The Blood-Brain Barrier in Health and Disease (Colloquium Integrated Systems Physiology: From Molecule to Function to Disease) [1 ed.] 9781615047390, 9781615047406, 1615047395

Table of contents :
Introduction
Characteristics of the Blood-Brain Barrier
2.1 Development of the Blood-Brain Barrier
2.2 Endothelial Transport Systems
Ultrastructural Components of the Blood-Brain Barrier
3.1 Tight Junctional Proteins
3.1.1 Occludin
3.1.2 Claudin
3.1.3 Junctional Adhesion Molecule
3.1.4 Accessory Proteins
3.2 Adherens Junctions
Cellular Components of theBlood-Brain Barrier
4.1 Astrocytes
4.2 Pericytes
4.3 Neurons
4.4 Microglia
Compromising the Blood-Brain Barrier
5.1 Site of Disruption of the Blood-Brain-Barrier
5.2 Seizures/Acute Hypertension
5.3 Neuroinflammatory Diseases
5.4 Diabetes
5.5 Traumatic Brain Injury
5.6 Cerebral Ischemia/Stroke
Summary
References
About the Authors
Blank Page

Citation preview

Integrated Systems Physiology

Series ISSN: 2154-560X

From Molecule to Function to Disease

Series Editors: D. Neil Granger, LSU Health Sciences, Shreveport Joey Granger, University of Mississippi Medical Center

The blood-brain barrier (BBB) is a complex and dynamic structure that protects the brain from cells within the vasculature, from the immune system and from pathogens. This barrier is present in arterioles, capillaries and venules and is formed at the level of adjacent endothelial cells, which are coupled to astrocytes, microglia, neurons and pericytes. The structure of this endothelial barrier is unique among endothelia of other organ systems and is composed of complexes made up of tight, gap and adherens junctions. In addition, it is the responsibility of the surrounding cellular elements to maintain the integrity of the junctional complexes and restrict the entry of substances from the blood into the brain. Changes in permeability of the BBB during physiologic and pathophysiologic conditions involve alterations in specific transporters at the level of the endothelium, activation of specific cellular second messenger pathways and/or the dissolution of the junctional complexes composing the BBB. This book focuses on various aspects that account for the formation and maintenance of the BBB, and on disease states that compromise this barrier.

THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

William G. Mayhan, Sanford School of Medicine, University of South Dakota Denise M. Arrick, Sanford School of Medicine, University of South Dakota



The Blood-Brain Barrier in Health and Disease

MAYHAN • ARRICK

Colloquium Lectures on

About Morgan & Claypool Publishers This volume is a printed version of a work that appears in the Colloquium Digital Library of Life Sciences. Colloquium books provide concise, original presentations of important research topics, authored by invited experts. All books are available in digital & print formats. For more information, visit store.morganclaypool.com morgan & claypool

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LIFE SCIENCES

The Blood-Brain Barrier in Health and Disease William G. Mayhan Denise M. Arrick

Colloquium Lectures on

Integrated Systems Physiology From Molecule to Function to Disease

Series Editors: D. Neil Granger & Joey Granger

The Blood-Brain Barrier in Health and Disease

ii

Colloquium Digital Library of Life Sciences The Colloquium Digital Library of Life Sciences is an innovative information resource for researchers, instructors, and students in the biomedical life science community, including clinicians. Each PDF e-book available in the Colloquium Digital Library is an accessible overview of a fast-moving basic science research topic, authored by a prominent expert in the field. They are intended as time-saving pedagogical resources for scientists exploring new areas outside of their specialty. They are also excellent tools for keeping current with advances in related fields, as well as refreshing one’s understanding of core topics in biomedical science. For the full list of available books, please visit: colloquium.morganclaypool.com Each book is available on our website as a PDF download. Access is free for readers at institutions that license the Colloquium Digital Library. Please e-mail [email protected] for more information.

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Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease Editors D. Neil Granger Louisiana State University Health Sciences Center Joey P. Granger University of Mississippi Medical Center Physiology is a scientific discipline devoted to understanding the functions of the body. It addresses function at multiple levels, including molecular, cellular, organ, and system. An appreciation of the processes that occur at each level is necessary to understand function in health and the dysfunction associated with disease. Homeostasis and integration are fundamental principles of physiology that account for the relative constancy of organ processes and bodily function even in the face of substantial environmental changes. This constancy results from integrative, cooperative interactions of chemical and electrical signaling processes within and between cells, organs and systems. This eBook series on the broad field of physiology covers the major organ systems from an integrative perspective that addresses the molecular and cellular processes that contribute to homeostasis. Material on pathophysiology is also included throughout the eBooks. The state-of the-art treatises were produced by leading experts in the field of physiology. Each eBook includes stand-alone information and is intended to be of value to students, scientists, and clinicians in the biomedical sciences. Since physiological concepts are an ever-changing work-in-progress, each contributor will have the opportunity to make periodic updates of the covered material. Published titles (for future titles please see the website, www.morganclaypool.com/toc/isp/1/1)

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Copyright © 2017 by Morgan & Claypool All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means—electronic, mechanical, photocopy, recording, or any other except for brief quotations in printed reviews, without the prior permission of the publisher. The Blood-Brain Barrier in Health and Disease William G. Mayhan and Denise M. Arrick www.morganclaypool.com ISBN: 9781615047390 paperback ISBN: 9781615047406 ebook DOI: 10.4199/C00148ED1V01Y201612ISP072 A Publication in the COLLOQUIUM SERIES ON INTEGRATED SYSTEMS PHYSIOLOGY: FROM MOLECULE TO FUNCTION TO DISEASE Lecture #72 Series Editors: D. Neil Granger, LSU Health Sciences Center, and Joey P. Granger, University of Mississippi Medical Center ISSN 2154-560X  print ISSN 2154-5626  electronic

The Blood-Brain Barrier in Health and Disease William G. Mayhan and Denise M. Arrick

Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota

COLLOQUIUM SERIES ON INTEGRATED SYSTEMS PHYSIOLOGY: FROM MOLECULE TO FUNCTION TO DISEASE #72

M &C

MORGAN

& CLAYPOOL LIFE SCIENCES

vi

ABSTRACT

The blood-brain barrier (BBB) is a complex and dynamic structure that protects the brain from cells within the vasculature, from the immune system and from pathogens. This barrier is present in arterioles, capillaries and venules and is formed at the level of adjacent endothelial cells, which are coupled to astrocytes, microglia, neurons and pericytes. The structure of this endothelial barrier is unique among endothelia of other organ systems and is composed of complexes made up of tight, gap and adherens junctions. In addition, it is the responsibility of the surrounding cellular elements to maintain the integrity of the junctional complexes and restrict the entry of substances from the blood into the brain. Changes in permeability of the BBB during physiologic and pathophysiologic conditions involve alterations in specific transporters at the level of the endothelium, activation of specific cellular second messenger pathways and/or the dissolution of the junctional complexes composing the BBB. This book focuses on various aspects that account for the formation and maintenance of the BBB, and on disease states that compromise this barrier.

