Table Of Contentvii
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
