Ponatinib-induced ischemic stroke in larval zebrafish for drug screening

• DOI: 10.1016/j.ejphar.2020.173292
• Publication Date: 2020-07-12T13:55:07Z
• Authors: Xiao-Yu Zhu; Bo Xia; Ting Ye; Ming-Zhu Dai; Hua Yang; Chun-Qi Li; Ping Li
• Keywords: 0301 basic medicine; Drug Evaluation, Preclinical; Imidazoles; Antineoplastic Agents; Brain Ischemia; 3. Good health; Animals, Genetically Modified; Pyridazines; Disease Models, Animal; 03 medical and health sciences; Larva; Animals; Platelet Aggregation Inhibitors; Zebrafish; Ischemic Stroke

Conventional mammalian ischemic stroke models for drug screening are technically challenging, laborious and time-consuming. In this study, using Ponatinib as an inducer, we developed and characterized a zebrafish ischemic stroke model. This zebrafish ischemic stroke had the cerebral vascular endothelial injury, thrombosis, reduced blood flow, inflammation and apoptosis as well as the reduced motility. The zebrafish ischemic stroke model was validated with 6 known human therapeutic drugs of ischemic stroke (Aspirin, Clopidogrel, Naoxintong capsules, Edaravone, Xingnaojing injection, Shuxuening injection). The mRNA levels of the neovascularization-related gene (vegfaa) and vascular endothelial growth factor receptor gene (VEGFR), neurodevelopment related genes (mbp and α1-tubulin), brain-derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF) were significantly downregulated; whereas apoptosis-related genes (caspase-3, caspase-7, caspase-9 and bax/bcl-2), and inflammatory factor genes (IL-1β, IL-6, IL-10, TNF-α and NF-κB) were remarkably upregulated in the model. These results suggest that the pathophysiology of Ponatinib-induced zebrafish ischemic stroke is similar to that of human ischemic stroke patients and this whole animal model could be used to study the complex cellular and molecular pathogenesis of ischemic stroke and to rapidly identify therapeutic agents.