Neural Plasticity and Regeneration

353 Pages·2000·46.71 MB·English

by  F.J. Seil (Eds.)

List of Contributors
S.A. Azizi, Center for Gene Therapy, MCP Hahnemann University, Philadelphia, PA
19102, USA
M.S. Beattie, Department of Neuroscience, Ohio State University, 333 West 10th Avenue,
Columbus, OH 43210, USA
A. Belhaj-Sa~'f, Department of Molecular and Integrative Physiology, University of Kansas
Medical Center, Kansas City, KS 66160-7336, USA
J.R. Bethea, The Miami Project to Cure Paralysis, University of Miami School of Medicine,
1600 NW 10th Avenue, R-48, Miami, FL 33136, USA
M.M. Bolton, Department of Neurobiology, Box 3209, Duke University Medical Center,
101 Research Drive, Durham, NC 27710, USA
J.C. Bresnahan, Department of Neuroscience, Ohio State University, Columbus, OH 43210,
USA
J.G. Broton, The Miami Project to Cure Paralysis and Department of Neurological Surgery,
University of Miami School of Medicine, 1600 NW 10th Avenue, R-48, Miami, FL
33136, USA
B. Calancie, The Miami Project to Cure Paralysis and Department of Neurological Surgery,
University of Miami School of Medicine, 1600 NW 10th Avenue, R-48, Miami, FL
33136, USA
J.K. Chapin, Department of Physiology and Pharmacology, SUNY Downstate Health
Science Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
P.D. Cheney, Mental Retardation and Human Development Research Center, University of
Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7336, USA
S. De Lacalle, Department of Biology and Microbiology, California State University, Los
Angeles, CA 90032, USA
M. Del Rosario Molano, The Miami Project to Cure Paralysis and Department of
Neurological Surgery, University of Miami School of Medicine, 1600 NW 10th Avenue,
R-48, Miami, FL 33136, USA
B.H. Dobkin, Department of Neurology and Reed Neurologic Research Center, University
of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095, USA
R. Drake-Baumann, Neurology Research, AV Medical Center, Portland, OR 97201, USA
M.E. Emborg, Department of Neurological Sciences and Research Center for Brain Repair,
Rush University, Chicago, IL 60612, USA
.I Fischer, Department of Neurobiology and Anatomy, MCP Hahnemann University, 3200
Henry Avenue, Philadelphia, PA 19129, USA
H.M. Geller, Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical
School, 675 Hoes Lane, Piscataway, NJ 08854, USA
.W Gottschalk, Unit on Synapse Development and Plasticity, Laboratory of Developmental
Neurobiology, NICHD, NIH, Bethesda, MD 20892-4480, USA
vi
R.S. Hartley, The Center for Neurodegenerative Disease Research, Department of Pathol-
ogy and Laboratory of Medicine, University of Pennsylvania School of Medicine,
Philadelphia, PA 19104, and Layton Bioscience, Inc., Atherton, CA 94025, USA
J. Hill-Karrer, Department of Molecular and Integrative Physiology, University of Kansas
Medical Center, Kansas City, KS 66160-7336, USA
J.A. Hoffer, School of Kinesiology, Faculty of Applied Sciences, Simon Fraser University,
8888 University Drive, Burnaby, BC V5A 1 $6, Canada, and NeuroStream Technologies,
Inc., Burnaby, BC, Canada
L.B. Jakeman, Department of Physiology and Cell Biology, Ohio State University, Colum-
bus, OH 43210, USA
J.H. Kaas, Department of Psychology, Vanderbilt University, 301 Wilson Hall, 111 21st
Avenue South, Nashville, TN 37240, USA
K.W. Kafitz, Institute for Physiology, Technical University of Munich, Biedersteinerstrasse
29, D-80802 Munich, Germany
K. KallesCe, School of Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6,
Canada
