Contributors Numbers in parentheses indicate the pages on which the authors’ JohnA.Duncan (361), Department of Clinical Neurosciences contributions begin. (Program in Neurosurgery), and Department of Pathology (Neuropathology Division), Brown Medical School and Rhode Island Hospital, Providence, Rhode Island, USA PerAlm (191), Department of Pathology, University Hospital, RichardD.Egleton (107), Department of Pharmacology, Lund, Sweden College of Medicine, University of Arizona, Tucson, EricAnderson (547), Center for Neurovirology and Neuro- Arizona, USA degenerative Disorders and the Departments of Pathology Britta Engelhardt (19), Max-Planck-Institute for Physiological and Microbiology, University ofNebraska Medical Center, and Clinical Research, W.G. Kerckhoff-Institute, Department Omaha, Nebraska, USA of Vascular Cell Biology, Bad Nauheim, Germany, and Max-Planck-Institute, Münster, Germany SusanneAngelow (33), Institut für Biochemie, Westfälische Wilhelms-Universität Münster, Münster, Germany Hans-Joachim Galla (33), Institut für Biochemie, Westfälische Wilhelms-Universität Münster, Münster, Germany KennethL.Audus (47), Department of Pharmaceutical Chem- istry, University ofKansas, Lawrence, Kansas, USA HowardE.Gendelman (547), Center for Neurovirology and Neurodegenerative Disorders and the Departments of William A. Banks (73,99) Division of Geriatrics, Department Pathology and Microbiology, and Internal Medicine, of Internal Medicine, Veterans Affairs Medical Center– University ofNebraska Medical Center, Omaha, Nebraska, St.Louis and Saint Louis University School of Medicine, USA St.Louis,Missouri, USA TakujiIgarashi (419), Chiba University, Department of HanneloreBauer (1), Institute of Molecular Biology, Austrian Neurological Surgery, Chiba, Japan Academy of Sciences, Salzburg, Austria ConradE.Johanson (361), Department of Clinical Neuro- Hans-ChristianBauer (1), Institute of Molecular Biology, sciences (Program in Neurosurgery), and Department of Austrian Academy of Sciences, Salzburg, Austria Pathology (Neuropathology Division), Brown Medical DavidJ.Begley (83), Centre for Neuroscience Research, School and Rhode Island Hospital, Providence, Rhode Kings College, London, United Kingdom Island, USA IngolfE.Blasig (11), Forschungsinstitut für Molekulare OsamuKakinohana (385), Anesthesiology Research Labora- Pharmakologie, Berlin, Germany tory, University of California, San Diego La Jolla, California, USA Albertus G. de Boer (63), Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, AbbaJ.Kastin (57,395), VA Medical Center and Tulane Leiden, The Netherlands University School of Medicine, New Orleans, Louisiana, USA Douwe D. Breimer (63), Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, GerdKrause (11), Forschungsinstitut für Molekulare Phar- Leiden, The Netherlands makologie, Berlin, Germany ThomasP.Davis (107), Department of Pharmacology, College JoséV.Lafuente (533), Department of Neurosciences Uni- of Medicine, University of Arizona, Tucson, Arizona, USA versity of the Basque Country, Bilbao, Spain MelanieLaschinger (19), Max-Planck-Institute for Physio- PrasantaKumarDey (299), Neurophysiology Research Unit, logical and Clinical Research, W.G. Kerckhoff-Institute, Department of Physiology, Institute of Medical Sciences, Department of Vascular Cell Biology, Bad Nauheim, Banaras Hindu University, Varanasi, India Germany, and Max-Planck-Institute, Münster, Germany ChristineD.Dijkstra (409), Department of Molecular Cell StefanLiebner (561), Vascular Biology, FIMO-FIRC Institute Biology, VU Medical Center, Amsterdam, The Netherlands of Molecular Oncology Via Serio, Milano, Italy CurtisE.Doberstein (361), Department of Clinical Neuro- NinoMaida (419), Department of Neurological Surgery, sciences (Program in Neurosurgery), and Department of University ofCalifornia, San Francisco, California, USA Pathology (Neuropathology Division), Brown Medical School and Rhode Island Hospital, Providence, Rhode JozefMarsala (385), Institute of Neurobiology Slovak Island, USA Academy of Sciences Kosice, Soltesovej, Slovak Republic vii viii CONTRIBUTORS Martin Marsala (385), Anesthesiology Research Laboratory, Peter Silverstein (47), Department of Pharmaceutical Chem- University of California, San Diego La Jolla, California, USA istry, University ofKansas, Lawrence, Kansas, USA PaulN.McMillan (361), Department of Clinical Neuro- EdwardG.Stopa (361), Department of Clinical Neuro- sciences (Program in Neurosurgery), and Department of sciences (Program in Neurosurgery), and Department of Pathology (Neuropathology Division), Brown Medical School Pathology (Neuropathology Division), Brown Medical and Rhode Island Hospital, Providence, Rhode Island, USA