α‐Lipoic acid alleviates ferroptosis in the MPP+‐induced PC12 cells via activating the PI3K/Akt/Nrf2 pathway

Abstract Parkinson's disease (PD) is a typical neurodegenerative disease. α‐Lipoic acid (α‐LA) can reduce the incidence of neuropathy. The present study explored the role and mechanism of α‐LA in 1‐methyl‐4‐phenylpyridinium (MPP + )‐induced cell model of PD. The PD model was induced via treating PC12 cells with MPP + at different concentrations. MPP + and α‐LA effects on PC12 cells were assessed from cell viability and ferroptosis. Cell viability was detected using the cell counting kit‐8 assay. Malondialdehyde (MDA), 4‐hydroxynonenal (4‐HNE), iron, reactive xygen species (ROS), and glutathione (GSH) concentrations, and ferroptosis‐related protein SLC7A11 and GPx4 expressions were used for ferroptosis evaluation. p‐PI3K, p‐Akt, and nuclear factor erythroid 2‐related factor 2 (Nrf2) protein levels were detected. The PI3K/Akt/Nrf2 pathway inhibitors were applied to verify the role of the PI3K/Akt/Nrf2 pathway in α‐LA protection against MPP + ‐induced decreased cell viability and ferroptosis. MPP + ‐reduced cell viability and induced ferroptosis as presented by increased MDA, 4‐HNE, iron, and ROS concentrations, and reduced levels of GSH and ferroptosis marker proteins (SLC7A11 and GPx4). α‐LA attenuated MPP + ‐induced cell viability decline and ferroptosis. The PI3K/Akt/Nrf2 pathway was activated after α‐LA treatment. Inhibiting the PI3K/Akt/Nrf2 pathway weakened the protection of α‐LA against MPP + treatment. We highlighted that α‐LA alleviated MPP + ‐induced cell viability decrease and ferroptosis in PC12 cells via activating the PI3K/Akt/Nrf2 pathway.