Metformin Inhibits Ferroptosis by Inducing Autophagy in MPTP/MPP+ Models of Parkinson’s Disease

Abstract

Abstract To assess whether and how Metformin (Met) functions in regulating ferroptosis in Parkinson’s disease (PD), we investigated the role and relative mechanism of Met in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model and a 1-methyl-4-phenylpyridinium (MPP+)-induced PC12 cell model of PD. We found that Met significantly relieved motor deficits induced by MPTP and improved the degeneration of substantia nigra (SN) compacta dopaminergic neurons. In addition, we found that Met reversed the changes in tyrosine hydroxylase (TH), α-synuclein and glutathione peroxidase 4 (GPX4) induced by MPTP in the SN. Then, our studies showed that Met weakened MPP+-induced morphological damage and inhibited neuronal ferroptosis in PC12 cells. Moreover, our results indicated that the neuroprotective effect of Met could be partially blocked by 3-MA (an autophagy inhibitor) and RSL3 (a ferroptosis inducer) in PC12 cells. Taken together, these findings reveal that Met exerts a neuroprotective effect by inhibiting ferroptosis via autophagy in models of PD. Our results demonstrate that the modulation of autophagy and ferroptosis may act as an effective method for PD and that Met may be a promising drug for dopaminergic neuron degeneration.