A. Konnerth, Institute for Physiology, Technical University of Munich, Biedersteinerstrasse
29, D-80802 Munich, Germany
G.C. Kopen, Center for Gene Therapy, MCP Hahnemann University, Philadelphia, PA
19102, USA
J.H. Kordower, Department of Neurological Sciences and Research Center for Brain
Repair, Rush University, 2242 West Harrison Street, Chicago, IL 60612, USA
D.J. Krupa, Department of Neurobiology, Box 3209, Duke University Medical Center,
Bryan Research Building, Room 333, 101 Research Drive, Durham, NC 27710, USA
V.M.-Y. Lee, Center for Neurodegenerative Disease Research, Department of Pathology
and Laboratory Medicine, University of Pennsylvania Hospital, 3rd Floor Maloney
Building, 3600 Spruce Street, Philadelphia, PA 19104-4283, USA
Q. Li, Department of Neuroscience, Ohio State University, Columbus, OH 43210, USA
.Y Liu, Department of Neurobiology and Anatomy, MCP Hahnemann University, Philadel-
phia, PA 19129, USA
D.C. Lo, Department of Neurobiology, Duke University Medical Center, Durham, NC
27710, USA
F.M. Longo, Department of Neurology, VA Medical Center and University of California
San Francisco, V-127, 4150 Clement Street, San Francisco, CA 94121, USA
B. Lu, Unit on Synapse Development and Plasticity, Laboratory of Developmental Neuro-
biology, NICHD, NIH, Bldg 49, Rm 5A38, 49 Convent Drive, MSC 4480, Bethesda,
MD 20892-4480, USA
S. Marty, INSERM U-106, H6pital de la Salp~tri~re, B~timent de P~diatrie, 47 Boulevard
de l'H6pital, 73651 Paris Cedex ,31 France
M. Mayer-Proschel, Department of Oncological Sciences (HCI), University of Utah
Medical School, Salt Lake City, UT 84132, USA
B.J. McKiernan, Department of Molecular and Integrative Physiology, University of
Kansas Medical Center, Kansas City, KS 66160-7336, USA
D.M. McTigue, Department of Physiology and Cell Biology, Ohio State University,
Columbus, OH 43210, USA
S. Meiners, Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School,
Piscataway, NJ 08854, USA
M.L.T. Mercado, Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical
iiv
School, Piscataway, NJ 08854, USA
S. MUller, Department of Physiology, University of Bonn, D-53111 Bonn, and Klinikum
Karlsbad-Langensteinbach, Karlsbad-Langensteinbach, Germany
.M Murray, Department of Neurobiology and Anatomy, MCP Hahnemann University, 3200
Henry Avenue, Philadelphia, PA 19129, USA
A. Nanassy, Department of Physiology, University of Bonn, D-53111 Bonn, and Klinikum
Kadsbad-Langenstei~bach, Karlsbad-Langensteinbach, Germany
M.A.L. Nicolelis, Department of Neurobiology, Duke University Medical Center, Durham,
NC 27710, USA
M.C. Park, Department of Molecular and Integrative Physiology, University of Kansas
Medical Center, Kansas City, KS 66160-7336, USA
K.G. Pearson, Department of Physiology, University of Alberta, Edmonton, AB T6G 2H7,
Canada
D.G. Phinney, Center for Gene Therapy, MCP Hahnemann University, Philadelphia, PA
19102, USA
P.G. Popovich, Department of Molecular Virology, Immunology and Medical Genetics,
College of Medicine and Public Health, Ohio State University, Columbus, OH 43210,
USA
D.J. Prockop, SL99, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans,
LA 70112, USA
A. Ram6n-Cueto, Neural Regeneration Group, Institute of Biomedicine, Spanish Council
for Scientific Research (CSIC), Jaime Roig ,11 46010 Valencia, Spain
M.S. Rao, Department of Neurobiology and Anatomy, University of Utah Medical School,
50 North Medical Drive, Salt Lake City, UT 84132, USA
C.R. Rose, Institute for Physiology, Technical University of Munich, Biedersteinerstrasse
29, D-80802 Munich, Germany