School and Rhode Island Hospital, Providence, Rhode LindaJ.Noble (419), Department of Neurological Surgery, Island, USA University ofCalifornia, San Francisco, California, USA SusanSwindells (547), Department of Internal Medicine, FredNyberg (519), Department of Pharmaceutical Bio- University ofNebraska Medical Center, Omaha, Nebraska, sciences, Biomedical Center, Uppasla University Uppsala, USA Sweden JohoTokumine (385), Anesthesiology Research Laboratory, DonaldE. Palm (361), Department of Clinical Neurosciences University of California, San Diego La Jolla, California, (Program in Neurosurgery), and Department of Pathology USA (Neuropathology Division), Brown Medical School and AndreasTraweger (1), Institute of Molecular Biology, Rhode Island Hospital, Providence, Rhode Island, USA Austrian Academy of Sciences, Salzburg, Austria WeihongPan (57,395), VA Medical Center and Tulane DarkhanI.Utepbergenov (11), Forschungsinstitut für Molek- University School of Medicine, New Orleans, Louisiana, ulare Pharmakologie, Berlin, Germany USA PeterVajkoczy (19), DepartmentofNeurosurgery, University RanjanaPatnaik (299), Department of Biomedical Engineer- Hospital, Mannheim, Germany ing, Institute of Technology, Banaras Hindu University, IvoVanicky (385), Institute of Neurobiology Slovak Academy Varanasi,India of Sciences Kosice, Soltesovej, Slovak Republic GesaRascher-Eggstein (561), Institute of Pathology, Uni- HelgaE.deVries (409), Department of Molecular Cell versity of Tübingen, Tübingen, Germany Biology, VU Medical Center, Amsterdam, The Netherlands AmitKumarRay (299), Department of Biomedical Engineer- Joachim Wegener (33), Institut für Biochemie, Westfälische ing, Institute of Technology, Banaras Hindu University, Wilhelms-Universität Münster, Münster, Germany Varanasi,India Antonie Rice (47), Department of Pharmaceutical Chemistry, JanWestman (329) Laboratory of Neuroanatomy, Department University ofKansas, Lawrence, Kansas, USA of Medical Cell Biology, Biomedical Center, Uppsala University, Uppsala, Sweden LisaRyan (547), Center for Neurovirology and Neurodege- nerative Disorders and the Departments of Pathology and KenA.Witt (107), Department of Pharmacology, College of Microbiology, University of Nebraska Medical Center, Medicine, University of Arizona, Tucson, Arizona, USA Omaha, Nebraska, USA HartwigWolburg (561), Institute of Pathology, University of Inez C.J. van der Sandt (63), Leiden/Amsterdam Center for Tübingen, Tübingen, Germany Drug Research, Division ofPharmacology, Leiden University, HuanguiXiong (547), Center for Neurovirology and Neuro- Leiden, The Netherlands degenerative Disorders and the Departments of Pathology AnkeSchmidt (11), Forschungsinstitut für Molekulare Phar- and Microbiology, University ofNebraska Medical Center, makologie, Berlin, Germany Omaha, Nebraska, USA Hari Shanker Sharma (117, 159, 191, 231, 299, 329, 437, 519) JialinZheng (547), Center for Neurovirology and Neuro- Laboratory of Neuroanatomy, Department of Medical Cell degenerative Disorders and the Departments of Pathology Biology, Biomedical Center, Uppsala University, Uppsala, and Microbiology, University ofNebraska Medical Center, Sweden Omaha, Nebraska, USA Foreword The contents of the interstitial fluid in the central nervous system (CNS) are contributed to by endothelium, neurons, glia and pericytes but the constancy of the fluid’s composition is regulated primarily by the endothelium. As the first and contin- uous cell layer between blood and interstitial fluid, the non- fenestrated endothelium stands as the selective gateway for the exchange of hydrophilic solutes and of cells between the two fluids. The endothelial cells are able to exert this control because the paracellular cleft between them is occluded by belts of tight junctions. This seal prevents the passive, continuous, paracel- lular flow of plasma constituents that would otherwise inundate the interstitial clefts. As a consequence, the endothelium can exert selective entry into the CNS of nutrients, ions and regu- latory proteins, while, in non-primate mammals, expelling other solutes through a P-glycoprotein efflux pump. Although the tight junction is only one structural component of the barrier, its centrality in the regulation of the interstitial fluid’s composi- tion,is reflected in this book by the discussions on the molec- ular structure of the junction and that of its associated cyto- plasmic proteins, structures and interrelations that are still beingelucidated. The barrier has been further defined here by the different ways in which it is exerted. Attempts have been made to delineate how proteins and peptides, because of their importance in many functions, leave