodegenerative disorder, 50, 243 progressive supranuclear palsy, 185 proliferation, 8, 9, 16, 17, 18, 19, 20, 21, 22, 23, 25, 29, 32, 37, 42, 58, 65, 67, 73, 88, 136, 193, 203, 204, 206, 208 promoter, 124, 135, 136, 137, 138, 244 propagation, 15, 31, 132, 201 prostaglandins, 98, 230, 231, 236 protective factors, 20, 149 protective mechanisms, 43 protective role, 32, 98, 213 protein conformations, 173 protein kinase C, 58 protein kinases, 20, 56, 90, 104 protein misfolding, 70, 172 protein oxidation, 168, 186 protein synthesis, 142 proteins, 9, 19, 33, 38, 41, 43, 47, 60, 68, 71, 72, 90, 91, 94, 96, 109, 121, 123, 124, 125, 126, 133, 134, 135, 151, 154, 157, 160, 162, 166, 168, 169, 170, 171, 173, 174, 176, 177, 187, 198, 209, 244, 247, 249 proteoglycans, 225, 228 proteolysis, 71, 176, 188 proto-oncogene, 105 pulmonary hypertension, 247 pulse, 203 pumps, 198

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272

Q quality control, 169 quinolinic acid, 160, 166

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R radiation, 37 radical formation, 216 range, 71, 96, 166, 176, 188, 199, 203, 209 RANTES, 28, 30, 31, 124, 229, 245, 246 reactive oxygen, 30, 33, 48, 50, 51, 66, 68, 85, 86, 99, 113, 120, 125, 164, 166, 176, 178, 186, 198, 201, 227, 230 recalling, 118 receptors, 6, 10, 28, 31, 34, 35, 39, 48, 51, 60, 61, 62, 64, 65, 67, 68, 70, 72, 73, 81, 88, 92, 94, 95, 96, 97, 102, 110, 111, 120, 123, 124, 127, 129, 130, 135, 140, 141, 144, 147, 148, 150, 154, 155, 163, 165, 166, 174, 181, 184, 198, 200, 208, 211, 214, 233, 244, 246, 247, 250, 254 recognition, 28, 54, 123, 164, 212 recombination, 244 recovery, 53, 59, 202, 226, 227, 232, 233, 234, 235, 237, 239 recruiting, 125, 227 redistribution, 244 reduction, 45, 47, 53, 99, 114, 118, 122, 130, 134, 138, 164, 167, 177, 209, 226, 228, 229, 242, 246 regenerate, 50 regeneration, 3, 17, 22, 43, 67, 68, 81, 101, 162, 177, 226, 228, 231, 233, 236 regulation, 4, 8, 19, 20, 30, 34, 35, 37, 39, 47, 59, 66, 71, 72, 74, 75, 76, 90, 98, 105, 112, 121, 127, 132, 136, 137, 138, 139, 140, 143, 149, 151, 152, 153, 155, 172, 174, 183, 185, 199, 208, 212, 230 regulators, 144, 178, 182, 229, 235 relapses, 36, 246 relationship, 13, 21, 156, 164, 181, 198, 219 relevance, 19, 61, 76, 78, 133, 140, 186, 191 remission, 52, 53 remodelling, 60 remyelination, 51, 57 repair, 4, 11, 25, 30, 43, 72, 205, 210, 223 repression, 62, 148 residues, 96, 167, 172, 176, 187 resistance, 151, 183, 197, 246 respiration, 50, 55, 70, 187, 247, 253 respiratory, 29, 35, 96, 100, 118, 166, 170, 184, 247 reticulum, 7

rheumatoid arthritis, 12, 15, 227 ribose, 58, 170, 213, 234, 247, 257 risk, 68, 121, 126, 131, 135, 141, 143, 146, 147, 149, 151, 160, 163, 165, 168, 174, 175, 182, 187, 190, 192 risk factors, 192 RNA, 16, 77, 123, 139, 148, 170, 176, 187, 190, 234 rodents, 15, 69, 90, 94, 198, 201, 205, 206 rosiglitazone, 136

