Inhibition of Lipid Peroxidation in SCI

描述（由申请人提供）：我们之前已经证明，在脊髓损伤（SCI）后的第一个小时内，强效活性氮物质（RNS）过氧亚硝酸盐（PN）的产生是通过脂质过氧化（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成分造成氧化损伤的原因。PN介导的氧化损伤导致脑线粒体功能障碍并最终衰竭。作为线粒体功能（包括钙（Ca++）缓冲）的氧化损害的结果，创伤后细胞内Ca++过载加剧，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，用有效的LP抑制剂U-83836 E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，这种影响的窗口至少是受伤后12小时。然而，我们的初步结果显示，即使在损伤后的前15分钟内给予LP抑制剂，损伤后LP相关的神经损伤也会部分减弱，这强烈地指出了抗氧化剂神经保护策略的逻辑，该策略将LP抑制剂U-83836 E与LP衍生的脂质醛4-羟基壬烯醛（4-HNE）清除剂苯乙肼组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以下假设：在多个点中断创伤后继发性氧化损伤将产生定量更大的神经保护作用，具有更小的变异性，这将在未来的SCI临床试验中获得更大的转化成功机会。该组合方法不仅应增加最大神经保护作用，而且还可延长抑制TBI后继发性脑损伤的治疗窗。 公共卫生相关性：该项目将研究当靶向氧化性继发性损伤机制的多种神经保护化合物一起施用时，在大鼠胸脊髓挫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，包括有效的脂质过氧化抑制药物U-83836 E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）。每种化合物也将单独进行检测，以与联合治疗进行比较。

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.