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Therapeutic Interventions Following Mammalian Spinal Cord Injury
Alexander G. Rabchevsky, PhD;
George M. Smith, PhD
Arch Neurol. 2001;58:721-726.
INTRODUCTION
Every year in the United States spinal cord injuries (SCIs) occur in
approximately 12 000 individuals, resulting in chronic, debilitating
functional deficits in most of these patients. Owing to the extremely high
costs associated with hospitalization, subsequent rehabilitation, and outpatient
care, it is becoming evident that effective treatments for SCI could drastically
reduce health care costs and, more importantly, improve the quality of life
for thousands of individuals. In this review, we will briefly discuss the
pathological events that contribute to the poor regenerative capacity of the
injured spinal cord and describe experimental methods that are being used
to both minimize tissue damage and promote the regrowth of injured spinal
cord axons.
THE PATHOLOGY OF SCI
The pathophysiology of acute SCI involves a complex cascade of events
resulting in compromised function below the level of the injury. This is due
to significant neuronal death and the failure of damaged spinal axons to either
propagate signals or regenerate. Damage caused by the initial trauma seems
to be immediate and irreversible, which can have catastrophic consequences
leading to paraplegia or quadriplegia. This primary injury is followed by
a progressive wave of secondary damage that destroys neighboring intact nerve
fibers critical for limb function below the injury site. Microcirculatory
impairments and rupture of the blood–spinal cord barrier create a harmful
microenvironment with increased levels of extracellular ions, excitatory amino
acids, and metabolic stress induced by free radical formation (Figure 1, A).1 A critical event that
contributes to the loss of intact nerve fibers following SCI is the immediate
and prolonged death of oligodendrocytes. Ironically, however, these and other
specialized glial cells can express inhibitory molecules that produce a "nonpermissive"
environment and hinder regeneration of severed spinal cord axons.
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Schematic illustrations of (A) contusive spinal cord injury showing
the pathological and cellular reactions resulting from early cytotoxic events,
(B) neuron with an injured axon encountering reactive neuroglial cells, which
secrete factors known to contribute to growth inhibition, and (C) a neuron
successfully extending the growth cone of its axon through a supporting neuroglial
matrix expressing proregenerative factors. A, Despite the presence of surviving
neural elements above the injury site, a ruptured blood–spinal cord
barrier leads to extravasation of blood cells and plasma constituents, including
high levels of iron and glutamate, with ensuing hemorrhagic necrosis. Mononuclear
phagocytes clear cellular debris and secrete factors involved in immunological
responses to tissue repair, but they also express potentially toxic molecules
such as reactive oxygen ( ) species. This contributes to
further destruction of proximal neurons and demyelination of neighboring intact
axons, with ensuing apoptotic events distal to the injury site. Collectively,
these events result in the physiological and morphological activation of microglia
and astrocytes, which soon completely surround the necrotic region and govern
the regenerative success or failure of injured axons. B, An injured axon undergoing
Wallerian degeneration encounters numerous growth-inhibitory obstacles. Demyelination
itself releases the potent oligodendrocyte growth-inhibitory molecules myelin-associated
glycoprotein (MAG) and Nogo-A (NOGO). The neuroglial cicatrix that forms at
the severed nerve endings expresses both noxious agents (N)
and potentially harmful cytokines such as tumor necrosis factor
 (TNF-),
as well as the inhibitory extracellular matrix molecules tenascin-R (Tenascin)
and chondroitin sulfate proteoglycan (CSPG). C, Axonal growth cones have the
potential of extending into the neuroglial matrix if appropriate growth-promoting
substrates such as laminin and cell adhesion molecules (CAMs) are present.
The local production of growth factors and cytokines by reactive neuroglia
helps to create a proregenerative extracellular milieu. In addition, increasing
cyclic nucleoside levels (such as cyclic adenosine monophosphate [cAMP]) in
the growth cone may convert inhibitory stimuli into growth promotion.