KEY WORDS

blood-brain barrier, review, tight junctions, adherens junctions, pathophysiology, neurovascular unit, capillaries, arterioles, venules

vii

Contents 1 Introduction��������������������������������������������������������������������������������������������������������������������������� 1 2

Characteristics of the Blood-Brain Barrier��������������������������������������������������������������������� 5 2.1 Development of the Blood-Brain Barrier �������������������������������������������������������� 7 2.2 Endothelial Transport Systems ������������������������������������������������������������������������ 8

3

Ultrastructural Components of the Blood-Brain Barrier ����������������������������������������� 13 3.1 Tight Junctional Proteins�������������������������������������������������������������������������������� 13 3.1.1 Occludin�������������������������������������������������������������������������������������������� 15 3.1.2 Claudin���������������������������������������������������������������������������������������������� 15 3.1.3 Junctional Adhesion Molecule���������������������������������������������������������� 15 3.1.4 Accessory Proteins ���������������������������������������������������������������������������� 16 3.2 Adherens Junctions ���������������������������������������������������������������������������������������� 16

4

Cellular Components of the Blood-Brain Barrier������������������������������������������������������� 19 4.1 Astrocytes�������������������������������������������������������������������������������������������������������� 19 4.2 Pericytes���������������������������������������������������������������������������������������������������������� 21 4.3 Neurons���������������������������������������������������������������������������������������������������������� 21 4.4 Microglia�������������������������������������������������������������������������������������������������������� 22

5

Compromising the Blood-Brain Barrier ����������������������������������������������������������������������� 23 5.1 Site of Disruption of the Blood-Brain-Barrier ���������������������������������������������� 23 5.2 Seizures/Acute Hypertension�������������������������������������������������������������������������� 24 5.3 Neuroinflammatory Diseases�������������������������������������������������������������������������� 27 5.4 Diabetes���������������������������������������������������������������������������������������������������������� 28 5.5 Traumatic Brain Injury ���������������������������������������������������������������������������������� 29 5.6 Cerebral Ischemia/Stroke�������������������������������������������������������������������������������� 30

6 Summary������������������������������������������������������������������������������������������������������������������������������� 33 References����������������������������������������������������������������������������������������������������������������������������� 35

About the Authors �������������������������������������������������������������������������������������������������������������� 67

1

CHAPTER 1

Introduction The central nervous system (CNS) is separated from the rest of the body by three distinct barrier systems that either selectively allow or totally restrict the passage of substances between these compartments (Figure 1.1). Two distinct blood-cerebrospinal fluid (CSF) barriers exist. First, epithelial cells of the choroid plexus form the blood-CSF barrier to separate the blood from the CSF and second, the arachnoid epithelium, which lies under the dura mater, encases the brain, forming the CSF-blood barrier [1–3]. However, the most critical barrier within the brain is the blood-brain barrier (BBB) which separates brain tissue from the peripheral circulation [3–6]. This barrier restricts the free movement of many potentially harmful substances into the brain and also prevents the movement of protein from the blood into the brain, which would damage neurons and upset water homeostasis within the brain. The BBB also plays a critical role in the transport of nutrients into the brain and removal of metabolites from the brain via specific transport systems [3,5,7,8]. Thus, the maintenance of these critical barriers provides protection and nutrition for the optimal function of the neuronal environment. The BBB is present in the endothelium of cerebral arteries, arterioles, capillaries, venules and veins [2, 8–10], although some have questioned the use of pial vessels as a model for the BBB [11]. There are, however, specialized areas of the brain in which the BBB is absent: e.g., the circumventricular organs (pineal gland, area postrema, median eminence, neurohypophysis, subfornical organ and organum vasculosum of the lamina terminalis) (Figure 1.2) [12–14]. The endothelium in these select areas of the brain are fenestrated and allow for direct communication between the brain and the peripheral blood. Although these areas of the brain contain fenestrated endothelium, there is a barrier present at the level of the epithelial cells to restrict the transport of water-soluble molecules [15–17]. The epithelial cells in some of these regions (i.e., neurohypophysis, median eminence, pineal gland and choroid plexus) have a secretory function and produce the CSF and brain-derived hormones, while the other circumventricular organs (i.e., subfornical organ, organum vasculosum of the lamina terminalis and area postrema) serve a sensory role and allow the brain to monitor information from the blood and CSF to maintain homeostasis [18–23]. The barrier, secretory and sensory functions of these specialized epithelial cells are maintained by the expression of many transport systems that allow the movement of ions and nutrients into the CSF, as well as the removal of toxic agents out of the brain and into the blood. Many disease states can alter the permeability characteristics of these barriers, leading to disruption of the milieu within the brain and producing abnormalities of the electrophysiological,

2

THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

structural and neurochemical profiles of brain function. This alteration in brain function will ultimately lead to the manifestation of neuronal dysfunction common to many disease states that affect the BBB [5, 24–27]. In this article, we focus on current knowledge relating to the structural and functional characteristics of the BBB during physiologic states and during disease states that may lead to abnormal brain function.

FIGURE 1.1: Distinct barriers of the brain. There are three barrier sites between the blood and the brain. (a) Depicts the blood-brain barrier present between adjacent endothelial cells. (b) Depicts the blood-cerebrospinal (CSF) barrier. This barrier lies at the choroid plexus and it is characterized by fenestrated capillary endothelial cells with tight junctions between adjacent epithelial cells at the CSF-facing layer of the epithelium. (c) Depicts the arachnoid barrier. The brain is covered by the arachnoid membrane lying under the dura mater. The arachnoid contains several layers of epithelial cells that are connected by tight junctions. Used with permission from Abbott et al. [2].

1. INTRODUCTION

FIGURE 1.2: Circumventricular organs of the adult rat brain. Sensory circumventricular organs (CVOs) include the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO) and the area postrema (AP). The secretory CVOs include the median eminence (ME) and the neurohypophysis (NH). The pineal gland and the choroid plexus are also regarded as secretory CVOs because they have fenestrated capillaries and release brain-derived hormones and cerebrospinal fluid. Used with permission from Miyata [23].

3

5

CHAPTER 2

Characteristics of the Blood-Brain Barrier The existence of a barrier between the peripheral circulation and the brain was first identified by Ehrlich in 1885 [28]. In these studies, trypan blue dye was injected into the peripheral circulation of an adult rat. The dye penetrated into the majority of peripheral tissues, but surprisingly was restricted from entering brain tissue. Erlich [28] surmised that the dye had a very low affinity for binding to brain tissue. However, subsequent experiments by Goldman [29, 30] found that systemic injection of trypan blue dye did not stain the brain and that direct injection of trypan blue dye into brain did not produce staining of brain tissue, and thus the affinity of the dye for binding to brain tissue was similar to that in peripheral organ systems (Figure 2.1). These findings led to the conclusion that the brain is unique from peripheral organ systems in that it possesses a barrier that restricts the movement of substances from the circulation into brain tissue. The term bloodbrain barrier (bluthirnschranke) was coined by Lewandowsky [31] in experiments that examined the neurotoxic effects of ferrocyanate in the brain. These studies found that ferrocyanate affected brain function only when injected directly into the brain, but not when injected into the vasculature, thus supporting the existence of a barrier. The cellular nature of the BBB was much debated for the next several decades until the classic studies of Reese and Karnovsky [32] and, later, of Brightman et al. [33]. Using horseradish peroxidase as an intravascular tracer and electron microscopy to examine the cellular locations of horseradish peroxidase, they report that horseradish peroxidase was visible within the vascular lumen and in a small number of pinocytotic vesicles within the cerebral endothelium, but horseradish peroxidase ultimately failed to penetrate beyond the endothelium and into brain tissue (Figure 2.2) [32,33]. Thus, these studies supported the concept that the BBB resided at the level of the cerebral endothelium.

6

THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

FIGURE 2.1: Illustration of Edwin Goldman’s discovery of the restrictive nature of the Blood-BrainBarrier. (a) Shows a dorsal view of the brain and spinal cord after systemic injection of trypan blue dye. (b) Shows the ventral view of the brain after the injection of trypan blue dye. There is a clear absence of staining of the brain tissue following injection of the dye, indicating the presence of bloodbrain and blood-CSF barriers. Used with permission from Bentivoglio et al. [320].

2. CHARACTERISTICS OF THE BLOOD-BRAIN BARRIER

FIGURE 2.2: Photomicrographs from Reese and Karnovsky showing the blood-brain barrier after the injection of horseradish peroxidase. Panel A shows tissue of the cerebral cortex (about 50 microns thick; magnification of 175) following intravenous injection of horseradish peroxidase. The reaction product is found only in blood vessels of the cortex and does not enter brain tissue. Used with permission from Reese and Karnovsky [32].

