Metformin Enhances Antioxidant Defenses and Limits Lipid Peroxidation Through the Modulation of Nrf2/KEAP1 Pathway in...

Oxidative stress is an early and important feature of Alzheimer's disease (AD) that contributes to synaptic dysfunction and neurodegeneration. Soluble amyloid-β oligomers (AβOs) are major contributors to oxidative damage and have been shown to impair neuronal antioxidant defenses. The Nrf2/KEAP1 pathway is a central regulator of cellular redox homeostasis; however, its activity is compromised in AD, increasing neuronal vulnerability to oxidative stress. Metformin (Met), a widely used antidiabetic drug, has emerged as a potential modulator of antioxidant signaling pathways in the nervous system. In the present study, we investigated whether Met enhances antioxidant defenses in primary fetal rat hippocampal neurons exposed to AβOs. Neuronal cultures were treated with Met (2.5 mM for 24 h) prior to exposure to AβOs (500 nM for 6 h). We evaluated Nrf2 and KEAP1 protein levels, Nrf2 nuclear localization, antioxidant enzyme expression and activity, and lipid peroxidation. Met treatment promoted Nrf2 nuclear accumulation, preserved a favorable Nrf2/KEAP1 profile under amyloid stress, and enhanced the expression and activity of key antioxidant enzymes, including superoxide dismutase (SOD1 and SOD2), catalase (CAT), and glutathione peroxidase (GPx1/2). In addition, Met attenuated AβOs-induced lipid peroxidation, supporting its protective effects against amyloid-associated oxidative damage. Collectively, these findings indicate that Met strengthens neuronal antioxidant defenses and promotes redox resilience under amyloid-associated oxidative stress. Our results support modulation of the Nrf2/KEAP1 pathway as a mechanism contributing to the neuroprotective actions of Met and identify the coordinated enhancement of antioxidant defenses and reduction of lipid peroxidation as key components of neuronal redox resilience against AβOs-induced stress.