Activation of the Akt/FoxO3 signaling pathway enhances oxidative stress-induced autophagy and alleviates brain damage in a rat model of ischemic stroke

Autophagy has been implicated in stroke. Our previous study showed that the FoxO3 transcription factor promotes autophagy after transient cerebral ischemia/reperfusion (I/R). However, whether the Akt/FoxO3 signaling pathway plays a regulatory role in autophagy in cerebral I/R-induced oxidative stress injury is still unclear. The present study aims to investigate the effects of the Akt/FoxO3 signaling pathway on autophagy activation and neuronal injury in vitro and in vivo. By employing LY294002 or insulin to regulate the Akt/FoxO3 signaling pathway, we found that insulin pretreatment increased cell viability, decreased reactive oxygen species production, and enhanced the expression of antiapoptotic and autophagy-related proteins following [H.sub.2][O.sub.2] injury in HT22 cells. In addition, insulin significantly decreased neurological deficit scores and infarct volume and increased the expression of antiapoptotic and autophagy-related proteins following I/R injury in rats. However, LY294002 showed the opposite effects under these conditions. Altogether, these results indicate that Akt/FoxO3 signaling pathway activation inhibited oxidative stress-mediated cell death through activation of autophagy. Our study supports a critical role for the Akt/FoxO3 signaling pathway in autophagy activation in stroke. Key words: Akt/FoxO3 signaling pathway, autophagy, apoptosis, hydrogen peroxide, stroke
Introduction Stroke, which is widely considered to be a leading cause of disability and death, causes a tremendous global health and economic burden (Virani et al. 2021). Cerebral ischemia/reperfusion (I/R) [...]