Cerebal Ischemia During Anesthesia and Surgery

描述（申请人摘要中的逐字逐句） 麻醉期间脑缺血的风险以及心脏、神经血管和 颈动脉手术这引起了人们对确定代理人的兴趣 保护大脑免受缺血性损伤麻醉剂是合乎逻辑的 候选神经保护剂，因为它们减少兴奋性毒性损伤。一 许多研究表明，麻醉剂具有神经保护作用。在这些 在研究中，损伤仅在短暂的恢复期后进行评估。最近 数据表明缺血后脑损伤是一个动态过程， 神经元在初始局部缺血后继续死亡很长一段时间。大部分 这种迟发性神经元死亡是由细胞凋亡引起的。麻醉剂是否可以 提供长期永久的神经保护是未知的。本 建议，麻醉剂的长期神经保护功效将是 测定将被检验的假设是麻醉剂减少早期 兴奋性毒性引起的神经元损伤，但它们不能防止迟发性 由细胞凋亡引起的神经元死亡以及麻醉剂和 抗凋亡剂可能产生强有力的和永久的神经保护。在 第一阶段，巴比妥类药物剂量相关的神经保护作用 戊巴比妥和挥发性麻醉剂异氟烷将在一项 局灶性脑缺血模型。受伤将在两个短（2） 天）和较长（2周到3个月）的恢复期，以确定是否 神经保护是暂时的或永久的。在第二阶段， 麻醉剂对缺血后脑细胞凋亡过程的影响 将被确定。具体而言，细胞色素c释放的时间曲线， 半胱天冬酶9、8和3以及c-Jun-N-末端激酶（JNK）的活化 缺血后脑将通过免疫组织化学、Western blot 免疫印迹法检测caspase和JNK的活性。 形态学损伤将通过光学和电子显微镜以及 TUNEL染色。在这一阶段，每一个人的相对贡献 导致细胞凋亡的过程以及麻醉剂对这些过程的影响 过程将被确定。在第三阶段， 麻醉剂（抗兴奋毒性）和抗凋亡剂的组合 将在局灶性缺血模型中进行评价。具体而言， 半胱天冬酶9、3、8和JNK与麻醉剂联合抑制对 缺血性脑损伤将在短期和长期恢复期后确定。 拟议的实验将提供深入了解的机制， 麻醉剂影响缺血性脑损伤的病理生理学， 可以识别应被视为潜在保护的药剂， 临床设置。这项研究的长期目标是防止 麻醉患者缺血性脑损伤的发生率， 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.