R.A. Saavedra, 10301 Grosvenor Place, Apt. 712, Rockville, MD 20852, USA
M. Schwartz, Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100,
Israel
E.J. Schwarz, Center for Gene Therapy, MCP Hahnemann University, Philadelphia, PA
19102, USA
EJ. Seil, Office of Regeneration Research Programs (P3-R&D-35), AV Medical Center
and Departments of Neurology and Cell and Developmental Biology, Oregon Health
Sciences University, 3710 SW US Veterans Hospital Road, Portland, OR 97201, USA
N.T. Sherwood, Division of Biology, 216-76, California Institute of Technology, Pasadena,
CA 91125, USA
B.T. Stokes, Department of Physiology and Cell Biology, Ohio State University, 228
Meiling Hall, 370 .W 9th Avenue, Columbus, OH 43210-1238, USA
A. Tessler, Department of Neurobiology and Anatomy, MCP Hahnemann University, and
AV Medical Center, Philadelphia, AP 19129, USA
H. Thoenen, Max-Planck-Institute of Neurobiology, Department of Neurobiochemistry,
Am Klopferspitz 18a, D-82152 Martinsried, Germany
P.A. Tresco, W.M. Keck Center for Tissue Engineering, University of Utah, 20 South 2030
East, Biopolymers Research Building, Rm 108D, Salt Lake City, UT 84112, USA
J.Q. Trojanowski, Center for Neurodegenerative Disease Research, Department of Pathol-
ogy and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadel-
phia, AP 19104, USA
iiiv
A. Wernig, Department of Physiology, University of Bonn, Wilhelmstrasse 31, D-53111
Bonn, and Klinikum Karlsbad-Langensteinbach, Karlsbad-Langensteinbach, Germany
.Y Xie, Department of Neurology, AV Medical Center and University of California San
Francisco, San Francisco, CA 94121, USA
xi
Preface
The proceedings of the Eighth International Symposium on Neural Regeneration are pre-
sented in this volume. The meeting, which was held at the Asilomar Conference Center
in Pacific Grove, California from 8 to 21 December, 1999, was cosponsored by the US
Department of Veterans Affairs (Medical Research Service), the Paralyzed Veterans of
America (Spinal Cord Research Foundation), the National Institutes of Health (National
Institute of Neurological Disorders and Stroke), the Christopher Reeve Paralysis Founda-
tion and the Eastern Paralyzed Veterans Association. The Program Planning Committee
for the symposium included Drs. Susan .V Bryant (University of California, Irvine), Mary
Bartlett Bunge (University of Miami School of Medicine), Edward D. Hall (Parke-Davis
Pharmaceutical Research, Ann Arbor), Marston Manthorpe (Vical, Inc., San Diego), Ken
Muneoka (Tulane University), Marion Murray (MCP Hahnemann University), John H.
Peacock (VA Medical Center and University of Nevada, Reno), Fredrick J. Seil AV(
Office of Regeneration Research Programs, VA Medical Center, Portland and Oregon
Health Sciences University) and Suzanne Szollar (VA Medical Center and University of
California, San Diego). Guest participants during the planning process were Drs. Vivian
Beyda (Eastern Paralyzed Veterans Association) and Paul M. Hoffman (Medical Research
Service, Department of Veterans Affairs) and Ms. Lisa A. Hudgins (Paralyzed Veterans of
America).
The volume is organized into 6 topic sections, including: (I) Strategies for Spinal
Cord Injury Repair, (II) Plasticity of the Injured Spinal Cord: Retraining Neural Circuits
to Promote Motor Recovery, (III) Impact of Neuroprosthetic Applications on Functional
Recovery, (IV) Neurotrophins and Activity-Dependent Plasticity, (V) Candidate Cells for
Transplantation into the Injured CNS, and (VI) New Directions in Regeneration Research.
