Prostaglandin D(2) is the most abundant prostaglandin in the brain. It has long been described as a modulator of the neuroinflammatory process, but little is known regarding the role of its Galpha(s)-coupled receptor, DP1. Therefore, in this study, the effect of the DP1 receptor on the outcome of cerebral ischemia in wildtype (WT) and DP1 knockout (DP1(-/-)) C57Bl/6 mice was investigated. Ischemia-reperfusion injury was produced by a 90-min occlusion of the right middle cerebral artery followed by a 4-day reperfusion. Infarct size was 49.0 +/- 11.0% larger in DP1(-/-) mice (n = 11; P < 0.01) than in WT mice (n = 9 per group). However, no differences were detected in the relative cerebral blood flow (CBF) or any of the physiological parameters measured (n = 5 per group) or in the large blood vessel anatomy (n = 3 per group). To further address whether the DP1 protective role in the brain could be extended to neurons, mouse primary corticostriatal neuronal cultures were exposed to the DP1-selective agonist, BW245C, which provided dose-dependent protection against excitotoxicity induced by glutamate. Protection was significant at a dose as low as 0.05 microm. The results indicate that the DP1 receptor is neuroprotective in both in vivo and in vitro paradigms. Development of drugs to stimulate the DP1 receptor in brain could provide a new therapeutic strategy against cerebral ischemia and potentially other neurological conditions.