Peroxynitrite-Induced Oxidative Damage in TBI

过氧亚硝酸盐诱导的 TBI 氧化损伤

• 批准号: 7014578
• 负责人: EDWARD D. HALL
• 金额: $ 33.26万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014578
• 关键词: adenine nucleoside; antioxidants; behavior test; brain disorder chemotherapy; brain injury; calcium channel blockers; calcium flux; carboxylation; cytoskeleton; free radical oxygen; free radical scavengers; high performance liquid chromatography; hydroxylation; immunocytochemistry; laboratory mouse; mitochondrial disease /disorder; nerve injury; neural degeneration; neuroprotectants; nitration; oxidative stress; penicillamine; peroxidation; peroxynitrites; western blottings

DESCRIPTION (provided by applicant): Extensive evidence now supports the concept that the reactive oxygen species (ROS)-mediated oxidative damage to lipids, proteins and nucleic acids plays a major role in the acute pathophysiology of traumatic brain injury (TBI), and that antioxidant drugs which inhibit this damage will reduce secondary brain injury and improve neurological recovery. However, the optimal design of antioxidant treatment for TBI requires a more complete understanding of the source and characteristics of ROS formation. Recent work indicates that mitochondria can become an important source of ROS when they become dysfunctional as a result of the massive TBI-induced rise in intracellular calcium (Ca++). Other work suggests that a key ROS formed by mitochondria is peroxynitrite (PON). PON-derived nitrogen dioxide (,NO2), carbonate (,CO3) and hydroxyl (,OH) radicals can cause oxidative damage to mitochondrial lipids (lipid peroxidation) and proteins (carbonylation, nitration) exacerbating intracellular Ca++ overload and triggering calpain-mediated cytoskeletal degradation and neurodegeneration. The specific aims of this proposal are to test the following hypotheses: 1) that post-traumatic oxidative damage in both diffuse and focal TBI is mediated by PON and that the time course of PON-mediated damage to lipids and proteins precedes calpain-mediated cytoskeletai damage and neurodegeneration, 2) that mitochondrial dysfunction is a major source of PON, and that mitochondria are an initial site of lipid and protein oxidative damage, 3) that pharmacological scavengers of PON or PON-derived oxygen radicals can protect isolated brain mitochondria from oxidative damage and dysfunction and 4) that pharmacological scavenging of PON or PON-dedved oxygen radicals will effectively inhibit post-TBI oxidative damage and dysfunction in brain mitochondria and attenuate downsteam cytoskeletal degradation and neurodegeneration. Experiments will be carried out in models of moderate and severe diffuse and focal TBI. A systematic investigation of the role of PON in acute TBI, and a careful examination of the neuroprotective efficacy of compounds which scavenge it after it is formed or that block PON-induced oxidative damage is expected to lead to a clinically effective and practical antioxidant neuroprotective strategy for acute TBI.

描述（申请人提供）：广泛的证据现在支持这样的概念：反应性氧（ROS）介导的对脂质，蛋白质和核酸的氧化性损害在创伤性脑损伤（TBI）的急性病理生理学中起主要作用，并抑制这种抗氧化药物会损害这种损伤并改善二级脑损伤。但是，对TBI的抗氧化剂治疗的最佳设计需要对ROS形成的来源和特征有更全面的了解。最近的工作表明，由于TBI诱导的细胞内钙（Ca ++）的大量诱导的升高，线粒体会成为ROS的重要来源。其他工作表明，线粒体形成的关键ROS是过氧亚硝酸盐（PON）。围栏衍生的二氧化氮（，NO2），碳酸盐（，CO3）和羟基（，OH）自由基会对线粒体脂质（脂质过氧化）和蛋白质（碳纤维过氧化）和蛋白质（碳化，硝化）造成氧化损害神经变性。 The specific aims of this proposal are to test the following hypotheses: 1) that post-traumatic oxidative damage in both diffuse and focal TBI is mediated by PON and that the time course of PON-mediated damage to lipids and proteins precedes calpain-mediated cytoskeletai damage and neurodegeneration, 2) that mitochondrial dysfunction is a major source of PON, and that线粒体是脂质和蛋白质氧化损伤的初始部位，3）3）pON或PON衍生的氧自由基的药理学清除剂可以保护孤立的脑线粒体免受氧化性损伤和功能障碍以及4）的药理清除型PON或PON型脑损伤，并有效地损害了PON或PON型的氧气损伤。线粒体和衰减下降的细胞骨架降解和神经变性。实验将在中等和重度弥漫性和局灶性TBI模型中进行。对PON在急性TBI中的作用的系统研究，以及对化合物的神经保护功效进行仔细检查，这些化合物在形成后清除它，或者该阻塞PON诱导的氧化损伤预计会导致临床有效且实用的抗氧化剂神经保护剂的急性TBI策略。