Role of Mitochondrial Permeability Transition in Ischemic Neuronal Cell Death

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The present study was aimed to determine biochemical characteristics of mitochondrial, permeability transition (mPT) in brain mitochondria, and to clarify its role in neuronal injury following transient forebrain ischemia. Mitochondria were isolated from rat brain and liver. Changes in mitochondrial volume were measured via light absorbance at 540 nm. By Western blot analysis, we examined release of mitochondrial cytochrome c under these conditions. Transient forebrain ischemia was induced by 5-min occlusion of the bilateral common carotid artery in the gerbil. Cyclosporin A (CsA) and/or trifluoperazine were given 30 min before and 24 hour after ischemia. The number of surviving neurons in hippocampal CA1 sectors was counted 7 days after ischemia. Calcium, but not pro-oxidants, induced a decrease of light absorbance in brain mitochondria, which was inhibited by CsA. However, both stimuli led to a much larger decrease of light absorbance in liver mitochondria. Under these conditions, calcium induced a release of cytochrome c from brain mitochondria, which was not inhibited by CsA. However, the same stimulus led to a release of larger amount of cytochrome c from liver mitochondoria. Selective neuronal injury due to transient forebrain ischemia was significantly ameliorated by treatment with high-dose CsA. The protective effect was enhanced by trifluoperazine. These results suggest that mPT does not readily occur in brain mitochondria, and that cytochrome c is released from brain mitochondria through mPT-independent mechanism. However, the findings from transient forebrain ischemia indicate the possibility of region-specific difference in sensitivity for mPT and/or cytochrome c release in the brain.