Metformin in Neurodegenerative Diseases: Mechanisms and Therapeutic Implications.

Abstract

As the global burden of neurodegenerative disorders continues to rise with aging populations, there is growing interest in identifying widely available drugs that can be repurposed to target shared metabolic and inflammatory mechanisms underlying these conditions. Increasing evidence suggests that metabolic dysfunction, mitochondrial impairment, and chronic neuroinflammation play central roles in the pathogenesis of neurodegeneration, demonstrating the need for therapeutics that can modulate these interconnected pathways. Metformin has served as the gold standard for the management of type 2 diabetes for 7 decades. It offers a superior safety profile, established metabolic advantages, and affordability. Recent studies suggest that, in addition to its antihyperglycemic actions, it could also be repurposed to treat several inflammatory complications and infectious diseases. Further, recent preclinical and clinical studies suggest that, by regulating AMPK, mTOR, and mitochondrial function, metformin could also control the initiation and progression of neurodegenerative diseases. Several studies also indicate that metformin suppresses neuroinflammation by inhibiting the NF-κB signaling pathway and the NLRP3 inflammasome, thereby improving insulin signaling and metabolic homeostasis. This review integrates metabolic, inflammatory, and mitochondrial mechanisms to present a unified mechanistic framework to explain how metformin may modulate the onset and progression of neurodegeneration. Specifically, we discuss recent studies showing the therapeutic significance of metformin in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, this review highlights metformin as a potential therapeutic candidate for future development in neurodegenerative diseases.