Powerful cyclosporin inhibition of calcium-induced permeability transition in brain mitochondria
Powerful cyclosporin inhibition of calcium-induced permeability transition in brain mitochondria
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DOI：
10.1016/s0006-8993(02)03798-8
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发表时间：
2003-01-17
期刊：
影响因子：
2.9
通讯作者：
Elmér, E
中科院分区：
文献类型：
--
作者：
Hansson, MJ;Persson, T;Elmér, E
线粒体通透性转换（mPT）被认为是细胞凋亡和坏死的重要介质，并被环孢菌素A（CsA）特异性阻断。在急性神经损伤和神经退行性疾病的各种动物模型中，CsA在允许穿过血脑屏障时已显示出在体内发挥有效的神经保护作用。CsA的神经保护作用被认为是通过特异性抑制线粒体通透性转换孔（mPTP）和通过抑制神经元钙调磷酸酶活性介导的。mPT的表征主要在肝脏和心脏线粒体中进行，一些脑研究报告了CsA的抑制作用降低，并质疑mPT在脑源性线粒体中的重要性。我们已经使用了断电肿胀模型来检查脑源性非突触体线粒体中的mPT。通过电子显微镜和测量光散射中的分光光度变化来评价Ca2+诱导的溶胀。在广泛的Ca2+水平范围内，大多数线粒体容易诱导渗透性转变，并被CSA强烈抑制，其半数最大效应与23 nM CsA相似。肿胀动力学和CsA的影响与先前在断电的肝脏和心脏线粒体中的发现相当。仔细表征mPT和CsA在脑源性线粒体中的作用是评估新开发的CsA类似物能够穿过血脑屏障并优先进入大脑的第一步。CsA的重要性引起的线粒体对Ca2+的敏感性在神经系统疾病的转变进行了讨论。(C)2002 Elsevier Science B.V.保留所有权利。
The mitochondrial permeability transition (mPT) is considered to be an important mediator of apoptosis and necrosis, and is specifically blocked by cyclosporin A (CsA). CsA has been shown to exert a potent neuroprotective action in vivo when allowed to cross the blood-brain barrier in various animal models of acute neurological insults and neurodegenerative disease. The neuroprotective effect of CsA is considered to be mediated through specific inhibition of the mitochondrial permeability transition pore (mPTP) and through inhibition of neuronal calcineurin activity. Characterization of mPT has mainly been performed in liver and heart mitochondria, and some brain studies have reported a decreased inhibitory effect of CsA and questioned the importance of mPT in brain-derived mitochondria. We have used the de-energized model of swelling to examine the mPT in brain-derived non-synaptosomal mitochondria. Ca2+-induced swelling was evaluated by electron microscopy and by measurement of spectrophotometric alterations in light scattering. Permeability transition was readily induced in a majority of the mitochondria at a wide range of Ca2+ levels and was powerfully inhibited by CSA with a half-maximal effect at similar to23 nM CsA. The swelling kinetics and CsA effects were comparable to previous findings in de-energized liver and heart mitochondria. Careful characterization of mPT and CsA effects in brain-derived mitochondria is the first step in evaluating newly developed CsA analogues capable of crossing the blood-brain barrier and preferentially entering the brain. The importance of CsA causing a shift of the mitochondrial sensitivity to Ca2+ in neurological disorders is discussed. (C) 2002 Elsevier Science B.V. All rights reserved.