CNS injuries: cellular responses and pharmacological strategies

223 Pages·1999·11.155 MB·English

by  Berry, M., Logan, Ann

CNS I
NJURIES
Cellular Responses and
Pharmacological Strategies
Edited by
Martin Berry
Ann Logan
CRC Press

Boca Raton New York
Contact Editor: Liz Covello
Project Editor: Maggie Mogck
Marketing Manager: Becky McEldowney
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Library of Congress Cataloging-in-Publication Data
CNS injuries : cellular responses and pharmacological strategies / edited by Martin Berry, Ann Logan.
p. cm. -- (Pharmacology and toxicology)
Includes bibliographical references and index.
ISBN 0-8493-8309-9 (alk. paper).
1. Central nervous system--Wounds and injuries--Pathophysiology. 2. Central nervous system--Wounds
and injuries--Chemotherapy. 3. Brain--Wounds and injuries--Pathophysiology.
I. Berry, M. (Martin) II. Logan, Ann. III. Series: Pharmacology & toxicology (Boca Raton, Fla.)
[DNLM: 1. Central Nervous System--injuries. 2. Central Nervous System--drug effects.
3. Nerve Regeneration--drug effects. 4. Nerve Growth Factors--therapeutic use. 5. Protease Inhibitors--
therapeutic use. 6. Cytokines--therapeutic use. 7. Macrophages--physiology. 8. Microglia--physiology.
WL 300 C651 1998]
RD594.C632 1998
616.8′047—dc21
DNLM/DLC
for Library of Congress
97-52407
CIP
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Preface
The basic science of the cellular and molecular responses of the brain to injury is
a rapidly expanding area of research which is providing evidence of growing oppor-
tunities for pharmacological intervention in the clinic. This book collates up-to-date
reviews of most of the important areas of study and discusses possible therapeutic
strategies for the manipulation of major events in the injury response, including
inflammatory and immune reactions, scarring, neuron death, demyelination, remy-
elination, axonal regeneration, and the reestablishment of neural connectivity. All
these events are controlled and modulated by complex intercellular chemical signals
mediated by an ever-increasing number of cell adhesion molecules, vascular/leuko-
cyte addressins, cytokines, and growth factors, and in which, additionally, proteases
play a central role. The cellular responses to brain injury which initiate the production
of the above factors and ultimately become influenced by them, partly through
interaction with cell surface receptors and co-receptors, are equally multifactorial
and complex. There is immediate haemorrhage into the lesion and an accumulation
of haematogenous macrophages and immune-competent cells, associated with
appropriate vascular reactions. Microglia and astrocyte activation quickly follows
and, later, meningeal fibroblasts and new blood vessels invade the wound, leading
to the deposition of a glial/collagen scar. Superimposed on this sequence of reactions
there is usually a massive destruction of neurons and axons, accompanied by myelin
sheath disruption and changes in the oligodendrocyte population. Subsequently, since
neither neural replication nor sustained axon regrowth occur in the adult CNS, little
or no recovery of neural connectivity ensues and lost functions are never restored.
As the database of knowledge on the subject expands, a growing optimism about
the prospects of recovery from penetrant brain injury has developed based on exper-
imental evidence demonstrating that most phases of the CNS injury response are
therapeutically accessible. Accordingly, acute inflammation has been reduced,
immune responses moderated, scar deposition lessened, neuron death and demyeli-
nation prevented, and axon regeneration promoted by pharmacological interventions
which target vulnerable phases of the injury response, often with results graded in
relation to the time of application. For example, cytokines mediate injury-responsive
cellular reactions through a temporal cascade of factors, and thus therapy early in
the cascade precipitates broad effects, like the inhibition of glial/collagen scarring
with acute-phase administration of TGF-β antagonists, whilst delayed therapy does
not influence inflammation but neutralises more specific downstream cellular
responses such as matrix deposition mediated by CNTF, for which TGF-β is a late-
phase activator. Future potential clinical applications will draw on laboratory expe-
rience in the use of neutralising antibodies, cytokine antagonist and protagonist,
neurotrophins, and protease inhibitors, administered either as recombinant molecules
or through gene vector delivery techniques.
©1999 CRC Press LLC
Each chapter in the monograph is self-contained and designed to benefit the
casual reader, the active researcher, and the medical practitioner by providing a
record of recent advances which point the way to future developments ultimately
applicable in the clinic.

