GLP-1 Receptor Agonists Show Preclinical Neuroprotection but Inconsistent Clinical Efficacy in Parkinson's and Other Movement Disorders

Movement disorders, including Parkinson's disease (PD), represent a significant unmet medical need due to their progressive neurodegenerative nature and lack of disease-modifying treatments. Current therapies primarily manage symptoms, failing to halt disease progression. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for type 2 diabetes and obesity, have garnered interest for their potential neuroprotective properties. These agents modulate key pathogenic pathways such as neuroinflammation, mitochondrial dysfunction, oxidative stress, and impaired proteostasis, with GLP-1R widely expressed in motor-related brain regions, suggesting a plausible therapeutic mechanism.

This narrative review systematically summarized the current mechanistic, preclinical, and clinical evidence regarding GLP-1RAs across the spectrum of movement disorders. The authors conducted a comprehensive literature search, including preclinical studies, randomized clinical trials, observational data, and pharmacovigilance analyses. The review aimed to synthesize findings on the role of GLP-1RAs in conditions like Parkinson's disease, multiple system atrophy, Huntington's disease, and essential tremor, evaluating their potential as disease-modifying agents. No specific GLP-1RA compound or dose was the sole focus, but rather the class as a whole, with specific examples discussed.

Preclinical studies consistently demonstrated neuroprotective effects of GLP-1RAs, including the preservation of dopaminergic neurons, a reduction in α-synuclein aggregation, and significant improvements in motor function across various animal models. Clinical evidence is most advanced in Parkinson's disease, where early randomized trials of exenatide and lixisenatide suggested modest motor benefits and potential disease-modifying effects. However, subsequent larger studies, including the phase III Exenatide-PD3 trial, failed to demonstrate significant clinical benefit, highlighting translational challenges. Preliminary signals for GLP-1RAs have been reported in multiple system atrophy, indicating a potential avenue for further investigation. Evidence for their efficacy in Huntington's disease, essential tremor, and other movement disorders remains largely confined to preclinical stages, with human data still sparse or absent. The review concluded that while biologically plausible, GLP-1RAs are an as yet unproven disease-modifying strategy. > Preclinical studies consistently show GLP-1RAs preserve dopaminergic neurons and reduce α-synuclein aggregation, improving motor function in animal models.