S safety, 250 sampling, 168 saturation, 50 sclerosis, 34, 242 scores, 177 search, 36 second generation, 90, 176 secondary tissue, 226 secrete, 31, 42, 66, 85, 100, 121, 161, 163, 164, 178, 179 secretion, 36, 42, 48, 53, 55, 67, 114, 126, 127, 129, 132, 134, 137, 138, 140, 141, 160, 203, 251 segregation, 214 self, 12, 120, 125, 131, 132, 173, 177, 178, 179, 212, 242 senile dementia, 20, 146, 156 sensitivity, 8, 55, 67, 71, 76, 215 sensitization, 201 sensors, 31 septic shock, 128 septum, 166 series, 70, 228 serum, 6, 32, 85, 92, 93, 108, 123, 145, 170, 187, 251 severity, 7, 10, 11, 51, 53, 59, 111, 119, 130, 133, 163, 167, 184, 200, 206, 225, 231, 235, 246 sex steroid, 81 shape, 7, 67 shares, 118 shear, 93 sheep, 16, 200, 216 shock, 65, 154 short term memory, 118 signal transduction mechanisms, 69, 135 signaling pathways, 30, 77, 90, 135, 148, 170 signalling, 46, 50, 53, 54, 56, 57, 58, 59, 75 signalling pathways, 46 signals, 6, 64, 66, 67, 68, 71, 90, 95, 162, 226, 229

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Index siRNA, 137 sites, 13, 52, 65, 69, 81, 90, 118, 164, 182, 187, 222, 232, 244, 250 skeletal muscle, 135 skills, 119 skin, 239 sodium, 66, 76, 239 specialisation, 236 species, 8, 15, 30, 33, 36, 50, 51, 56, 66, 68, 70, 85, 86, 99, 113, 120, 125, 164, 166, 167, 168, 169, 170, 171, 172, 176, 178, 186, 198, 201, 223, 227, 230, 243 specificity, 137 spectroscopy, 189, 249 spectrum, 6, 11, 32, 67, 126, 162, 214, 229, 244, 250 spin, 249 spinal cord, 10, 11, 16, 19, 21, 22, 23, 30, 35, 50, 60, 68, 75, 178, 218, 221, 222, 223, 224, 227, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 242 spinal cord injury, 10, 16, 23, 30, 68, 221, 232, 233, 234, 235, 237, 239, 240 Sprague-Dawley rats, 223 sprouting, 68, 180 stability, 148, 189 stabilization, 90, 93, 139 stages, 13, 39, 92, 118, 122, 131, 133, 138, 162, 171, 176, 197, 198, 202 stars, 79 stasis, 85 statin, 248 stellate, 7 stimulant, 14 stimulus, 12, 13, 64, 145, 206 storage, 122 strain, 8, 222, 236 strategies, 4, 51, 73, 94, 105, 120, 138, 148, 178, 192, 225 strength, 64 stress, 37, 48, 51, 61, 79, 80, 89, 90, 104, 121, 150, 154, 157, 159, 162, 166, 167, 168, 170, 171, 172, 173, 180, 182, 184, 186, 188, 199, 245, 249, 254, 257 striatum, 20, 39, 56, 69, 72, 153, 159, 166, 167, 174, 176, 177, 178, 181, 187, 191, 192, 198 stroke, 11, 19, 75, 80, 85, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 100, 101, 105, 106, 107, 108, 109, 110, 111, 112, 114, 197, 203, 205, 206, 208, 209, 216, 241, 242, 243, 244, 248, 250, 251, 252, 256 stromal cells, 19