©1999 CRC Press LLC
Editors
Martin Berry, M.B., Ch.B., B.Sc., Ph.D., D.Sc., M.D., FRCPath, is currently
investigating in vivo neurotrophin stimulation of axonal regeneration and inhibition
of scarring in the visual system, cerebral cortex, and spinal cord, as well as growth
factor control of the development of oligodendrocytes in the anterior medullary
velum at Guy’s Hospital in London. He accepted the post of Professor of Anatomy
and Chairman of the Division of Anatomy and Cell Biology at the hospital in 1982,
where he continued research into scarring and regeneration of axons in the CNS,
the development of CNS glia, and myelination and remyelination.
He is a graduate of Birmingham University and obtained a Lectureship in the
Department of Anatomy at the university in 1969, where he pursued a career in
teaching of basic medical science and research into development of the cerebral and
cerebellar cortices.
Professor Berry is a member of the Scientific Committee of the International
Spinal Research Trust, Scientific Advisory Panel of the Brain Research Trust, Chair-
man of the Neuroscience Centre at UMDS in London, Editorial Board of the Journal
of Neurocytology, and the Core Advisory Group for the Royal College of Surgeons.
Ann Logan, Ph.D., received her B.Sc. from the University of London in 1974 and
her Ph.D. in Endocrinology from the University of Birmingham in 1978. After post-
doctoral training at the University of Leeds and in the laboratory of Dr. Andrew
Baird at The Whittier Institute in La Jolla, CA, Dr. Logan established her own
Molecular Neuroscience Group at the University of Birmingham in 1990. She is
currently Reader in Molecular Neuroscience in the Department of Medicine.
She also is an Affiliate Researcher at the Lawson Research Institute in London,
Ontario, Canada and an Honorary Research Fellow at the United Medical and Dental
Schools of Guy’s Hospital in London, UK. Dr. Logan is a member of the Editorial
Boards of the Journal of Endocrinology, Growth Factor and Cytokine Reviews, and
the Canadian Journal of Physiology and Pharmacology, and is currently Secretary
to the Liaison Committee of the British Endocrine Societies. She served as Pro-
gramme Secretary to the British Growth Factor Group between 1991 and 1996.
Dr. Logan’s research interests center on the role of growth factors in the scarring
and regeneration responses of the mammalian CNS. She is particularly interested
in the role of TGF-β in scar formation in the brain and spinal cord and is currently
investigating the therapeutic potential of TGF-β antagonists as antifibrotic agents in
the injured CNS. In addition she is currently investigating the potential for combined
treatments of antifibrotic agents with neurotrophic factors in order to promote func-
tional reconstruction of damaged neural pathways in the brain, visual system, and
spinal cord.
©1999 CRC Press LLC
Contributors
Martin Berry Peter Heiduschka
Division of Anatomy and Cell Department of Experimental
Biology Opthamology
UMDS (Guy’s Campus) University Eye Hospital
London Bridge Domagkstrasse 15-D-48149
London SE1 9RT England Munster, Germany
K. Alun Brown Mannfred A. Hollinger
Department of Immunology Department of Medical Pharmacology
The Rayne Institute and Toxicology
St. Thomas’ Hospital UC/Davis School of Medicine
London SE1 7EH England Davis, CA 95616
Arthur Butt
Ann Logan
Division of Physiology
Department of Medicine
UMDS, St. Thomas’ Hospital
University of Birmingham
Lambeth Palace Road
Edgbaston, Birmingham B15 2TH
London SE1 7EH England
England
Norman A. Gregson
Behdad Afzali Khoshkbijar
Department of Neurology
Department of Immunology
UMDS (Guy’s Campus)
UMDS, St. Thomas’ Hospital
London Bridge
Lambeth Palace Road
London SE1 9RT England
London SE1 7EH England
Claudia Grothe
Hannover Medical School William L. Maxwell
Center of Anatomy Laboratory of Human Anatomy
OE 4140 IBLS, University of Glasgow
D-30623 Hannover, Germany Glasgow G12 8QQ Scotland
Theo Hagg Christof Meisinger
Department of Anatomy and Institute of Anatomy II
Neurobiology University of Freiburg
Dalhousie University Albertstr. 17
Halifax, Nova Scotia B3H 4H7 Canada D-79104 Frieburg, Germany
©1999 CRC Press LLC
Rita Naskar Solon Thanos
Department of Experimental Department of Experimental
Opthamology Opthamology
University Eye Hospital University Eye Hospital
Domagkstrasse 15-D-48149 Domagkstrasse 15-D-48149
Munster, Germany Munster, Germany
Wolfgang J. Streit Abhi J. Vora
Department of Neuroscience Department of Immunology
University of Florida Brain Institute UMDS, St. Thomas’ Hospital
1600 Archer Road MSB M-249 Lambeth Palace Road
Gainesville, FL 32610 London SE1 7EH England
Konstantin Weweker
Hannover Medical School
Center of Anatomy
OE 4140
D-30623 Hannover, Germany