and enter the CNS. For example, some peptides are intrinsic hormone-releasing factors which must traverse endothelium to leave the brain for peripheral targets, such as migration which, in the future, will be more fully compre- endocrine glands. Conversely, certain regulatory peptides e.g., hended as new information is gleaned on the structures that lie insulin and leptin, secreted by peripheral tissues, are destined outside of endothelium. for transport into the CNS where they act to regulate appetite. Such future directions lead beyond the endothelium to the Some peptides, including therapeutic ones, can be brought into extracellular matrix. The effects of the perivascular astrocyte on the CNS by saturable transport mechanisms. Other peptides, brain endothelium have been well documented, the effects of native and basic, synthetic ones, bind to negatively charged sites the pericyte to a lesser extent and the influence attributable to on the luminal surface of the endothelium to be transferred the extracellular matrix least of all. The extracellular matrix across it by adsorptive transcytosis. A more specific vesicular affects the structure and function of the endothelial tight transport is by way of receptor-mediated transcytosis which junction [1], the passage of leukocytes between blood and the transfers proteins and peptides into brain when they are con- CNS interstitium [2] and, conceivably, the storage and regu- jugated to a vector antibody against, e.g., the ubiquitous trans- lated release [3] of, vascular and glial growth factors. The ferrin receptors situated on endothelium throughout the brain. copious perivascular matrix of neuroendocrine circumventricular A saturable transport system can likewise bring oligonu- organs might likewise bind circulating factors exuding from cleotides into CNS. This transporter facilitates the entry into their fenestrated, permeable, vessels or secreted by their over- CNS of, e.g., circulating antisense molecules directed at lying epithelium. A future discussion of the interaction between amyloid-β precursor protein, thereby reducing the amount of matrix and brain cells may provide a more complete context this protein in brain and ameliorating memory deficits. Viral in which to further explore how all of the components of vectors containing gene fragments for the encoding of the blood–brain and blood–CSF barriers interact to modulate molecules deficient in the brain or spinal cord are also being endothelial and epithelial permeability. explored. Another topic of broad interest discussed in this Milton Brightman volume is the passage of leukocytes across CNS vessels, a Bethesda, MD ix x FOREWORD References 1. Tilling, T., Korte, D., Hoheisel, D., and Galla, H.J. (1998). Basement and 10, play decisive roles in T cell recruitment across the blood- membrane proteins influence brain capillary endothelial barrier and brain barrier in experimental autoimmune encephalomyelitis. J.Cell function in vitro. J. Neurochem.71,1151–1157. Biol.153,933–946. 2. Sixt, M., Engelhardt, B., Pausch, F., Hallmann, R., Wendler, O., and 3. Taipale, J., and Keski-Oja, J. (1997). Growth factors in the extra- Sorokin, L.M. (2001). Endothelial cell laminin isoforms, laminins 8 cellular matrix. FASEB J.11,51–59. Introduction The search for a precise anatomical substrate of blood–brain barrier (BBB) breakdown has yielded somewhat discrepant results. For a number of years the opening of tight junctions (TJ) was considered a primary pathway. However, later researchers demonstrated in several models of vasogenic edema that the majority of interendothelial junctions remained intact. However, it was also proved that osmotically opening TJ does not necessarily lead to brain edema or even to brain damage. Meanwhile, a large amount of new information has been accumulated. In the present volume edited by Sharma and Westman, many authors stressed that TJ-related proteins are also involved in signal transduction linking TJs to the regulation of gene expression (Baueretal., Chapter1). The sequence domains of zona occludens protein 1 and occludin have been identified. Furthermore there is evidence on the effect of nitric oxide (NO) and NO-related species on TJ proteins sealing the BBB (Schmidtetal., Chapter2); therefore, drugs influencing NO metabolism clearly influence the BBB and the blood–spinal cord barrier (BSCB) in diseases afflicting the central nervous system (CNS) (Sharma and Alm, Chapter 14). The role of the BBB in inflammatory diseases of the CNS isclarified through the mechanism of lymphocyte recruitment by the adhesion of chemokines to the endothelium (Engelhardt etal., Chapter3). Also, the action of monocyte-derived macro- phages