Review : Apoptosis and Spinal Cord Injury

Beattie, Michael S.; Shuman, Sheri L.; Bresnahan, Jacqueline C.

doi:10.1177/107385849800400312

Cited by 28 publications

(15 citation statements)

References 61 publications

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“…We have demonstrated previously that short term infusion of vMIPII also results in neuronal survival. Because apoptotic cell death after acute spinal cord injury has been postulated to play a pivotal role in the secondary injury cascade (Beattie et al, 1998; Lou et al, 1998), we determined whether the survival of neurons in antagonist infused spinal cord was a result of reduced apoptosis. Because bcl‐2 has been suggested to be one of the proteins preventing apoptosis in a variety of cells, vehicle and vMIPII infused spinal cord sections at 3 and 6 weeks post‐injury were stained with anti bcl‐2 antibody.…”

Section: Resultsmentioning

confidence: 99%

Chemokine antagonist infusion promotes axonal sparing after spinal cord contusion injury in rat

Ghirnikar

Lee

Eng

2001

J of Neuroscience Research

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Spinal cord injury produced by mechanical contusion causes the onset of acute and chronic degradative events. These include blood brain barrier disruption, edema, demyelination, axonal damage and neuronal cell death. Posttraumatic inflammation after spinal cord injury has been implicated in the secondary injury that ultimately leads to neurologic dysfunction. Studies after spinal cord contusion have shown expression of several chemokines early after injury and suggested a role for them in the ordered recruitment of inflammatory cells at the lesion site (McTigue et al. [1998] J. Neurosci. Res. 53:368-376; Lee et al., [2000] Neurochem Int). We have demonstrated previously that infusion of the broad-spectrum chemokine receptor antagonist (vMIPII) in the contused spinal cord initially attenuates leukocyte infiltration, suppresses' gliotic reaction and reduces neuronal damage after injury. These changes are accompanied by increased expression of bcl-2, the endogenous apoptosis inhibitor, and reduced neuronal apoptosis (Ghirnikar et al. [2000] J. Neurosci. Res. 59:63-73). We demonstrate that 2 and 4 weeks of vMIPII infusion in the contusion-injured spinal cord also results in decreased hematogenous infiltration and is accompanied by reduced axonal degeneration in the gray matter. Luxol fast blue and MBP immunoreactivity indicated reduced myelin breakdown in the dorsal and ventral funiculi. Increased neuronal survival in the ventral horns of vMIPII infused cords was seen along with increased bcl-2 staining in them. Immunohistochemical identification of fiber phenotypes showed increased presence of calcitonin gene related peptide, choline acetyl transferase and tyrosine hydroxylase positive fibers as well as increased GAP43 staining in treated cords. These results suggest that sustained reduction in posttraumatic cellular infiltration is beneficial for tissue survival. A preliminary report of this study has been published (Eng et al. [2000] J. Neurochem. 74(Suppl):S67B). In contrast to vMIPII, infusion of MCP-1 (9-76), a N-terminal analog of the MCP-1 chemokine showed only a modest reduction in cellular infiltration at 14 and 21 dpi without significant tissue survival after spinal cord contusion injury. Comparing data on tissue survival obtained with vMIPII and MCP-1 (9-76) further validate the importance of the use of broad-spectrum antagonists in the treatment of spinal cord injury. Controlling the inflammatory reaction and providing a growth permissive environment would enhance regeneration and ultimately lead to neurological recovery after spinal cord injury. J. Neurosci. Res. 64:582-589, 2001. Published 2001 Wiley-Liss, Inc.

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Section: Resultsmentioning

confidence: 99%

Chemokine antagonist infusion promotes axonal sparing after spinal cord contusion injury in rat

Ghirnikar

Lee

Eng

2001

J of Neuroscience Research

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“…Injury to the white matter is characterized by the widespread distribution of injured axons, which, in the acute post-traumatic stage, appear as swollen fibers containing accumulated cytoskeletal proteins (39). Over time, these swollen axons eventually undergo complete axotomy reminiscent of Wallerian degeneration (86), a process that is associated with death of oligodendrocytes (5). Traumatic oligodendrocyte death may also be induced by the reactive microglia and astrocytes present in the white matter (23, 39, 102).…”

