The roles of mitochondrial permeability transition in brain ischemia
Kobayashi, T.
Hokkaido Journal of Medical Science 75(4): 243-252
2000
ISSN/ISBN: 0367-6102 PMID: 10976404 Document Number: 516320
Mitochondrial permeability transition (MPT) is a phenomenon which occurs under adverse conditions such as an increase in mitochondrial calcium content and oxidative stress. The MPT causes the opening of mitochondrial megachannels, loss of mitochondrial membrane potential, and uncoupling of mitochondrial respiration, leading to cellular energy failure. Recent experiments have suggested that the MPT also releases specific proteins from mitochondria and activates the cascades of programmed cell death. Although many investigators have reported that ischemia-reperfusion leads to apoptosis in the brain tissue, there are only a few studies on the roles of MPT in ischemia-reperfusion injury in the brain. The present study was aimed to assess the effects of calcium, pH, temperature and free radicals on permeability transition of brain mitochondria in vitro, by the use of spectrophotometry. The effect of cyclosporin A (CsA), which is known to be a potent suppressor of MPT in other organs such as liver and heart, was also evaluated. The author also studied the protective effects of CsA on delayed neuronal death in CA1 sector, using transient forebrain ischemia model of the gerbil. Non-synaptosomal (free) mitochondria isolated from the forebrain of the rat had well-coupled respiration. MPT was induced by more than 10 microM of calcium. However, oxygen free radicals derived from t-butyl hydroperoxide and xanthine/xanthine oxidase could not induce MPT. Acidosis and low temperature significantly suppressed calcium-induced MPT. CsA (0.1-10 microM) but not FK506 (0.1-1 microM) inhibited MPT. CsA (50 mg/kg, i.p.) dramatically protected CA1 neurons in the hippocampus for 7 days after 5-min forebrain ischemia in the gerbil. These results suggest that calcium is the major inducer of MPT of the brain mitochondria, and that CsA can potentially inhibit MPT and ameliorate the ischemic tissue injury of the brain.