Cyclosporin A, but not FK 506, protects mitochondria and neurons against hypoglycemic damage and implicates the mitochondrial permeability transition in cell death
Cyclosporin A, but not FK 506, protects mitochondria and neurons against hypoglycemic damage and implicates the mitochondrial permeability transition in cell death
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DOI：
10.1523/jneurosci.18-14-05151.1998
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发表时间：
1998-07-15
影响因子：
5.3
通讯作者：
Wieloch, T
中科院分区：
文献类型：
--
作者：
Friberg, H;Ferrand-Drake, M;Wieloch, T
线粒体通透性转换（MPT）的诱导与细胞凋亡和缺血再灌注损伤有关。在MPT过程中，线粒体内膜中的通道，线粒体巨通道，打开并导致孤立的线粒体肿胀。MPT和线粒体肿胀被环孢菌素A（CsA）抑制，环孢菌素A还可以抑制一些细胞中的细胞凋亡。在胰岛素诱导的低血糖等电位持续30分钟之前30分钟给药时，显示出脑损伤的显著减少。齿状回的超微结构检查显示，在低血糖损伤的树突和线粒体显着肿胀。在CsA治疗的动物中，线粒体在低血糖损伤期间和之后恢复正常和收缩的外观。FK 506（2 mg/kg，i. v.）处理，具有类似于CsA的免疫抑制作用的化合物没有保护作用。从海马分离的线粒体的肿胀动力学的研究表明，CsA，但不是FK 506，抑制钙离子诱导的MPT。我们得出结论，CsA治疗低血糖昏迷抑制MPT，减少损害，线粒体和MPT可能参与低血糖脑损伤的发展在大鼠。
Induction of the mitochondrial permeability transition (MPT) has been implicated in cellular apoptosis and in ischemia-reperfusion injury. During MPT, a channel in the inner mitochondrial membrane, the mitochondrial megachannel, opens and causes isolated mitochondria to swell. MPT and mitochondrial swelling is inhibited by cyclosporin A (CsA), which may also inhibit apoptosis in some cells.Treatment with CsA (50 mg/kg, i.v.) showed a robust reduction of brain damage when administered 30 min before insulin-induced hypoglycemic isoelectricity of 30 min duration. Ultrastructural examination of the dentate gyrus revealed a marked swelling of dendrites and mitochondria during the hypoglycemic insult. In CsA-treated animals, mitochondria resumed a normal and contracted appearance during and after the hypoglycemic insult. Treatment with FK 506 (2 mg/kg, i.v.), a compound with immunosuppressive action similar to that of CsA, was not protective. Studies on the swelling kinetics of isolated mitochondria from the hippocampus showed that CsA, but not FK 506, inhibits calcium ion-induced MPT.We conclude that CsA treatment during hypoglycemic coma inhibits the MPT and reduces damage and that mitochondria and the MPT are likely to be involved in the development of hypoglycemic brain damage in the rat.