Time-dependent progression of hemorrhagic transformation after transient ischemia and its association with GPR68-dependent protection.

Hemorrhagic transformation (HT) following ischemia is one complication which worsens stroke outcome. During and after ischemia-reperfusion, persistent reduction of brain pH occurs. In a recent study, we found that GPR68 functions as a neuronal proton receptor and mediates a protective pathway in brain ischemia. Here, we asked whether GPR68 contributes HT after ischemia. At 24 hr after transient middle cerebral artery occlusion (tMCAO), 58% of the wild-type (WT) mice exhibited some degrees of mild HT. At 72 hr, 95% of the WT showed HT with 42% exhibited large "parenchymal" type hemorrhage. In the GPR68-/- mice, there was a trend of increase in both the incidence and severity of HT at both time points. Mice with severe hemorrhage exhibited significantly larger infarct than those with no to mild hemorrhage. Next, we compared % infarct of GPR68-/- vs WT based on their HT categories. GPR68 deletion increased % infarct when the HT severity is mild. In contrast, for mice exhibiting large area HT, the two genotypes had no difference in % infarct. These data showed that GPR68-dependent signaling leads to protection when HT is mild.