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GLIOSIS AND ABORTIVE REGENERATION
The morphological activation of astrocytes and microglial cells (also
termed reactive gliosis) is systematically associated
with injury to the nervous system. Reactive gliosis controls the extracellular
microenvironment in the spinal cord by regulating the blood–spinal cord
barrier and ionic concentrations, and it plays a critical role in the uptake
and metabolism of the potentially excitotoxic amino acid glutamate (Figure 1). Moreover, it also produces various
growth factors and cytokines, some of which are neuroprotective and aid the
survival of damaged neurons. Activated microglia-derived brain macrophages
also promote neovascularization of the lesion, which is a critical step in
the wound-healing process, by ensuring the delivery of trophic factors and
nutrients to support cell migration and growth into the damaged area. In addition
to being beneficial for the regenerative process, reactive neuroglia also
express and secrete molecules that are potentially detrimental for regeneration.2
In the first week after SCI there is dramatic proliferation of microglia-derived
brain macrophages and an enormous recruitment of blood-derived monocytes (Figure 1, A). The primary functions of these
macrophages during tissue repair include removal of dead tissue and debris
through phagocytosis as well as lipid recycling.3
Brain macrophages also aid the progression of wound healing and gliosis with
the release of cytokines, growth factors, and extracellular matrix molecules.
Additionally, these phagocytes remove putative inhibitory molecules produced
by oligodendrocytes by clearing myelin debris from the injury site. Activating
resident microglia by injecting pyrogenic bacterial lipopolysaccharide into
the injured spinal cord reduces cavitation and density of the astrocytic scar
in addition to enhancing both vascularization and neuritic regeneration.3
Injury-induced cytokines produced by reactive microglia initiate a cascade
of cellular responses that greatly influence other neuroglia, including astrocytes.1, 3 These reactive astrocytes have the
responsibility of not only repairing the damage, but they must also reestablish
the integrity of the microenvironment surrounding the lesion to maintain the
function of nondamaged circuits. Thus, they function to both promote regeneration
adjacent to the damaged region while preventing growth into the lesion. Initially,
astrocytic processes delineate the necrotic area, forming a dense glial lining
with basal lamina completely enveloping infiltrating mesodermal elements such
as fibroblasts and Schwann cells. This serves to restore the blood–spinal
cord barrier and ionic homeostasis in the injured area, but the dense astroglial
scars are also thought to inhibit successful axonal growth because of their
deposition of neurite growth–inhibiting extracellular matrix molecules,
most notably, chondroitin sulfate proteoglycan (Figure 1, B).2 Mature oligodendrocytes
also express potent inhibitory molecules that significantly contribute to
the poor regenerative potential of severed spinal cord axons.
Two relatively modest regenerative processes occur after SCI. Terminal
sprouts are often formed by cut axons, and collateral sprouts may come from
adjacent undamaged axons. Passage of axonal sprouts through damaged spinal
cord tissue depends on the clearance of inhibitory molecules and the presence
of appropriate guidance cues. Changes in the balance of positive vs inhibitory
factors alter the local environment and ultimately influence the amount of
regeneration that takes place in the injured spinal cord.
The ongoing challenge for research focused on spinal cord regeneration
is to modulate the astrocyte's response to injury so as to gain from its potential
neurotrophic effects while at the same time tempering its scarring effect.
Future successes in this challenging field of research will stem from invaluable
information obtained from using current methods that encompass pharmacological
intervention, cell transplantation, and gene therapy.
WHAT ARE APPROPRIATE MODELS FOR EXPERIMENTAL SCI?
Numerous methods of SCI exist for the rodent. The most commonly used
include transection, resection, hemisection, or aspiration lesions. These
lesions definitively cut axon tracts, but these types of injuries are not
typically seen clinically. Reproducibility is very difficult to attain, and
few studies have demonstrated significant regeneration of supraspinal pathways
across a transection site unless a cellular or prosthetic graft is used to
"bridge" the host-lesion interface. In this regard, using these models of
SCI in combination with transplantation experiments have been instrumental
in discovering what cell types are proregenerative or growth-inhibiting.
Compression injuries to the spinal cord precipitated by fractured vertebrae
following blunt-force trauma are the most common type of SCI seen clinically.1 The weight-drop technique for contusion SCI in dogs
was first developed by Alfred Allen Reginald and later modified for the rat.4 As with most SCI models, a principle caveat is that
a laminectomy is required prior to contusion of the exposed cord. To ensure
reproducibility, the original technique was modified by stabilizing the spinal
column and developing computer-controlled electronic feedback devices to control
and monitor compression parameters (displacement). However, calibration of
such devices is difficult because the force at the time of impact cannot be
ascertained. Therefore, more advanced devices use force rather than displacement
to control contusion injuries. In most clinical cases, fractured vertebrae
impinge on the spinal cord causing ischemia as well as compression. Accordingly,
other experimental models have been developed to examine the effects of ischemia
on SCI, such as the occlusion of the descending aorta with balloon catheters
or the application of aneurysm clips to the spinal cord. The latter model
is considered more clinically relevant because the clip can be applied at
various forces for specific amounts of time.
