Metformin as a potential neuroprotective agent: Molecular mechanisms, clinical evidence and therapeutic repurposing in neurodegenerative disorders

Metformin, a widely prescribed first-line therapy for type 2 diabetes mellitus, has recently attracted increasing attention for potential neuroprotective effects beyond glycaemic control. Growing epidemiological and experimental evidence suggests that metformin may influence several biological pathways implicated in neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. At the molecular level, metformin modulates cellular energy metabolism through activation of AMP-activated protein kinase (AMPK) and downstream suppression of mammalian target of rapamycin (mTOR) signaling, mechanisms that promote autophagy and may facilitate the clearance of toxic protein aggregates. Additional effects include attenuation of neuroinflammation through inhibition of NLRP3 inflammasome signaling, enhancement of antioxidant responses via Nrf2 activation, and regulation of mitochondrial function. Emerging experimental findings also suggest roles for metformin in promoting neurogenesis and supporting oligodendrocyte precursor cell differentiation, processes relevant to neuronal repair and remyelination. These mechanistic insights have stimulated growing clinical interest in repurposing metformin for neurological indications, with several ongoing trials investigating its effects on cognitive decline, neurodegeneration, and remyelination outcomes. Nevertheless, important questions remain regarding optimal dosing strategies, variability in blood–brain barrier penetration, and potential adverse effects such as vitamin B12 deficiency during long-term therapy. Overall, current evidence supports continued investigation of metformin as a candidate for therapeutic repurposing in neurodegenerative diseases.