2.1

DEVELOPMENT OF THE BLOOD-BRAIN BARRIER

There has been much debate regarding the existence of a functioning BBB during fetal development and in perinatal animals [34–37]. An early, but incorrect, view suggested that the BBB during embryonic development and in the newborn is immature, poorly formed, leaky and/or absent [34, 37, 38]. These conclusions were based on studies that utilized techniques that unfortunately produced marked damage to the brain during examination. These studies used multiple injections of large volumes of dye to show staining of the brain in newborn rabbits and in postnatal mice. See Saunders et al. [37] for review. It is now widely accepted that there is a structural and functional BBB in embryos and newborns in most, if not all, animals, including humans. Shortly after the pivotal experiments of Erlich

7

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THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

[28] and Goldman [29, 30], demonstrating the existence of a BBB in adult animals, others found that injection of trypan blue dye into embryos and newborns failed to penetrate into brain tissue, except in areas devoid of a BBB (i.e., circumventricular organs). In addition, studies conducted 50 years ago using human fetal tissue obtained from legal abortions found that injection of trypan blue dye remained outside of brain tissue, provided the dye was injected within 10 minutes following placental separation [39]. However, if the BBB was examined at later time points, the dye was found to stain brain tissue, indicating the onset of processes that led to damage of the BBB. Further experiments [39] using rabbit fetuses suggested that the lack of oxygen at these later time points of examination could account for the increase in staining of the brain. These early studies have been supported by other studies that injected intravascular tracers to demonstrate a functional BBB in rat (embryonic day 15) and mouse (embryonic day 13) embryos [40, 41], and very early in development in the opossum [42]. Finally, others have examined the presence of tight junctional proteins during development. These studies found that brains of fetuses and newborns expressed endothelial tight junctional proteins (occludin and claudin-5) to a similar degree as observed in adults [34, 38, 42]. Thus, it appears that with the advancement of methods and techniques to examine the BBB, we can confidently conclude that the BBB forms early in embryonic development and is well formed at birth. What remains to be determined are the molecular mechanisms and cellular components that trigger the formation of the BBB during development, and whether the susceptibility of the BBB to disruption differs during development.

2.2

ENDOTHELIAL TRANSPORT SYSTEMS

The endothelium that composes the BBB is feely permeable to small lipophilic substances and gases (e.g., oxygen, carbon dioxide, nitrogen, helium, xenon and most gaseous anesthetics), and are mostly permeable to water. However, the BBB remains relatively impermeable to larger hydrophilic molecules (glucose, amino acids, peptides and proteins). The BBB also regulates the transport of leukocytes and innate immune elements into brain tissue via a complex interaction with adhesion molecules on the surface of these cellular elements and the vascular endothelium. The basis of most neuroinflammatory diseases of the brain involves the ability of leukocytes to traverse the BBB and enter brain tissue [43–47]. There are two major transport routes across the BBB; paracellular and transcellular (Figure 2.3). Paracellular (between adjacent endothelial cells) transport does not occur to any great extent in the brain owing to the presence of tight junctions and is limited mostly to very small hydrophilic (polar) molecules. However, when there is damage to the BBB, the release of a host of inflammatory mediators (e.g., histamine, bradykinin, vascular endothelial growth factor (VEGF), arachidonic acid, leukotrienes, etc…) can activate cellular second messenger pathways (cAMP, cGMP, PKC, MLC), which can produce contraction of stress fibers within adjacent endothelial cells to separate

2. CHARACTERISTICS OF THE BLOOD-BRAIN BARRIER

tight junctions and provide a pathway for the movement of small and large molecules from the blood into the brain using a paracellular route [36,48]. Transcellular (across endothelial cells) transport is by far the most viable mechanism for the movement of large and small molecules from blood to brain, and from brain to blood (retrograde transport). There are several transcellular transport systems (carrier-mediated transport) responsible for the movement of molecules across the BBB (Figure 2.3). First, the carrier simply transports the compound equally across the membrane (facilitated diffusion) according to the existing electrochemical gradient. Second, the carrier actively pumps the compound from the blood to the brain, against the electrochemical gradient. Thus, carrier-mediated influx may occur passively, down a concentration gradient, or via secondary active transport to facilitate the transport of nutrients (e.g., glucose, amino acids, vitamins and nucleosides) through the cell membrane and into brain tissue. Third, there are efflux carriers that actively transport solutes from the brain to blood, against the electrochemical gradient. The compounds transported using these carriers are polar and cannot normally diffuse through the cell membrane. Thus, the transport of these compounds is generally regulated by metabolic demand in the brain and by the concentration of these agents in plasma. One example of such a transport system is the insulin-independent glucose transporter (GLUT-1). Endothelial cells, astrocytes and cells of the choroid plexus express the GLUT-1 transporter, and this transporter becomes up-regulated during periods of hypoglycemia [49–51]. In addition to the GLUT-1 transporter, there are GLUT-4 transporters on endothelium and GLUT-3 transporters on neurons, which provide for the direct influx of glucose into these structures. Other examples of compounds that are transported via a carrier-mediated process are hexoses (e.g., glucose, mannose and galactose), neutral amino acids (e.g., tyrosine, phenylalanine and isoleucine), acidic amino acids (glutamate and aspartate), basic amino acids (e.g., arginine and lysine) and nucleosides (adenine, adenosine and guanosine), see Serlin et al. [36] and Prasad [52]. Transcytosis can account for the movement of many substances across the BBB. The process of transcytosis begins with endocytosis, in which a solute is engulfed into the cell via an energy-dependent process (Figure 2.3). The movement of the engulfed material from the apical surface of the cell membrane, across the cytoplasm of the cell to the basolateral surface of the cell membrane, and then into brain tissue would therefore be termed transcytosis. Transcytosis can occur via receptor-mediated transcytosis or via absorptive-mediated transcytosis. In receptor-mediated transcytosis, the solute becomes bound to a receptor on an area of the cell membrane known as “coated pits,” which are composed of cellular proteins (mainly clathrin). When the solute becomes bound to a ligand, the pits invaginate into the cytoplasm of the cell, freeing them from the cell membrane, to form vesicles that are carried to the basolateral surface of the cell membrane where the compound is released into brain tissue. Examples of substances that are transported across the BBB using receptor-mediated transcytosis include peptides and large proteins, including cytokines, hormones, insulin, transferrin, leptin and low-density lipoproteins. Absorptive-mediated transcyto-

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10 THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

sis is elicited by an electrostatic interaction between a positively charged solute and the negatively charged glycocalyx that resides on the cell membrane [53, 54]. This process appears to be promising in the delivery of larger-molecular-weight drugs into the brain for therapeutic purposes. Associating therapeutics with polycationic molecules would greatly increase their ability to traverse the BBB. However, limitations regarding tissue specificity have constrained the overall success of this methodology in the treatment of CNS disorders. In summary, scientists first conceptualized the BBB more than 130 years ago. This barrier is at the level of the endothelium and appears to develop early during embryonic development. The BBB restricts, but does not completely retard, the movement of molecules from blood into the brain. The major route of movement of molecules across this barrier appears to be the transcellular route and is important in the delivery of nutrients to brain tissue and for the removal of toxic substances from the brain into the blood. Understanding specific targeting of these cellular transport processes will be critical in the delivery of therapeutic agents into the brain for the treatment of many pathophysiologic states.

2. CHARACTERISTICS OF THE BLOOD-BRAIN BARRIER 11

FIGURE 2.3: Schematic showing transport (paracellular and transcellular) pathways of the BBB. (1) Shows the paracellular route. This route restricts water-soluble and polar molecules from crossing the BBB. (2) Shows a transcellular route by which lipid soluble molecules are able to penetrate the BBB by passing through the lipid membrane of endothelial cells. (3) Shows the transport of molecules across the BBB via carrier-mediated transport. There are carriers on the endothelial cell membrane that transport glucose, amino acids and other nucleosides. These carriers can either transport molecules down a concentration gradient (energy independent) or require energy to transport molecules across the BBB (P-glycoprotein). (4) Shows receptor-mediated transcytosis. Certain substances, insulin and transferrin, are transported across the BBB by specific receptor-mediated processes. (5) shows adsorptive transcytosis. Some molecules, including albumin and other plasma proteins, are poorly permeable across the BBB, but cationization can increase their uptake by adsorptive transcytosis. Used with permission from Abbott et al. [101].