Both clinical and experimental animal studies are presented in the first three sections, while
predominantly basic research is the focus of the second half of the book. Not included in
this volume are the keynote address by .rD Martin Raff (University College, London) and
featured presentations by Drs. Glenn I. Hatton (University of California, Riverside) and
John R. Sladek, .rJ (The Chicago Medical School), plus the poster presentations, all of
which contributed greatly to the excitement of the symposium, but are beyond the scope of
a proceedings publication.
While a cure for spinal cord injury remains elusive, the contents of the volume
convey a sense of progress toward this goal. More has been learned about the primary
and secondary consequences of spinal cord injury and more is being understood about
recovery mechanisms that are intrinsic to the nervous system and that might be further
encouraged. Expanding the control capacity of uninjured portions of the nervous system
may be one approach to improving the functional capabilities of those afflicted with this
disorder. New therapies in the form of transplantable cells that can encourage growth or
myelination or prevent secondary damage or that can substituted for injured cells appear
promising for future applications. Genetic and tissue engineering studies give us further
hope, and under continuous development are novel drugs with greater specificity and fewer
detrimental effects and improved delivery methods for such drugs. Much more progress
can be expected in the two year interval before the next of these symposia.
Fredrick J. Seil
Director, VA Office of
Regeneration Research Programs
Portland, OR, USA
F.J. S~il (Ed.)
ssergorP ni Braih ,hcraeseR Vol. ! 28
© 2000 Elsevier Science B.V. All rights reserved
CHAPTER 1
Strategies for spinal cord injury repair
Dana M. McTigue ,1 Phillip G. Popovich 2 Lyn B. Jakeman 1 and Bradford .T Stokes *,1
1 Department of Physiology and Cell Biology, The Ohio State University, 304 Hamilton Hall,
1645 Neil Avenue, Columbus, OH 43210, USA
2 Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, 228 Meiling Hall,
370 W 9th Avenue, Columbus, OH 43210, USA
Introduction that may also prove beneficial in repairing the injured
spinal cord.
Traumatic injury to the spinal cord results in varying
degrees of motor and sensory loss below the site of Rat contusion injury model
injury. Although the deficits associated with a spinal
cord injury (SCI) may diminish somewhat over time Preclinical studies in reliable animal models of SCI
due to incipient reparative events, the majority of are a necessary component of all clinical trial strate-
the neurological problems remain with patients for gies. One such commonly used and well character-
the rest of their lives. Recent progress in experi- ized model is contusion injury of the rat spinal cord
mental strategies to repair the injured spinal cord (Noble and Wrathall, 1985; Bresnahan et al., 1991).
have shed new light on possible mechanisms for im- This injury paradigm results in a typical pathology
proving the outcome after SCI. Indeed, the potential consisting of marked cavitation at the lesion site,
use of stem cells, antagonists of inhibitory myelin i.e., epicenter, and a surrounding rim of surviving
proteins, polyethylene glycol, and various forms of axons, many of which may be dysfunctional. The
transplantation (e.g., Schwann cells, olfactory en- lesion typically extends into the rostral and caudal
sheathing cells, peripheral nerves, fetal spinal tissue spinal gray and white matter as a function of time
and cells genetically engineered to produce neu- after injury, particularly in the dorsal funiculus. The
rotrophins) have recently led to exciting results in three-dimensional morphology of the lesion in ro-
the field of spinal cord trauma (Bregman et al., 1995; dents (Bresnahan et al., 1991) also mimics that seen
Cheng et al., 1996; Giovanini et al., 1997; Grill et in a large proportion of human spinal injuries (Kaku-