In summary, it must be emphasized that there is no particular model
of SCI that can address all aspects of regeneration or functional recovery.
In fact, the use of multiple paradigms has greatly advanced our current understanding
of the pathophysiology following spinal cord trauma. Equally important is
the need to standardize behavioral outcome measures for the different injury
models because nonstandardized assessment of functional recovery adds to the
complexity of correlating behavioral recovery with histological alterations.
PHARMACOLOGICAL THERAPY FOLLOWING SCI
Numerous studies over the past several years have explored novel pharmacological
therapies for the treatment of SCI, some of which have been tried clinically.
Ideally, effective treatments should create the type of milieu (at the injury
site and in adjacent areas) that promotes regenerative activity on the part
of the surviving neural elements. Therefore, any therapeutic intervention
designed to foster regeneration of injured spinal axons must first diminish
the secondary tissue damage to provide a requisite cellular substrate for
regenerating axons.
Current clinical approaches to reduce the spread of cell death and tissue
degeneration following the initial injury include early pharmacological intervention
with high-dose steroids.5, 6 The
synthetic glucocorticoid methylprednisolone sodium succinate is the standard
treatment following SCI in humans based on its reported neuroprotective effects.
Unfortunately, the functional improvements reported in early human trials
remain controversial, and benefits of methylprednisolone sodium succinate
are limited to a narrow therapeutic window (first 8 hours) and primarily to
incomplete injuries. Despite its clinical use, it is not fully understood
how methylprednisolone sodium succinate produces its beneficial actions. Reductions
in edema, inflammatory cytokine production, and lipid peroxidation are thought
to play roles, but the beneficial effects of methylprednisolone sodium succinate
range from moderate improvements to none at all, depending on the animal model
of SCI used and the severity of the injury.6, 7
Similarly, ganglioside GM1 (Sygen; FIDIA Pharmaceutical Co, Troy,
Mich) has recently been used clinically without conclusive demonstration of
significant functional recovery in rodent models of SCI, and its mechanisms
of action are not at all clear.1, 7
Although not used clinically, various pharmacological interventions
have demonstrated significant anatomical and behavioral effects after experimental
SCI in rodents. Some of the more novel therapies have included cycloheximide, -melanocyte–stimulating
hormone, tacrolimus (FK-506), iloprost, tetrodotoxin, clenbuterol, and blockers
of the -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)
and/or kainate and N-methyl-D-aspartate (NMDA) receptors.1, 7, 8 In light of evidence
that free radicals contribute to the pathogenesis of trauma to the central
nervous system, others have used the free radical scavengers -phenyl-N-tert-butyl-nitrone (PBN) and lazaroids, albeit with limited
success in SCI models.
Paradoxically, damage to the spinal cord is accompanied by the production
of both proinflammatory mediators as well as factors that promote neuroprotection
and self-repair (Figure 1, C). The
temporal progression of neuronal apoptosis and degeneration provides a window
of opportunity for augmenting the potentially beneficial effects of protective
factors, such as nerve growth factor, neurotrophin-3, brain-derived neurotrophic
factor, basic fibroblast growth factor, and interleukin 10.1, 8, 9, 10
Of these factors, basic fibroblast growth factor seems to have more success
than the others following acute SCI, based on its neuroprotective and proregenerative
properties.
Oligodendroglia express at least 2 proteins that may directly inhibit
axonal regeneration: myelin-associated glycoprotein and Nogo-A.2, 9
Nogo-A is an endoplasmic reticular protein with minor expression on the surface
of oligodendrocytes (Figure 1, B).
On injury and myelin degradation, Nogo-A may be released with its inhibitory
domain exposed to regenerating axons. An antibody (IN-1) designed to neutralize
the inhibitory function of Nogo-A was shown to significantly increase the
length that some axons regenerated; however, recovery of motor and sensory
function was insignificant.9 Although individually
these interventions demonstrate small effects, they function to alter only
one component of a very complex series of events (Figure 1). This suggests that future therapies that combine various
agents to reduce tissue destruction, promote neuronal survival, and increase
axonal regeneration may prove the most efficacious in enhancing functional
recovery.
