Network pharmacological combined with in vivo and in vitro validation reveals the mechanisms of atrazine-induced Parkinson's disease-related neurotoxicity.

Authors

Yaqin Liu, Li Wang, Guanhan Xiang, Yi Huang, Jiahui Wang, Qian Cai

Published in

Toxicology and applied pharmacology. Pages 118030. Sep 12, 2026. Epub Sep 12, 2026.

Abstract

Atrazine (ATR), a common triazine herbicide, is closely linked to neuroinflammation, yet the molecular mechanism underlying its neurotoxic potential remains poorly defined. This work explored ATR-provoked neuroinflammation focusing on microglial activation and the PI3K/AKT/JNK cascade via network pharmacology, molecular simulation and multilevel experiments. Potential ATR-PD intersecting targets were screened for PPI, GO and KEGG enrichment. Molecular docking and 100 ns dynamics simulations verified stable binding between ATR and hub molecules. ATR-triggered microglial activation, proinflammatory cytokine release and PI3K/AKT/JNK phosphorylation were detected in BV2 cells, which were reversed by AKT inhibitor MK2206. Transwell coculture and conditioned medium assays confirmed that ATR-stimulated microglia caused HT22 neuronal synaptic damage, rescued by MK2206. In chronically ATR-exposed C57BL/6 mice, motor dysfunction, substantia nigra lesion, microgliosis, pathway hyperactivation and neuronal loss (NeuN-positive neurons) were observed. Collectively, ATR facilitates microglia-dependent neuroinflammation and nigral neuronal damage by perturbing PI3K/AKT/JNK signaling. AKT suppression alleviates ATR-mediated neurotoxicity under the present experimental conditions. Notably, the in vitro (40 μM) and in vivo (25 mg/kg/d) doses used in this study are substantially higher than typical human environmental exposure levels; these findings cannot be directly extrapolated to human health risk assessment. This study provides a candidate intervention strategy for ATR-associated neuronal injury observed in the experimental model.

PMID:
42731642
Bibliographic data and abstract were imported from PubMed on 13 Sep 2026.

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