Anderson Michelle F, Nilsson Michael, Sims Neil R
Centre for Neuroscience, Flinders Medical Research Institute and Department of Medical Biochemistry, School of Medicine, Flinders University, SA, Adelaide, Australia.
Neurochem Int. 2004 Feb;44(3):153-9. doi: 10.1016/s0197-0186(03)00133-5.
Glutathione is a central component in the antioxidant defences of cells. We have recently reported an early and selective loss of total (reduced plus oxidised) glutathione from mitochondria isolated from rat brain following occlusion of the middle cerebral artery. This mitochondrial glutathione depletion showed an apparent association with the tissue damage that developed during subsequent reperfusion, suggesting that it could be an important determinant of susceptibility to cell loss. In the present study, we have investigated whether in vivo treatment with glutathione ethyl ester can modulate mitochondrial glutathione in the brain and whether this treatment can influence the response to focal ischemia. In further support of our previous findings, middle cerebral artery occlusion caused a duration-dependent partial loss of mitochondrial glutathione. Bilateral injections of glutathione ethyl ester immediately prior to induction of unilateral focal ischemia resulted in a substantial increase in glutathione in mitochondria from the striatum of both the non-ischemic hemisphere (190% of saline-treated controls) and the ischemic hemisphere (240% of controls) at 2h after arterial occlusion. Total tissue glutathione was not affected by the ester treatment at this time. A smaller increase in mitochondrial glutathione was observed at 3h of occlusion in the non-ischemic striatum following ester treatment but at this time point glutathione was not significantly altered in mitochondria from the ischemic hemisphere. Pre-ischemic treatment with glutathione ester did not significantly change the volume of tissue infarction assessed at 48 h following ischemia for 2 or 3h. These studies demonstrate that glutathione ethyl ester is a highly effective modulator of the mitochondrial glutathione pool in the intact brain and provides a useful means for further investigating the role of this antioxidant in the development of tissue damage in ischemia and other brain disorders.
谷胱甘肽是细胞抗氧化防御系统的核心成分。我们最近报道，大脑中动脉闭塞后，从大鼠脑部分离出的线粒体中总（还原型加氧化型）谷胱甘肽会早期且选择性地丧失。这种线粒体谷胱甘肽耗竭与随后再灌注过程中发生的组织损伤明显相关，表明它可能是细胞丢失易感性的重要决定因素。在本研究中，我们调查了用谷胱甘肽乙酯进行体内治疗是否能调节脑中的线粒体谷胱甘肽，以及这种治疗是否会影响对局灶性缺血的反应。为进一步支持我们之前的发现，大脑中动脉闭塞导致线粒体谷胱甘肽出现持续时间依赖性的部分丧失。在单侧局灶性缺血诱导前立即双侧注射谷胱甘肽乙酯，导致动脉闭塞后2小时，非缺血半球纹状体和缺血半球纹状体线粒体中的谷胱甘肽大幅增加（分别为盐水处理对照组的190%和240%）。此时，酯处理对总组织谷胱甘肽没有影响。酯处理后，在闭塞3小时时，非缺血纹状体线粒体中的谷胱甘肽有较小幅度增加，但此时缺血半球线粒体中的谷胱甘肽没有明显变化。缺血前用谷胱甘肽乙酯治疗，在缺血2小时或3小时后48小时评估的组织梗死体积没有显著改变。这些研究表明，谷胱甘肽乙酯是完整大脑中线粒体谷胱甘肽池的高效调节剂，为进一步研究这种抗氧化剂在缺血及其他脑部疾病中组织损伤发展中的作用提供了有用的手段。
