Cordycepin alleviates aluminium chloride-induced neurodevelopmental toxicity in zebrafish embryos by modulating inflammation and Wnt signaling
- Neurochem Int. 2026 Sep:198:106207. doi: 10.1016/j.neuint.2026.106207.
- 1. Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Clinical Research Center of Affiliated Hospital of Jinggangshan University, School of Basic Medicine, Jinggangshan University, Ji'an, Jiangxi, 343009, China; Birth Defect Group, Translational Research Institute of Brain and Brain-like Intelligence, Shanghai Fourth People's Hospital, Department of Epidemiology, School of Public Health, School of Medicine, Tongji University, Shanghai, 200434, China.
- 2. Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Clinical Research Center of Affiliated Hospital of Jinggangshan University, School of Basic Medicine, Jinggangshan University, Ji'an, Jiangxi, 343009, China; College of Biology and Food Engineering, Key Laboratory of Embryo Development and Reproductive Regulation of Anhui Province, Fuyang Normal University, Fuyang, Anhui, 236041, China.
- 3. Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Clinical Research Center of Affiliated Hospital of Jinggangshan University, School of Basic Medicine, Jinggangshan University, Ji'an, Jiangxi, 343009, China.
- 4. Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Clinical Research Center of Affiliated Hospital of Jinggangshan University, School of Basic Medicine, Jinggangshan University, Ji'an, Jiangxi, 343009, China; School of Nursing, Jinggangshan University, Ji'an, Jiangxi, 343009, China.
- 5. Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Clinical Research Center of Affiliated Hospital of Jinggangshan University, School of Basic Medicine, Jinggangshan University, Ji'an, Jiangxi, 343009, China. Electronic address: [email protected].
- 6. Birth Defect Group, Translational Research Institute of Brain and Brain-like Intelligence, Shanghai Fourth People's Hospital, Department of Epidemiology, School of Public Health, School of Medicine, Tongji University, Shanghai, 200434, China. Electronic address: [email protected].
- 7. Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Clinical Research Center of Affiliated Hospital of Jinggangshan University, School of Basic Medicine, Jinggangshan University, Ji'an, Jiangxi, 343009, China; Jiangxi Branch of State Key Laboratory for Macromolecule Drugs and Large-scale Preparation & National Engineering Research, Center of Cell Growth Factor Drugs and Protein Biologics, Center for Genetic Development and Regenerative Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province, 341000, China. Electronic address: [email protected].
Background: Cordycepin, a major bioactive constituent of Cordyceps militaris, exhibits diverse pharmacological properties including anti-inflammatory and antioxidant activities. However, its neuroprotective effects against aluminum-induced neurotoxicity in aquatic organism models remain largely unexplored.
Methods: In this study, we investigated the neuroprotective effects and intrinsic regulatory pathways by which cordycepin alleviates aluminium chloride (AlCl3)-induced neurotoxicity in zebrafish (Danio rerio) embryos using behavioral, molecular, and transcriptomic approaches.
Results: Exposure to low-dose AlCl3 significantly induced developmental neurotoxicity, as manifested by reduced body length and reduced heart rate. AlCl3-treated larvae displayed locomotor deficits and cognitive dysfunction. Notably, cordycepin treatment markedly attenuated these AlCl3-induced neurodevelopmental abnormalities and aluminum chloride (AlCl3)-induced locomotor and anxiety-related behavioral impairments.RNA-Seq analysis revealed 605 upregulated and 241 downregulated genes following co-exposure to cordycepin and AlCl3. Functional enrichment analyses based on Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) screened out defense reaction and inflammatory signaling cascades as the remarkably enriched functional pathways, which implied these biological processes exert key functions in the nerve protection produced by cordycepin. Furthermore, pharmacological inhibition targeting the Wnt cascade via IWR-1-endo (IWR-1) markedly counteracted cordycepin's protective capacity to reverse AlCl3-triggered behavioral impairments, indicating that Wnt signaling is essential for its neuroprotective action.
Conclusion: Collectively, these findings demonstrate that cordycepin effectively mitigates AlCl3-induced neurotoxicity and AlCl3-induced locomotor and anxiety-related behavioral impairments in zebrafish by regulating inflammatory reactions and the Wnt signal cascade, highlighting its promising value for the clinical intervention of AD.