Cerebal Ischemia During Anesthesia and Surgery

描述(逐字摘自申请人的摘要)有相当多的 麻醉期间脑缺血的风险以及心脏、神经血管和 颈动脉手术。这培养了人们对识别特工的兴趣 这可能会保护大脑免受缺血损伤。麻醉药合乎逻辑 候选神经保护剂，因为它们减少了兴奋性毒性损伤。一个 许多研究表明麻醉剂具有神经保护作用。在这些 研究表明，只有在短暂的恢复期后才对损伤进行评估。近期 资料表明，脑缺血后损伤是一个动态的过程，在这个过程中 神经元在最初的缺血后持续很长一段时间的死亡。大部分 这种迟发性神经元死亡是由细胞凋亡引起的。麻醉药是否可以 提供长期的永久性神经保护尚不清楚。在现在 建议，麻醉剂的长期神经保护效果将是 下定决心。将要检验的假设是麻醉剂早期减少。 兴奋性毒性引起的神经元损伤，但不能防止迟发性 细胞凋亡引起的神经元死亡以及麻醉药和药物的联合应用 抗细胞凋亡剂可能产生强大而持久的神经保护作用。在……里面 第一阶段，巴比妥酸盐的剂量相关神经保护作用 戊巴比妥和挥发性麻醉剂异氟醚的评估将在 局灶性脑缺血模型。损伤将在两次短时(2)后进行评估 天)和较长的恢复期(2周至3个月)以确定 神经保护是暂时的或永久的。在第二阶段， 麻醉药对导致脑缺血后细胞凋亡过程的影响 将会被确定。具体地说，细胞色素c释放的时间分布， Caspase9、8、3和c-Jun-N末端激酶(JNK)的激活 脑缺血后将通过免疫组织化学，Western 免疫印迹和半胱氨酸天冬氨酸氨基转移酶(JNK. 形态损伤将通过光学和电子显微镜以及 TUNEL染色。在这个阶段，每个人的相对贡献 导致细胞凋亡的过程以及麻醉剂对这些细胞的影响 进程将被确定。第三阶段，神经保护作用 麻醉药(抗兴奋性毒性)和抗细胞凋亡剂的组合 将在局灶性缺血模型中进行评估。具体地说， 麻醉药物联合抑制半胱氨酸氨基转移酶9、3、8和JNK的作用 缺血性脑损伤将在短恢复期和长恢复期后确定。 拟议中的实验将为深入了解 麻醉药物对缺血性脑损伤病理生理的影响 可能会确定应被视为在 临床环境。这项研究的长期目标是防止 麻醉和手术患者发生缺血性脑损伤的临床研究 做手术。

DESCRIPTION (Verbatim from the applicant's abstract) There is a considerable risk of cerebral ischemia during anesthesia and cardiac, neurovascular and carotid artery surgery. This has fostered an interest in identifying agents that might protect the brain against ischemic injury. Anesthetics are logical candidate neuroprotective agents because they reduce excitotoxic injury. A number of studies have shown that anesthetics are neuroprotective. In these studies, the injury was evaluated after only a short recovery period. Recent data indicate that post-ischemic brain injury is a dynamic process in which neurons continue to die for a long period after the initial ischemia. Much of this delayed neuronal death is caused by apoptosis. Whether anesthetics can provide long-term permanent neuroprotection is not known. In the present proposal, the long term neuroprotective efficacy of anesthetics will be determined. The hypothesis that will be tested is that anesthetics reduce early neuronal injury caused by excitotoxicity but they do not prevent delayed neuronal death caused by apoptosis and that the combination of anesthetics and anti-apoptotic agents might produce robust and permanent neuroprotection. In the first phase, the dose-related neuroprotective efficacy of the barbiturate pentobarbital and of the volatile anesthetic isoflurane will be evaluated in a model of focal cerebral ischemia. Injury will be evaluated after both short (2 days) and long (2 weeks to 3 months) recovery periods to determine whether neuroprotection is transient or permanent. In the second phase, the effect of anesthetics on the processes that lead to apoptosis in the post-ischemic brain will be determined. Specifically, the temporal profile of cytochrome c release, activation of caspases 9, 8 and 3 and of c-Jun-N-terminal kinase (JNK) in the post-ischemic brain will be determined by immunohistochemistry, Western blotting and the measurement of the activities of the caspases and (JNK. Morphologic injury will be evaluated by light and electron microscopy and by TUNEL staining. In this phase, the relative contribution of each of the processes that lead to apoptosis and the impact of anesthetic agents on these processes will be determined. In the third phase, the neuroprotective efficacy of a combination of anesthetics (anti-excitotoxic) and anti-apoptotic agents will be evaluated in a model of focal ischemia. Specifically, the effect of inhibition of caspases 9, 3, 8 and JNK in combination with anesthetic agents on ischemic brain injury will be determined after short and long recovery periods. The proposed experiments will provide insight into the mechanisms by which anesthetic agents influence the pathophysiology of ischemic cerebral injury and may identify agents that should be considered as potentially protective in the clinical setting. The long term goals of the research are to prevent the occurrence of isehemic brain injury in patients undergoing anesthesia and surgery.