Neuroprotective effects of microglial P2Y receptors against ischemic neuronal injury.

Extracellular ATP, which is released from damaged cells after ischemia, activates P2 receptors. P2Y receptors (P2YR) 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 P2YR 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 P2YR to provide neuroprotective effects following ischemic stress. Cerebral ischemia resulted in increased microglial P2YR expression. The number of injured hippocampal neurons was significantly higher in P2Y R knockout (KO) mice than wildtype mice after forebrain ischemia. Propidium iodide (PI) uptake, a marker for dying cells, was significantly higher in P2YR 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 P2YR in microglia. In summary, these data suggest that microglial P2YR mediate neuroprotective effects against ischemic stress and OGD insult.