vii Numbers in parentheses indicate the pages on which the authors’ contributions begin. Per Alm (191), Department of Pathology, University Hospital, Lund, Sweden Eric Anderson (547), Center for Neurovirology and Neuro- degenerative Disorders and the Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA Susanne Angelow (33), Institut für Biochemie, Westfälische Wilhelms-Universität Münster, Münster, Germany Kenneth L. Audus (47), Department of Pharmaceutical Chem- istry, University of Kansas, Lawrence, Kansas, USA William A. Banks (73, 99) Division of Geriatrics, Department of Internal Medicine, Veterans Affairs Medical Center– St. Louis and Saint Louis University School of Medicine, St. Louis, Missouri, USA Hannelore Bauer (1), Institute of Molecular Biology, Austrian Academy of Sciences, Salzburg, Austria Hans-Christian Bauer (1), Institute of Molecular Biology, Austrian Academy of Sciences, Salzburg, Austria David J. Begley (83), Centre for Neuroscience Research, Kings College, London, United Kingdom Ingolf E. Blasig (11), Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany Albertus G. de Boer (63), Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands Douwe D. Breimer (63), Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands Thomas P. Davis (107), Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA Prasanta Kumar Dey (299), Neurophysiology Research Unit, Department of Physiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India Christine D. Dijkstra (409), Department of Molecular Cell Biology, VU Medical Center, Amsterdam, The Netherlands Curtis E. Doberstein (361), Department of Clinical Neuro- sciences (Program in Neurosurgery), and Department of Pathology (Neuropathology Division), Brown Medical School and Rhode Island Hospital, Providence, Rhode Island, USA John A. Duncan (361), Department of Clinical Neurosciences (Program in Neurosurgery), and Department of Pathology (Neuropathology Division), Brown Medical School and Rhode Island Hospital, Providence, Rhode Island, USA Richard D. Egleton (107), Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA Britta Engelhardt (19), Max-Planck-Institute for Physiological and Clinical Research, W.G. Kerckhoff-Institute, Department of Vascular Cell Biology, Bad Nauheim, Germany, and Max-Planck-Institute, Münster, Germany Hans-Joachim Galla (33), Institut für Biochemie, Westfälische Wilhelms-Universität Münster, Münster, Germany Howard E. Gendelman (547), Center for Neurovirology and Neurodegenerative Disorders and the Departments of Pathology and Microbiology, and Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA Takuji Igarashi (419), Chiba University, Department of Neurological Surgery, Chiba, Japan Conrad E. Johanson (361), Department of Clinical Neuro- sciences (Program in Neurosurgery), and Department of Pathology (Neuropathology Division), Brown Medical School and Rhode Island Hospital, Providence, Rhode Island, USA Osamu Kakinohana (385), Anesthesiology Research Labora- tory, University of California, San Diego La Jolla, California, USA Abba J. Kastin (57, 395), VA Medical Center and Tulane University School of Medicine, New Orleans, Louisiana, USA Gerd Krause (11), Forschungsinstitut für Molekulare Phar- makologie, Berlin, Germany José V. Lafuente (533), Department of Neurosciences Uni- versity of the Basque Country, Bilbao, Spain Melanie Laschinger (19), Max-Planck-Institute for Physio- logical and Clinical Research, W.G. Kerckhoff-Institute, Department of Vascular Cell Biology, Bad Nauheim, Germany, and Max-Planck-Institute, Münster, Germany Stefan Liebner (561), Vascular Biology, FIMO-FIRC Institute of Molecular Oncology Via Serio, Milano, Italy Nino Maida (419), Department of Neurological Surgery, University of California, San Francisco, California, USA Jozef Marsala (385), Institute of Neurobiology Slovak Academy of Sciences Kosice, Soltesovej, Slovak Republic Contributors viii CONTRIBUTORS Martin Marsala (385), Anesthesiology Research Laboratory, University of California, San Diego La Jolla, California, USA Paul N. McMillan (361), Department of Clinical Neuro- sciences (Program in Neurosurgery), and Department of Pathology (Neuropathology Division), Brown Medical School and Rhode Island Hospital, Providence, Rhode Island, USA Linda J. Noble (419), Department of Neurological Surgery, University of California, San Francisco, California, USA Fred Nyberg (519), Department of Pharmaceutical Bio- sciences, Biomedical Center, Uppasla University Uppsala, Sweden Donald E. Palm (361), Department of Clinical Neurosciences (Program in Neurosurgery), and Department of Pathology (Neuropathology Division), Brown Medical School and Rhode Island Hospital, Providence, Rhode Island, USA Weihong Pan (57, 395), VA Medical Center and Tulane University School of Medicine, New Orleans, Louisiana, USA Ranjana Patnaik (299), Department of Biomedical Engineer- ing, Institute