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Protection Provided by Cyclosporin A against Excitotoxic Neuronal Death Is Genotype Dependent
Author(s) -
Santos Julia Belen,
Schauwecker Paula Elyse
Publication year - 2003
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1046/j.1528-1157.2003.66302.x
Subject(s) - kainate receptor , pharmacology , neurotoxicity , programmed cell death , glutamate receptor , excitotoxicity , kainic acid , neuroprotection , mitochondrial permeability transition pore , hippocampal formation , nmda receptor , medicine , toxicity , anesthesia , biology , apoptosis , ampa receptor , receptor , biochemistry
Summary: 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.