13

CHAPTER 3

Ultrastructural Components of the Blood-Brain Barrier Early studies examining the ultrastructure of the BBB found that the morphological site of the BBB resided at the level of the vascular endothelium [32, 33]. The inter-endothelial space of cerebral blood vessels is characterized by the presence of tight and adherens junctions [4, 5, 55, 56]. There is also evidence to suggest that adjacent endothelial cells of cerebral blood vessels may contain gap junctions [57]. These gap junctions allow for inter-endothelial cell communication. However, it is the tight and adherens junctions that account for the formation of a continuous membrane that provides a high diffusional restraint between the blood and the brain.

3.1

TIGHT JUNCTIONAL PROTEINS

On an ultrastructural level, tight junctions are the sites of fusion between the plasma membranes of adjacent endothelial cells (Figure 3.1). Tight junctions are formed by three primary transmembrane proteins, occludin, claudin and junctional adhesion molecules [4, 56, 58, 59]. In addition, there are several cytoplasmic accessory proteins, including zona occludens-1, -2 and -3 (ZO-1, -2 and -3), cingulin, AF-6 and 7H6 [60–63], that appear to provide binding sites for the transmembrane components, which then link to the actin cytoskeleton within the endothelial cell.

14 THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

FIGURE 3.1: Schematic overview of tight and adherens junctions that form the BBB. Claudins make up the backbone of the tight junction by binding to claudins on adjacent endothelial cells to produce the primary seal of the tight junction. Occludin functions as a regulatory protein to increase the integrity of the tight junction. Loss of occludin will increase the permeability of the BBB. The tight junction is also composed of many accessory proteins that provide structural support (ZO-1, ZO-2, ZO-3, 7H6, cigulin and AF-6). The adherens junction contains the membrane protein cadherin that mediates cell-to-cell adhesion. The cytoplasmic components of cadherins will bind to betaor gamma-catenin, which then are linked to the cytoskeleton of the cell via alpha-catenin and vinculin. This arrangement will stabilize the adherens junctional complex, and in turn the tight junction. Used with permission from Huber et al. [321].

3. ULTRASTRUCTURAL COMPONENTS OF THE BLOOD-BRAIN BARRIER 15

3.1.1

OCCLUDIN

Occludin is a 65-kDa phosphoprotein that was first identified in 1993 [64] in chickens and then in 1996 in mammals (humans, mice and dogs) [65]. Occludin has four transmembrane domains, a long COOH-terminal cytoplasmic domain and a short NH2-terminal cytoplasmic domain [8, 64, 65]. Extracellular loops of occludin and claudin originating from adjacent endothelial cells form the paracellular barrier of the tight junction (Figure 3.1). The cytoplasmic domain of occludin joins with the zona occludens proteins to regulate contraction of endothelial cells, and thus endothelial permeability, by its association with the actin cytoskeleton within the cytoplasm of the cell [66]. The expression of occludin is much higher in endothelial cells of the brain when compared with endothelium in peripheral organ systems, which helps explain the restrictive nature of the BBB when compared with that of peripheral organ systems [67].

3.1.2

CLAUDIN

Claudins are the major components of the tight junction and are much smaller than occludins— about 22-kDa with four transmembrane domains. Claudins were first identified as critical components of the BBB in 1998 [68]. To date, there are at least 24 members of the claudin family. Typically, claudins associated with one endothelial cell bind to their counterparts on an adjacent endothelial cell to form the primary seal of the tight junction [59, 69]. In the brain, claudin-1 and -5 have been shown to be present in the tight junctional complex forming the BBB [70, 71]. The importance of claudins (namely claudin-5) in maintaining the integrity of the BBB is demonstrated by studies showing changes in permeability of the BBB during manipulations in claudin-5 expression [72–75].

3.1.3

JUNCTIONAL ADHESION MOLECULE

Junctional adhesion molecules ( JAM-1, -2 and -3) are 40-kDa proteins that are thought to provide integrity to the tight junction, although their precise role has yet to be precisely determined [76]. JAM-1 is believed to mediate the attachment of membranes from adjacent endothelial cells via homophilic interactions and subsequent binding with ZO-1 and/or cingulin [77]. Given that ZO-1 and cingulin bind with the actin cytoskeleton of the cell, it is thought that the complex formed by junctional adhesion molecues with ZO-1 and cingulin helps provide the structural support to the endothelium composing the BBB [77]. JAM-2 and JAM-3 are also present in the endothelium and lymphatic cells, although JAM-2 is probably not present in the endothelium of the BBB [78]. Junctional adhesion molecules are also thought to regulate the transendothelial movement of leukocytes [79]. Once leukocytes traverse the BBB, they can release many inflammatory substances that will alter the expression of junctional adhesion proteins disrupt the integrity of the BBB [80].

16 THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

3.1.4

ACCESSORY PROTEINS

Zona occludens (ZO-1, -2 and -3) are cytoplasmic accessory proteins that aid in the formation of the BBB [8, 60, 63, 81]. ZO-1 is a 220-kDa protein that was the first protein identified to be associated with tight junctions [82]. However, ZO-1 may also be expressed in endothelial and epithelial cells, and other cell types (including astrocytes), that may not have tight junctions [83]. ZO-1 links transmembrane proteins to the actin cytoskeleton and appears to be critical to the stability and function of the tight junction [81, 84]. Dissociation of ZO-1 from the actin cytoskeleton is associated with an increase in permeability [85–87]. It has also been suggested that ZO-1 may serve as a signaling molecule to communicate the state of the tight junction. ZO-2 is a 160-kDa protein that has high homology to ZO-1. Although less is known about the functional significance of ZO-2, it also appears to bind to structural components of the tight junction and signaling molecules, indicating that it has a similar role as ZO-1 in maintaining the integrity of the tight junction [88]. In cultured brain microvascular endothelial cells, ZO-2 seems to be located along the cell membrane at cell-to-cell contacts, but in cerebral microvessel fragments ZO-2 seems to be more diffusely distributed within the cell [86]. ZO-3 is a 130-kDa protein that has been found in some tissues that contain tight junctions, but it may not be present in the cerebral endothelium that composes the BBB [89]. Thus, the role of ZO-3 in maintaining the integrity of the tight junction and in cell-to-cell signaling is not completely understood. Other important cytoplasmic accessory proteins include cingulin, AF-6 and 7H6. Cingulin is a 140-160-kDa protein that associates with ZO-1, JAMs and actin to presumably provide structural support for endothelial tight junctions [62]. AF-6 is a 180-kDa protein that interacts with ZO-1 to assist with structural support between adjacent endothelial cells [75]. 7H6 is a 155-kDa protein that can reversibly dissociate from the tight junctional complex during cellular ATP depletion [90]. However, the precise function of 7H6 in maintaining the integrity of the tight junction, and hence the BBB, is not known.

3.2

ADHERENS JUNCTIONS

Adherens junctions are universal to blood vessels and serve to adhere adjacent endothelial cells (Figure 3.1). These adherens junctions contain the membrane protein cadherin, a calcium-regulated protein that mediates cell-to-cell adhesion via homophilic interactions between the extracellular domains of similar proteins expressed on the surface of adjacent endothelial cells [8]. The cytoplasmic components of cadherins will bind to the proteins beta- or gamma-catenin, which then are linked to the cytoskeleton of the cell via alpha-catenin and vinculin [91–94]. This arrangement stabilizes the adherens junctional complex, which then plays a key role in the stabilization of the tight junction. The components of adherens junctions have been identified in microvessels of the

3. ULTRASTRUCTURAL COMPONENTS OF THE BLOOD-BRAIN BARRIER 17

BBB in rats, and alterations or disruption of the adherens junctions may produce an increase in the permeability of the BBB [95, 96]. However, most evidence supports the concept that primary responsibility for maintaining the integrity of the BBB resides with the tight junctions. In contrast, a recent study has challenged the concept that disruption of the BBB during ischemia/reperfusion injury is related to alterations in tight junctional and/or adherens junctional proteins [97], but is more related to endothelial cell degeneration. Thus, although it is clear that tight and adherens junctions are critical for maintaining the BBB, there is still some debate as to the role of these junctional complexes during pathophysiologic states.

