Neurobiology of Spinal Cord Injury PDF
Preview Neurobiology of Spinal Cord Injury
Neurobiology of Spinal Cord Injury Contemporary Neuroscience Neurobiology ofS pinal Cord Injury, Molecular Mechanisms ofD ementia, edited by Robert G. Kalb and edited by Wilma Wasco and Stephen M. Strittmatter, 2000 Rudolph E. Tanzi, 1997 Cerebral Signal Transduction: From Neurotransmitter Transporters: Struc First to Fourth Messengers, edited ture, Function, and Regulation, by Maarten E. A. Reith, 2000 edited by Maarten E. A. Reith, Central Nervous System Diseases: 1997 Innovative Animal Models from Lab Motor Activity and Movement Disorders: to Clinic, edited by Dwaine F. Research Issues and Applications, Emerich, Reginald L. Dean, III, edited by Paul R. Sanberg, Klaus and Paul R. Sanberg, 2000 Peter Ossenkopp, and Martin Mitochondrial Inhibitors and Neurode Kavaliers, 1996 generative Disorders, edited by Paul Neurotherapeutics: Emerging Strate R. Sanberg, Hitoo Nishino, and gies, edited by Linda M. Pullan and Cesario V. Borlongan, 2000 Jitendra Patel, 1996 Cerebral Ischemia: Molecular and Neuron-Glia Interrelations During Cellular Pathophysiology, edited by Phylogeny: II. Plasticity Wolfgang Walz, 1999 and Regeneration. edited by Antonia Cell Transplantation for Neurological Vernadakis and Betty I. Roots, 1995 Disorders, edited by Thomas B. Neuron-Glia Interrelations During Freeman and Hakan Widner, 1998 Phylogeny: I. Phylogeny Gene Therapy for Neurological and Ontogeny of Glial Cells, edited Disorders and Brain Tumors, edited by Antonia Vernadakis by E. Antonio Chiocca and Xandra and Betty I. Roots, 1995 0. Breakefield, 1998 The Biology ofN europeptide Y and Highly Selective Neurotoxins: Basic Related Peptides, edited and Clinical Applications, edited by by William F. Colmers and Claes Richard M. Kostrzewa, 1998 Wahlestedt, 1993 Neuroinjlammation: Mechanisms and Psychoactive Drugs: Tolerance and Management, edited by Paul L. Sensitization, edited Wood, 1998 by A. J. Goudie and M. W. Neuroprotective Signal Transduction, Emmett-Oglesby, 1989 edited by Mark P. Mattson, 1998 Clinical Pharmacology of Cerebral Experimental Psychopharmacology, Ischemia, edited by Gert J. Ter edited by Andrew J. Greenshaw Horst and Jakob Korf, 1997 and Colin T. Dourish, 1987 Neurobiology of Spinal Cord Injury Edited by Robert G. Kalb, MD Stephen M. Strittmatter, MD, PHD School of Medicine, Yale University New Haven, CT Springer Science+B usiness Media, LLC © 2000 Springer Science+Business Media New York Originally published by Humana Press Inc in 2000 Softcover reprint of the hardcover 1st edition 2000 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All authored papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. This publication is printed on acid-free paper. @ ANSI 239.48-1984 (American Standards Institute) Permanence of Paper for Printed Library Materials. Cover design by Patricia F. Cleary. Cover illustration: A motor neuron and its synaptic inputs. Immunohistology for synaptophysin (green puncta), a marker for presynaptic terminals, is combined with Dii labeling of a motor neuron axon, proximal dendrites, and cell body. Optimizing motor function after spinal cord injury will depend on improving the ability of excitatory synapses to drive motor neuron activation. Photograph by Drs. Laising Yen and Robert Kalb. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee ofUS $10.00 per copy, plus US $00.25 per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. 10 9 8 7 6 5 4 3 2 I Library of Congress Cataloging-in-Publication Data Neurobiology of spinal cord injury I edited by Robert G. Kalb, Stephen M. Strittmatter. p. em. -- (Contemporary neuroscience) Includes bibliographical references and index. ISBN 978-1-61737-126-4 ISBN 978-1-59259-200-5 (eBook) DOI 10.1007/978-1-59259-200-5 I. Spinal cord--Wounds and injuries--Pathophysiology. I. Kalb, Robert G. II. Strittmatter, Stephen M. III. Series. [DNLM: I. Spinal Cord Injuries--physiopathology. 2. Neurobiology. 3. Spinal Cord Injuries--therapy. WL 400 N4938 2000] RD594.3.N4686 2000 61 7.4' 82044--dc21 DNLM/DLC for Library of Congress 99-23563 CIP Preface Neurobiological Research in SCI Suggests a Multimodality Approach to Therapy Neuroscientists representing a wide variety of disciplines are drawn to the problem of spinal cord injury (SCI). One of the many reasons for this is humanistic: the severity of neurologic deficits can have a devastating impact on most aspects of an individual's functioning. As compassionate individuals we cannot help but believe that a small lesion, tragically local ized, can be amenable to a therapeutic intervention. Interest in spinal cord injury research also stems from the view that the overall problem can be broken down into a number of understandable and experimentally tractable smaller problems (see Table 1) . The clearness and discreteness of the issues to be addressed help focus the research effort. The hope is that if one could amalgamate the progress made in these smaller arenas, a