on the BBB as a site of entry for inflammatory cells during the process of lesion formation in multiple sclerosis is presented (de Vries and Dijkstra, Chapter 20). In many chapters, the psychological aspects of the BBB are emphasized. Different authors summarized the relevance of results obtained through in vitro models (Angelow et al. An original part of the book deals with neuropschycological Chapter 4; Riceetal., Chapter 5). An unexpected role of the aspects of the blood–CNS barriers. The state of the BBB and BBB in the pathophysiology of obesity is presented (Kastin and BSCB under stressful situations is reviewed in different com- Pan, Chapter 6) that surprised me. However, these findungs are munications. There are reasons to believe that stress-induced of clinical importance, as hyperglycemia may upregulate breakdown of the BBB and BSCB could be one of the key transport systems for leptin, urocortin, and galanin-like peptide, factors in inducing brain pathology (Sharma, Chapter 15). New whereas fasting can downregulate leptin and galanin-like data presented in this volume suggest that breakdown of the peptide transport. The influences of serotonin as one of the key blood–brain and blood–spinal cord barriers following hyper- mediators of the BBB and BSCB and histamine as one of the thermia and spinal cord trauma plays important roles in cell important neurotransmitters involved in the pathophysiology injury and heat shock protein expression (Sharma and Westman, ofcerebrovascular barriers are investigated indetail (Sharma, Chapter 17). Studies on morphine-dependent rats suggest that Chapters 12 and 13). These findings have relevance in many morphine withdrawal stress has the capacity to induce break- clinical situations. down of blood–brain and blood–CSF barriers (Sharma et al., Modified and unmodified antisense molecules that interact Chapter 16). These observations clearly suggest that BBB and with and cross the BBB should be useful tools in investigating BSCB are influenced in several neuropsychiatric diseases and the treatment of diseases of the CNS. Several strategies are require additional investigation. being investigated for modifying antisense to improve its ability Alterations of cerebrovascular barriers in disease conditions to cross the BBB (Banks, Chapter 10). A number of strategies are resumed in two miscellaneous sections. In a chapter dealing have also been proved effective in the experimental delivery of with morphologic studies, the role of the endothelial glycocalyx peptides to the CNS (Egletonetal., Chapter 11). is stressed (Noble et al., Chapter22). In a number of animal xi xii INTRODUCTION studies using pharmacological approaches, specific antagonists ficance in spinal cord pathology is discussed (Sharma, and inhibitors or factors, which modulate BBB opening follow- Chapter23). The last section deals with interesting aspects of ing global and focal cerebral ischemia, have proved effective HIV-1-associated dementia (Andersonetal., Chapter 26) and (Marsalaetal., Chapter19). However, in clinical studies,no clear- human gliomas (Rascler et al., Chapter 27) related to the cut beneficial effect was demonstrated after a qualitatively microenvironment and its dependence on the BBB. comparable pharmacologic treatment. This is a very common I firmly believe that this book will open new avenues for situation concerning results obtained in animal experiments. research on blood–brain and blood–spinal cord barriers in Spinal cord injury at different locations with different types relation to neurological and neuropathological diseases and in and severity of lesion is associated with different patterns finding suitable therapeutic strategies to treat them in the of upregulation of the transport system (Pan and Kastin, nearfuture. Chapter20). The importance of microvascular permeability Jordi Cervós-Navarro disturbances and edema formation and their functional signi- Barcelona, Spain Preface Recent advances in the understanding of the spinal cord and its To our knowledge, this is the first book that deals with prob- reaction to various kinds of insult generated an enormous amount lems of the blood–spinal cord barrier in great detail, ranging of new knowledge. This basic information is mainly coveredin from psychological to pathological aspects. In addition, basis several scientific journal articles and reviews. The strategy of aspects of the blood–central nervous system (CNS) barriers are spinal cord injury (SCI) is thus divided into various disciplines also presented. This book is a refereed collection of 27 chapters and deals mainly with the fields of neurology, neurosurgery and written by renowned experts engaged in research on various orthopedics. Scientists engaged in different disciplines see the aspects of the blood–brain and blood–spinal cord barriers in spinal cord from different perspectives and thus various theories different parts of the world. exist to explain spinal cord pathology following traumatic, This book is divided into seven sections. Section I deals with metabolic, or ischemic insults. basic aspects of the cerebrovascular barriers and is covered in With the advent of new technology on cellular and molecular three chapters. The structure and function of tight junctions and neurobiology, immunocytochemistry, electron microscopy, and associated proteins are described by Bauer et al.