期刊
EPILEPSIA
卷 44, 期 8, 页码 995-1002出版社
BLACKWELL PUBLISHING INC
DOI: 10.1046/j.1528-1157.2003.66302.x
关键词
seizures; mouse strain; kainate; mitochondria; excitotoxicity; resistance
资金
- NINDS NIH HHS [NS38696-01] Funding Source: Medline
Purpose: Previous studies have shown that the immunosuppressant cyclosporin A (CsA), a specific blocker of the mitochondrial permeability transition (MPT) pore, can dramatically ameliorate the selective neuronal necrosis resulting from ischemia-reperfusion, traumatic brain injury, and N-methyl-D-aspartate (NMDA)-evoked neurotoxicity. The purpose of this study was to determine whether two different immunosuppressants, CsA and FK-506, could ameliorate the neuronal damage observed after kainate-induced seizures in strains that are differentially susceptible to excitotoxin-induced cell death. Methods: Excitotoxin-resistant (C57BL/6) or -susceptible (FVB/N) mice were administered kainate alone (30 mg/kg), CsA alone (5, 10, or 20 mg/kg), or one of the immunosuppressants (CsA, 5 mg/kg or 10 mg/kg; FK-506, 0.5 mg/kg) followed by kainate. After drug administration, mice were monitored continuously for the onset and extent of seizure activity. After a survival of 7 days, animals were assessed for hippocampal damage. Results: Whereas CsA alone induced no epileptogenic effects and both immunosuppressants were without effect on the induction of kainate-induced seizures, administration of CsA to excitotoxin-susceptible mice (FVB/N) virtually eliminated neuronal cell death. In contrast, induction of neuronal cell death was evident when CsA was administered to excitotoxin-resistant mice (C57BL/6). Administration of FK-506, another commonly used immunosuppressant, which lacks an effect on the MPT, had no effect on modification of susceptibility to kainate-induced cell death in either strain. Conclusions: As our data show differential protection of hippocampal neurons against excitotoxic cell death by pretreatment with CsA, these results suggest that strain-dependent differences in mitochondrial integrity and function may exist.
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