Physical exercise improves the neuronal function in ischemic stroke via microglial CB2R/P2Y12 signaling

Physical exercise (PE) may be the single most important and accessible lifestyle habit throughout life, it inhibits the neuroinflammatory response and protects the brain against damage. As the innate cells in brain, microglia undergo morphological and functional changes to communicate with neurons protecting other neurons from injury. Herein, aiming at exploring the effect of PE on the communication microglia - neuron during acute ischemic cerebral infarction, we carried out running wheel training before the conduction of transient middle cerebral artery occlusion (tMCAO) in Cx3cr1-GFP mice. We found that microglial P2Y12 expression in the peri-infarct area was decreased, microglial dynamics and microglia - neuron communications were impaired, using in vivo two-photon imaging. PE upregulated microglial P2Y12 expression, increased microglial dynamics, and promoted the contact of microglia with neurons. As a result, PE inhibited neuronal Ca2+ overloads and protected against damage of the neuronal mitochondria in acute tMCAO. Mechanistically, PE increased the cannabinoid receptor 2 (CB2R) in microglia, promoted the phosphorylation of Nrf2 (NF-E2-related factor 2) at ser-344, increased the transcription factor level of Mafk, and up-regulated the level of P2Y12, whereby PE increased the levels of CB2R to promote microglia-neuron contacts to monitor and protect neuronal functioning.