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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
Author(s) -
Khaspekov Leonid,
Friberg Hans,
Halestrap Andrew,
Viktorov Ilja,
Wieloch Tadeusz
Publication year - 1999
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1999.00743.x
Subject(s) - mitochondrial permeability transition pore , programmed cell death , neuroprotection , mitochondrion , calcineurin , ciclosporin , pharmacology , biology , cyclophilin , inner mitochondrial membrane , chemistry , endocrinology , apoptosis , medicine , biochemistry , transplantation , kidney , gene
When mouse hippocampal neuronal cultures, 2–3 weeks in vitro, were transiently exposed to combined glucose and oxygen deprivation (100% argon, 5% CO 2 , 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.