al., 1997; Menei et al., 1998; Ram6n-Cueto et al., las, 1984; Bunge et al., 1993, 1997). The animals
1998; McDonald et al., 1999; Shi et al., 1999). As an exhibit an initial paralysis followed by a predicable
overview of the section on strategies for spinal cord improvement in hindlimb function that is propor-
injury repair, we will review additional approaches tional to the severity of the lesion (Basso et al.,
1996). This injury model has been used to evaluate
and describe deleterious and reparative events that
occur endogenously after SCI (Beattie et al., 1997;
* Corresponding author: .rD Bradford .T Stokes, Depart-
ment of Physiology and Cell Biology, The Ohio State Uni- Crowe et al., 1997; Wrathall et al., 1998; Popovich et
versity, 822 Meiling Hall, 073 W 9th Avenue, Columbus, al., 1999). For instance, in the acutely injured spinal
HO 43210-1238, USA. Fax: [phone]; E-mail: cord, several mechanisms of destruction are initiated
[email protected] including hemorrhage and edema due to disrupted
s i ~ n e ~ l g n a ' ~
egamaD riapeR rison and McDonald, 1977; Griffiths and McCul-
loch, 1983). Oligodendrocyte remyelination likely
occurs as a result of proliferation and differentia-
,hemorrhage .ECM deposition
tion of oligodendrocyte progenitors normally found
• edema
• oxygen radicals .regeneration throughout the CNS (Gensert and Goldman, 1997;
• excitotoxicity .synaptogenesis
Carroll et al., 1998; Keirstead et al., 1998; McTigue
• Ca ÷2 influx .sculpting
• apoptosis .remyellnaUon et al., 1999), although some would argue that ma-
• demyelination ,inflammation
ture differentiated oligodendrocytes can play a role
• glial scar formation .functional recovery
-inflammation in remyelination (Wood and Bunge, 1991; Wood
Fig. .1 After trauma to the spinal cord, several events occur that and Mora, 1993). However, the endogenous pro-
may lead to further tissue destruction or, in contrast, may result cesses of remyelination are insufficient to produce
in tissue remodeling and repair. Damaging events include acute adequate functional recovery. This may be due in
phenomena such as hemorrhage and Ca +2 influx as well as more
part to the failure of normal cues for axon remyeli-
protracted events, e.g., apoptosis and demyelination. Reparative
nation. For example, the remyelinated internodes do
processes such as angiogenesis and axon growth also typically
occur in the injured spinal cord. Depending on the extent of not achieve the same thickness or length as in the
these processes, functional recovery may be limited to nearly normal CNS (Gledhill and McDonald, 1977; Har-
complete. Interestingly, inflammation in the injured spinal cord rison and McDonald, 1977). Recent trials with the
precipitates both deleterious and beneficial events in time and
drug 4-aminopyridine (4-AP), which increases ax-
space after SCI.
onal conduction by blocking + K channels, reveal
blood vessels at the epicenter, lipid peroxidation and some functional enhancements suggesting that en-
calcium influx/excitotoxic cell death (Fig. .)1 Neu- dogenous remyelination processes can be improved
rons and certain glial cells are highly susceptible to upon (Blight et al., 1991; Hansebout et al., 1993;
excitotoxicity in the central nervous system (CNS), Hayes et al., 1994). Thus, if oligodendrocyte pro-
which contributes to the massive cell death observed genitors are important for remyelination, agents that
in the traumatized spinal cord. can further augment their proliferation and differ-
entiation could potentially be important treatments
Oligodendrocyte death, demyelination and for SCI. For example, recent preliminary data from
remyelination our laboratory revealed that the neurotrophins, brain-
derived neurotrophic factor and neurotrophin-3 may
In addition to the necrotic cell death known to be augment oligodendrocyte progenitor proliferation af-
prevalent after SCI, recent evidence from Beattie and ter SCI (McTigue et al., 1999).
