Exercise-induced Neuroprotection Against Cerebral Ischemia/reperfusion Injury is Mediated Via Alleviating Inflammasome-induced Pyroptosis

As a primary nonpharmacological tool, exercise training is neuroprotective after experimental ischemic stroke by relieving neuroinflammation. However, the specific mechanism of which and anti-inflammatory effect of exercise at different intensities require in-depth investigations. To explore the issue, middle cerebral artery occlusion-reperfusion (MCAO-r) in mice were utilized, with subsequent exercise training at different intensities (high-intensity interval training versus moderate-intensity continuous training, i.e. HIIT vs. MICT) during an early phase post-modeling. The neurobehavioral assessment showed that MICT improved the performance of neurological deficit scores and rotarod test earlier, while HIIT appeared to be more efficacious to meliorate locomotor impairments and aerobic fitness at the end of intervention. Both exercise regimens inhibited the expressions of NLRP3 inflammasome components (NLRP3, ASC, and Cl.caspase-1) and pyroptosis-associated proteins (GSDMD, Cl.IL-1β, and Cl.IL-18) as indicated by western blot and immunofluorescence co-staining. Multiplex assay panel revealed that both exercise regimens reduced the levels of pro-inflammatory cytokines and upregulated anti-inflammatory cytokine. Furthermore, an increased proportion of M2-like microglia and a diminished proportion of M1-like microglia in the peri-infarct zone were observed by colocalization analysis, which was jointly validated by western blot. Here, for the first time, our study demonstrated that HIIT elicited better improvements at functional and cardiovascular levels than MICT after ischemic stroke, and anti-inflammatory effect of exercise might result from suppression in inflammasome-mediated pyroptosis by shifting microglial polarization toward neuroprotective M2 phenotype.