Multi-Mechanism Inhibition of Lipid Peroxidation in TBI

描述（由申请人提供）：我们之前已经证明，在创伤性脑损伤（TBI）后的最初72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。我们初步表明，在小鼠TBI模型中，用强力LP抑制剂U-83836E、LP衍生的脂质醛4-羟基壬烯醛（4-HNE）清除剂苯elzine或线粒体通透性过渡抑制剂环孢素（CsA）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，即使在损伤后单独使用任何这些抗氧化剂化合物，损伤后lp相关的神经损伤也只有部分衰减。这种部分神经保护作用有力地指出了一种抗氧化神经保护策略的逻辑，这种策略结合了两种或三种机制互补的抗氧化化合物，以达到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一种假设，即在多个点中断创伤后继发性LP氧化损伤将在数量上产生更大的神经保护作用，而变异性更小，这将具有一个重要的影响

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.