Institute of Physiology, Academy of Sciences of the Czech Republic, vvi, Vídenská 1083, 142 20 Prague 4, Czech Republic.
Neurochem Int. 2010 Feb;56(3):394-403. doi: 10.1016/j.neuint.2009.11.011. Epub 2009 Nov 18.
Our previous work demonstrated the marked decrease of mitochondrial complex I activity in the cerebral cortex of immature rats during the acute phase of seizures induced by bilateral intracerebroventricular infusion of dl-homocysteic acid (600 nmol/side) and at short time following these seizures. The present study demonstrates that the marked decrease ( approximately 60%) of mitochondrial complex I activity persists during the long periods of survival, up to 5 weeks, following these seizures, i.e. periods corresponding to the development of spontaneous seizures (epileptogenesis) in this model of seizures. The decrease was selective for complex I and it was not associated with changes in the size of the assembled complex I or with changes in mitochondrial content of complex I. Inhibition of complex I was accompanied by a parallel, up to 5 weeks lasting significant increase (15-30%) of three independent mitochondrial markers of oxidative damage, 3-nitrotyrosine, 4-hydroxynonenal and protein carbonyls. This suggests that oxidative modification may be most likely responsible for the sustained deficiency of complex I activity although potential role of other factors cannot be excluded. Pronounced inhibition of complex I was not accompanied by impaired ATP production, apparently due to excess capacity of complex I documented by energy thresholds. The decrease of complex I activity was substantially reduced by treatment with selected free radical scavengers. It could also be attenuated by pretreatment with (S)-3,4-DCPG (an agonist for subtype 8 of group III metabotropic glutamate receptors) which had also a partial antiepileptogenic effect. It can be assumed that the persisting inhibition of complex I may lead to the enhanced production of reactive oxygen and/or nitrogen species, contributing not only to neuronal injury demonstrated in this model of seizures but also to epileptogenesis.
我们之前的工作表明，在双侧侧脑室注射 dl-高半胱氨酸（600nmol/侧）诱导的癫痫发作急性期以及这些发作后短时间内，不成熟大鼠大脑皮层中线粒体复合物 I 活性明显降低。本研究表明，在这些发作后长达 5 周的存活期间，即该癫痫发作模型中自发发作（癫痫发生）发展的时期，线粒体复合物 I 活性明显降低（约 60%）。这种降低是复合物 I 的选择性降低，与组装的复合物 I 的大小变化或复合物 I 的线粒体含量变化无关。复合物 I 的抑制伴随着平行的、持续长达 5 周的显著增加（15-30%），有三个独立的线粒体氧化损伤标志物，即 3-硝基酪氨酸、4-羟基壬烯醛和蛋白质羰基。这表明氧化修饰可能是复合物 I 活性持续缺乏的最可能原因，尽管不能排除其他因素的潜在作用。复合物 I 的明显抑制并没有伴随着 ATP 产生的受损，这显然是由于复合物 I 的过剩能力，这一能力是通过能量阈值来证明的。使用选定的自由基清除剂治疗可显著减少复合物 I 的减少。用（S）-3,4-DCPG（III 型代谢型谷氨酸受体亚型 8 的激动剂）预处理也可以减轻这种情况，它也具有部分抗癫痫发生作用。可以假设，复合物 I 的持续抑制可能导致活性氧和/或氮物质的产生增加，不仅对该癫痫发作模型中显示的神经元损伤有贡献，而且对癫痫发生也有贡献。
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