significant overall benefit would be available for patients. This book highlights the major areas of basic science research in which progress is being made today in our battle against the problem of spinal cord injury. Important advances in developing effective intervention to promote functional recovery after spinal cord injury depends on animal models. The utility of complete or partial spinal cord transection models is complemented by studies in which the spinal cord is injured by dropping a weight of known mass from a fixed distance onto the cord. This has led to reproducible lesions and functional deficits. There is a remarkable concordance between this experimentally induced lesion and that seen in postmortem specimens from injured human spinal cords. In their chapter, Drs. Beattie and Bresnahan describe a number of important insights gleaned from this model system. First, there is a significant amount of delayed apoptotic death of neurons and glia both at the lesion site and remotely. It stands to reason that prevention of this cell death will have important consequences for recovery of function. Second, anatomical studies of the cystic lesion induced by the trauma reveal a complex mix of astrocytes, Schwann cells, inflammatory cells, as well as axons of dorsal root ganglion cells and spared descending axons in various states of demyelination. Some of the cellular components of the contusion lesion matrix appear to arise from ependymal progenitor cells. If new neurons or glial cells were incorporated to the contusion site, v Preface Vl they might integrate into functional circuitry and/or help form tissue bridges for regrowing axons. Though the glial component of the injury is important (as we will see), one of the major reasons for functional impairment after spinal cord injury is the death of neurons. Effective neuroprotective strategies after spinal cord insult will therefore depend on understanding the mechanisms of neuronal death. A major advance in this field has come from the focus on intracellular Ca2+. Intracellular Ca2+ is a fundamental regulator of cellular physiology and, as such, its concentration and subcellular distribution is highly regu lated. Derangement of this regulation plays a central role in neuronal death. In their chapter, Chu et al. discuss the controversies surrounding the mecha nism by which rises in intracellular Ca2+ lead to cell death. In particular they focus on the extent to which pathogenic deregulation of Ca2+ homeostasis is a function of the ion's intracellular concentration, its spatial distribution, or the route of entry into cells. After injury to the cervical or thoracic spinal cord, the neural elements in the lumbar enlargement are deprived of inputs from higher command centers (brainstem and cortex), but are in a certain sense otherwise intact. Can the isolated lumbar enlargement generate the patterned muscle activa tion required for locomotion or is this capacity dependent on information encoded by the descending inputs? The functional capacity of the deaf ferented lumbar cord has been investigated in lamprey, rodents, and cats and under certain experimental conditions exhibits a remarkable ability to generate the neural activity subserving locomotion. Thus, there is great in terest in understanding the functional capacity of the isolated lumbar cord. Rossignol et al. describe a set of experiments using cats to define the intrin sic capacity of the isolated lumbar cord to generate locomotion. Through a combination oflesion studies and pharmacological manipulations, this work is beginning to outline the cellular and biochemical mechanisms involved. A particularly exciting set of experiments provides compelling evidence for spinal learning-the ability of the isolated cord to make adaptations to new environmental demands (such as stepping over an obstruction or walking on a tilted surface). The circuitry inherent within the isolated lumbar spinal cord and its ability to adapt to changing demands may form an important substrate for therapeutic intervention. A more detailed anatomical and electrophysiological analysis of the neu ral substrate underlying the locomotor generating ability of the isolated lumbar spinal cord requires a more experimentally accessible system. Dr. Cazalets has pioneered the use of an ex vivo neonatal rat spinal cord Preface Vll preparation and details work on the location and properties of the major central pattern generator for fictive locomotion. Though many regions within the spinal cord can be experimentally manipulated to generate oscillatory firing of neurons, the neural circuitry of the lower thoracic and upper lumbar spinal cord are likely to be the dominant central pattern generator for hindlimb locomotor activity. The region around the central canal, particu larly ventrally, appears to be key. If this region is undamaged after a spinal cord insult, then stimulation by regrowing axons or pharmacological means might form the basis for functional restitution. Assuming