Section: Regional Cell Death Patterns Following Tbimentioning

confidence: 99%

Cell Death Mechanisms Following Traumatic Brain Injury

2004

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Neuronal and glial cell death and traumatic axonal injury contribute to the overall pathology of traumatic brain injury (TBI) in both humans and animals. In both head-injured humans and following experimental brain injury, dying neural cells exhibit either an apoptotic or a necrotic morphology. Apoptotic and necrotic neurons have been identified within contusions in the acute post-traumatic period, and in regions remote from the site of impact in the days and weeks after trauma, while degenerating oligodendrocytes and astrocytes have been observed within injured white matter tracts. We review and compare the regional and temporal patterns of apoptotic and necrotic cell death following TBI and the possible mechanisms underlying trauma-induced cell death. While excitatory amino acids, increases in intracellular calcium and free radicals can all cause cells to undergo apoptosis, in vitro studies have determined that neural cells can undergo apoptosis via many other pathways. It is generally accepted that a shift in the balance between pro- and anti-apoptotic protein factors towards the expression of proteins that promote death may be one mechanism underlying apoptotic cell death. The effect of TBI on cellular expression of survival promoting-proteins such as Bcl-2, Bcl-xL, and extracellular signal-regulated kinases, and death-inducing proteins such as Bax, c-Jun N-terminal kinase, tumor-suppressor gene, p53, and the calpain and caspase families of proteases are reviewed. In light of pharmacologic strategies that have been devised to reduce the extent of apoptotic cell death in animal models of TBI, our review also considers whether apoptosis may serve a protective role in the injured brain. Together, these observations suggest that cell death mechanisms may be representative of a continuum between apoptotic and necrotic pathways.

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“…Neurons that survive axotomy can also contribute to recovery, even in the absence of regeneration, if they remain part of spinal circuitry rostral to the injury. The recognition that retrograde neuron death has many of the features of apoptosis (Crowe et al, 1997; reviewed by Beattie et al, 1998) has suggested several different therapeutic strategies for increasing neuron survival and recovery. These strategies include administration of growth factors, which require specific cell-surface receptors, or intervention at an intracellular level in the process of cell death by administration of antiapoptotic agents.…”

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confidence: 99%

DNA plasmid that codes for human Bcl-2 gene preserves axotomized Clarke's nucleus neurons and reduces atrophy after spinal cord hemisection in adult rats

et al. 1999

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Spinal cord injury in adult mammals causes atrophy or death of some axotomized neurons. The product of the antiapoptotic gene Bcl‐2 prevents neuron death in vivo. We delivered Bcl‐2 by intraspinal injection of a DNA plasmid encoding this gene to determine if axotomized neurons destined to undergo retrograde death could be rescued. Axons of the right side Clarke's Nucleus (CN) were cut unilaterally in adult Sprague‐Dawley rats by T8 hemisection, leaving the contralateral (left) CN as an intact control. Two months postoperatively, there was ∼35% loss of total CN neurons in the right L1 segment. Only 15% of large CN neurons (>400 μm2), whose axons project to the cerebellum, survived—indicating atrophy and/or death of 85% of these cells. We injected a DNA plasmid encoding the human Bcl‐2 gene and the bacterial reporter gene LacZ, which was complexed with cationic lipids, into the right side of segment T8 of the normal spinal cord, or just caudal to the hemisection site. The reporter gene was expressed in the perikarya of right CN neurons at L1 for up to 7 days, but not 14 days. Two months following T8 hemisection and Bcl‐2/LacZ DNA injection, there was no significant loss of CN neurons ipsilateral to the lesion. Surprisingly, 61% of large neurons survived, indicating partial protection from atrophy. In contrast, a DNA plasmid that codes for the LacZ reporter gene, but not Bcl‐2, did not prevent CN neuron death or atrophy. Administration of the Bcl‐2 gene in adult rats and its expression in these CNS neurons prevents retrograde cell death, and also minimizes atrophy. These results may serve as the basis for developing novel gene therapy strategies for patients with spinal cord injury. J. Comp. Neurol. 404:159–171, 1999. © 1999 Wiley‐Liss, Inc.

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Review : Apoptosis and Spinal Cord Injury

Cited by 28 publications

References 61 publications

Chemokine antagonist infusion promotes axonal sparing after spinal cord contusion injury in rat

Chemokine antagonist infusion promotes axonal sparing after spinal cord contusion injury in rat

Cell Death Mechanisms Following Traumatic Brain Injury

DNA plasmid that codes for human Bcl-2 gene preserves axotomized Clarke's nucleus neurons and reduces atrophy after spinal cord hemisection in adult rats

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