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

Area of Science:

• Neuroscience
• Biochemistry
• Toxicology

Background:

• Parkinson's disease (PD) pathogenesis is linked to oxidative stress and mitochondrial dysfunction.
• Rotenone, an environmental toxin, is used to model PD pathology due to its ability to induce these features.

Purpose of the Study:

• To investigate the neuroprotective potential of metformin against rotenone-induced toxicity in SH-SY5Y neuroblastoma cells.
• To elucidate the molecular mechanisms underlying metformin's protective effects.

Main Methods:

• Induction of experimental Parkinson's disease model using rotenone in SH-SY5Y cells.
• Treatment with metformin to assess its protective effects on cell viability.
• Measurement of reactive oxygen species (ROS) levels, mitochondrial function, and expression of key regulatory proteins (PGC-1α, glutathione, superoxide dismutase, Nrf2, HO-1, AKT).

Main Results:

• Metformin significantly rescued SH-SY5Y cells from rotenone-induced death.
• Metformin reduced cytosolic and mitochondrial reactive oxygen species levels and restored mitochondrial function.
• Metformin upregulated PGC-1α, glutathione, and superoxide dismutase, key players in mitochondrial biogenesis and antioxidant defense.
• The protective effects were mediated by the activation of the AKT/Nrf2/HO-1 pathway, enhancing the cellular antioxidant system.

Conclusions:

• Metformin demonstrates significant neuroprotective effects against rotenone-induced toxicity in a cellular model of Parkinson's disease.
• Metformin combats oxidative stress and mitochondrial dysfunction by activating the AKT/Nrf2/HO-1 pathway and boosting the endogenous antioxidant system.
• These findings suggest metformin as a potential therapeutic agent for Parkinson's disease by targeting key pathological mechanisms.