TRANSPLANTATION
Fetal Spinal Cord Tissue and Stem Cells
Over the years, neural tissue transplantation has served as an effective
tool for investigating the nature of various cellular interactions in the
injured spinal cord and determining whether it promotes functional recovery.11 While this approach seems to be promising, based
on the neuronal viability and plasticity of embryonic tissue the collective
results have demonstrated varying degrees of success with respect to recovery
or regeneration. Graft-mediated functional recovery may be achieved if combined
with other cell types or interventions designed to stimulate axonal growth,
such as growth factor treatment.7 The isolation
of donor cells using specific culturing protocols and isolation techniques
in tissue culture allows the greatest control over transplant composition.
In this regard, the recent advent of embryonic stem cell isolation has provided
a method for grafting progenitor cells (most notably neurons) into the chronically
injured spinal cord. Such grafts have been reported to improve functional
recovery, but the mechanisms by which the transplanted cells ameliorate behavior
are unclear.1 Specifically, because stem cells
are pluripotent, it is not known whether their differentiation into neurons
or glial cells is responsible for these improvements.
Schwann Cells and Olfactory Ensheathing Cells
The success of peripheral nerve grafts in promoting spinal cord regeneration
can be directly attributed to the accompanying Schwann cells, which normally
insulate axons in the peripheral nervous system. Schwann cells that are grafted
into lesions of irradiated spinal cords to eliminate endogenous proliferating
glia are very capable of remyelinating spinal axons, thereby restoring normal
conduction properties. This is also true of olfactory ensheathing cells (unique
glia isolated from the olfactory bulb, which demonstrate similar morphological
and physiological properties to Schwann cells). Both glial populations can
reduce posttraumatic cystic cavitation and astrocytic scar formation when
injected into the site of an acute compression lesion.12, 13
Importantly, after being placed into resection cavities of spinal cords, considerable
axonal growth occurs through polymeric tubes filled with cultured Schwann
cells seeded in a special biomatrix.14 This
growth response is augmented with cografted olfactory ensheathing cells.15 More recently, genetically modified Schwann cells
engineered to secrete trophic factors have been shown to enhance these regenerative
responses.16 Despite significant ingrowth of
brainstem and spinal axons through the Schwann cell and/or olfactory ensheathing
cell grafts, only 2 studies reported functional improvement following transplantation
of olfactory ensheathing cells alone.17, 18
Oligodendrocytes
Transplantation of cultured oligodendrocytes into the injured spinal
cord can lead to sufficient remyelination of denuded axons so that normal
axonal conduction properties are restored, often resulting in significant
behavioral improvements.19, 20
However, oligodendrocytes also have a negative influence on regenerating spinal
cord axons through their expression of inhibitory molecules. In this context,
while grafting oligodendrocytes following SCI seems to be an approach to remyelinate
and rescue denuded axons, it also introduces the possibility of increasing
the inhibitory milieu for regenerating axons.
Astrocytes
Contrary to the theory that astroglial scars are the major impediment
for successful axonal regeneration, under certain circumstances astrocytes
can also provide a matrix to support axonal growth during development and
regrowth in the injured spinal cord. Transplantation of cultured astrocytes
into the injured spinal cord results in their extensive migration, and they
are reported to enhance remyelination and reduce scar formation.21
Additionally, grafting immature astrocytes into the injured adult rat spinal
cord can stimulate axonal regeneration,22 suggesting
that reintroducing an immature glial environment at the lesion site improves
regenerative responses.
Microglial Cells
Unlike other neuroglial cell populations, microglial cell transplantation
has not been extensively investigated until recently. While some have proposed
that microglial cells exacerbate lesions of the central nervous system through
production of putative cytotoxic molecules, they also secrete a variety of
beneficial cytokines and growth factors.3 Accordingly,
grafting cultured microglial cells into the injured spinal cord promotes the
ingrowth of microvascular elements, neuritic processes, peripheral Schwann
cells, and many other heterotypic cellular elements.3
When introduced with fetal spinal cord transplants, cultured microglial cells
also enhance the regeneration of primary sensory axons into the grafts following
dorsal root injuries. These results strongly support the concept that posttraumatic
microgliosis and brain macrophage formation are critical for postinjury tissue
repair, neuronal regeneration, and neuritic outgrowth. This may be reflected
in the transplantation of peripheral macrophages that, when stimulated with
sciatic nerve–conditioned medium, have recently been shown to promote
functional recovery following complete spinal cord transection.23
Genetically Modified Fibroblasts
The use of genetically modified fibroblasts designed to secrete certain
molecules of interest is another novel approach in the field of transplantation.1, 8 While these cells do not provoke adverse
immunological reactions in the host spinal cord, they have been shown to promote
various cellular responses, including remyelination and regeneration.24, 25 It is important to note that while
these cells eventually disappear over time or lose their secretory properties,
their survival after a critical period of recovery may not be necessary.
