Background
Neuroinflammation and oxidative stress are important pathological mechanisms underlying cerebral ischemic stroke. Increasing evidence suggests that regulation autophagy in ischemic stroke may improve neurological functions. In this study, we aimed to explore whether exercise pretreatment attenuates neuroinflammation and oxidative stress in ischemic stroke by improving autophagic flux.
Conclusions
Exercise pretreatment has the potential to improve the prognosis of ischemic stroke patients, and it can exert neuroprotective effects in ischemic stroke by inhibiting neuroinflammation and oxidative stress, which might be due to the TFEB-mediated autophagic flux. And targeting autophagic flux may be promising strategies for the treatment of ischemic stroke.
Methods
2,3,5-Triphenyltetrazolium chloride staining was used to determine the infarction volume, and modified Neurological Severity Scores and rotarod test were used to evaluate neurological functions after ischemic stroke. The levels of oxidative stress, neuroinflammation, neuronal apoptosis and degradation, autophagic flux, and signaling pathway proteins were determined using immunofluorescence, dihydroethidium, TUNEL, and Fluoro-Jade B staining, western blotting, and co-immunoprecipitation.
Results
Our results showed that, in middle cerebral artery occlusion (MCAO) mice, exercise pretreatment improved neurological functions and defective autophagy, and reduced neuroinflammation and oxidative stress. Mechanistically, after using chloroquine, impaired autophagy abolished the neuroprotection of exercise pretreatment. And transcription factor EB (TFEB) activation mediated by exercise pretreatment contributes to improving autophagic flux after MCAO. Furthermore, we showed that TFEB activation mediated by exercise pretreatment in MCAO was regulated by the AMPK-mTOR and AMPK-FOXO3a-SKP2-CARM1 signaling pathways. Conclusions: Exercise pretreatment has the potential to improve the prognosis of ischemic stroke patients, and it can exert neuroprotective effects in ischemic stroke by inhibiting neuroinflammation and oxidative stress, which might be due to the TFEB-mediated autophagic flux. And targeting autophagic flux may be promising strategies for the treatment of ischemic stroke.