Volatile anesthetic effects on aging brain

挥发性麻醉剂对衰老大脑的影响

• 批准号: 8293755
• 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
• 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/8293755
• 关键词: Acids; Acute; Age; Aging; Alzheimer' 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; Interleukins; 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

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. PUBLIC HEALTH RELEVANCE: Patients, especially the elderly, can develop significant dysfunction of learning and memory after anesthesia and surgery. We would like to determine whether drugs that are used to put patients to sleep during surgery contribute to this problem and how this problem occurs in old animals. The intention of this project is to provide information that ultimately may help improve quality of life for patients after anesthesia and surgery.

描述(申请人提供)：全世界每年约有2亿人接受手术。大多数患者在手术中将以挥发性麻醉药为主要麻醉药进行全身麻醉。虽然挥发性麻醉药通常被认为是安全的，但它们在术后认知功能障碍(POCD)的发展中的可能贡献已经引起了人们的极大关注。POCD是一种有充分证据的临床实体，更常发生在老年患者中。因为这个问题显然很重要，所以迫切需要消除麻醉剂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，临床相关浓度的异氟醚损害了老年大鼠的学习和记忆。静脉注射利多卡因可以减轻这种对老年大鼠的有害影响，利多卡因是一种具有抗炎特性的局部麻醉剂。异氟醚增加了促炎症细胞因子的表达，并似乎减弱了学习诱导的海马区-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体GluR1亚单位的磷酸化，这是学习和记忆的关键过程。利多卡因也阻断了这些异氟醚的作用。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和药剂特定的，是由于神经炎症和学习和记忆潜在的生化过程的中断。在本项目中，我们将确定：1)异氟醚诱导的学习和记忆障碍是否具有浓度依赖性；2)新型挥发性麻醉药七氟醚和地氟烷导致学习和记忆障碍，利多卡因可减轻这些损害；3)异氟烷诱导海马区轻度炎症反应，利多卡因减少这种异氟烷引起的神经炎症；以及4)异氟醚中断学习和记忆诱导的生化反应。我们将使用老年成年雄性大鼠，在存在或不存在利多卡因的情况下，将它们暴露在挥发性麻醉剂中。学习和记忆将通过巴恩斯迷宫和恐惧条件反射进行评估。大脑将被采集进行生化检查。这些研究不仅将确定挥发性麻醉剂引起的学习和记忆损害的特征，而且还将确定这些损害的机制。这些信息还将帮助我们更好地了解挥发性麻醉剂在大脑中的药理作用，并开发方法来改善这些常用药物的安全性。 公共卫生相关性：麻醉和手术后，患者，特别是老年人，可能会出现明显的学习和记忆障碍。我们想要确定在手术过程中用来让患者入睡的药物是否会导致这个问题，以及这个问题是如何在老年动物身上发生的。这个项目的目的是提供信息，最终可能有助于改善麻醉和手术后患者的生活质量。