NEUROPROTECTION AFTER TRAUMATIC INJURY

创伤后的神经保护

• 批准号: 6112028
• 负责人: TRACY K. MCINTOSH
• 金额: $ 17.32万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112028
• 关键词: NMDA receptors; aminoacid inhibitor; axon; brain injury; calcium; calcium channel; calcium flux; calpain; cell death; cytoskeleton; excitatory aminoacid; glutamates; guinea pigs; laboratory rat; miniature swine; neural transmission; neuropharmacology; neuroprotectants; protease inhibitor; trauma

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.

细胞内钙的过度增加似乎是一个关键 创伤后遗症的许多组织病理学后遗症中的病理生理事件 脑损伤。 尽管最近受到了相当大的关注 药物拮抗剂的潜在神经保护作用 N-甲基-D-天冬氨酸 (NMDA) 受体（其作用是减少钙 通过谷氨酸受体相关离子通道流入神经元）， 这些药物不太可能对所有类型都特别有效 脑损伤。 此外，由于神经化学细胞和 TBI 的分子后遗症多种多样，很可能有些 联合（鸡尾酒）疗法的形式将最有效地 扭转中枢神经系统创伤的继发后果。 使用协调的 一套实验室模型，以及我们在药理学方面的经验 干预，我们建议评估新的药理化合物 可以影响钙诱导的细胞死亡并检查以下内容 假设：1）轴突损伤后的神经元损伤主要是 涉及细胞骨架降解，并将受到最佳保护 减轻或预防细胞骨架损伤的治疗剂，以及 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) 孤立性皮质损伤后的神经元损伤涉及 受体介导的功能障碍，因此可能更容易 针对受体系统（NMDA、非 NMDA 和 钙通道）被认为参与创伤后钙流入 （非 NMDA 拮抗剂 GYK152466，竞争性 NMDA 拮抗剂 LY233053，突触前谷氨酸释放阻滞剂 BW619C89，或新型 钙通道/血清素拮抗剂（s）-emopamil）； 3）那 混合轴突/皮质损伤的实验模型，例如侧向损伤 液体冲击脑损伤，将最大程度地受益于组合 两种药物疗法的（鸡尾酒）。