(Chapter 1). electrophysiology, our understanding of basic spinal cord cir- Using surface plasmon resonance (SPR) spectroscopy for the cuitry is greatly expanded. New methods of receptor recogni- first time to study online association of the blood–brain barrier tion revealed many new kinds of neurochemical receptors and proteins zona occludens protein 1 (ZO-1) and occludin, their function for improved communication within the spinal Schmidt et al.(Chapter 2) suggest a direct effect of nitric oxide cord. With the development of pharmacochemistry, several new (NO) and NO-related species on the tight junction proteins. compounds that may act as neurochemical agonist and antago- Employing an animal model of CNS inflammation, i.e., nists have now been synthesized. Application of these new experimental autoimmune encephalomyelitis (EAE) in which compounds either invivo or invitro gave novel information circulating lymphocytes and monocytes/macrophages cross the about the functional mechanisms of the spinal cord under blood–brain barrier (BBB) readily and gain access to the CNS, normal and abnormal conditions. New strategies of pharma- leading to edema, inflammation, and demyelination, Engelhardt cotherapy developed in the past few years to minimize the etal.(Chapter 3) summarize currentknowledge on the traffic outcome of spinal cord injuries are thus dealt with in detail. signals involved in T lymphocyte recruitment across healthy Emphasis is made on various pharmacological and immuno- and inflamed BBB invitroand invivoinvestigations. logical agents, which may be the future tool for therapy in In Section II, technical and functional aspects of the reducing cell changes in the spinal cord at the cellular, molecu- cerebrovascular barriers invitroare presented in two chapters. lar, or ultrastructural levels. Epithelial cells of the choroid plexus (CP) are the structural However, the vast new knowledge about the spinal cord is basis of the blood–cerebrospinal fluid (CSF) barrier. Recent widely distributed in several scientific disciplines. In order to progress in isolating CP epithelial cells from porcine brains, expand our fundamental understanding of the spinal cord and culturing them invitro,and using confluent layers of these cells its reaction to various kinds of insults or injuries, the new on permeable supports as a physiologically active model of the knowledge must be assimilated with the existing one to have a blood–CSF barrier is presented by Angelow et al.(Chapter 4). speculative synthesis of spinal cord structure and function. This This model could be extremely useful in exploring the transport book by no means attempts to cover a thorough understanding characteristics of CP epithelial cells and in investigating the of the new knowledge that has emerged in the last 10 years in passage of drugs from the circulating bloodstream into the CSF. the field. Moreover, emphasis is made on the morphological In Chapter 5, Rice et al.present a brief history of the develop- aspect of SCI with particular emphasis on the microvascular ment of invitromodels used to investigate the molecular and permeability, edema, and cell changes in this treatise, which cellular significance of the BBB. The relevance of the use of was largely ignored in the past. In our opinion, spinal cord astrocyte cocultures and applications of the bovine brain micro- cellular mechanisms and their microenvironment are key vessel endothelial cell (BMEC) models for future investigations elements for the normal function of the spinal cord. Alteration are discussed. in the microfluid environment or cellular environment could be Section III is devoted to the physiological aspects of the the gateway of various disease processes. This aspect is dealt cerebrovascular barriers comprising six chapters. In this section, with in view of the previous published works andin the light of special emphasis is given to the transport mechanisms across recent literature in the field. Based on our own observations