Inhibition of Lipid Peroxidation in SCI

SCI 中脂质过氧化的抑制

基本信息

批准号：
8239698
负责人：
EDWARD D. HALL
金额：
$ 22.28万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8239698
关键词：
3-nitrotyrosine 4 hydroxynonenal Acute Aldehydes Antioxidants Attenuated Bladder Control Brain Brain Injuries Buffers Calcium Calpain Carbonates Cell physiology Clinical Trials Contusions Cytoplasm Cytoskeletal Proteins Dose Early treatment Elements Failure Free Radicals Functional disorder Future Generations Goals Hour Hydroxyl Radical Impairment Injury Lead Lipid Peroxidation Lipids Locomotor Recovery Logic Mediating Membrane Lipids Mental Depression Mitochondria Modeling Mus Nerve Degeneration Neurologic Neurological outcome Nitric Oxide Synthase Nitrogen Dioxide Peroxonitrite Pharmaceutical Preparations Phenelzine Post-Translational Protein Processing Production Proteolysis Rattus Reactive Nitrogen Species Reactive Oxygen Species Recovery Spinal Cord Spinal Cord Contusions Spinal cord injury Stress Testing Therapeutic Thoracic spinal cord structure Tissues Traumatic Brain Injury Treatment Efficacy Tyrosine Work attenuation controlled cortical impact improved lipid peroxidation inhibitor mitochondrial dysfunction neuroprotection neurotoxic nitration oxidative damage perhydroxyl radical relating to nervous system research study respiratory success tempol treatment strategy uptake white matter

项目摘要

DESCRIPTION (provided by applicant): We have previously shown 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 hrs after spinal cord injury (SCI). 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 further shown that treatment with the potent LP inhibitor U-83836E 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 showing a partial attenuation of post-injury LP-related neural damage' even when the LP inhibitor is administered within the first 15 min. after injury, strongly point to the logic of an antioxidant neuroprotective strategy that combines a LP inhibitor U-83836E with the LP-derived lipid aldehyde 4-hydroxynonenal (4-HNE) scavenger phenelzine 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 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 SCI 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. PUBLIC HEALTH RELEVANCE: This project will examine the potentially greater benefits that might be obtained in the rat thoracic spinal cord contusion injury model when multiple neuroprotective compounds that target oxidative secondary injury mechanisms are administered together. Specifically, we will test a dual treatment strategy involving the combination of the potent lipid peroxidation-inhibiting drug U-83836E with phenelzine, a commercially available compound that scavenges the neurotoxic lipid peroxidation-derived lipid aldehyde 4-hydroxynonenal (4-HNE). Each of the compounds will also be tested by themselves in order for comparison to the combination treatments.

描述（由申请人提供）：我们之前已经表明，强效活性氮（RNS）过氧亚硝酸盐（PN）的产生是脂质过氧化（LP）和蛋白质修饰（羰基化和酪氨酸硝化）对线粒体和其他细胞造成氧化损伤的原因。脊髓损伤（SCI）后最初几个小时内的细胞成分。 PN 介导的氧化损伤导致脑线粒体功能障碍并最终衰竭。由于线粒体功能（包括钙 (Ca++) 缓冲）氧化受损，创伤后细胞内 Ca++ 超载加剧，导致钙蛋白酶介导的细胞骨架降解、神经变性和神经损伤。我们进一步表明，在小鼠 TBI 模型中，使用强效 LP 抑制剂 U-83836E 治疗可以部分减轻创伤后脑 LP 损伤、线粒体功能障碍和钙蛋白酶介导的细胞骨架损伤。最重要的是，这种效果的窗口期至少是受伤后 12 小时。然而，我们的初步结果显示，即使在前 15 分钟内施用 LP 抑制剂，损伤后 LP 相关的神经损伤也会部分减弱。损伤后，强烈指出抗氧化神经保护策略的逻辑，该策略将 LP 抑制剂 U-83836E 与 LP 衍生的脂醛 4-羟基壬烯醛 (4-HNE) 清除剂苯乙肼相结合，以实现更大程度的神经保护。因此，所提出的实验的总体目标是探索这样的假设：在多个点中断创伤后继发性氧化损伤将产生数量上更大的神经保护作用，且变异性更小，这将在未来的 SCI 临床试验中获得更大的转化成功机会。联合治疗不仅可以增加最大的神经保护作用，还可以延长抑制 TBI 后继发性脑损伤的治疗窗。公共健康相关性：该项目将研究当同时施用多种针对氧化继发性损伤机制的神经保护化合物时，在大鼠胸脊髓挫伤损伤模型中可能获得的潜在更大益处。具体来说，我们将测试一种双重治疗策略，涉及强效脂质过氧化抑制药物 U-83836E 与苯乙肼的组合，苯乙肼是一种市售化合物，可清除神经毒性脂质过氧化衍生的脂质醛 4-羟基壬烯醛 (4-HNE)。每种化合物也将进行自身测试，以便与组合治疗进行比较。