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）后的最初几个小时内，强效活性氮物种（RNS）过氧亚硝酸盐（PN）的产生负责脂质过氧化（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元件的氧化损伤。pn介导的氧化损伤导致脑线粒体功能障碍并最终衰竭。由于线粒体功能（包括钙缓冲）的氧化损害，创伤后细胞内钙超载加剧，导致钙蛋白酶介导的细胞骨架降解、神经变性和神经损伤。我们进一步证明，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calpain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，即使在损伤后的前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衰减，这有力地指出了一种抗氧化神经保护策略的逻辑，该策略将LP抑制剂U-83836E与LP衍生的脂质醛4-羟基壬烯醛（4-HNE）清除剂苯乙胺结合起来，以实现更大程度的神经保护。因此，本实验的总体目标是探索这样一种假设，即在多个点中断创伤后继发性氧化损伤将在数量上产生更大的神经保护作用，并且变异性更小，这将有更大的机会在未来的SCI临床试验中获得转化成功。联合用药不仅可以增加最大的神经保护作用，而且可以延长脑外伤后继发性脑损伤的治疗窗口期。

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.