Abstracts

RATIONALE: Cyclosporin A (CsA) is a blocker of the mitochondrial permeability transition pore (MPTP) observed in mitochondria that have accumulated calcium and been subjected to oxidative stress. This study investigated whether secondary mitochondrial failure precedes the tissue damage observed after kainic acid (KA) administration, and if CsA prevents such deterioration. Thus, we compared the effects of CsA pre-treatment on susceptibility to excitotoxic cell death induced by KA in mouse strains previously identified as resistant (C57BL/6) and vulnerable (FVB/N). METHODS: CsA was administered (10,20,40 mg/kg) to adult C57BL/6 and FVB/N mice 30 mins. prior to KA (30 mg/kg). Mice were monitored for 4 hrs. for the onset and extent of seizure activity following KA. After 7 days, mice were assessed for histopathological outcome using selective silver stains and a Nissl stain. Gliosis was assessed by immunostaining sections for glial fibrillary acidic protein, and conducting area measures. RESULTS: Administration of KA alone induced extensive cell death of hippocampal neurons in FVB/N mice, while FVB/N mice pre-treated with CsA displayed little to no cell death throughout the dentate hilus and areas CA3 and CA1. In contrast, C57BL/6 mice showed little evidence of degeneration or cell death following KA alone, but pre-treatment with CsA elicited significant cell death throughout the dentate hilus and areas CA3 and CA1. CONCLUSIONS: CsA markedly ameliorated neuronal damage caused by KA administration in FVB/N mice, lending further support for the notion that the MPTP may play a significant role in events resulting in cell death. In addition, CsA elicited a phenotypic switch in C57BL/6 mice from excitotoxin-resistant to -susceptible following KA. These results suggest that there are genetically determined differences in susceptibility to cell death resulting from CsA pre-treatment, and may help identify critical molecular events involved in the sequence from mitochondrial dysfunction to cell death. [Supported by the Baxter Foundation & NIH grant NS38696-01. TVN was supported by the L.K. Whittier Foundation]