Inhibition of Lipid Peroxidation in SCI

描述(由申请人提供)：我们先前已经证明，在脊髓损伤(SCI)后的第一个小时内，通过脂质过氧化(LP)和蛋白质修饰(羰化和酪氨酸硝化)对线粒体和其他细胞元素造成氧化损伤，产生有效的反应性氮物种(RNS)过氧亚硝酸盐(PN)。PN介导的氧化损伤导致脑线粒体功能障碍，最终导致脑功能衰竭。由于线粒体功能的氧化损害(包括钙(Ca++)缓冲)，创伤后细胞内钙超载加剧，导致钙蛋白介导的细胞骨架降解、神经变性和神经功能损害。我们进一步证明，用有效的LP抑制剂U-83836E治疗可以部分减轻小鼠脑创伤后的LP损伤、线粒体功能障碍和Calain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，即使在头15分钟内给予LP抑制剂，也能部分减轻损伤后LP相关的神经损伤。损伤后，强烈指出抗氧化性神经保护策略的逻辑，该策略将LP抑制剂U-83836E与LP衍生的脂质醛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，拟议实验的总体目标是探索这样一种假设，即在多个点上阻断创伤后继发性氧化损伤将产生更大的神经保护效果，而变异性更小，从而在未来的脊髓损伤临床试验中有更大的翻译成功机会。联合应用不仅可以提高最大的神经保护作用，而且可以延长抑制脑损伤继发性损伤的治疗窗口。

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.