Peroxynitrite-mediated oxidative damage to brain mitochondria: Protective effects of peroxynitrite scavengers
Peroxynitrite-mediated oxidative damage to brain mitochondria: Protective effects of peroxynitrite scavengers
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DOI：
10.1002/jnr.21360
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发表时间：
2007-08-01
影响因子：
4.2
通讯作者：
Hall, Edward D.
中科院分区：
文献类型：
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作者：
Singh, Indrapal N.;Sullivan, Patrick G.;Hall, Edward D.
过氧亚硝酸盐介导的氧化损伤与创伤性脑损伤（TBI）后的脑线粒体呼吸功能障碍有关，TBI发生在神经元丢失之前。本研究的目的是研究过氧亚硝酸盐供体SIN-1（3-morpholinosydnonimine）对分离的脑线粒体的有害影响，并筛选青霉胺，化学计量（1：1）过氧亚硝酸盐清除剂，和tempol，过氧亚硝酸盐衍生的自由基的催化清除剂，作为抗氧化线粒体保护剂。暴露于SIN-1的分离的线粒体引起呼吸控制率的显著剂量依赖性降低，并伴随着状态11呼吸的显著增加，随后显著降低这些功能改变与线粒体蛋白羰基（PC）、脂质过氧化相关的4-羟基壬烯醛（4-HNE）、和3-硝基酪氨酸（3-NT）含量。盐酸青霉胺（10 μ M）部分但显著（P < 0.05）防止SIN-1诱导的状态III和V的降低。然而，2.5 μ M浓度的tempol能够显著拮抗4倍摩尔过量（10 μ M）浓度的SIN-1，其效果与更高浓度的tempol一样，与tempol通过催化机制工作的可能性一致。青霉胺和tempol对线粒体呼吸的保护作用与PC，4-HNE和3-NT的衰减平行发生。这些结果表明，SIN-1导致线粒体氧化损伤和复合物I功能障碍，并且靶向过氧亚硝酸根或其自由基的抗氧化剂化合物可能是治疗神经损伤的有效线粒体保护剂。(c)2007 Wiley-Liss，Inc.
Peroxynitrite-mediated oxidative damage has been implicated in brain mitochondrial respiratory dysfunction after traumatic brain injury (TBI), which precedes the onset of neuronal loss. The aim of this study was to investigate the detrimental effects of the peroxynitrite donor SIN-1 (3-morpholinosydnonimine) on isolated brain mitochondria and to screen penicillamine, a stoichiometric (1:1) peroxynitrite-scavenging agent, and tempol, a catalytic scavenger of peroxynitrite-derived radicals, as antioxidant mitochondrial protectants. Exposure of the isolated mitochondria to SIN-1 caused a significant dose-dependent decrease in the respiratory control ratio and was accompanied by a significant increase in state 11 respiration, followed by significant decreases (P < 0.05) in states III and V. These functional alterations occurred together with significant increases in mitochondrial protein carbonyl (PC), lipid peroxidation-related 4-hydroxynonenal (4-HNE), and 3-nitrotyrosine (3-NT) content. Penicillamine hydrochloride (10 mu M) partially but significantly (P < 0.05) protected against SIN-1-induced decreases in states III and V. However, a 2.5 mu M concentration of tempol was able to significantly antagonize a 4-fold molar excess (10 mu M) concentration of SIN-1 as effectively as were higher tempol concentrations, consistent with the likelihood that tempol works by a catalytic mechanism. The protection of mitochondrial respiration by penicillamine and tempol occurred in parallel with attenuation of PC, 4-HNE, and 3-NT. These results indicate that SIN-1 causes mitochondrial oxidative damage and complex I dysfunction and that antioxidant compounds that target either peroxynitrite or its radicals may be effective mitochondrial protectants in the treatment of neural injury. (c) 2007 Wiley-Liss, Inc.