Bcl-x<sub>L</sub>Expression after Contusion to the Rat Spinal Cord

Qiu, Jingxin; Nešić, Olivera; Ye, Ziming; Rea, Harriett C.; Westlund, Karin N.; Xu, Guo Ying; McAdoo, David J.; Hulsebosch, Clarie E.; Perez‐Polo, J. Regino

doi:10.1089/089771501317095304

Cited by 37 publications

(30 citation statements)

References 48 publications

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“…Groups of rats were subjected to SCI using the NYU Impactor (see Materials and Methods), and the molecular signatures of apoptosis were examined 24 h after contusion. In agreement with previous reports (Qiu et al, 2001;Nesic-Taylor et al, 2005), we found that SCI decreased Bcl-x L mRNA (Fig. 4 A) and protein (Fig.…”

Section: Methylprednisolone Inhibits Sci-induced Apoptosissupporting

confidence: 94%

Methylprednisolone Protects Oligodendrocytes But Not Neurons after Spinal Cord Injury

Yan

Xiao

et al. 2008

J. Neurosci.

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Methylprednisolone (MP) is used to treat a variety of neurological disorders involving white matter injury, including multiple sclerosis, acute disseminated encephalomyelitis, and spinal cord injury (SCI). Although its mechanism of action has been attributed to antiinflammatory or antioxidant properties, we examined the possibility that MP may have direct neuroprotective activities. Neurons and oligodendrocytes treated with AMPA or staurosporine died within 24 h after treatment. MP attenuated oligodendrocyte death in a dose-dependent manner; however, neurons were not rescued by the same doses of MP. This protective effect was reversed by the glucocorticoid receptor (GR) antagonist (11, 17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one (RU486) and small interfering RNA directed against GR, suggesting a receptor-dependent mechanism. MP reversed AMPA-induced decreases in the expression of anti-apoptotic Bcl-x L , caspase-3 activation, and DNA laddering, suggesting anti-apoptotic activity in oligodendrocytes. To examine whether MP demonstrated this selective protection in vivo, neuronal and oligodendrocyte survival was assessed in rats subjected to spinal cord injury (SCI); groups of rats were treated with or without MP in the presence or absence of RU486. Eight days after SCI, MP significantly increased oligodendrocytes (CC-1-immunoreactive cells) after SCI, but neuronal (neuronal-specific nuclear protein-immunoreactive cells) number remained unchanged; RU486 reversed this protective effect. MP also inhibited SCIinduced decreases in Bcl-x L and caspase-3 activation. Consistent with these findings, the volume of demyelination, assessed by Luxol fast blue staining, was attenuated by MP and reversed by RU486. These results suggest that MP selectively inhibits oligodendrocyte but not neuronal cell death via a receptor-mediated action and may be a mechanism for its limited protective effect after SCI.

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Section: Methylprednisolone Inhibits Sci-induced Apoptosissupporting

confidence: 94%

Methylprednisolone Protects Oligodendrocytes But Not Neurons after Spinal Cord Injury

Yan

Xiao

et al. 2008

J. Neurosci.

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“…Vehicle-treated injured spinal cords showed significant increases in cytosolic oligonucleosomes when compared to sham rats treated with vehicle (Fig. 2), in agreement with our earlier reports Qiu et al, 2001;Nesic-Taylor et al, 2005) that showed that significant apoptotic cell death occurs during the first 24 h after injury. As expected, Tat-Bcl-x L treatment significantly decreased levels of cytosolic oligonucleosomes, confirming the anti-apoptotic effectiveness of Tat-Bcl-x L .…”

Section: Anti-apoptotic Effects Of Tat-bcl-x Lsupporting

confidence: 92%

“…The Bcl-2 family of proteins, containing pro-apoptotic (Bax, Bad, Bid) and anti-apoptotic (Bcl-2, Bcl-x L ) members, is central to the regulation of both caspase-dependent and caspase-independent apoptosis, by modulating mitochondrial outer membrane permeability (Tsujimoto, 2003;Sharpe et al, 2004). Among the Bcl-2 family, Bcl-x L is the principal anti-apoptotic member in the postnatal and adult central nervous system (Gonzalez-Garcia et al, 1994;Gonzalez-Garcia et al, 1995;Alonso et al, 1997;Parsadanian et al, 1998); where it is highly expressed in neurons and oligodendrocytes in the rat spinal cord (Qiu et al, 2001;Nesic-Taylor et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Detrimental effects of antiapoptotic treatments in spinal cord injury

