Neuroprotective effects of microglial P2Y₁ receptors against ischemic neuronal injury

Extracellular ATP, which is released from damaged cells after ischemia, activates P2 receptors. P2Y₁ receptors (P2Y₁R) have received considerable attention, especially in astrocytes, because their activation plays a central role in the regulation of neuron-to-glia communication. However, the functions or even existence of P2Y₁R in microglia remain unknown, despite the fact that many microglial P2 receptors are involved in several brain diseases. Herein, we demonstrate the presence and functional capability of microglial P2Y₁R to provide neuroprotective effects following ischemic stress. Cerebral ischemia resulted in increased microglial P2Y₁R expression. The number of injured hippocampal neurons was significantly higher in P2Y₁ R knockout (KO) mice than wildtype mice after forebrain ischemia. Propidium iodide (PI) uptake, a marker for dying cells, was significantly higher in P2Y₁R KO hippocampal slices compared with wildtype hippocampal slices at 48 h after 40-min oxygen–glucose deprivation (OGD). Furthermore, increased PI uptake following OGD was rescued by ectopic overexpression of P2Y₁R in microglia. In summary, these data suggest that microglial P2Y₁R mediate neuroprotective effects against ischemic stress and OGD insult.