Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges

Parkinson disease (PD) is a severe neurodegenerative disorder that affects around 2% of the population over 65 years old. It is characterized by the progressive loss of nigrostriatal dopaminergic neurons, resulting in motor disabilities of the patients. At present, only symptomatic cures are available, without suppressing disease progression. In this frame, the anti-diabetic drug metformin has been investigated as a potential disease modifier for PD, being a low-cost and generally well-tolerated medication, which has been successfully used for decades in the treatment of type 2 diabetes mellitus. Despite the precise mechanisms of action of metformin being not fully elucidated, the drug has been known to influence many cellular pathways that are associated with PD pathology. In this review, we present the evidence in the literature supporting the neuroprotective role of metformin, i.e., autophagy upregulation, degradation of pathological alpha-synuclein species, and regulation of mitochondrial functions. The epidemiological studies conducted in diabetic patients under metformin therapy aimed at evaluating the correlation between long-term metformin consumption and the risk of developing PD are also discussed. Finally, we provide an interpretation for the controversial results obtained both in experimental models and in clinical studies, thus providing a possible rationale for future investigations for the repositioning of metformin for PD therapy.

Automated summary

This article reviews the potential mechanisms and clinical applications of metformin in the treatment of Parkinson's disease. Studies have shown that metformin may exert neuroprotective effects by regulating cellular pathways such as autophagy, degradation of pathological proteins, and mitochondrial function. Epidemiological studies on the correlation between long-term metformin use and the risk of developing Parkinson's disease are also discussed. However, there is controversy regarding the results obtained from experimental models and clinical studies, and further research is needed to clarify the mechanisms and efficacy of metformin in the treatment of Parkinson's disease.