Modern medicine is faced with a growing geriatric population and with an increase in the number of elderly patients who require surgical procedures under general anesthesia. Ketamine and nitrous oxide (N2O, laughing gas) are used common as general anesthetics for patients of all ages, and in some cases are considered the agents of choice for elderly patients. Both of these agents are frequently used in combination with other general anesthetic agents, and sometimes are used in combination with one another, especially for elderly patients who cannot tolerate the cardiopulmonary depressant properties of other general anesthetics. It has been known for some time that ketamine, a non-competitive N-methyl-D- aspartate neurons of adult rats. This is a property of ketamine shares with other NMDA antagonist drugs. Over the years, N2O has been considered safe for patients of all ages, although very little insight has been gained into its mechanism of action. Recently the applicant disocver4ed that N2O acts by the same mechanism as ketamine- it blocks NMDA glutamate receptors and has all of the same properties as other NMDA antagonists-it blocks NMDA glutamate receptors and has all of the same properties as other NMDA antagonists, including the same neurotoxic properties, The applicant has also observed that when N2O is administered together with ketamine to young adult rats the two agents appear to potentiate one another's neurotoxicity, i.e., the toxicity is augmented to a degree that is greater than can be explained by simple additivity. In other pilot studies, we have observed that the NMDA antagonist, MK801, at a given dose induces much more severe brain damage in aged than in young adult rats. This raises questions about whether N2O and ketamine, either alone or in combination, might contribute to the post-operative delirious state (agitation, delusions, hallucinations, disorientation, confusion, memory impairment) that sometimes occurs post-operatively, and is known to occur much more frequently in elderly than young adult patients. Therefore, we propose studies in young adult and aged rats to clarify the nature and degree of risk associated with exposing the aged brain to N2O and ketamine, either individually or in combination. The experiments will be designed in a way that will help clarify the mechanism underlying the observed increased toxicity of MK801 in aged rats. In addition, we will explore pharmacological mechanisms by which the neurotoxic side effects of these two agents can be prevented.
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