Stroke is a leading cause of mortality and morbidity. In recent studies, we have identified a class of prostaglandin receptors that protect brain tissue in rodent models of stroke. Misoprostol is a PGE2 receptor agonist that is widely prescribed in patients for prophylaxis against non-steroidal anti-inflammatory drug (NSAID) induced ulcer disease. In a recent study, we have demonstrated that misoprostol significantly reduces infarct size and improves neurological scores in a mouse model of middle cerebral artery occlusion-reperfusion (MCAO-RP) when given 2 hours after MCAO. We have further determined that misoprostol exerts this protective effect by activating the G1-coupled PGE2 EP2 and EP4 receptors in brain. We have also identified a protective effect of pharmacologic activation of the EP4 receptor in vitro and in vivo in models of cerebral ischemia. EP2 and EP4 receptor agonists therefore represent attractive therapeutic candidates in cerebral protection. These two protective PGE2 receptors may exert their cerebroprotective effects via one or more mechanisms, including (1) enhancement of neuronal and endothelial survival, (2) vasodilatory effects on cerebral vasculature, and (3) suppression of inflammation. The primary goal of this proposal is test efficacy of misoprostol in improving long term functional recovery in a rat model of transient focal ischemia. In Aim 1, efficacy will be tested in a model of transient focal ischemia to identify the dose response and the time window of action of misoprostol after onset of ischemia. Studies will assess efficacy using long term functional and cognitive outcome measures. In Aim 2, we will test efficacy of misoprostol in aged rodents to confirm whether these compounds will also be protective. Successful demonstration of efficacy in aged rodents will provide a rationale for expanded pre-clinical investigation of misoprostol in other models of cerebral ischemia and in higher animal models of stroke. PUBLIC HEALTH RELEVANCE: We have identified a class of protective prostaglandin receptors that protect brain tissue in a rodent model of stroke and that are activated by an agonist called misoprostol, a medication that is already prescribed and in use in patients for ulcer prophylaxis. In this proposal, we will confirm the protective effects of misoprostol in a model of cerebral ischemia in young and aged rodents. Successful validation of this compound in aged rodent stroke will allow for future expanded pre-clinical studies for human stroke.