Abstract
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 α-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.
Highlights
Parkinson disease (PD) is the second most common and fastest-growing neurological disorder in the world [1]
Several works recently suggested that metformin may be used as a promising therapeutic strategy to counteract the progression of neurodegenerative disorders, including PD
The prolonged consumption of metformin at a relatively high dosage might induce serious side effects that could worsen the risk of developing PD over time
Summary
Parkinson disease (PD) is the second most common and fastest-growing neurological disorder in the world [1]. PD is still an incurable disorder and the currently available therapeutic approaches focus on stimulation of dopaminergic signaling, such as levodopa (L-DOPA), DOPA decarboxylase inhibitors, catechol-O-methyltransferase inhibitors, dopamine agonists, and inhibitors of the enzyme monoamine oxidase type B [3] All these treatments can only provide symptomatic relief but they do not hamper the clinical and pathological progression of the disorder. In the quest for new potential therapeutic compounds against PD progression, the knowledge of the pathological mechanisms involved in its etiopathogenesis and the comparative analysis for their potential roles in other disorders could help speed up drugs’ repurposing In this frame, we recently analyzed the literature data supporting a direct association between type 2 diabetes mellitus (T2DM) and an increased probability to develop PD, suggesting a potential molecular mechanism underlying such a correlation [6]. We will present a critical appraisal of the use of metformin in both experimental PD models and clinical studies, highlighting the challenge in data interpretation and evaluation of metformin effectiveness as a disease modifier for PD
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