PGD2 DP1 receptor stimulation following stroke ameliorates cerebral blood flow and outcomes

Abstract

Stroke is a leading cause of death and morbidity worldwide, yet effective treatments are lacking. The association of prostaglandin D2 and its DP1 receptor with vasculature and blood propelled us to examine whether the clinically tested DP1 receptor agonist BW245C had beneficial effects following stroke. To determine if BW245C affects basal cerebral blood flow (CBF), C57BL/6 WT and DP1−/− mice were given a single i.p. injection of vehicle or BW245C, and CBF was recorded for 2h. To test the effect of BW245C on stroke, WT and DP1−/− mice were subjected to middle cerebral artery occlusion followed by a single i.p. injection of vehicle or 0.02, 0.2, or 2.0-mg/kg BW245C immediately before reperfusion. Functional and anatomical outcomes were determined at 96h. We also determined the effect of BW245C on CBF in peri-infarct and core during occlusion and reperfusion. Furthermore, we tested the effect of BW245C on bleeding time and ex vivo coagulation. BW245C treatment increased the basal CBF significantly in WT but not in DP1−/− mice. The BW245C treatment also significantly improved functional outcome and lowered infarction volume. The multisite CBF monitoring by laser-Doppler flowmetry shows that BW245C significantly increased the CBF in peri-infarct, with a significant inverse correlation between infarction and CBF. The significantly higher infarction volume in DP1−/− mice remained unchanged with BW245C treatment. Moreover, BW245C preserves hemostasis in non-stroke conditions. Combined, these data suggest that the DP1 receptor is an endogenous target that can rescue the brain following stroke by regulating CBF and hemostasis.