The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice.
The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice.
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DOI：
10.1523/jneurosci.6303-11.2012
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发表时间：
2012-02-29
期刊：
影响因子：
--
通讯作者：
Ten VS
中科院分区：
文献类型：
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作者：
Niatsetskaya ZV;Sosunov SA;Matsiukevich D;Utkina-Sosunova IV;Ratner VI;Starkov AA;Ten VS
氧化应激和钙中毒是缺氧缺血性脑损伤的机制。这项工作研究了线粒体呼吸链的部分抑制是否通过限制再灌注过程中氧化自由基的产生来保护HI-brain。复合物-i （C-I）抑制剂、嘧达宾(P)或对照物处理的p10小鼠产生hi损伤。P可显著降低HI损伤程度。从p处理动物的缺血半球分离的线粒体显示H2O2排放减少，线粒体基质氧化损伤减轻，对ca2 ++的耐受性增强，引发通透性过渡孔打开。当暴露于100% O2增强再灌注驱动的氧化应激时，P的保护作用也被观察到，这只会加重v处理小鼠的脑损伤。在体外实验中，完整的脑线粒体在高氧条件下会显著增加H2O2的排放，导致钙离子缓冲能力的大量丧失。然而，在C-I抑制剂鱼藤酮或抗氧化剂过氧化氢酶的存在下，高氧的这些影响被消除。我们的数据表明，再灌注驱动的C-I依赖线粒体呼吸的恢复不仅有助于细胞存活，而且还会对线粒体造成氧化损伤，从而增强ca2 +缓冲能力的丧失。这突出了一种针对hi脑损伤的新的神经保护策略，其中主要的治疗原则是药物衰减，而不是早期再灌注时线粒体氧化代谢的增强。
Oxidative stress and Ca++ toxicity are mechanisms of hypoxic-ischemic (HI) brain injury. This work investigates if partial inhibition of mitochondrial respiratory chain protects HI-brain by limiting generation of oxidative radicals during reperfusion. HI-insult was produced in p10 mice treated with complex-I (C-I) inhibitor, pyridaben (P), or vehicle. Administration of P significantly decreased extent of HI injury. Mitochondria isolated from the ischemic hemisphere in P-treated animals showed reduced H2O2 emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to Ca++ triggered opening of permeability transition pore. Protective effect of P administration was also observed when the reperfusion-driven oxidative stress was augmented by the exposure to 100% O2 which exacerbated brain injury only in V-treated mice. In vitro, intact brain mitochondria dramatically increased H2O2 emission in response to hyperoxia, resulting in substantial loss of Ca++ buffering capacity. However, in the presence of C-I inhibitor, rotenone, or antioxidant, catalase, these effects of hyperoxia were abolished. Our data suggest that the reperfusion-driven recovery of C-I dependent mitochondrial respiration contributes not only to the cellular survival, but also causes an oxidative damage to the mitochondria, potentiating a loss of Ca++ buffering capacity. This highlights a novel neuroprotective strategy against HI-brain injury where the major therapeutic principle is a pharmacological attenuation, rather than an enhancement of mitochondrial oxidative metabolism during early reperfusion.