Axonal Regeneration in the Central Nervous Syst. - N. Ingoglia, M. Murray (Marcel Dekker, 2001) WW

735 Pages·2001·70.92 MB·English

Axonal
Regeneration
in the
Central Nervous
System

NEUROLOGICAL
DISEASE AND THERAPY

Advisory Board

Louis R. Caplan, M.D.
Professor of Neurology
Harvard University School of
Medicine
Beth Israel Deaconess Medical Center
Boston, Massachusetts

William Koller, M.D.
National Parkinson Foundation
Miami, Florida

John C. Morris, M.D.
Friedman Professor of Neurology
Co-Director, Alzheimer’s Disease
Research Center
Washington University School of
Medicine
St. Louis, Missouri

Jerome Murphy,
M.D.
Professor of Neurology
University of Missouri School of
Medicine
Chief of Neurology
Children’s Mercy Hospital
Kansas City, Missouri

Kapil Sethi, M.D.
Professor of Neurology
Director, Movement Disorders
Program
Medical College of Georgia
Augusta, Georgia

Mark Tuszynski, M.D., Ph.D.
Associate Professor of Neurosciences
Director, Center for Neural Repair
University of California - San Diego
La Jolla, California

1. Handbook of Parkinson’s Disease, edited by William C. Keller
2. Medical Therapy of Acute Stroke, edited by Mark Fisher
3. Familial Alzheimer’s
Disease: Molecular
Genetics
and Clinical Per-
spectives, edited by Gary D. Miner, Ralph W. Richter, John P. B/ass,
Jimmie L. Valentine, and Linda A. Winters-Miner
4. Alzheimer’s Disease: Treatment and Long-Term Management,
edited by
Jeffrey L. Cummings and Bruce L. Miller
5. Therapy of Parkinson’s Disease, edited by William C. Keller and George
Paulson
6. Handbook of Sleep Disorders, edited by Michael J. Thorpy
7. Epilepsy and Sudden Death, edited by Claire M. Lathers and Paul L.
Schraeder
8. Handbook of Multiple Sclerosis, edited by Stuart D. Cook
9. Memory Disorders: Research and Clinical Practice, edited by Takehiko
Yanagihara and Ronald C. Petersen
10. The Medical Treatment of Epilepsy, edited by Stanley R. Resor, Jr., and
Henn Kutt
11. Cognitive Disorders: Pathophysiology and Treatment, edited by Leon J.
Thai, Walter H. Moos, and Elkan R. Gamzu

12. Handbook
of Amyotrophic
Lateral Sclerosis, edited by Richard A/an
Smith
13. Handbook
of Parkinson’s Disease: Second Edition, Revised and Ex-
panded, edited by William C. Ko//er
14. Handbook of Pediatric Epilepsy, edited by Jerome V. Murphy and Ferey-
doun Dehkharghani
15. Handbook
of Tourette’s
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and Related Tic and Behavioral
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16. Handbook of Cerebellar Diseases, edited by Richard Lechtenberg
17. Handbook of Cerebrovascular Diseases, edited by Harold P. Adams, Jr.
18. Parkinsonian Syndromes, edited by Matthew B. Stem and William C.
Keller
19. Handbook of Head and Spine Trauma, edited by Jonathan Greenberg
20. Brain Tumors: A Comprehensive
Text, edited by Robert A. Moran& and
John W. Walsh
21. Monoamine Oxidase Inhibitors in Neurological Diseases, edited by Abra-
ham Lieberman,
C. Warren Olanow, Moussa 6. H. Youdim, and Keith
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22. Handbook of Dementing Illnesses, edited by John C. Mom%
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24. Handbook of Neurorehabilitation,
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25. Therapy with Botulinum Toxin, edited by Joseph Jankovic and Mark
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26. Principles of Neurotoxicology, edited by Louis W. Chang
27. Handbook of Neurovirology, edited by Robert R. McKenda// and William
G. Stroop
28. Handbook of Neuro-Urology, edited by David N. Rushton
29. Handbook of Neuroepidemiology,
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30. Handbook of Tremor Disorders, edited by Leslie J. Findley and William
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31. Neuro-Ophthalmological Disorders: Diagnostic Work-Up and Management,
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32. Handbook of Olfaction and Gustation, edited by Richard L. Doty
33. Handbook of Neurological Speech and Language
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34. Therapy of Parkinson’s Disease: Second Edition, Revised and Ex-
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35. Evaluation and Management
of Gait Disorders, edited by Barney S.
Spivack
36. Handbook of Neurotoxicology, edited by Louis W. Chang and Robert S.
Dyer
37. Neurological Complications of Cancer, edited by Ronald G. Wiley
38. Handbook of Autonomic Nervous System Dysfunction, edited by Amos
D. Korczyn

39. Handbook of Dystonia, edited by Joseph King Ching Tsui and Donald B.
Calne
40. Etiology of Parkinson’s Disease, edited by Jonas l-l. Ellenberg, William C.
Keller, and J. William Langston
41. Practical Neurology of the Elderly, edited by Jacob I. Sage and Margery
H. Mark
42. Handbook of Muscle Disease, edited by Russell J. M. Lane
43. Handbook of Multiple Sclerosis: Second Edition, Revised and Expanded,
edited by Stuart D. Cook
44. Central Nervous System Infectious Diseases and Therapy, edited by
Karen L. Roos
45. Subarachnoid
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Clinical Management,
edited by Takehiko
Yanagihara, David G. Piepgras, and John L. D. Atkinson
46. Neurology
Practice Guidelines,
edited by Richard Lechtenberg
and
Henry S. Schutta
47. Spinal Cord Diseases: Diagnosis and Treatment,
edited by Gordon L.
Angler, Jonathan Cole, and W. Louis Merton
48. Management
of Acute Stroke, edited by Ashfaq Shuaib and Larry B.
Goldstein
49. Sleep Disorders and Neurological Disease, edited by Antonio Culebras
50. Handbook of Ataxia Disorders, edited by Thomas Klockgether
51. The Autonomic
Nervous System in Health and Disease, David S.
Goldstein
52. Axonal Regeneration in the Central Nervous System, edited by Nicholas
A. lngoglia and Marion Murray

