Aucubin provides protection against cerebral ischaemia-reperfusion injury by suppressing neuronal apoptosis, oxidative stress, and inflammation through the modulation of the AKT-GSK-3β-Nrf2 signal cascade.

Aucubin (AU) is a naturally occurring iridoid glycoside known to possess a wide range of pharmacological properties and exhibit a notable protective effect against various pathological conditions. Studies have shown that AU has neuroprotective properties in different neurological diseases. However, its potential protective effects against cerebral ischemia-reperfusion (CIR) injury have not been thoroughly investigated. This study aimed to investigate the impact of AU on CIR injury and explore the underlying mechanism. Cultured neurons treated with AU showed a significant reduction in apoptosis, oxidative stress, and inflammation caused by oxygen-glucose deprivation and reoxygenation (OGD/R). In a rat model of CIR, treatment with AU resulted in a significant decrease in cerebral infarct size and neurological deficits. AU treatment also reversed the increased apoptosis, oxidative stress, and inflammation in the brains of CIR rats. Furthermore, AU was found to enhance the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2), accompanied by increased phosphorylation of serine/threonine-protein kinase AKT and glycogen synthase kinase-3 beta (GSK-3β). The activation of Nrf2 induced by AU was reversed when the AKT-GSK-3β cascade was blocked. Additionally, the neuroprotective effect of AU was significantly reduced when Nrf2 was pharmacologically suppressed. In conclusion, these findings suggest that AU exerts a neuroprotective effect on CIR injury, and this effect is mediated by the activation of Nrf2 through the AKT-GSK-3β axis. This work highlights the potential of AU as a drug candidate for the treatment of CIR injury.