273

structural protein, 203 subcortical nuclei, 156 substitutes, 56 substrates, 173, 247, 249 sugar, 50 suicide, 47 sulfur, 167 Sun, 20, 34, 61, 106, 109, 112, 115, 140, 212, 215 supply, 129, 229 suppression, 29, 59, 92, 177, 178, 179, 190 surprise, 12 surveillance, 5, 144, 165, 183, 203 survival, 4, 20, 42, 43, 50, 60, 66, 69, 70, 71, 72, 76, 81, 95, 143, 161, 183, 206, 219, 223, 226, 228, 238, 249 survival rate, 223, 238 susceptibility, 32, 35, 36, 50, 56, 67, 103, 113, 132, 183, 186, 191, 197, 199, 203, 212, 220, 246, 251 suture, 27 swelling, 200, 226 switching, 47 symptom, 94 symptoms, 118 synapse, 79, 164 synaptic plasticity, 77, 154 synaptic transmission, 64, 65, 75, 79, 154 syndrome, 103, 140, 146, 151, 157, 164, 173, 192 synergistic effect, 33 synthesis, 28, 29, 36, 38, 48, 70, 73, 77, 81, 96, 126, 129, 132, 141, 168, 176, 182, 221, 222, 228, 230, 243, 253 systems, 99, 119, 164, 174, 211

T T cell, 12, 19, 29, 37, 38, 53, 54, 59, 61, 124, 164, 165, 168, 174, 177, 178, 179, 182, 183, 195, 242, 246, 251 T lymphocytes, 12, 36, 38, 60, 124, 164, 178, 183 targets, 12, 56, 73, 75, 99, 102, 107, 135, 152, 170, 172, 241, 244, 245, 246, 249 tau, 118, 125, 157, 243, 246, 253, 256 TBI, 221, 222, 223, 224, 226, 227, 229, 230, 231 T-cell receptor, 182 TCR, 164 technology, 208 temperature, 37, 69, 111, 235 temporal lobe, 148 tension, 171 terminals, 61, 130, 159, 177

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TGF, 28, 29, 30, 31, 66, 73, 95, 96, 126, 132, 139, 156, 166, 179, 206, 217, 228, 233, 235 thalamus, 217 T-helper cell, 29 theory, 13 therapeutic approaches, 176 therapeutic interventions, 179 therapeutic targets, 91 therapeutics, 104, 178, 210, 248, 255 therapy, 73, 75, 78, 93, 97, 105, 106, 108, 120, 133, 149, 195, 217, 241, 242, 246, 251 thrombin, 6, 92 thyroid, 216 time, 7, 13, 14, 21, 32, 39, 53, 101, 113, 118, 128, 131, 132, 133, 159, 199, 201, 203, 206, 222, 223, 224, 225 timing, 73, 101, 200, 201, 202 TIMP, 115, 194 TIMP-1, 194 tissue, 5, 6, 11, 14, 15, 20, 25, 35, 42, 43, 46, 53, 57, 72, 73, 77, 78, 80, 81, 85, 87, 93, 97, 100, 101, 103, 106, 107, 109, 112, 115, 118, 120, 124, 135, 155, 156, 160, 161, 162, 167, 176, 178, 181, 188, 189, 194, 198, 201, 203, 204, 205, 206, 207, 208, 209, 211, 221, 222, 224, 225, 226, 228, 229, 234, 236, 245, 250, 253, 255 tissue homeostasis, 15, 160, 161 tissue plasminogen activator, 74, 77, 80, 81, 93, 103, 107, 109, 115 tissue remodelling, 181 TLR, 30 TLR4, 87 TNF, 10, 28, 29, 30, 31, 32, 36, 37, 38, 47, 48, 49, 51, 53, 54, 60, 65, 67, 68, 69, 70, 73, 90, 91, 93, 94, 95, 96, 110, 122, 125, 126, 129, 131, 132, 133, 136, 137, 141, 147, 154, 163, 165, 174, 175, 177, 184, 198, 200, 202, 206, 213, 223, 226, 227, 238, 239, 240, 242, 245, 249, 250, 254 TNF-alpha, 36, 38, 60, 110, 147, 184, 238, 239 TNF-α, 10, 32, 47, 48, 49, 51, 65, 67, 69, 70, 73, 90, 93, 94, 95, 131, 165 toxic effect, 98, 119, 168 toxicity, 35, 38, 51, 57, 58, 72, 75, 124, 127, 140, 155, 167, 172, 176, 180, 183, 186, 190, 191, 192, 193, 213 toxin, 46, 174, 191 TPA, 91 transcription, 28, 30, 47, 56, 72, 73, 81, 89, 90, 91, 105, 121, 127, 129, 130, 135, 136, 137, 138, 148, 182, 224, 225, 237