19

CHAPTER 4

Cellular Components of the Blood-Brain Barrier Although the structural components of the BBB were historically understood to involve the endothelium and tight junctions between adjacent endothelial cells, it is now well known that the integrity of the BBB involves many cell types, including astrocytes, pericytes, neurons and microglia. The inclusion of these cellular elements in the concept of a BBB has led to the development of the term “neurovascular unit” [63, 98–100]. This term encompasses all of these important cell types in the regulation of the BBB and recognizes their important contributions to the structural and functional aspects of this barrier (Figure 4.1).

4.1

ASTROCYTES

Astrocytes are located between endothelium, pericytes and neurons (Figure 4.1). Early studies indicated that, because of the location of astrocytes and astrocytic foot processes (i.e., surrounding endothelial cells of cerebral capillaries), these components provided a structural base to the BBB and/or released substances that maintained the structural integrity of the BBB [101–106]. Elegant studies that transplanted brain tissue/vessels into peripheral sites and peripheral tissue/vessels into the brain provided evidence that direct contact of astrocytes to endothelium was necessary to develop an optimal BBB [107]. In addition, cell culture studies have shown that introducing astrocytes or astrocyte-conditioned media onto endothelial monolayers produced an increase in transendothelial resistance, suggesting that a factor or factors released by astrocytes contribute to the induction of the characteristics that define the BBB [102, 108].

20 THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

FIGURE 4.1: Schematic representation of the organization of the neurovascular unit. The cerebral capillary endothelium is joined by tight junctions and is in close proximity to pericytes, astrocytes, neurons, microglia and smooth muscle. These cellular components can act in synergy to regulate vascular diameter and permeability of the BBB. The basal lamina is denoted by BL. Used with permission from Wolff et al. [322].

However, the concept that astrocytes contribute to the formation and integrity of the BBB is not universally accepted. Some have argued that astrocytes help maintain the integrity of the BBB, but don’t necessarily contribute to its development [109]. Others have indicated that the role of astrocytes in cell culture studies may be an artifact of that environment. Still others, using in vivo methodologies, have shown that cerebral microvessels transplanted to areas of the brain in which astrocytes have been lost continue to maintain a BBB [110], although more recent studies using similar techniques seem to suggest that astrocytes do play a critical role in barrier formation [111, 112]. It has also been proposed that astrocytes act along with, or as intermediates to, neurons to help maintain the integrity of the BBB [4, 112]. It appears that astrocytes, neurons and endothelium can communicate via dynamic calcium wave signaling [113–115]. This process would involve an exchange of calcium signals by intracellular IP3- and gap junction-dependent mechanisms. In recent studies, it was found that dilation of cerebral arterioles contained within rat brain slices in response to an increase in neuronal activity was dependent upon calcium oscillations in astrocytes [114, 116]. In addition, direct stimulation of astrocytes resulted in dilation of cerebral arterioles, which was then blocked by inhibition of the cyclooxygenase pathway [114, 116]. Thus, in addition to influencing vas-

4. CELLULAR COMPONENTS OF THE BLOOD-BRAIN BARRIER 21

cular diameter, it is conceivable that interactions between astrocytes, neurons and the endothelium may also play a role in regulating the transport of small and large molecules across the BBB.

4.2

PERICYTES

Pericytes are cells that are in close proximity to capillaries, but may also be contained around cerebral arterioles and venules (Figure 4.1) [117]. Pericytes are thought to provide structural support and may provide a means to control diameter of the vessels they surround because pericytes contain cytoskeletal proteins [118–124]. Contraction of these cytoskeletal components may also provide a means by which pericytes can regulate endothelial paracellular junctions, and thus provide a pathway for the movement of molecules across the BBB. Changes in pericytes can occur during disease states, and there is evidence to suggest that there is a loss and/or degeneration of pericytes and a loss in the interaction between pericytes and brain capillaries during several diseases (chronic hypertension, diabetes and hyperhomocysteinemia) [125–127]. Loss of, or changes to, pericytes may contribute to disruption of the BBB during these disease states. In addition, pericytes have also been shown to migrate to sites of injury in the brain where the BBB has been compromised [128, 129]. This suggests that pericytes may play a role in the induction, repair and/or maintenance of the BBB. The mechanisms by which pericytes can regulate functional changes in permeability of the BBB are not clear, but may relate to the ability of pericytes to inhibit the expression of substances that increase the permeability of the BBB and/or inhibit the infiltration of cells that may lead to disruption of the BBB [41]. However, further studies using both in vivo and in vitro techniques are necessary to precisely determine the fundamental role of pericytes in the integrity of the BBB.

4.3

NEURONS

Neurons are an integral component of the neurovascular unit (Figure 4.1). One of the main functions of the BBB is to maintain a homeostatic environment for neurons. Given the nature of neuronal activity in the brain at any moment, it is critical that cerebral blood flow be able to match changes in neuronal/metabolic activity. In addition to the regulation of cerebral blood flow in the face of changes in metabolic demand, it is also critical that neurons be able to signal cerebral blood vessels in order to regulate the delivery of solutes/solvents across the BBB. To accomplish this regulation in transport, there is direct innervation of astrocytic foot processes and the endothelium by noradrenergic, cholinergic, serotonergic and GABA-ergic neurons [130–141]. Studies have shown that direct stimulation of adrenergic neurons in close contact with cerebral endothelium can increase the transport of molecules across the BBB [142–144]. In addition, evidence suggests that inhibition/stimulation of adrenergic input to cerebral blood vessels influenced the vulnerability of the BBB to disruption during acute and chronic hypertension [145–151]. Protection by sympathetic nerves may be directed at cerebral venules and cerebral venular pressure, which seems to be

22 THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

critical for disruption of the BBB during acute and chronic hypertension [146,152–155]. Finally, stimulation of the sphenopalatine ganglion (cholinergic) produced fast, yet reversible, changes in permeability of the BBB to large and small molecules [156]. Thus, it appears that stimulation of neurons can influence the permeability of the BBB during both physiologic and pathophysiologic conditions. However, the precise role of direct innervation of the components of the neurovascular unit on the formation and/or maintenance of the BBB are yet to be determined.

4.4

MICROGLIA

Microglia account for 10-15% of all cells within the brain, and are the first and main form of active immune defense in the CNS (Figure 4.1). Microglia are involved in many different processes within the brain, mainly those related to monitoring and maintaining homeostasis. During chronic pathophysiologic conditions, microglia can react to produce numerous neurotoxic and neuroinflammatory mediators for an extended period of time, which probably contributes to neuronal death. Thus, in addition to their role in immune defense, these cells may actually contribute to the pathogenesis of many neuroinflammatory diseases (Alzheimer’s disease, Parkinson’s disease, HIV-related dementia, stroke, etc.). The effects of the microglia on the BBB also appear to relate to microglia’s ability to stimulate the release of cytokines and inflammatory mediators. Microglia can activate endothelial cells by stimulating the release of oxygen radicals and various cytokines (e.g., interleukins 1 and 6 (IL-1 and IL-6) and tumor necrosis factor (TNF)) [157–165]. These actions by microglia will produce an increase in the transport of small and large molecules across the BBB. In addition, it has been suggested that microglia may promote regrowth/repair of neuronal tissue by the recruitment of neurons and astrocytes to areas of brain damage [166]. Thus, although it is not entirely clear, it is possible that in addition to contributing to neuroinflammation, microglia may also contribute to neurorepair and maintaining the integrity of the BBB. In summary, there are many cellular components that play a significant role in maintaining the integrity of the BBB. These cellular components make up what is known as the neurovascular unit. Although the precise role of these cell types is not entirely understood, it is believed that alterations in any of these components can directly influence the movement of molecules across the BBB. Future studies are necessary to further delineate the role of each of these components, as well as the mechanisms by which these components interact with one another to maintain the integrity of the BBB and/or to allow for the transport of molecules across the BBB.