and the blood–CNS barriers. One of the most interesting aspects of in relation with the existing information, we made an attempt to peptide transport across the BBB is described by Kastin and understand the spinal cord function with this angle. Pan (Chapter 6), which has profound clinical relevance xiii xiv PREFACE nowadays. As obesity becomes an increasing health problem, a Section V is based on neuropsychological aspects of cere- number of endogenous peptides can affect the ingestion of food. brovascular barriers in stressful situations. This section contains New research presented in this chapter suggests that the avail- three chapters. It seems likely that prolonged stress induces ability of ingestive peptides to CNS targets is modulated by immediate early gene expression and alters the function of theBBB. In Chapter 7, van der Sandt et al.present new aspects neurochemical receptors causing abnormal brain function. of the multidrug transporter P-glycoprotein (Pgp), which Using various animal models of stress, a selective and specific influences the pharmacokinetics of drugs. It appears that chem- increase in blood–brain and blood–spinal cord barriers is icals, environmental conditions, and genetic factors influence described in Chapter 15 (Sharma). New observations suggest Pgp expression, which could be responsible for interindividual that stress-induced breakdown of the cerebrovascular barriers is differences in the drug disposition. The exchange of peptides or instrumental in brain pathology. In Chapter 16, Sharma etal. regulatory proteins between the CNS and the blood due to present new evidence indicating that stress associated with communication between the peripheral tissues and the CNS is morphine withdrawal is capable of inducing breakdown of the meticulously described by Banks (Chapter 8). The physio- blood–brain and blood–CSF barriers. Several stressful situations logical role of CNS efflux transporters that regulate or attenuate or ischemic and metabolic insults induce the expression of CNS entry of many potentially neurotoxic and neuroactive stress proteins in the CNS, commonly known as “heat shock substances is reviewed by Begley in Chapter 9. Neuroactive proteins (HSP).” During CNS injuries, HSP expression is often drugs are the substrates for these transporters located in the associated with hemeoxygenase (HO) upregulation. Sharma blood–brain interfaces and thus present a major challenge to the and Westman (Chapter 17) review the role of blood–brain or pharmaceutical industry for the drug delivery to the brain. blood–spinal cord barrier disruption in HSP and HO upregu- Another approach for the treatment of CNS diseases with anti- lation in the light of current literature and their own investi- sense appears to be promising despite rapid degradation in the gations in CNS injuries. circulation and limited transport of unmodified antisense across Section VI deals with the neurological aspects of cerebrovas- the BBB. The use of modified and unmodified antisense mole- cular barriers in disease conditions using several experimental cules as tools to investigating their transport to the brain and to animal models. This section is divided into eight chapters. their potential therapeutic use in the CNS is discussed in Redistribution and upregulation of several growth factors in Chapter 10 (Banks). Over the last decade, the biotech industries brain or spinal cord ischemia occur that may contribute to produced a large number of drugs to treat neurological disorders; neuronal repair. In Chapter 18, Johansson et al. provide new however, the availability of peptide neuropharmaceuticals still evidence that the epithelium of the CP secretes numerous remains small. A number of effective strategies for the experi- peptides and proteins into CSF that is transported to the neurons mental delivery of peptides to the CNS that can be useful for the at the damage sites by volume transmission. Marsala et al. development of neuropharmaceutical agents in the future is (Chapter 19) present evidence for the multifactorial opening of presented by Egleton et al.