Mechanistic Insights of Zonisamide in Parkinson's Disease: A Systematic Review

ABSTRACT Zonisamide is an antiepileptic agent used as adjunctive therapy for Parkinson's Disease in Japan and studied more selectively elsewhere. Preclinical and early translational studies suggest that zonisamide may modulate several pathways relevant to Parkinson's Disease pathobiology, including dopaminergic neurotransmission, oxidative stress, neuroinflammation, and apoptosis. This systematic review critically appraises and synthesizes the existing evidence of the molecular and cellular neuroprotective pathways zonisamide exerts in Parkinson's Disease across human, animal, and in vitro studies. The review protocol was registered on PROSPERO (CRD420251274891). A literature search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science using MeSH terms and keywords for Parkinson's Disease and zonisamide limited to English‐language was employed. Clinical trials, mechanistic studies, and pre‐clinical models were included, with case reports and reviews excluded. Thirty‐six studies met the eligibility criteria and were included. Out of the 36 studies, most were beneficial; however, two studies were non‐beneficial (1 harmful, 1 mixed/dose‐dependent), indicating potential context‐ and dose‐sensitivity pertaining to the effect of zonisamide. Across the mechanistic domains, neurotransmission, oxidative stress, and neuroinflammation reduction, as well as anti‐apoptosis, were identified as the key drivers of neuroprotection. Overall, zonisamide demonstrates mechanistic promise, but interpretation is constrained by the predominantly preclinical, geographically concentrated evidence base, heterogeneity across models and endpoints, and limited human mechanistic data.