23

CHAPTER 5

Compromising the Blood-Brain Barrier 5.1

SITE OF DISRUPTION OF THE BLOOD-BRAIN-BARRIER

Many early studies that examined disruption of the BBB during a variety of situations (e.g., acute hypertension, stroke, cerebral ischemia/reperfusion, hyperosmolar solutions, inflammation) reported that arterioles and capillaries, but not veins and venules, were the primary sites for disruption of the BBB [167–171]. Many of these early studies used electron microscopy and electron dense tracers that may have limited a comprehensive assessment of all components of the vascular network with regard to identifying the sites of disruption of the BBB. Later studies, using intravital microscopy, suggested an important involvement of veins and venules as sites of disruption of the BBB during a variety of conditions (Figure 5.1) [152, 172]. In addition, more recent studies using isolated cerebral veins and immunofluorescent imaging, which allows for a more precise examination of the segments of the vascular tree, have continued to emphasize that veins and venules are important sites of disruption of the BBB during a variety of stimuli [173–176]. It is possible that differences in sensitivity between the segments of the vascular network may account for the discrepancy between studies that have reported the primary site(s) of disruption of the BBB. This difference in sensitivity may be related to structural integrity surrounding arterioles, capillaries and venules and/or site-specific cellular interactions that impact the BBB. For example, pericytes and astrocytes, which have been shown to contribute to the restrictive properties associated with the BBB, are in direct contact with endothelium of capillaries and post-capillary venules. However, in larger veins, this direct contact is separated by a perivascular space and, in arterioles, this contact is further impeded by the presence of smooth muscle. In a recent study [177], it was shown that the expression of the structural elements that form the tight junctions between cerebral endothelial cells are similar along the vascular network, but the density of pinocytotic vesicles was highest in arteries/arterioles. The overall significance of these findings relates to an understanding of the susceptibility of the sites of the vasculature to disruption during various disease states, and the hope of developing therapeutic approaches targeting those specific sites. In addition, the cellular mechanisms that contribute to disruption of the BBB, either in arterioles, capillaries or venules, are not well understood. Beginning to decipher the cellular mechanisms that contribute to disruption of the BBB along the vascular

24 THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

FIGURE 5.1: Picture of the cerebral microcirculation of a rat following injection of FITC-dextran70K and after infusion of phenylephrine to induce acute hypertension. Extravasation of FITC-dextran-70K following acute hypertension is primarily from cerebral venules and veins. Used with permission from Mayhan and Heistad [172].

network during disease states may lead to new therapeutic strategies to target these segments of the vasculature for the treatment of neurovascular disorders.

5.2

SEIZURES/ACUTE HYPERTENSION

Many early studies extensively examined the influence of chemically-induced seizures and acute elevations in blood pressure on the integrity of the BBB. Many investigators found that seizures induced with various convulsive agents or with electrical stimulation produced marked increases in permeability of the BBB [178–182]. Various mechanisms and interventions have been examined to determine the factors that contribute to changes in permeability of the BBB during seizures. Structurally, it appears that seizures produce an increase in the formation of pinocytotic vesicles within cerebral endothelium, and these vesicle account for the transport of molecules across the BBB (Figure 5.2) [179, 183, 184]. It was initially thought that heightened neuronal activity during the induction of a seizure might contribute to the formation of pinocytotic vessels, and thus disruption

5. COMPROMISING THE BLOOD-BRAIN BARRIER 25

FIGURE 5.2: Schematic representing permeability of the BBB during normal conditions (a) and during disease states (b). In Panel A, endothelial cells of the cerebral circulation are joined by tight junctions (TJ) and adherens junctions (AJ). These junctions are composed of transmembrane proteins that are anchored to cytoskeletal proteins. Endothelium also contain a paucity of pinocytotic vesicles (PV) and are tethered to the extracellular matrix (EM) through connections with transmembrane integrins. During disease states (b) there is the synthesis/release of many inflammatory stimuli that can interact with receptors on endothelial cells to activate several cellular second messenger pathways, including protein kinases (PKs), RhoA/Rho kinase (Rock), and mitogen-activated protein kinases (MAPK). The influx of calcium into the cell can also activate nitric oxide synthase (eNOS) and myosin light chain kinase (MLCK). The activation of these pathways can lead to phosphorylation of tight and adherens junctional proteins to cause the junction to dissociate from the cytoskeleton, leading to a separation of endothelial junctions. In addition, activation of these pathways may lead to an increase in the number of pinocytotic vesicles within endothelium, to provide a pathway for the movement of molecules across the BBB. The movement of leukocytes across the BBB may also stimulate the release of inflammatory cytokines to influence the permeability of the BBB. Finally, excitation of these pathways can impair the attachment of endothelium to the extracellular matrix to further increase the permeability of the BBB. Modified with permission from Cardoso et al. [323].

26 THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

of the BBB. However, others suggested that changes in cerebral blood flow to increase shear rate/ stress on the endothelium and/or increases in arterial blood pressure to increase force on cerebral endothelium were primary stimulants for the formation of pinocytotic vesicles and disruption of the BBB during seizures. This latter suggestion arose from studies that found a lowering of blood pressure/cerebral blood flow with barbiturate anesthesia lessened seizure-induced changes in permeability of the BBB [180, 185]. In addition to mechanical changes at the level of the endothelial cell, others have examined cellular mechanisms that may contribute to changes in permeability of the BBB during seizures. Early experiments by Oztas [186] found that treatment of rats with nifedipine, a calcium channel antagonist, decreased disruption of the BBB following bicuculline-induced seizures. The author sirmises that this protective effect is related to the effect of nifedipine on arterial blood pressure. In other experiments, Oztas et al [187] found that inhibition of oxidative stress with selenium or vitamin E slightly, but significantly, decreased the intravascular extravasation of Evans blue dye onto the brain of rats subjected to pentylenetetrazole-induced seizures. Although the precise cellular mechanisms by which seizures increase oxidative stress are not clear, the authors suggest that it may involve an increase in the synthesis/release of arachidonic acid. Finally, there appear to be sex-related differences in disruption of the BBB following induction of seizures [182, 188, 189]. The findings from these studies indicate that females are more susceptible to seizure-induced disruption of the BBB, but the mechanisms that account for this sex-related difference remain unknown. Acute increases in arterial blood pressure, beyond the autoregulatory capacity of cerebral arteries/arterioles, produce a dramatic increase in pressure within cerebral arterioles, passive dilation of cerebral arterioles, marked increases in cerebral blood flow and disruption of the BBB [147, 190–192]. Ultrastructural analysis of the BBB following acute increases in arterial blood pressure has shown an increase in the formation of pinocytotic vesicles within cerebral endothelium, primarily in cerebral arterioles and capillaries, but also in venules [167–169, 193]. These data are supported by studies that have shown that transport of molecules across the BBB during acute hypertension is independent of molecular size, indicating a vesicular (transcellular) transport process [172]. Direct observation of the BBB following injection of fluorescent labeled tracers has indicated that the primary site for disruption of the BBB during acute hypertension is in cerebral veins and venules (Figure 5.1), with the stimulus appearing to involve an increase in cerebral venular pressure [152, 172]. Cellular mechanisms that account for disruption of the BBB in cerebral veins and venules during acute hypertension have been difficult to pinpoint. Studies have examined the roles of activation of protein kinase C [194], of synthesis/release of inflammatory mediators [195, 196], and of nitric oxide [197] without much success. Thus, it is conceivable that rapid dramatic increases in arterial blood pressure to increase cerebral venular pressure disrupts the BBB via a mechanical injury to the cerebral endothelium/tight junctions at the level of cerebral venules (Figure 5.2). However, more studies are necessary to examine the role of other cellular processes in disruption of the BBB

5. COMPROMISING THE BLOOD-BRAIN BARRIER 27

during acute hypertension. An understanding of the structural and functional consequences of acute hypertension on the BBB will lead to new therapeutic approaches for the protection of the BBB during hypertensive encephalopathy, and may translate to other disease processes that disrupt the BBB via a traumatic insult.