sufficient numbers of neurons and glia can be coaxed to survive the primary and secondary wave of cell death and that the pattern generators for locomotion are intact, a central concern focuses on restoring the continuity between the brain and the distal spinal cord. Steeves and Tetzlaff provide an overview of molecules known to promote axonal regen eration in SCI and those which inhibit regeneration. Growth-promoting molecules include proteins expressed within regenerating neurons, such as GAP-43 and Tal-tubulin. In addition, a number ofneurotrophins can in duce axonal sprouting, and the effects of these molecules in SCI are re viewed. The ability of certain axonal guidance molecules, such as CAMs, semaphorins, netrins, and ephrins, to promote axonal regeneration is also discussed. The major inhibitory factors are those derived from CNS myelin and from astrocytes. In SCI, the growth inhibitors exert a predominant effect over the growth-promoting factors. To increase functional recovery after SCI, intervention to both decrease growth-inhibiting effects and increase growth-promoting effects must be considered. The extension of axons is primarily regulated from their distal end, a special ization termed the growth cone. A number of endogenous macro-molecules, including some present in injured spinal cords, can repel axons and prevent axonal regeneration. We review the molecular events that transduce the presence of extracellular signals into a cessation of axonal extension. Par ticular emphasis is placed on the mechanism of action of the semaphorins, since they are well studied, and on components of CNS myelin, because they are likely to underlie the failure of axonal regeneration after SCI. As the normal functioning of the growth cone becomes understood, pharmacological methods to overcome the failure of axonal growth cone advance in SCI might be come obvious. If the milieu that a growing axon encounters is permissive or even promotes growth, ultimately the axon elaboration machinery must be en gaged. Peter Baas reviews the role of microtubules in forming axon struc- viii Preface ture and determining axonal elongation rates. The biochemistry and cell biology of microtubules are reviewed with special focus on their contribu tion to axonal extension. Evidence suggests that microtubules are nucleated from a site near the centrosome and then transported into axons. The protein dynein is the motor responsible for transporting microtubules into and down the axon. A number of microtubule associated proteins (MAPs) are likely to regulate microtubule formation and transport. Although the functional orga nization of these proteins in developing axons is becoming clear, their role in facilitating or preventing axonal regeneration remains less so. Further investigation of such mechanisms in SCI might provide novel opportunities to promote axon regeneration and recovery of function. From the perspective of problems incurred by spinal cord injury that may be amenable to therapeutic intervention in the near future, three have received the most attention: (1) How do we keep the maximal number of neurons and glial cells alive after the injury? (2) How do we promote the extension of axons past the lesion site? (3) How can we promote myelina tion of surviving or newly formed axons so that they can efficiently transmit action potentials distally? Remarkably, research from a number of different labs has indicated that cell transplants and neurotrophic factors may have utility for each of these problems. Work from Barbara Bregman's lab indi cates that transplanting fetal spinal cord tissue and similtaneously providing neurotrophic factors can have a beneficial effect on both neuronal survival and axon growth. Though it has long been clear that trophic factors are important for the survival and differentiation of immature neurons, it has only been recently that evidence has been accrued that they also play a role in mature neuronal survival. One important advance is the recognition that different neurons (i.e., brainstem, cortical, etc.) have distinct trophic factor dependence for survival and axon elaboration. When combined with a suitable substrate for growth (such as fetal spinal cord transplants), trophic factors remarkably enhance neuronal survival and promote axonal growth and sprouting. These interventions lead to functionally significant improve ment in animal behavior, particularly when applied to immature animals. The challenge will be to adapt this strategy to maximize the benefits for mature animals. Since cell transplantation strategies hold great hope for functional recovery after SCI, what other choices exist beyond the use of fetal spinal cord tissue? Bartolomei and Greer consider the various cell transplantation strategies now being developed. Transplanted tissue has included fetal nervous system, peripheral nervous system Schwann cells, and more recently olfactory ensheathing cells. 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