of Technology, Banaras Hindu University, Varanasi, India Gesa Rascher-Eggstein (561), Institute of Pathology, Uni- versity of Tübingen, Tübingen, Germany Amit Kumar Ray (299), Department of Biomedical Engineer- ing, Institute of Technology, Banaras Hindu University, Varanasi, India Antonie Rice (47), Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas, USA Lisa Ryan (547), Center for Neurovirology and Neurodege- nerative Disorders and the Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA Inez C.J. van der Sandt (63), Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands Anke Schmidt (11), Forschungsinstitut für Molekulare Phar- makologie, Berlin, Germany Hari Shanker Sharma (117, 159, 191, 231, 299, 329, 437, 519) Laboratory of Neuroanatomy, Department of Medical Cell Biology, Biomedical Center, Uppsala University, Uppsala, Sweden Peter Silverstein (47), Department of Pharmaceutical Chem- istry, University of Kansas, Lawrence, Kansas, USA Edward G. Stopa (361), Department of Clinical Neuro- sciences (Program in Neurosurgery), and Department of Pathology (Neuropathology Division), Brown Medical School and Rhode Island Hospital, Providence, Rhode Island, USA Susan Swindells (547), Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA Joho Tokumine (385), Anesthesiology Research Laboratory, University of California, San Diego La Jolla, California, USA Andreas Traweger (1), Institute of Molecular Biology, Austrian Academy of Sciences, Salzburg, Austria Darkhan I. Utepbergenov (11), Forschungsinstitut für Molek- ulare Pharmakologie, Berlin, Germany Peter Vajkoczy (19), Department of Neurosurgery, University Hospital, Mannheim, Germany Ivo Vanicky (385), Institute of Neurobiology Slovak Academy of Sciences Kosice, Soltesovej, Slovak Republic Helga E. de Vries (409), Department of Molecular Cell Biology, VU Medical Center, Amsterdam, The Netherlands Joachim Wegener (33), Institut für Biochemie, Westfälische Wilhelms-Universität Münster, Münster, Germany Jan Westman (329) Laboratory of Neuroanatomy, Department of Medical Cell Biology, Biomedical Center, Uppsala University, Uppsala, Sweden Ken A. Witt (107), Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA Hartwig Wolburg (561), Institute of Pathology, University of Tübingen, Tübingen, Germany Huangui Xiong (547), Center for Neurovirology and Neuro- degenerative Disorders and the Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA Jialin Zheng (547), Center for Neurovirology and Neuro- degenerative Disorders and the Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA ix 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 being elucidated. 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 endocrine glands. Conversely, certain regulatory peptides e.g., insulin and leptin, secreted by peripheral tissues, are destined for transport into the CNS where they act to regulate appetite. Some peptides, including therapeutic ones, can be brought into the CNS by saturable transport mechanisms. Other peptides, native and basic, synthetic ones, bind to negatively charged sites on the luminal surface of the endothelium to be transferred across it by adsorptive transcytosis. A more specific vesicular transport is by way of receptor-mediated transcytosis which transfers proteins and peptides into brain when they are con- jugated to a vector antibody against, e.g., the ubiquitous trans- ferrin receptors situated on endothelium throughout the brain. A saturable transport system can likewise bring oligonu- cleotides into CNS. This transporter facilitates the entry into CNS of, e.g., circulating antisense molecules directed at amyloid-β precursor protein, thereby reducing the amount of this protein in brain and ameliorating memory deficits. Viral vectors containing gene fragments for the encoding of molecules deficient in the brain or spinal cord are also being explored. Another topic of broad interest discussed in this volume is the passage of leukocytes across CNS vessels, a migration which, in the future, will be more fully compre- hended as new information is gleaned on the structures that lie outside of endothelium. Such future directions lead beyond the endothelium to the extracellular matrix. The effects of the perivascular astrocyte on brain endothelium have been well documented, the effects of the pericyte to a lesser extent and the influence attributable to the extracellular matrix least of all. The extracellular matrix affects the structure and function of the endothelial tight junction [1], the passage of leukocytes between blood and the CNS interstitium [2] and, conceivably, the storage and regu- lated release [3] of, vascular and glial growth factors. The copious perivascular matrix of neuroendocrine circumventricular organs might likewise bind circulating factors exuding from their fenestrated, permeable, vessels or secreted by their over- lying epithelium. A future discussion of the interaction between matrix and brain cells may provide a more complete context in which to further explore how all of the components of the blood–brain and blood–CSF barriers interact to modulate endothelial and epithelial permeability. Milton Brightman Bethesda, MD Foreword x FOREWORD References 1. Tilling, T., Korte, D., Hoheisel, D., and Galla, H.J. (1998). Basement membrane proteins influence brain capillary endothelial barrier and function in vitro. J. Neurochem. 