5.3

NEUROINFLAMMATORY DISEASES

The transport characteristics of the BBB can be altered during conditions that involve injury to the brain and/or disease states that produce inflammation (Figure 5.2). These pro-inflammatory diseases, Alzheimer’s disease, multiple sclerosis, Parkinson’s disease and HIV-associated dementia, alter the integrity of the BBB and allow for the infiltration of leukocytes into the brain [25, 45]. The migration of leukocytes into brain tissue leads to the activation of several cellular processes that ultimately contribute to the loss of tight junctional proteins, leading to an increase in the permeability of the BBB [6, 25, 198]. Alzheimer’s disease is a progressive neurodegenerative disease that usually strikes the elderly and is the most common cause of dementia in the elderly. It is characterized by the deposition of amyloid within neurons, the presence of amyloid plaques, neurofibril tangles, neuronal death and extensive synaptic loss. Many disease states predispose to Alzheimer’s disease, although there is no clear understanding of the processes that link these disease states to Alzheimer’s. In Alzheimer’s disease, the microglia and astrocytes become activated by amyloid protein, setting off a cascade of events that leads to the synthesis/release of many pro-inflammatory substances that then contribute to neuronal damage and synaptic loss. The pro-inflammatory substances that are released include IL-1, IL-6, tumor necrosis factor (TNF), transforming growth factor (TGF), reactive oxygen species, and nitric oxide [161, 199–204]. These substances are then free to act on endothelial tight junctions, specific transport pathways and/or cellular elements that normally maintain the integrity of the BBB (Figure 5.2). Studies have shown that Alzheimer’s disease disrupts the BBB in animal models and in human subjects, and this has been associated with cognitive decline [24, 205–212]. Alzheimer’s disease also has been shown to impair efflux transporter activity in the brain [213, 214] and increase the migration of leukocytes into brain tissue, which could compromise the BBB [45]. Unfortunately, strategies to prevent this cascade of events have yet to be developed. However, recent evidence suggests that targeting annexin A1, a potent anti-inflammatory protein, or poly (ADP-ribose) polymerase 1 (PARP) might be promising therapeutic approaches [215–217]. Multiple sclerosis is a demyelinating disease of the CNS and is one of the most common autoimmune disorders affecting the that system. Damage to nerve cells produces a variety of physical, mental and psychiatric problems. Although the precise cause of multiple sclerosis is not known, it is thought to be exacerbated by other disease states. Ultimately, the activation of macrophages causes the synthesis/release of pro-inflammatory cytokines (interferon gamma, TNF and IL-3) and nitric

28 THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

oxide. These agents can damage the BBB and interfere with nerve myelination [201, 218–220]. The BBB has been shown to be compromised in animal models and in human subjects with multiple sclerosis [221–223], which may be associated with a down-regulation of tight junctional proteins [224]. Therapeutic approaches for the treatment of dysfunction of the BBB during multiple sclerosis might include the development of agents that can be used to target specific inflammatory cytokines and to decrease risk factors that may be associated with the development of this neuroinflammatory disease.

5.4

DIABETES

Overwhelming evidence has shown that type 1 and type 2 diabetes impair endothelial nitric oxide synthase (eNOS)- and neuronal nitric oxide synthase (nNOS)-dependent dilation of cerebral arteries and arterioles [225–232]. Although diabetes produces abnormalities of the endothelium that impair reactivity of cerebral arteries and arterioles, and it disrupts the neurovascular unit/neurovascular coupling, which increases the risk of many disorders via cognitive dysfunction, dementia and stroke [210, 225, 233–239], there is a paucity of information regarding the influence of diabetes on the permeability of the BBB. While in vivo and vitro studies seem to indicate that basal permeability of the BBB may be elevated in diabetes, the findings are not universal, and the outcomes (e.g., cognitive decline) related to this increase in BBB permeability remain uncertain. Several studies have shown that short-term and long-term diabetes do not produce any discernable increase in basal permeability of the BBB to large and small molecules [240–244]. However, others have shown that diabetes actually produces a decrease in basal permeability of the BBB to small molecules [242, 245, 246]. In contrast, others have shown that short-term and long-term diabetes increases basal permeability of the BBB to large and small molecules in animal models [233, 247–251], and there is some evidence that the permeability of the BBB may be compromised in human subjects with diabetes [252, 253]. The mechanism for this increase in basal permeability of the BBB during diabetes may be related to an increase in the synthesis/release of pro-inflammatory cytokines, an increase in the production of reactive oxygen/nitrogen species and/or a decrease in the expression of tight junctional proteins (Figure 5.2) [52, 244, 254–260]. The discrepancy between studies regarding an influence of diabetes on basal permeability of the BBB is not entirely clear, but the diversity in the findings emphasizes the need for more studies to examine the regional characteristics of the BBB during diabetes. Given that there appears to be a correlation between increased permeability of the BBB during diabetes and neurological deficits [225, 233, 253, 261], it is conceivable that an increase in permeability of the BBB can contribute to the pathogenesis of many CNS-associated diseases, including stroke, Alzheimer’s disease, dementia, epilepsy and multiple sclerosis.

5. COMPROMISING THE BLOOD-BRAIN BARRIER 29

In addition to studies that have examined basal permeability of the BBB during diabetes, a limited number of studies have examined whether the susceptibility of the BBB to disruption might be altered by diabetes. Some studies have shown that the susceptibility of the BBB to disruption by acute hypertension and ischemia/reperfusion injury are increased by diabetes [262, 263], while others have shown no differences in susceptibility to acute hypertension between non-diabetic and diabetic rats [264]. Only one study has examined whether the BBB during diabetes is more susceptible to disruption during stimulation with pro-inflammatory mediators [251]. The rationale for these studies was based on studies of peripheral organ systems showing an increase in susceptibility of the microcirculation to changes in permeability in response to pro-inflammatory mediators during diabetes [265]. However, in contrast to studies of peripheral organ systems, the BBB was found to be less susceptible to disruption during stimulation with a pro-inflammatory mediator (histamine) [251]. Thus, there are inherent differences in the response of the BBB to pro-inflammatory stimuli than that observed for the peripheral circulation. Whether this is directed at specific cell types and/or serves as a protective mechanism in the brain remains to be determined.

5.5

TRAUMATIC BRAIN INJURY

Traumatic brain injury is manifested by an external force on the skull/brain that produces an alteration in brain function and/or brain pathology. Traumatic brain injury can occur during a variety of events, including accidents, sporting events, and military conflicts [266, 267]. Traumatic brain injuries continue to have a high incidence of morbidity and mortality, and account for as many as one-third of all injury-related deaths in the United States [268]. The initial insult during a traumatic event results in concussive injury to the brain, diffuse injury to axons, and brain hematomas with damage to the cerebral vasculature [269–272]. Disruption of the BBB is central to the pathogenesis of cerebral edema associated with traumatic brain injury (Figure 5.2). Cerebral edema has been characterized as vasogenic and cytotoxic [273]. Vasogenic edema occurs when there is an initial increase in the permeability of the BBB to large-molecular-weight substances, and then water follows to expand the extracellular space. This increase in permeability of the BBB can occur via damage to cerebral blood vessels and/or the release of cytokines to disrupt endothelial tight junctions [163, 274–281]. Cytotoxic edema occurs when brain cells (e.g., endothelium, astrocytes and glia) swell due to dysfunction of ionic and osmotic flux, but the properties of the BBB remain mostly intact. Cytotoxic edema, with its associated cell swelling, is not necessarily damaging to the brain, and studies suggest that this process can actually be protective by helping to normalize neuronal activity and scavenging oxygen radicals [282, 283]. However, cell swelling in the face of a disrupted BBB can be especially detrimental to the brain. The coupling of cytotoxic and vasogenic edema can contribute to an increase in volume in the brain and cellular destruction by increasing intracranial pressure. This increase in intracranial pressure will compress the brain, decreasing cere-

30 THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE

bral perfusion pressure and cerebral blood flow, and producing further damage to the brain. Several therapeutic approaches have been used to alleviate brain damage following traumatic brain injury [284–289], but precise molecular mechanisms accounting for brain damage following traumatic brain injury remain unknown.