(Chapter 11). the BBB following transient or permanent cerebral or spinal Pharmacological aspects of the neurochemical mediators on ischemia. The new findings in thischapter suggest a direct or the blood–brain and blood–spinal cord barriers are described in indirect influence of several agents, e.g., excitatory amino acids, Section IV, which comprises three chapters. New data suggest cytokines (TNF-α, IL-1), prostanoids, NO, and/or oxygen-free that serotonin is one of the key players in the BBB and BSCB radicals, on ischemia-induced BBB disruption. Using radio- dysfunction (Chapter 12, Sharma). Thus, drugs modifying labeled compounds, Pan and Kastin (Chapter 20) show that SCI serotonergic transmission and/or capable of influencing sero- is related to time- and region-specific changes of the BBB tonergic receptors could be the promising candidates for the function to various cytokines and neurotrophic peptides/proteins treatment of several neurological diseases in which BBB or that could be due either to simple diffusion or to specific BSCB permeability is compromised. Because no single chemical transport systems. The initial cellular events underlying new compound or factor alone is responsible for the breakdown of multiple sclerosis (MS) lesion formation are provided by the BBB or BSCB in in vivosituations, it appears that a large deVries and Dijkstra (Chapter 21). The authors emphasize the number of equally important neurochemicals are involved in role of monocyte-derived macrophages and the BBB as a site cerebrovascular dysfunction in CNS diseases. The role of hista- ofentry for inflammatory cells. The morphologic basis of barrier mine in influencing the blood–spinal cord and brain barriers disruption after SCI and the subsequent CNS response to barrier following a variety of CNS insults that has largely been ignored breakdown, as well as its influence on functional recovery, are in the recent past is reviewed in Chapter 13 (Sharma). New discussed by Noble et al.in Chapter 22. The state of the BSCB evidence presented in the chapter suggests that histamine following a focal trauma to the spinal cord is reviewed in influences signal transducing agents in CNS microvessels, Chapter 23 (Sharma). leading to BBB or BSCB disruption and vasogenic edema Focus is given on the relationship between microvascular formation. This indicates that histamine agonists and antago- permeability disturbances and edema formation in relation to nists have therapeutic potential in CNS injuries. In Chapter 14, cell damage. The basic aspects of growth hormone permeability Sharma and Alm present new information showing an across CNS microvessels, as well as its therapeutic effect on involvement of nitric oxide (NO) in the BBB and BSCB SCI, are discussed in Chapter 24 (Nyberg and Sharma). New breakdown in several forms of CNS insults. It appears that NOS observations suggest that growth hormone, if supplied exoge- inhibitors or NOS antiserum is capable of attenuating alter- nously on the traumatized spinal cord, can exert powerful ations in BBB and BSCB disruption, edema formation, and neuroprotective effects through a receptor-mediated mechanism. early cell reactions in CNS injuries. In an animal model of minimal cortical lesion, Lafuente PREFACE xv (Chapter 25) suggests that the vascular endothelial growth proinflammatory factors, namely cytokines, chemokines, factor is a major mediator of angiogenesis, vascular permeabil- platelet-activating factor, arachidonic acid and its metabolites, ity, and brain edema. New evidence presented in this chapter NO, quinolinic acid, progeny virions, and viral structural and indicate that increased extravascular water and proteins further regulatory proteins. In Chapter 27, Rascheretal.emphasize the complicate nutrient exchange and cause profound metabolic role of the BBB regarding the treatment of brain tumors, tumor stress, leading to cell and tissue injury. Thus, new information angiogenesis, and the permeability of tumor vessels in clinical presented in this section clearly suggests that BBB and BSCB conditions. permeability are compromised in a wide variety of CNS injuries It is hoped that new aspects of the blood–brain and that could be primarily responsible for cell and tissue damage. blood–spinal cord barriers presented in this volume will serve This indicates that the basic mechanisms of CNS injury are as strong stimuli to the scientific community for further research quite similar in nature irrespective of the models used. using new pharmacotherapeutic strategies to minimize CNS The importance of cerebrovascular barriers in clinical con- injuries and/or insults in the near future. ditions is presented in Section VII, which contains two chapters. Anderson et al. (Chapter 26) discuss compromised mental Hari Shanker Sharmaand Jan Westman function in HIV infection that may be associated with several Uppsala, Sweden Acknowledgments This volume would not be possible without the tireless editorial assistance of Cindy Minor throughout the incubation period. We also sincerely appreciate the outstanding support, encouragement, and all-around help of Publishing Editor, Hilary Rowe whenever we needed it. We acknowledge with thanks the assistance of Marcy Barnes-Henrie in production. The editors, HSS and JW xvi