colleagues has revealed that cells are lost through
apoptosis both acutely within the lesion epicenter Extracellular matrix in the injured spinal cord
and in the rostro-caudal lesion extensions (see Chap-
ter 2). Interestingly, this distal apoptosis can occur In addition to changes in the cellular components
for up to 6-8 weeks after injury and typically occurs at the injury site, another facet of remodeling is the
in oligodendrocytes and microglia found in regions formation of a glial scar and the deposition of extra-
of progressive Wallerian axonal degeneration (Crowe cellular matrix (ECM) molecules. The total number
et al., 1997; Shuman et al., 1997). The apoptotic loss and molecular composition of ECM molecules that
of oligodendrocytes may contribute to the demyeli- accumulate is unknown, is likely to be injury-spe-
nation that is consistently found in acutely injured cific, and may depend on the animal model of SCI.
spinal cords from a variety of species (Gledhill et al., For instance, recent experiments using contusion in-
1973; Bresnahan et al., 1976; Balentine, 1978; Banik jury in mice reveal a very different lesion evolution
et al., 1980; Blight, 1985). than that seen in rats. Rhther than cavitation, the
Following traumatic SCI, the demyelinated ax- lesioned area typically undergoes significant depo-
ons do, for the most part, become remyelinated by sition of ECM molecules leading to marked scar
both oligodendrocytes and Schwann cells (Gledhill formation (Kuhn and Wrathall, 1998; Ma et al.,
et al., 1973; Gledhill and McDonald, 1977; Har- 1999; Steward et al., 1999; Jakeman et al., 2000).
This mouse contusion injury model may be useful plethora of chemokines and cytokines (both pro-
in modeling certain types of human SCI, particularly and anti-inflammatory) that are present locally in
those in which the meninges are compromised and a the spinal parenchyma and in the circulation after
subsequent solid tissue scar forms at the lesion site spinal cord trauma (Semple-Rowland et al., 1995;
(Kakulas, 1984; Bunge et al., 1997). McTigue et al., 1998, 2000; Streit et al., 1998). In a
The ECM molecule, laminin, is consistently recent study by Bethea et al. (1999) (also see Chapter
found in either type of injury site and is typi- 4), a single dose of the anti-inflammatory cytokine
cally thought to be permissive for growing axons. interleukin-10 (IL-10), administered 30 min after
However, GeUer et al. (see Chapter 3), using an injury, significantly improved anatomical and behav-
in vitro neurite growth system, have identified spe- ioral outcome in the rat. This would suggest that
cific subregions of laminin that appear to be growth inflammatory events early after SCI are deleterious.
inhibitory. It is likely that other ECM molecules However, the issue is not so straightforward. When
(e.g., tenascin-C) thought to be principally growth an additional dose of IL-10 was given at 3 days after
inhibitory (or permissive) will be shown to have injury, the protective effects were completely lost.
varying effects on axon growth depending on the The explanation of these results is not yet under-
molecular makeup of the in vivo microenvironment stood. Thus, the immune response to SCI is clearly
after SCI. Such variability might be precipitated by complex and furtherw ork to elucidate sites of action
the differential appearance of a variety of proteases of immunomodulators is of obvious importance.
known to be present after SCI. Thus, ECM depo- Because of the complex interactions of the im-
sition may be considered to either contribute to the mune cells in response to SCI, it has been im-
problems after SCI if the majority of molecules are portant to clearly identify the time course of mi-
growth inhibitory, or to be part of the endogenous croglial and macrophage activation, astroglial re-
reparative processes if the ECM mostly consists of sponse and leukocyte infiltration in the contused
growth permissive molecules. Evidence suggests that spinal cord (Popovich et al., 1997). Some of these
it is likely to be both, particularly over time as the results are summarized in Fig. 2. Early after SCI,
lesion evolves. The particular types of ECM pro- neutrophils invade and then quickly exit the injured
teins deposited in the lesioned tissue are also likely tissue. T-lymphocytes also enter after SCI, peaking
to be influenced by the distribution and local con- at approximately 1 week after injury. This cellular
centration of surface and secreted molecules, such as response corresponds closely to the time course of
growth factors and cytokines, which are found within chemokine and cytoklne expression in the same in-
the injury site. Therefore, with "the proper molecular jury model (Semple-Rowland et al., 1995; McTigue
tools, it may be possible to manipulate the ECM et al., 1998, 2000; Streit et al., 1998), suggesting that
composition such that a supportive environment for these cells may be responding to chemoattractive
sprouting and regenerating axons is created. moleculesp roduced in the injured spinal cord.
