Abstract
To date, there are no clinically effective neuroprotective or disease-modifying treatments that can halt Parkinson's disease (PD) progression. The current clinical approach focuses on symptomatic management. This failure may relate to the complex neurobiology underpinning the development of PD and the absence of true translational animal models. In addition, clinical diagnosis of PD relies on presentation of motor symptoms which occur when the neuropathology is already established. These multiple factors could contribute to the unsuccessful development of neuroprotective treatments for PD. Prodromal symptoms develop years prior to formal diagnosis and may provide an excellent tool for early diagnosis and better trial design. Patients with idiopathic rapid eye movement behavior disorder (iRBD) have the highest risk of developing PD and could represent an excellent group to include in neuroprotective trials for PD. In addition, repurposing drugs with excellent safety profiles is an appealing strategy to accelerate drug discovery. The anti-diabetic drug metformin has been shown to target diverse cellular pathways implicated in PD progression. Multiple studies have, additionally, observed the benefits of metformin to counteract other age-related diseases. The purpose of this viewpoint is to discuss metformin's neuroprotective potential by outlining relevant mechanisms of action and the selection of iRBD patients for future clinical trials in PD.
Highlights
Parkinson’s disease (PD) is the fastest growing neurodegenerative age-related disorder with numbers of patients projected to double by 2040 globally [1]
This approach may be flawed as post-mortem studies show that by 4 years after a clinical diagnosis of PD, there is already virtually complete nigrostriatal denervation of the dorsal putamen, profound nigral cell loss and abundant Lewy pathology, which raises the question of the possibility to achieve neuroprotection even in these “early motor stages” [16]
All clinical disease-modifying trials in PD have been performed in individuals in the manifested “in-life” motor stage, targeting either early “de novo” PD or treated PD and have all failed to show any convincing effects on neuroprotection
Summary
PD is the fastest growing neurodegenerative age-related disorder with numbers of patients projected to double by 2040 globally [1]. Most PD studies continue to mainly focus on motor endpoints despite PD being recognized to be a nonmotor disorder, with a complex range of non-motor symptoms (NMS) that span from prodromal to advance stages of the disease [21] These include dysphagia, autonomic dysfunction, sleep disorders, mood disturbances, cognitive impairment, and dementia [22, 23]. Most neuroprotective trials in PD have enrolled patients either in a “de novo untreated stage” or “early stable treated stage” in attempts to intervene at a point where the rescue of neurons is still feasible—yet the results have been uniformly negative [15] This approach may be flawed as post-mortem studies show that by 4 years after a clinical diagnosis of PD, there is already virtually complete nigrostriatal denervation of the dorsal putamen, profound nigral cell loss and abundant Lewy pathology, which raises the question of the possibility to achieve neuroprotection even in these “early motor stages” [16].
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