Volatile anesthetic effects on aging brain

描述（申请人提供）：全世界每年约有2亿人接受手术。他们中的大多数人将在手术期间使用挥发性麻醉药作为主要麻醉药进行全身麻醉。虽然挥发性麻醉剂通常被认为是安全的，但其可能导致术后认知功能障碍（POCD）的发展，这是一种在老年患者中更常见的临床实体，已引起了极大的关注。由于这个问题显然是重要的，因此迫切需要确定麻醉对学习和记忆的影响，并确定减轻这些影响的干预措施。我们的初步研究表明，异氟烷在临床相关浓度损害老年大鼠的学习和记忆。静脉注射利多卡因（一种具有抗炎作用的局部麻醉剂）可以减弱这种对老年大鼠的有害影响。异氟烷增加了促炎细胞因子的表达，并似乎减弱了海马中学习诱导的<$-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体GluR 1亚基的磷酸化，这是学习和记忆的关键过程。利多卡因也阻断了这些异氟烷效应。我们假设挥发性麻醉剂诱导的老年大鼠学习和记忆障碍是麻醉剂剂量依赖性和药物特异性的，是由于神经炎症和基础学习和记忆的生化过程的中断。在这个项目中，我们将确定：1）异氟烷诱导的学习和记忆障碍是否是浓度依赖性的; 2）较新的挥发性麻醉剂七氟烷和地氟烷引起学习和记忆障碍，利多卡因减轻这些障碍; 3）异氟烷诱导海马中的轻度炎症反应，利多卡因减轻这种异氟烷引起的神经炎症;和4）异氟烷中断学习和记忆诱导的生化反应。我们将使用年老的成年雄性大鼠，并在存在或不存在利多卡因的情况下将其暴露于挥发性麻醉剂。将通过巴恩斯迷宫和恐惧条件反射评价学习和记忆。将采集大脑进行生化检查。这些研究不仅将确定挥发性麻醉剂诱导的学习和记忆障碍的特征，而且还将确定这些障碍的机制。这些信息也将帮助我们更好地了解挥发性麻醉药在大脑中的药理学，并开发提高这些常用药物安全性的方法。

DESCRIPTION (provided by applicant): About 200 million people each year undergo surgery in the world. Most of them will have general anesthesia with volatile anesthetics as the primary anesthetics during surgery. Although volatile anesthetics generally are considered to be safe, their possible contribution to the development of post-operative cognitive dysfunction (POCD), a fairly-well documented clinical entity that occurs more frequently in elderly patients, has drawn significant attention. Because the issue is obviously significant, there is an urgent need to defin the anesthetic effects on learning and memory and to identify interventions to attenuate these effects. Our preliminary study showed that isoflurane at a clinically relevant concentration impaired the learning and memory of old rats. This detrimental effect on old rats was attenuated by intravenous lidocaine, a local anesthetic that has anti-inflammatory property. Isoflurane increased a proinflammatory cytokine expression and appeared to attenuate the learning-induced phosphorylation of the ¿-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluR1 subunit, a critical process for learning and memory, in the hippocampus. Lidocaine also blocked these isoflurane effects. We hypothesize that volatile anesthetic-induced learning and memory impairments in elderly rats are anesthetic dose-dependent and agent-specific and are due to neuroinflammation and interruptions of biochemical processes underlying learning and memory. In this project, we will determine whether: 1) isoflurane-induced learning and memory impairments are concentration- dependent; 2) the newer volatile anesthetics sevoflurane and desflurane cause learning and memory impairments and lidocaine attenuates these impairments; 3) isoflurane induces mild inflammatory responses in the hippocampus and lidocaine reduces this isoflurane-caused neuroinflammation; and 4) isoflurane interrupts learning and memory-induced biochemical responses. We will use old adult male rats and exposed them to volatile anesthetics in the presence or absence of lidocaine. Learning and memory will be evaluated by Barnes maze and fear conditioning. Brains will be harvested for biochemical examination. These studies will determine not only the characteristics of volatile anesthetics-induced impairments of learning and memory but also mechanisms for these impairments. This information also will help us better understand pharmacology of volatile anesthetics in the brain and develop approaches to improve the safety profile of these commonly used drugs.