Kumar_2026_Curr.Drug.Metab__

INTRODUCTION: Danio rerio, the zebrafish, serves as an excellent model in neuroprotective drug discovery due to its conserved nervous system organization, neurotransmitter pathways, antioxidant de-fenses, and genomic similarity to mammals. METHODS: A systematic literature search following PRISMA 2020 guidelines was conducted across Pub-Med, Scopus, Web of Science, and Google Scholar. Studies published between 2020 and 2025 were pri-oritized, with earlier key papers included for context. The data on larval, adult, and genetically modified zebrafish models were analyzed for neurotoxic effects, focusing on study design, toxicants, and neurobe-havioral or molecular outcomes. RESULTS: Neurotoxicants such as chlorpyrifos, bisphenol, triphenyl phosphate, aluminum, ammonium ac-etate, arsenic, zinc, acrylamide, methylmercury, and tris (1,3-dichloro-2-propyl) phosphate were shown to cross the zebrafish blood-brain barrier. These exposures caused significant behavioral alterations, neu-rotransmitter imbalances, oxidative stress, and gene or protein expression changes related to brain func-tion. Analysis of the transgenic zebrafish revealed notable alterations in neuronal development and axonal morphology upon exposure to various neurotoxic chemicals. DISCUSSION: Zebrafish display neurotoxic responses with a close resemblance to mammals, supporting their translational value in neurotoxicity and drug discovery studies. However, limitations such as a less complex brain compared to mammals, quick neuronal regeneration, limited tissue access, and difficulties in drug absorption quantification warrant refinements in zebrafish models. CONCLUSION: Zebrafish offer a versatile, cost-effective, and genetically tractable system for neurotoxicity and neuroprotection research. This systematic review highlights their crucial role in neuroprotective drug discovery while emphasizing the need for improved methodological approaches to enhance translational reliability.