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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Apoptosis

Cell cultures

Mitochondrial permeability transition

Neuronal death

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