Ergothioneine exerts neuroprotection in experimental ischemic stroke via activation of PI3K/Akt/Nrf2 pathway

BACKGROUND: Ischemic stroke is a leading cause of serious long-term disability and mortality worldwide. Ergothioneine (EGT), a natural dietary sulfur-containing amino acid, possesses potent antioxidant properties. This study investigates the neuroprotective potential of EGT in experimental ischemic stroke and elucidates its underlying molecular signaling pathway. METHODS: Two ischemic stroke models, the photochemical ischemia model and the middle cerebral artery occlusion (MCAO) model, were established to evaluate the neuroprotective effects of EGT. 2,3,5-Triphenyltetrazolium chloride staining was performed to assess infarct volume, and laser speckle contrast imaging was used to monitor cerebral blood flow. Immunofluorescence was employed to detect the activation of astrocytes and microglia. Proteins involved in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were analyzed by Western blot to explore the underlying mechanism of EGT. RESULTS: In both photochemical ischemia and middle cerebral artery occlusion models, EGT significantly reduced infarct volume, improved cerebral perfusion and attenuated glial cells activation. Mechanistically, EGT promoted PI3K/Akt phosphorylation, reduced cytoplasmic Kelch-like erythroid cell-derived homology-associated protein 1 expression, and enhanced nuclear Nrf2 translocation. Notably, PI3K inhibitor, LY294002, completely abolished the neuroprotective effects of EGT. CONCLUSION: EGT exhibits significant neuroprotection against experimental ischemic stroke by mitigating oxidative stress and neuroinflammation, and its efficacy is critically dependent on the activation of the PI3K/Akt/Nrf2 signaling pathway.