NEUROPROTECTION AFTER TRAUMATIC INJURY

细胞内钙的过度增加似乎是一个关键因素， 创伤后组织病理学后遗症中病理生理学事件 脑损伤 尽管最近已经给予了相当大的关注， 药理学拮抗剂的潜在神经保护作用 N-甲基-D-天冬氨酸（NMDA）受体（其通过减少钙 通过谷氨酸受体相关离子通道流入神经元）， 这些药物不太可能在所有类型中都特别有效 脑损伤 此外，由于神经化学细胞和 TBI的分子后遗症是多种多样的，很可能一些 一种联合（鸡尾酒）治疗的形式将是最有效的， 逆转中枢神经系统创伤的继发性后果。 使用协调的 一组实验室模型，以及我们的药理学经验， 干预，我们建议评估新的药理学化合物， 可以影响钙诱导的细胞死亡，并检查以下内容 假设：1）轴突损伤后神经元损伤主要是 涉及细胞骨架降解，并将得到最佳保护， 减轻或预防细胞骨架损伤的治疗剂， 蛋白水解（钙激活中性蛋白酶的特异性抑制剂 （CANP），包括钙蛋白酶抑制剂Ceph 1190和钙蛋白酶抑制剂），2） 孤立性皮层损伤后的神经元损伤 受体介导的功能障碍，因此可能更容易受到 靶向受体系统（NMDA、非NMDA和 钙通道）被认为参与创伤后钙内流 (the非NMDA拮抗剂GYK 152466，竞争性NMDA拮抗剂 LY 233053，突触前谷氨酸释放阻滞剂BW 619 C89，或新的 钙通道/5-羟色胺拮抗剂-依莫帕米）;和3） 混合轴突/皮质损伤的实验模型，如外侧 液体冲击脑损伤，将最大限度地受益于组合 （鸡尾酒）两种类型的药物治疗。

Excessive increases in intracellular calcium appear to be a critical pathophysiologic event in many histopathological sequelae of traumatic brain injury. Although considerable attention has been recently given to the potential neuroprotective effects of pharmacologic antagonists of the N-methyl-D-aspartate (NMDA) receptor (Which act by reducing calcium influx into neurons via glutamate receptor-associated ion channels), it is unlikely that these agents will be singularly efficacious in all types of brain injury. Moreover, since the neurochemical cellular and molecular sequelae of TBI are diverse and varied, it is likely that some form of combined (cocktail) therapy will be optimally effective in reversing the secondary consequences of CNS trauma. Using a coordinated set of laboratory models, and our experience with pharmacologic intervention, we propose to evaluate novel pharmacologic compounds that can affect calcium-induced cell death and examine the following hypotheses: 1) that neuronal damage following axonal injury primarily involves cytoskeletal degradation and will be optimally protected by therapeutic agents that attenuate or prevent cytoskeletal injury and proteolysis (specific inhibitors of calcium-activated neutral proteases (CANPs), including the calpain inhibitor Ceph 1190 and calpastatin), 2) that the neuronal damage following isolated cortical injury involves receptor-mediated dysfunction and may therefore be more amenable to pharmacotherapies targeted at receptor systems (NMDA, non-NMDA and calcium-channel) believed to be involved in post-traumatic calcium influx (the non-NMDA antagonist GYK152466, the competitive NMDA antagonist LY233053, the presynaptic glutamate release blocker BW619C89, or novel calcium-channel/serotonin antagonist (s)-emopamil); and 3) that experimental models of mixed axonal/cortical injury, such as lateral fluid-percussion brain injury, will maximally benefit from a combination (cocktail) of both types of pharmacotherapies.