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Peroxynitrite-Induced Oxidative Damage in TBI

过氧亚硝酸盐诱导的 TBI 氧化损伤

基本信息

批准号：
7209777
负责人：
EDWARD D. HALL
金额：
$ 32.3万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7209777
关键词：
Acute Address Adenine Nucleotides Adult Antioxidants Attenuated Behavioral Blood Vessels Brain Brain Injuries Buffers Calcium Calpain Carbonates Cerebrum Characteristics Classification Contusions Data Diffuse Elements End Point Esters Exposure to Extravasation Functional disorder Generations Human Development Hydroxyl Radical Injury Investigation Lead Link Lipid Peroxidation Lipids Mediating Mediator of activation protein Membrane Potentials Mitochondria Mitochondrial Proteins Modeling Modification Mus Nerve Degeneration Neurologic Neurons Nitric Oxide Synthase Nitrogen Dioxide Nucleic Acids Pathway interactions Penicillamine Peroxonitrite Pharmaceutical Preparations Pharmacologic Substance Play Post-Translational Protein Processing Production Proteins Rain Reactive Oxygen Species Recovery Relative (related person)Research Rodent Role Site Source Staging Testing Therapeutic Time Traumatic Brain Injury Tyrosine U-83836E Work central nervous system injury clinically relevant comparative concept day design improved inhibitor/antagonist injured innovation lipid peroxidation inhibitor male mitochondrial dysfunction mitochondrial membrane nitration novel prevent programs research study tempol tool

项目摘要

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（由申请人提供）：目前有大量证据支持以下概念：活性氧（ROS）介导的脂质、蛋白质和核酸氧化损伤在创伤性脑损伤（TBI）的急性病理生理学中起主要作用，抑制这种损伤的抗氧化剂药物将减少继发性脑损伤并改善神经恢复。然而，TBI抗氧化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。最近的研究表明，当线粒体由于TBI诱导的细胞内钙（Ca ++）大量升高而功能失调时，线粒体可以成为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）。PON衍生的二氧化氮（NO2）、碳酸根（CO3）和羟基（OH）自由基可导致线粒体脂质（脂质过氧化）和蛋白质（羰基化、硝化）的氧化损伤，加剧细胞内Ca ++过载并引发钙蛋白酶介导的细胞骨架降解和神经变性。本提案的具体目的是检验以下假设：1）弥漫性和局灶性TBI中的创伤后氧化损伤均由PON介导，并且PON介导的脂质和蛋白质损伤的时间过程先于钙蛋白酶介导的细胞骨架损伤和神经变性，2）线粒体功能障碍是PON的主要来源，并且线粒体是脂质和蛋白质氧化损伤的起始位点，3）PON或PON衍生的氧自由基的药理学清除剂可以保护分离的脑线粒体免受氧化损伤和功能障碍，以及4）PON或PON衍生的氧自由基的药理学清除将有效地抑制TBI后脑线粒体中的氧化损伤和功能障碍，并减弱下游细胞骨架降解和神经变性。实验将在中度和重度弥漫性和局灶性TBI模型中进行。PON在急性TBI中的作用的系统调查，并仔细检查化合物的神经保护功效，该化合物在其形成后抑制PON或阻断PON诱导的氧化损伤，预期将导致临床有效和实用的抗氧化剂神经保护策略用于急性TBI。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Selective death of newborn neurons in hippocampal dentate gyrus following moderate experimental traumatic brain injury.

DOI：
10.1002/jnr.21677
发表时间：
2008-08-01
期刊：
JOURNAL OF NEUROSCIENCE RESEARCH
影响因子：
4.2
作者：
Gao, Xiang;Deng-Bryant, Ying;Cho, Wongil;Carrico, Kimberly M.;Hall, Edward D.;Chen, Jinhui
通讯作者：
Chen, Jinhui

Antioxidant therapies for traumatic brain injury.

DOI：
10.1016/j.nurt.2009.10.021
发表时间：
2010-01
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
0
作者：
Hall ED;Vaishnav RA;Mustafa AG
通讯作者：
Mustafa AG

Lipid peroxidation in brain or spinal cord mitochondria after injury.