5.6

CEREBRAL ISCHEMIA/STROKE

Strokes are classified into two main categories: ischemic and hemorrhagic. Ischemic strokes are caused by interruption in the blood supply to the brain, and hemorrhagic strokes are caused by the rupture of blood vessels within the brain, mostly related to elevations in pressure and/or abnormal development of the vascular structure. As stated previously, the main function of the neurovascular unit is to maintain cerebral blood flow in the face of changes in metabolic demand [100, 140, 290]. This process assures that adequate neuronal function can be maintained without disturbance. In the setting of a stroke, blood flow to many areas of the brain is interrupted, producing a loss of both neuronal and vascular function. The loss of vascular function leads to a series of events that disrupts endothelial tight junctions and increases permeability of the BBB. The disruption of tight junctions following cerebral ischemia seems to be mediated by the synthesis/release of a host of inflammatory cytokines, cellular adhesion, calcium dysregulation, and/or enzymatic activity [43, 58, 291, 292]. More studies than can be referenced in this book have examined the role of many of these mediators/processes in the permeability of the BBB following cerebral ischemia/reperfusion injury in animal models and in patients following a stroke. This summary will concentrate on just of few of these studies. First, several previous studies have examined the role of inflammatory cytokines in disruption of the BBB following cerebral ischemia. Elevated levels of pro-inflammatory cytokines, (e.g., IL-1β and TNFα), VEGF and nitric oxide, have been reported in animal models of cerebral ischemia/reperfusion injury and in the CSF of human subjects following a stroke (Figure 5.2) [43, 291, 293–298]. The cellular components that contribute to the synthesis of these inflammatory cytokines appears to involve the endothelium and astrocytes [299, 300]. These inflammatory cytokines appear to increase the permeability of the BBB via an increase in transcytosis and endothelial gap formation, as demonstrated by cell culture studies [301]. Second, it has been shown that cerebral ischemia/stroke may alter the permeability characteristics of the BBB via an up-regulation of endothelial adhesion molecules to increase the adherence of leukocytes on the endothelium of cerebral microvessels [44, 292, 302–305]. This increase in leukocyte adhesion to the endothelium increases the transmigration of leukocytes across the endothelium and into brain tissue with the subsequent release of inflammatory mediators to damage the BBB. Studies have shown that inhibition of cellular adhesion molecules can reduce edema formation and brain damage following cerebral ischemia [302, 303, 305]. Third, it is possible that cerebral ischemia can lead to an increase in the permeability of the BBB via an alteration in tight junctional proteins. Studies have indicated that an up-reg-

5. COMPROMISING THE BLOOD-BRAIN BARRIER 31

ulation of endothelial and neutrophil adhesion molecules can lead to the loss of tight junctional proteins (occludin and ZO-1) and the redistribution of adherens junctional proteins [306]. Thus, it is possible that the adherence of leukocytes to the endothelium following an ischemic event may trigger a series of events that could lead to the disorganization of tight junctions/tight junctional proteins to disrupt the BBB. Fourth, it is possible that an ischemic event can alter the expression of several enzyme systems, which would lead to disruption of the BBB. Matrix metalloproteases (MMPs) are a family of zinc-binding proteolytic enzymes that have been shown to degrade the extracellular matrix. MMP-2 and MMP-9 break down the endothelial basal lamina to disrupt endothelial tight junctions and tight junctional proteins, including occludin and claudin-5 [307]. Several studies have shown that cerebral ischemia produces an increase in MMPs, which is associated with disruption of the BBB [244, 307–312]. The source of MMPs during cerebral ischemia is likely from cerebral endothelium, astrocytes, neurons, and/or leukocytes (primarily neutrophils) that infiltrate into the ischemic area [311–313]. The induction and activation of MMPs can also occur by the synthesis/release of inflammatory agents (e.g., TNF and IL-1β) by the ischemic tissue and/ or by the release of oxidants [307, 314–318]. In addition to MMPs, the phosphoinositide 3-kinases (PI3Ks) are a family of enzymes characterized by protein and lipid kinase activity and have been linked to neuroprotection during cerebral ischemia [319]. In addition, genetic deletion of PI3Kγ protects the BBB and decreases brain infarct volume following cerebral ischemia in mice [313]. The mechanism for the protective influence of inhibition of PI3Kγ on the brain was associated with a reduction of oxidative stress, reduced neutrophil infiltration and/or a decrease in the activity of MMP-9 [313]. Thus, several factors presumably acting in synergy can influence disruption of the BBB following cerebral ischemia/stroke.

33

CHAPTER 6

Summary Scientists first concepetualized the BBB more than 130 years ago. Since that time many, studies have been conducted to determine the structural and functional significance of this barrier to normal physiology and during pathophysiologic conditions. However, there are still challenges ahead. First, although we now appear to understand many of the components that make up the physical barrier between adjacent endothelial cells, we do not understand all of the components (and their purposes) and there may be structural proteins yet to be found. Second, on a macroscopic level, the brain is composed of arteries, arterioles, capillaries, venules, and veins, all of which appear to contain the cellular elements that are necessary for a functioning BBB. However, unlike in the peripheral vasculature where post-capillary venules are the primary sites for macromolecular transport, there appears to be a lack of consensus as to the primary site(s) of transport of molecules across the BBB during physiologic and pathophysiologic conditions. Understanding the primary sites of disruption of the BBB during pathophysiologic conditions may lead to the development of agents that can target these sites and more precisely treat diseases associated with disruption of the BBB. Third, although we appear to understand some of the complex interactions between the cellular elements that compose the neurovascular unit within the brain, there is still mystery regarding the signaling pathways between these cellular elements and how they relate to maintaining and regulating the integrity of the BBB during health and disease. Fourth, it remains uncertain whether changes in the cerebral vasculature and/or brain tissue that lead to disruption of the BBB are contributing factors in or merely consequences of early neurological symptoms (e.g., cognitive decline) associated with many devastating diseases (e.g., Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis). Fifth, there are very few studies that have examined sex-related differences in the permeability of the BBB during physiologic and pathophysiologic conditions. Many differences exist between genders regarding the control of vascular function, and it is equally certain that there will be critical differences between genders in the control of transport across the BBB. It will be important to identify the influence of gender on the BBB for the treatment of neurovascular disorders that are prominent in women. Finally, although much insight has been gained by studies using genetically manipulated animal models and cell cultures, these studies may not be directly translatable to the human condition. Thus, we must not lose sight of the importance of examining the BBB in genetically intact models during physiologic and pathophysiologic conditions. Future studies will need to clarify some of these controversies in order to develop new and innovative therapeutic approaches and targets for the treatment of neurological disorders.

35

 

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About the Authors Dr. William Mayhan is a Professor of Physiology and the Dean of Basic Biomedical Sciences in the Sanford School of Medicine at the University of South Dakota. Ms. Denise Arrick is an Instructor of Anatomy within the Division of Basic Biomedical Sciences in the Sanford School of Medicine at the University of South Dakota. Dr. Mayhan received his B.S. in Biology from Creighton University and his Ph.D. in Physiology from the University of Nebraska Medical Center. Ms. Arrick received her B.S. in Biology from the University of Nebraska at Omaha and her M.S. in Biomedical Sciences from the Department of Molecular and Cellular Physiology (Dr. D.N. Granger) at the Louisiana State University Health Sciences Center-Shreveport. Their current research is focused on the role of the endothelium in the control of vascular function and the blood-brain barrier during health and disease, and the influence of gender and exercise training on the cerebral microcirculation. Dr. Mayhan has served on the Editorial Boards for the American Journal of Physiology (Heart and Circulatory Physiology), Eye and Brain, Microcirculation, Microvascular Research and Stroke. They are both reviewers for several scientific journals. Dr. Mayhan has published over 200 peer-reviewed articles, reviews, and book chapters. Together, they have published over 25 articles on the cerebral microcirculation. Dr. Mayhan serves on several local, national and international societies, and on study sections for many extramural granting agencies, including the NIH and American Heart Association. His research has been funded continuously for over 30 years.