Cittelly¹,

Nešić²,

Johnson³

et al. 2008

Experimental Neurology

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Long term functional impairments due to spinal cord injury (SCI) in the rat result from secondary apoptotic death regulated, in part, by SCI-induced decreases in protein levels of the anti-apoptotic protein Bcl-x L . We have shown that exogenous administration of Bcl-x L spares neurons 24h after SCI. However, long term effects of chronic application of Bcl-x L have not been characterized. To counteract SCI-induced decreases in Bcl-x L and resulting apoptosis, we used the TAT protein transduction domain fused to the Bcl-x L protein (Tat-Bcl-x L ), or its anti-apoptotic domain BH4 (Tat-BH4). We used intrathecal delivery of Tat-Bcl-x L , or Tat-BH4, into injured spinal cords for 24h or 7 days, and apoptosis, neuronal death and locomotor recovery were assessed up to 2 months after injury. Both, Tat-Bcl-x L and Tat-BH4, significantly decreased SCI-induced apoptosis in thoracic segments containing the site of injury (T10) at 24h or 7 days after SCI. However, the 7 day delivery of Tat-Bcl-x L , or Tat-BH4, also induced a significant impairment of locomotor recovery that lasted beyond the drug delivery time. We found that the 7 day administration of TatBcl-x L , or Tat-BH4, significantly increased non-apoptotic neuronal loss and robustly augmented microglia/macrophage activation. These results indicate that the anti-apoptotic treatment targeting Bcl-x L shifts neuronal apoptosis to necrosis, increases the inflammatory response and impairs locomotor recovery. Our results suggest that a combinatorial treatment consisting of anti-apoptotic and anti-inflammatory agents may be necessary to achieve tissue preservation and significant improvement in functional recovery after SCI.

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“…BDNF may exerts this neuroprotective effects through calmodulin [48,49]. BDNF may also be involved in the suppression of injury-induced delayed apoptosis [50], possibly through the increase of the antiapoptotic molecule, Bcl-xl [51]. An alternative mechanism for the neuroprotective effect of BDNF could be a BDNFregulated reduction of the number of terminal clubs formed at the distal axonal stumps in the rostral cord [52].…”

Section: Discussionmentioning

confidence: 99%

Freeze-dried poly(d,l-lactic acid) macroporous guidance scaffolds impregnated with brain-derived neurotrophic factor in the transected adult rat thoracic spinal cord

et al. 2004

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The effects of poly(D,L-lactic acid) macroporous guidance scaffolds (foams) with or without brain-derived neurotrophic factor (BDNF) on tissue sparing, neuronal survival, axonal regeneration, and behavioral improvements of the hindlimbs following implantation in the transected adult rat thoracic spinal cord were studied. The foams were embedded in fibrin glue containing acidic-fibroblast growth factor. One group of animals received fibrin glue with acidic-fibroblast growth factor only. The foams were prepared by a thermally induced polymer-solvent phase separation process and contained longitudinally oriented macropores connected to each other by a network of micropores. Both foams and fibrin only resulted in a similar gliotic and inflammatory response in the cord-implant interfaces. With BDNF foam, up to 20% more NeuN-positive cells in the spinal nervous tissue close to the rostral but not caudal spinal cord-implant interface survived than with control foam or fibrin only at 4 and 8 weeks after implantation. Semithin plastic sections and electron microcopy revealed that cells and axons more rapidly invaded BDNF foam than control foam. Also, BDNF foam contained almost twice as many blood vessels than control foam at 8 weeks after implantation. Tissue sparing was similar in all three implantation paradigms; approximately 42% of tissue was spared in the rostral cord and approximately 37% in the caudal cord at 8 weeks post grafting. The number of myelinated and unmyelinated axons was low and not different between the two types of foams. Many more axons were found in the fibrin only graft. Serotonergic axons were not found in any of the implants and none of the axons regenerated into the caudal spinal cord. The behavioral improvements in the hindlimbs were similar in all groups. These findings indicated that foam is well tolerated within the injured spinal cord and that the addition of BDNF promotes cell survival and angiogenesis. However, the overall axonal regeneration response is low. Future research should explore the use of poly(D,L-lactic acid) foams, with or without axonal growth-promoting factors, seeded with Schwann cells to enhance the axonal regeneration and myelination response.

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Bcl-x_LExpression after Contusion to the Rat Spinal Cord

Cited by 37 publications

References 48 publications

Methylprednisolone Protects Oligodendrocytes But Not Neurons after Spinal Cord Injury

Methylprednisolone Protects Oligodendrocytes But Not Neurons after Spinal Cord Injury

Detrimental effects of antiapoptotic treatments in spinal cord injury

Freeze-dried poly(d,l-lactic acid) macroporous guidance scaffolds impregnated with brain-derived neurotrophic factor in the transected adult rat thoracic spinal cord

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Bcl-xLExpression after Contusion to the Rat Spinal Cord

Cited by 37 publications

References 48 publications

Methylprednisolone Protects Oligodendrocytes But Not Neurons after Spinal Cord Injury

Methylprednisolone Protects Oligodendrocytes But Not Neurons after Spinal Cord Injury

Detrimental effects of antiapoptotic treatments in spinal cord injury

Freeze-dried poly(d,l-lactic acid) macroporous guidance scaffolds impregnated with brain-derived neurotrophic factor in the transected adult rat thoracic spinal cord

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Bcl-x_LExpression after Contusion to the Rat Spinal Cord