Volatile anesthetic effects on aging brain

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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.