An update on drug repurposing in Parkinson's disease: Preclinical and clinical considerations.

The strategy of drug repositioning has historically played a significant role in the identification of new treatments for Parkinson's disease. Still today, numerous clinical and preclinical studies are investigating drug classes, already marketed for the treatment of metabolic disorders, for their potential use in Parkinson's disease patients. While drug repurposing offers a promising, fast, and cost-effective path to new treatments, these drugs still require thorough preclinical evaluation to assess their efficacy, addressing the specific neurodegenerative mechanisms of the disease. This review explores the state-of-the-art approaches to drug repurposing for Parkinson's disease, highlighting particularly relevant aspects. Preclinical studies still predominantly rely on traditional neurotoxin-based animal models, which fail to effectively replicate disease progression and are characterized by significant variability in model severity and timing of drug treatment. Importantly, for almost all the drugs analyzed here, there is insufficient data regarding the mechanism of action responsible for the therapeutic effect. Regarding drug efficacy, these factors may obviously render results less reliable or comparable. Accordingly, future preclinical drug repurposing studies in the Parkinson's disease field should be carried out using next-generation animal models like α-synuclein-based models that, unfortunately, have to date been used mostly for studies of disease pathogenesis and only rarely in pharmacological studies.