GENE THERAPY
Transference of DNA that encodes therapeutic genes directly into cells
that surround the lesion could enhance the resident cells to increase their
production of beneficial proteins. Genetically modifying endogenous cells
both reduces the prospect of further disruption of the cellular continuity
outside the damaged regions and modifies the growth-supportive nature of this
terrain. Genetically modifying cells to express neurotrophins or growth factors
within the damaged brain or spinal cord increases neuronal survival, sprouting,
and regeneration.10 The overexpression of these
factors most likely increases the intrinsic ability of axons to grow and potentially
allows the growth cone to overcome the elevated levels of inhibitory molecules
surrounding the wound site.10 Long-term expression
of these genes can be achieved primarily by viral-derived vector systems,
such as lentiviruses, adeno-associated viruses, and potentially gutless forms
of adenoviruses.
CONCLUSIONS
The neuroglial response after SCI results in a balance of conflicting
signals that function to (1) isolate the damaged region while preventing long-distance
regeneration of severed axons through the lesion itself and (2) support sufficient
growth to reestablish a functional environment for local circuitry. Individual
interventions attempt to tip the balance of these signals in favor of increasing
neuronal survival and growth promotion. However, to significantly increase
functional regeneration, multiple strategies are required to compensate for
the myriad of detrimental factors produced after injury.
AUTHOR INFORMATION
Accepted for publication October 20, 2000.
This work was supported by grants 9-21 (Dr Smith) and 9-17 (Dr Rabchevsky)
from the Kentucky Spinal Cord and Head Injury Research Trust, Frankfort, and
grants NS33776 and NS38126 from the National Institutes of Neurological Disorders
and Stroke, Bethesda, Md (Dr Smith).
The authors also greatly appreciate the efforts and creativity of Gisele
Rabchevsky for the production of the graphic illustration.
From the Sanders-Brown Center on Aging (Dr Rabchevsky) and the Department
of Physiology, Albert B. Chandler Medical Center (Dr Smith), University of
Kentucky, Lexington.
Reprints: George M. Smith, PhD, Department of Physiology, MS 508,
University of Kentucky, Albert B. Chandler Medical Center, Lexington, KY 40536-0298
(e-mail: gmsmith{at}pop.uky.edu).
REFERENCES
| |
1. McDonald JW. Repairing the damaged spinal cord. Sci Am. 1999;281:64-73.
ISI
| PUBMED
2. David S. Axon growth promoting and inhibitory molecules involved in regeneration
in the adult mammalian central nervous system. Ment Retard Dev Disabilities Res Rev. 1998;4:171-178.
3. Rabchevsky AG, Streit WJ. Role of microglia in postinjury repair and regeneration of the CNS. Ment Retard Dev Disabilities Res Rev. 1998;4:187-192.
FULL TEXT
4. Basso DM, Beattie MS, Bresnahan JC. Graded histological and locomotor outcomes after spinal cord contusion
using the NYU weight-drop device versus transection. Exp Neurol. 1996;139:244-256.
FULL TEXT
|
ISI
| PUBMED
5. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad
mesylate for 48 hours in the treatment of acute spinal cord injury: results
of the Third National Acute Spinal Cord Injury Randomized Controlled Trial.
National Acute Spinal Cord Injury Study. JAMA. 1997;277:1597-1604.
FREE FULL TEXT
6. Young W. Strategies for the development of new and better pharmacological treatments
for acute spinal cord injury. Adv Neurol. 1993;59:249-256.
