Abstract
Research advances have shed new insight into cellular pathways contributing to PD pathogenesis and offer increasingly compelling therapeutic targets. In this review, we made a broad survey of the published literature that report possible disease-modifying effects on PD. While there are many studies that demonstrate benefits for various therapies for PD in animal and human studies, we confined our search to human “randomised controlled trials” and with the key words “neuroprotection” or “disease-modifying”. It is hoped that through studying the results of these trials, we might clarify possible mechanisms that underlie idiopathic PD. This contrasts with studying the effect of pathophysiology of familial PD, which could be carried out by gene knockouts and animal models. Randomised controlled trials indicate promising effects of MAO-B inhibitors, dopamine agonists, NMDA receptor antagonists, metabotropic glutamate receptor antagonists, therapies related to improving glucose utilization and energy production, therapies related to reduction of excitotoxicity and oxidative stress, statin use, therapies related to iron chelation, therapies related to the use of phytochemicals, and therapies related to physical exercise and brain reward pathway on slowing PD progression. Cumulatively, these approaches fall into two categories: direct enhancement of dopaminergic signalling, and reduction of neurodegeneration. Overlaps between the two categories result in challenges in distinguishing between symptomatic versus disease-modifying effects with current clinical trial designs. Nevertheless, a broad-based approach allows us to consider all possible therapeutic avenues which may be neuroprotective. While the traditional standard of care focuses on symptomatic management with dopaminergic drugs, more recent approaches suggest ways to preserve dopaminergic neurons by attenuating excitotoxicity and oxidative stress.
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This work was supported by grants from the Ministry of Education (NUHSRO/2019/051/T1/Seed-Mar/04) and the National Medical Research Council of Singapore (HLCA21Jan-0019) and A*STAR Singapore.
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Ong, WY., Leow, D.MK., Herr, D.R. et al. What Do Randomized Controlled Trials Inform Us About Potential Disease-Modifying Strategies for Parkinson’s Disease?. Neuromol Med 25, 1–13 (2023). https://doi.org/10.1007/s12017-022-08718-x
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DOI: https://doi.org/10.1007/s12017-022-08718-x