Volatile anesthetic effects on aging brain

挥发性麻醉剂对衰老大脑的影响

基本信息

批准号：
8727057
负责人：
ZHIYI ZUO
金额：
$ 30.02万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727057
关键词：
Acids Acute Age Aging Alzheimer&apos s Disease Anesthesia procedures Anesthetics Animals Anti-Inflammatory Agents Anti-inflammatory Attention Attenuated Biochemical Biochemical Process Brain Calcium/calmodulin-dependent protein kinase Cardiac Surgery procedures Cell Death Cell membrane Cerebral cortex Characteristics Clinical Cyclic AMP-Responsive DNA-Binding Protein Data Dementia Development Dose Drug usage ERG gene Elderly Exposure to Functional disorder General Anesthesia General anesthetic drugs Harvest Hippocampus (Brain)Impaired cognition Impairment In Vitro Inflammatory Response Intention Interleukin-1 Interruption Intervention Intravenous Isoflurane Laboratory Research Learning Lidocaine Local Anesthetics Mediating Memory Memory impairment Mitogen-Activated Protein Kinases Molecular Mus Muscle Neurons Operative Surgical Procedures Patients Pharmacology Phosphorylation Postoperative Period Process Production Property Quality of life Rattus Risk Factors Safety Sleep Structure Synapses Tibial Fractures Unconscious State aging brain aging hippocampus amyloid peptide base body system calmodulin-dependent protein kinase II caspase-3 clinically relevant cognitive function conditioned fear cytokine density desflurane improved male middle age mortality neuroinflammation neuropathology neurotoxicity normal aging older patient receptor response sample fixation sevoflurane trafficking

项目摘要

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.

描述（由适用提供）：每年约2亿人接受全球手术。他们中的大多数人将在手术过程中进行全身麻醉性麻醉作为主要麻醉药。尽管通常认为挥发性麻醉剂是安全的，但它们可能贡献了可纠正的认知功能障碍（POCD），这是一个相当有记录的临床实体，在老年患者中更频繁地发生，引起了人们的重大关注。由于这个问题显然很重要，因此迫切需要定义对学习和记忆的麻醉作用，并确定干预措施以减轻这些影响。我们的初步研究表明，在临床相关的浓度下，异氟烷会损害老鼠的学习和记忆。这种对老鼠的有害作用被静脉内利多卡因（一种具有抗炎特性的局部麻醉剂）减弱。异氟烷增加了促炎性细胞因子的表达，并且似乎减弱了学习引起的„ -Amino-3-羟基-5-羟基-5-甲基-4-异恶唑股东酸受体Glur1亚基，这是Hippocampus的学习和记忆的关键过程。利多卡因还阻止了这些异氟醚作用。我们假设挥发性麻醉诱导的学习和记忆力障碍是大鼠的麻醉剂量依赖性和特定于药物的特定于剂量，这是由于神经炎症以及对学习和记忆的生化过程的中断引起的。在这个项目中，我们将确定：1）异氟烷引起的学习和记忆障碍是集中依赖的； 2）较新的挥发性麻醉剂七氟硫酸盐和Desflurane会导致学习和记忆力障碍，而利多卡因会减轻这些障碍； 3）异氟烷诱导海马和利多卡因的轻度炎症反应减少了这种氟烷引起的神经炎症； 4）异氟烷中断学习和记忆引起的生化反应。我们将在存在或不存在利多卡因的情况下使用老年雄性大鼠，并将其暴露于挥发性麻醉剂。学习和记忆将通过巴恩斯迷宫和恐惧调节来评估。将收集大脑进行生化检查。这些研究不仅会确定挥发性麻醉剂引起的学习和记忆障碍的特征，而且还决定了这些障碍的机制。这些信息还将帮助我们更好地了解大脑挥发性麻醉药的药理学，并开发方法以改善这些常用药物的安全性。