©1999 CRC Press LLC
Table of Contents
Chapter 1
Cellular Responses to Penetrating CNS Injury
Martin Berry, Arthur Butt, and Ann Logan
Chapter 2
Cellular Responses to Ischaemic CNS Injury
William L. Maxwell
Chapter 3
Immune Response and CNS Injury
Norman A. Gregson
Chapter 4
Haematogenous Cell Responses to CNS Injury
K. Alun Brown and Behdad Afzali Khoshkbijar
Chapter 5
Role of Macrophages and Microglia in the Injured CNS
Wolfgang J. Streit
Chapter 6
Cellular Trafficking
Abhi J. Vora and K. Alun Brown
Chapter 7
Microglia-Mediated Prevention of Traumatic Neurodegeneration
Solon Thanos, Rita Naskar, and Peter Heiduschka
Chapter 8
Transforming Growth Factor-β and CNS Scarring
Ann Logan and Martin Berry

©1999 CRC Press LLC
Chapter 9
Neurotrophic Factors
Theo Hagg
Chapter 10
Fibroblast Growth Factors
Claudia Grothe, Christof Meisinger, and Konstantin Wewetzer

©1999 CRC Press LLC
1 Cellular Responses to
Penetrating CNS Injury
Martin Berry, Arthur Butt and Ann Logan
CONTENTS
1.1 Introduction
1.2 Inflammation/Scarring Responses to Injury in the Adult CNS
1.2.1 Acute Haemorragic Phase — 0 to 3 Days Postinjury
1.2.2 Subacute Phase — 3 to 8 Days Postinjury
1.2.2.1 Reaction of Astrocytes to Injury
1.2.2.2 Reaction of Oligodendrocytes to Injury
1.2.2.3 Reaction of Microglia to Injury
1.2.3 Consolidation Phase — 8 to 20 Days Postinjury
1.3 Inflammation/Scarring Responses to Injury in the Foetal/Neonatal CNS
1.4 Responses of Neurons to Injury
References
1.1 INTRODUCTION
Three distinct sequential cellular responses characterise the reaction of the adult
spinal cord and brain to injury. An acute haemorrhagic phase immediately ensues
after wounding, in which haematogenous cells flood the lesion site. This is followed
by a subacute period during which macrophages clear necrotic debris, glial cell
reactions are mobilised, the clot becomes organised, and scarring is initiated. Finally,
the scar tissue contracts during a consolidation phase. Superimposed on the above
primary inflammatory/scarring responses are secondary neuronal degenerative and
regenerative reactions to injury, accompanied by demyelination and remyelination.
The interrelations between primary and secondary responses are not understood. It
was once thought that scarring arrested axon regeneration in the central nervous
system (CNS), but more recent experimental data indicate a contrary proposition
that regenerating axons actually prevent scarring, possibly by protease release, and
thus scarring could be a consequence rather than a cause of the failure of axons to
regenerate in the CNS.
Pharmacological strategies for the control of the cellular injury responses after
CNS injury aim to:
©1999 CRC Press LLC