transcription factors, 81, 89, 91, 135, 136, 225, 237 transduction, 38, 69, 95, 104, 147, 221, 234 transection, 17, 61, 183, 229 transfection, 137 transferrin, 171 transformation(s), 6, 7, 14, 87, 132, 163, 203 transforming growth factor, 9, 18, 19, 21, 31, 73, 95, 111, 156, 166, 184, 228, 233, 236 transition, 45, 56, 57, 62, 198, 247, 252 translation, 90, 172 translocation, 68, 104, 136, 220 transmission, 21, 75, 79 transport, 46, 59, 76, 166, 174, 254 transportation, 162 trauma, 3, 4, 5, 8, 33, 67, 69, 87, 222, 223, 224, 225, 226, 227, 229, 231, 233, 234, 235, 237, 238 traumatic brain injury, 21, 28, 32, 36, 65, 69, 124, 132, 141, 194, 220, 221, 232, 233, 234, 235, 236, 237, 238, 240 tremor, 159 trend, 14, 242 trial, 16, 93, 94, 106, 135, 139, 152, 177, 214, 242 triggers, 11, 34, 45, 50, 61, 70, 75, 78, 80, 85, 86, 89, 96, 101, 102, 103, 140, 207, 247 tuberculosis, 184 tumor, 31, 61, 73, 74, 75, 76, 78, 79, 88, 90, 109, 110, 120, 122, 128, 141, 144, 145, 148, 151, 152, 153, 163, 181, 183, 193, 198, 212, 223, 235, 237, 239, 242, 252 tumor cells, 128 tumor invasion, 120 tumor necrosis factor, 31, 61, 73, 74, 75, 76, 78, 79, 88, 90, 109, 110, 122, 141, 144, 145, 148, 151, 152, 153, 163, 181, 183, 193, 198, 212, 223, 235, 237, 239, 242, 252 turnover, 8, 17, 169 tyrosine, 9, 20, 22, 46, 167, 168, 172, 193 tyrosine hydroxylase, 193

U UK, 41, 109, 184 underlying mechanisms, 131, 134 United States, 136 urinary tract, 223

V vagus nerve, 131 values, 45

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Index

W warrants, 50, 174 water, 63, 79 white matter, 7, 10, 18, 32, 47, 65, 75, 172, 199, 200, 206, 210, 211, 212, 213, 215, 224, 231 wild type, 98, 100, 225, 226, 227, 230, 246 withdrawal, 7, 133 work, 3, 4, 6, 31, 32, 34, 63, 70, 87, 88, 92, 93, 94, 98, 99, 100, 101, 131, 180, 228, 232 wound healing, 11, 228

Y yeast, 147 young adults, 15

Z zinc, 214

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variability, 29, 127 variable, 93, 152, 170 variation, 32, 126, 151 vascular cell adhesion molecule, 91, 93, 108 vascular dementia, 149 vasculature, 85, 86 vasoactive intestinal peptide, 29 vasomotor, 98 VCAM, 91, 92, 93, 94, 108 vector, 96, 110, 177, 195 ventricle, 200 venules, 92 vertebrates, 190 very late activation, 93 vessels, 86, 93, 202 victims, 93 viral meningitis, 10, 17 viruses, 160 vision, 6, 172 visualization, 14 vitamin C, 112 VLA, 93, 94 vulnerability, 33, 34, 38, 54, 62, 67, 69, 72, 75, 76, 79, 98, 152, 193, 197, 198, 200, 210, 211, 215, 216

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