Metformin attenuates rotenone-induced oxidative stress and mitochondrial damage via the AKT/Nrf2 pathway

Oxidative stress and mitochondrial dysfunction are now widely accepted as the major factors involved in the pathogenesis of Parkinson's disease (PD). Rotenone, a commonly used environmental toxin also reproduces these principle pathological features of PD. Hence, it is used frequently to induce experimental PD in cells and animals. In this study, we evaluated the neuroprotective effects of metformin against rotenone-induced toxicity in SHSY5Y cells. Metformin treatment clearly rescued these cells from rotenone-mediated cell death via the reduction of the cytosolic and mitochondrial levels of reactive oxygen species and restoration of mitochondrial function. Furthermore, metformin upregulated PGC-1 alpha, the master regulator of mitochondrial biogenesis and key antioxidant molecules, including glutathione and superoxide dismutase. We demonstrated that the drug exerted its cytoprotective effects by activating nuclear factor erythroid 2-related factor 2 (Nrf2)/heme-oxygenase (HO)-1 pathway, which in turn, is dependent on AKT activation by metformin. Thus, our results implicate that metformin provides neuroprotection against rotenone by inhibiting oxidative stress in the cells by inducing antioxidant system via upregulation of transcription mediated by Nrf2, thereby restoring the rotenone-induced mitochondrial dysfunction and energy deficit in the cells.

Automated summary

Our study demonstrates that metformin provides neuroprotection against rotenone by activating the Nrf2/HO-1 pathway, promoting ROS clearance and restoration of mitochondrial function.