Rotenone Exposure in Zebrafish Parkinson's Disease Model Reveals NURR1-TOP2B Dysregulation and Gut-Brain Axis-Associated Pathology.

Authors

Dhanveer Ahamed Bathurutheen, Sharran Raja, Nurul Syahirah Ahmad Sayuti, Muzaimi Mustapha, Thenmoly Damodaran

Published in

Behavioural brain research. Pages 116436. Aug 12, 2026. Epub Aug 12, 2026.

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder in which early gastrointestinal dysfunction and oxidative stress are increasingly implicated through the gut-brain axis. Zebrafish (Danio rerio) offer a tractable model for PD research; However, to our knowledge, there is currently no consensus on the rotenone concentration that effectively mimics both brain and gut pathology, leaving the dose required to induce integrated central-peripheral pathology unresolved. Adult zebrafish were exposed to 2.5 or 5µg/L rotenone for 28 days, and behavioral, biochemical, histological, and transcriptional changes were assessed in the brain and intestine. Rotenone induced concentration-dependent impairments in locomotion, anxiety-like behavior, and cognition, with pronounced deficits at 5µg/L. Histopathological damage in both the brain and intestine was observed at 2.5 & 5µg/L. Oxidative stress was evident, with elevated reactive oxygen species (ROS) levels in the brain at both concentrations and in the intestine only at 5µg/L, accompanied by increased lipid peroxidation (LPO) at the higher concentration. Antioxidant enzyme activities, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), were significantly disrupted. Transcriptional analysis revealed upregulation of γ1-synuclein and top2b alongside downregulation of nr4a2a (Nurr1) in both tissues. Pro-inflammatory cytokines il6 and tnfa were also markedly elevated. In conclusion, these findings establish 5µg/L rotenone as an optimized exposure for inducing reproducible, systemically integrated PD-like pathology in zebrafish and underscore NURR1-TOP2B dysregulation as a molecular correlate of gut-brain axis-associated dysfunction.

PMID:
42586489
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.

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