Multi-Mechanism Inhibition of Lipid Peroxidation in TBI

TBI 中脂质过氧化的多机制抑制

基本信息

批准号：
8658871
负责人：
EDWARD D. HALL
金额：
$ 32.16万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658871
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole 3-nitrotyrosine 4 hydroxynonenal Aldehydes Antioxidants Attenuated Brain Brain Injuries Buffers Calcium Calpain Clinical Trials Complex Cyclosporine Dose Effectiveness Elements Extravasation Failure Free Radicals Functional disorder Future Generations Goals Human Impairment Injury Intervention Lesion Lipid Peroxidation Lipids Logic Mediating Membrane Lipids Mitochondria Modeling Molecular Motor Mus Nerve Degeneration Nervous System Trauma Neurologic Neurons Patients Permeability Peroxonitrite Pharmaceutical Preparations Phase III Clinical Trials Phenelzine Post-Translational Protein Processing Production Rattus Reactive Nitrogen Species Reactive Oxygen Species Recovery of Function Regimen Reporting Subarachnoid Hemorrhage Testing Therapeutic Tissues Translating Traumatic Brain Injury Traumatic Subarachnoid Hemorrhage Treatment Efficacy Treatment Protocols Tyrosine attenuation base cognitive function controlled cortical impact design improved inhibitor/antagonist injured lipid peroxidation inhibitor mitochondrial dysfunction mortality neuroprotection neurotoxic nitration oxidative damage protective effect public health relevance relating to nervous system research study respiratory response success treatment strategy

项目摘要

DESCRIPTION (provided by applicant): We have previously documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and protein modification (carbonylation and tyrosine nitration) to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). The PN-mediated oxidative damage leads to brain mitochondrial dysfunction and ultimately failure. As a consequence of oxidative compromise of mitochondrial function including calcium (Ca++) buffering), posttraumatic intracellular Ca++ overload is exacerbated leading to calpain-mediated cytoskeletal degradation, neurodegeneration and neurological impairment. We have preliminarily shown that treatment with the potent LP inhibitor U-83836E, with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine or with the mitochondrial permeability transition inhibitor cyclosporine (CsA) can partially attenuate posttraumatic brain LP damage, mitochondrial dysfunction and calpain-mediated cytoskeletal damage in a mouse TBI model. Most importantly, the window for this effect is at least 12 hrs post-injury. However, our preliminary results show only a partial attenuation of post-injury LP-related neural damage' even when any of these antioxidant compounds is individually administered after injury. This partial neuroprotective effect strongly points to the logic of an antioxidant neuroprotective strategy that combines either two or all three of these mechanistically complimentary antioxidant compounds to achieve a greater degree of neuroprotection. Therefore, the overall goal of the proposed experiments is to explore the hypothesis that interrupting post-traumatic secondary LP oxidative damage at multiple points will produce a quantitatively greater neuroprotective effect with less variability that will have a greater chance of translational success in future TBI clinical trials. The combination approach should not only increase the maximal neuroprotective effect, but may also prolong the therapeutic window for inhibition of secondary brain injury after TBI.

描述（由申请人提供）：我们先前已经证明，有效的反应性氮物种（RNS）过氧亚硝酸盐（PN）负责通过脂质过氧化（LP）和蛋白质修饰（Carbonylation和酪氨酸硝化）在第一个72 hr中通过脂质过氧化（LP）和蛋白质修饰（羰基化和酪氨酸硝化）造成氧化损伤。 PN介导的氧化损伤导致脑线粒体功能障碍，并最终导致失败。由于包括钙（CA ++）缓冲）的线粒体功能的氧化损害，创伤后CA ++过载会加剧，导致钙蛋白酶介导的细胞骨骼降解，神经变性，神经变性和神经学障碍。 We have preliminarily shown that treatment with the potent LP inhibitor U-83836E, with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine or with the mitochondrial permeability transition inhibitor cyclosporine (CsA) can partially attenuate posttraumatic brain LP damage, mitochondrial小鼠TBI模型中的功能障碍和钙蛋白酶介导的细胞骨架损伤。最重要的是，这种效果的窗口至少是受伤后的12小时。但是，我们的初步结果表明，即使在受伤后单独施用这些抗氧化剂化合物，与伤害后LP相关的神经损伤的部分衰减。这种部分神经保护作用强烈指出了抗氧化神经保护策略的逻辑，该策略结合了两种或所有这些机械上的补充抗氧化剂化合物，以实现更大程度的神经保护作用。因此，提出的实验的总体目标是探讨以下假设：在多个点上断创伤后二级LP氧化损伤将产生更大的神经保护作用，而可变性较小，而具有较小的可变性在未来的TBI临床试验中，转化成功的机会更大。组合方法不仅应增加最大的神经保护作用，而且还可以延长治疗窗口，以抑制TBI后的继发性脑损伤。