PUBMED
7. Taoka Y, Okajima K. Spinal cord injury in the rat. Prog Neurobiol. 1998;56:341-358.
FULL TEXT
| PUBMED
8. Gimenez y Ribotta M, Privat A. Biological interventions for spinal cord injury. Curr Opin Neurol. 1998;11:647-654.
PUBMED
9. Behar O, Mizuno K, Neumann S, Woolf CJ. Putting the spinal cord together again. Neuron. 2000;26:291-293.
PUBMED
10. Smith GM, Romero MI. Adenoviral-mediated gene transfer to enhance neuronal survival, growth,
and regeneration. J Neurosci Res. 1999;55:147-157.
FULL TEXT
|
ISI
| PUBMED
11. Zompa EA, Cain LD, Everhart AW, Moyer MP, Hulsebosch CE. Transplant therapy: recovery of function after spinal cord injury. J Neurotrauma. 1997;14:479-506.
ISI
| PUBMED
12. Blakemore WF. Olfactory glia and CNS repair: a step in the road from proof of principle
to clinical application. Brain. 2000;123:1543-1544.
FREE FULL TEXT
13. Franklin RJ, Barnett SC. Do olfactory glia have advantages over Schwann cells for CNS repair? J Neurosci Res. 1997;50:665-672.
FULL TEXT
|
ISI
| PUBMED
14. Xu XM, Guenard V, Kleitman N, Bunge MB. Axonal regeneration into Schwann cell–seeded guidance channels
grafted into transected adult rat spinal cord. J Comp Neurol. 1995;351:145-160.
FULL TEXT
|
ISI
| PUBMED
15. Ramon-Cueto A, Plant GW, Avila J, Bunge MB. Long-distance axonal regeneration in the transected adult rat spinal
cord is promoted by olfactory ensheathing glia transplants. J Neurosci. 1998;18:3803-3815.
FREE FULL TEXT
16. Menei P, Montero-Menei C, Whittemore SR, Bunge RP, Bunge MB. Schwann cells genetically modified to secrete human BDNF promote enhanced
axonal regrowth across transected adult rat spinal cord. Eur J Neurosci. 1998;10:607-621.
FULL TEXT
|
ISI
| PUBMED
17. Li Y, Field PM, Raisman G. Repair of adult rat corticospinal tract by transplants of olfactory
ensheathing cells. Science. 1997;277:2000-2002.
FREE FULL TEXT
18. Ramon-Cueto A, Cordero MI, Santos-Benito FF, Avila J. Functional recovery of paraplegic rats and motor axon regeneration
in their spinal cords by olfactory ensheathing glia. Neuron. 2000;25:425-435.
FULL TEXT
|
ISI
| PUBMED
19. Duncan ID. Glial cell transplantation and remyelination of the central nervous
system. Neuropathol Appl Neurobiol. 1996;22:87-100.
ISI
| PUBMED
20. Jeffery ND, Crang AJ, O'Leary MT, Hodge SJ, Blakemore WF. Behavioral consequences of oligodendrocyte progenitor cell transplantation
into experimental demyelinating lesions in the rat spinal cord. Eur J Neurosci. 1999;11:1508-1514.
PUBMED
21. Franklin RJ, Crang AJ, Blakemore WF. Transplanted type-1 astrocytes facilitate repair of demyelinating lesions
by host oligodendrocytes in adult rat spinal cord. J Neurocytol. 1991;20:420-430.
FULL TEXT
|
ISI
| PUBMED
22. Kliot M, Smith GM, Siegal JD, Silver J. Astrocyte-polymer implants promote regeneration of dorsal root fibers
into the adult mammalian spinal cord. Exp Neurol. 1990;109:57-69.
FULL TEXT
|
ISI
| PUBMED
23. Rapalino O, Lazarov-Spiegler O, Agranov E, et al. Implantation of stimulated homologous macrophages results in partial
recovery of paraplegic rats. Nat Med. 1998;4:814-821.
FULL TEXT
|
ISI
| PUBMED
24. McTigue DM, Horner PJ, Stokes BT, Gage FH. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte
proliferation and myelination of regenerating axons in the contused adult
rat spinal cord. J Neurosci. 1998;18:5354-5365.
FREE FULL TEXT
25. Liu Y, Kim D, Himes BT, et al. Transplants of fibroblasts genetically modified to express BDNF promote
regeneration of adult rat rubrospinal axons and recovery of forelimb function. J Neurosci. 1999;19:4370-4387.
FREE FULL TEXT
SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD
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