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Cyclosporin A and its nonimmunosuppressive analogue N‐Me‐Val‐4‐cyclosporin A mitigate glucose/oxygen deprivation‐induced damage to rat cultured hippocampal neurons

When mouse hippocampal neuronal cultures, 2–3 weeks in vitro, were transiently exposed to combined glucose and oxygen deprivation (100% argon, 5% CO2, in glucose‐free medium) for 90 min, extensive neuronal degeneration had occurred after 24 h of reoxygenation. When these cultures were preincubated with cyclosporin A, a calcineurin inhibitor and a blocker of the mitochondrial permeability transition, neuronal death diminished by 30–50%. Similarly, the cyclosporin A analogue, N‐Me‐Val‐4‐cyclosporin A, a potent blocker of the mitochondrial permeability transition with no significant calcineurin blocking activity, decreased cell death by 70–80%. Both cyclosporin A and N‐Me‐Val‐4‐cyclosporin A markedly attenuated calcium‐induced swelling of isolated mouse brain mitochondria by blocking the mitochondrial permeability transition. The potassium thiocyanate‐stabilized binding of cyclophilin D to mouse brain mitochondrial membranes was completely prevented by cyclosporin A and N‐Me‐Val‐4‐cyclosporin A. Our results strongly suggest that the mitochondrial permeability transition is involved in oxygen/glucose deprivation‐induced cell death in vitro. Cyclophilin D and other components of the mitochondrial permeability transition may be important targets for neuroprotective and anti‐ischaemic drugs.