As can be seen in Fig. 2, microglia are acti-
Inflammatory involvemenatf ter SCI vated early after SCI while monocyte infiltration is
delayed over a period of days. Unfortunately, once
Finally, inflammation represents an important pro- these cells become phagocytic, it is impossible using
cess in CNS trauma that likely plays a role in all routine immunohistochemical techniques and light
the events mentioned above. The initiation of an microscopy to distinguish between microglia and
inflammatory response by injury to the spinal cord blood-derived monocytes in the spinal cord. How-
has been known for some time, but only recently ever, Popovich has hypothesized that while these
has it received widespread attention. The issue is cells look similar morphologically, they play very
complicated by the fact that certain portions of the different roles in post-injury events (see Chapter 5).
inflammatory response likely promote tissue sparing To better identify the role of microglia in the injury
and functional repair while other events may con- site and minimize the influence of infiltrating mono-
tribute to tissue destruction (see Chapter 2). Part cytes, he has used a technique in rats that depletes
of the complexity of this response stems from the circulating monocytes acutely after spinal contusion
6
Days IP
)0.5 7 14 28
slihportuen
microglia Epi
)24xo(
R/C WM
monocytes
(EDl,0X42) Epi
I
R/C MW
phagocytosis
i i m
)1DE(
MHC class II
)6XO( Epi
R/C MW
setycohpmyl-T
)91xo(
Fig. 2. Illustration of temporal appearance and relative amounts of activated resident and infiltrating inflammatory cells in the epicenter
)ipE( dna and rostral caudal white matter (R/C )MW of receiving rats contusion spinal injuries. The intensity of staining (and presumably
cellular is activation) indicated by the density of lines for each cell type. Post-injury time (days PI) is indicated at the top of the figure.
The immunohistochemical stain used for identification is indicated below each Early category. after neutrophils injury, invade dna then
quickly exit the injury site. noita,~itcA of microglia dna initiation of phagocytosis begins early and continues for protracted times after
.yrujni Circulating monocytes dna enter T-lymphocytes the injured spinal cord during the first week after injury, while upregulation of
MHC class II is during observed the first these cells data that month illustrate inflammatory Collectively, after injury. contusion activated
rapidly enter the injured spinal cord, the throughout spread rostral/caudal axis, dna persist for periods extended of time after .yrujni
injury without affecting resident microglia (Popovich Thus, it is clear that while great strides have
et al., 1999; see also Chapter 5). The results demon- been made in understanding processes involved in
strate that reducing the contribution of peripherally destruction and repair of the injured spinal cord
derived macrophages produces an increase in tissue (Schwab and Bartholdi, 1996; Olson, 1997), there
sparing and promotes axonal growth at the epicenter is much to be learned about basic etiologic factors.
with significant improvements in locomotor recov- More fundamental studies are clear!y needed, in
ery. This targeted approach suggests an apparent both animals and available human tissue, to reveal
dichotomy in the actions of inflammatory ceils in the the events occurring endogenously in the injured
injured spinal cord and underlines the importance CNS. Armed with this ki~owledge, we may then
of understanding the timing of entry, activation, and begin to make more educated attempts at enhancing
interactions of immune cells and mediators (e.g., the apparently limited reparative processes while
cytokines, chemokines and growth factors) in the concomitantly downregulating those events that act
injured spinal cord. either passively or actively to restrict repair.