71, 1151–1157. 2. Sixt, M., Engelhardt, B., Pausch, F., Hallmann, R., Wendler, O., and Sorokin, L.M. (2001). Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood- brain barrier in experimental autoimmune encephalomyelitis. J. Cell Biol. 153, 933–946. 3. Taipale, J., and Keski-Oja, J. (1997). Growth factors in the extra- cellular matrix. FASEB J. 11, 51–59. xi 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 (Bauer et al., Chapter 1). 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 (Schmidt et al., Chapter 2); 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 is clarified through the mechanism of lymphocyte recruitment by the adhesion of chemokines to the endothelium (Engelhardt et al., Chapter 3). 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. Chapter 4; Rice et al., Chapter 5). An unexpected role of the BBB in the pathophysiology of obesity is presented (Kastin and Pan, Chapter 6) that surprised me. However, these findungs are of clinical importance, as hyperglycemia may upregulate transport systems for leptin, urocortin, and galanin-like peptide, whereas fasting can downregulate leptin and galanin-like peptide transport. The influences of serotonin as one of the key mediators of the BBB and BSCB and histamine as one of the important neurotransmitters involved in the pathophysiology of cerebrovascular barriers are investigated in detail (Sharma, Chapters 12 and 13). These findings have relevance in many clinical situations. Modified and unmodified antisense molecules that interact with and cross the BBB should be useful tools in investigating the treatment of diseases of the CNS. Several strategies are being investigated for modifying antisense to improve its ability to cross the BBB (Banks, Chapter 10). A number of strategies have also been proved effective in the experimental delivery of peptides to the CNS (Egleton et al., Chapter 11). An original part of the book deals with neuropschycological aspects of the blood–CNS barriers. The state of the BBB and BSCB under stressful situations is reviewed in different com- munications. There are reasons to believe that stress-induced breakdown of the BBB and BSCB could be one of the key factors in inducing brain pathology (Sharma, Chapter 15). New data presented in this volume suggest that breakdown of the blood–brain and blood–spinal cord barriers following hyper- thermia and spinal cord trauma plays important roles in cell injury and heat shock protein expression (Sharma and Westman, Chapter 17). Studies on morphine-dependent rats suggest that morphine withdrawal stress has the capacity to induce break- down of blood–brain and blood–CSF barriers (Sharma et al., Chapter 16). These observations clearly suggest that BBB and BSCB are influenced in several neuropsychiatric diseases and require additional investigation. Alterations of cerebrovascular barriers in disease conditions are resumed in two miscellaneous sections. In a chapter dealing with morphologic studies, the role of the endothelial glycocalyx is stressed (Noble et al., Chapter 22). In a number of animal Introduction xii INTRODUCTION studies using pharmacological approaches, specific antagonists and inhibitors or factors, which modulate BBB opening follow- ing global and focal cerebral ischemia, have proved effective (Marsala et al., Chapter 19). However, in clinical studies, no clear- cut beneficial effect was demonstrated after a qualitatively comparable pharmacologic treatment. This is a very common situation concerning results obtained in animal experiments. Spinal cord injury at different locations with different types and severity of lesion is associated with different patterns of upregulation of the transport system (Pan and Kastin, Chapter 20). The importance of microvascular permeability disturbances and edema formation and their functional signi- ficance in spinal cord pathology is discussed (Sharma, Chapter 23). The last section deals with interesting aspects of HIV-1-associated dementia (Anderson et al., Chapter 26) and human gliomas (Rascler et al., Chapter 27) related to the microenvironment and its dependence on the BBB. I firmly believe that this book will open new avenues for research on blood–brain and blood–spinal cord barriers in relation to neurological and neuropathological diseases and in finding suitable therapeutic strategies to treat them in the near future. Jordi Cervós-Navarro Barcelona, Spain