Additional Volumes in Preparation

Handbook of Multiple Sclerosis: Third Edition, edited by Stuart D. Cook

Axonal
Regeneration
in the
Central Nervous
System

edited by
Nicholas A. Ingoglia

New Jersey Medical School-UMDNJ
Newark, New Jersey

Marion Murray

Medical
College of Pennsylvania/Hahnemann
University
Philadelphia,
Pennsylvania

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AUTHOR’S
NOTE

The work described in these chapters summarizes the current state of research into
regeneration of axons in the Central Nervous System of vertebrates. We need to
remember that these advances are the result of basic scientific research carried out
by dedicated scientists in all fields of biology, even those apparently distant from
the issues of regeneration research. The remarkable developments in this research
give hope that greatly improved treatments for brain and spinal cord injuries will
soon be available. Indeed this work has also been stimulated by the appreciation
that we have for those who suffer from the devastating consequences of brain and
spinal injury and for their families. We would like to dedicate this volume to those
individuals - to the famous, such as Christopher Reeve, whose unstinting efforts to
raise awareness of the emotional, physical and monetary costs of spinal injury
have been so important to the recent advancement of the research efforts, and to
the less famous, such as Adam Shapiro, a boy struggling to recover and rebuild a
life after his spinal injury, who has reminded us of the courage, the hope, and ef-
fort and ultimately the optimism that this requires and who recently sent us this
note:

t;li. My name is Adam Shapiro and I am 15 years old In September of 1996 I
broke my neck (C3-C4) leaving me an incomplete quadriplegic. My mom and I
check the Internet every day to see if there is any new information on spinal cord
nerve regeneration. I have come a long way. I started off on a ventilator, and
could not move anything. It took me three months to get off the ventilator, and
that is when I started conditioning my body. At this time I am able to walk with a
walker, but my arms are considerably weaker than my legs.. If you could please
e-mail me back, I am very anxious to get involved in new treatments that you are
conducting now on humans, I would greatly appreciate it, or tf not please keep
me in mind in the future. Thank you so much for your time.. .

Finally, on a more personal note, we would like to dedicate this volume to our
friend, our teacher, our mentor and our colleague, Bernice Grafstein, who led us
into this field and so changed our scientific lives.

This Page Intentionally Left Blank

PREFACE

One of the most fundamental questions in neuroscience is why certain neurons
respond to axotomy by robustly regrowing a new axon while others do not. This
basic difference between neurons in lower vertebrates and mammalian peripheral
nerves on the one hand, and nerves found in the central nervous system (CNS) of
mammals on the other, has been the launching pad for the experimental lives of
countless former and current researchers and in many cases has led to lifelong
commitments to try to understand this elemental fact of neural life. What is per-
haps most vexing about our inability to understand the reasons why mammalian
central neurons fail to regenerate following injury is the enormous impact this has
on the human condition. Each year thousands of patients become victims of brain
or spinal cord injuries resulting in varying degrees of cognitive loss or paralysis.
Once these neurons have been severed they are not likely to recover. To these pa-
tients we can, at present, offer little in the way of treatment. But we offer much in
the way of hope. The hope springs from the enormous progress that has been made
in the past 30 or so years in understanding the molecular and cellular events occur-
ring in systems that are successful in regenerating new axons and, more recently,
in the analysis of mammalian central neurons where abortive regeneration and cell
death are still the general consequences of axotomy but where there is now clear
evidence for regrowth following certain experimental interventions.
Our view of the scientific problem and thus our approach to solving it,
has been shaped in large part by the studies of Santiago Ramon y Cajal (1928)
who wrote in the early part of this century: “My observations, made in the optic
nerve and spinal cord...demonstrated
also that the incapability of regeneration is
not a fatally irresistible law, but is a secondary outcome of a physical or chemical
environment unfavorable for the growth of the sprouts.... ” These observations
focused our thoughts and research strategies on the glial barriers (“scars”) to nerve
growth. But we know today that, while an impenetrable barrier (or inhibitory pro-
teins on the membranes of cells in the region of the injury) is likely to play an im-
portant role in the failure of a neuron to grow a new axon, other factors such as
cell survival, the genetic growth program of the darnaged neuron, the response of
neurons to growth and guidance factors and, perhaps, the failure of a cut axon to
reseal may all play roles in the successful regrowth of a new axon. As was true for
Cajal, modern researchers have generally favored the optic nerve and spinal cord
as models to study the issue of axonal regeneration and recovery of function, and
the contributions in this volume largely reflect those models. We believe, how-
ever, that the lessons learned from the optic nerve and spinal cord are general&-
able to other parts of the CNS.
The goal of this book is to summarize some of the major research contri-
butions in nerve regeneration reported over the past 30 years and then show how
these discoveries have led to the current strategies to promote axonal regeneration