Zhu Xiao-Yu, Xia Bo, Ye Ting, Dai Ming-Zhu, Yang Hua, Li Chun-Qi, Li Ping
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, PR China; Hunter Biotechnology, Inc, F1A, Building 5, No. 88 Jiangling Road, Binjiang Zone, Hangzhou City, Zhejiang Province, 310051, PR China.
Hunter Biotechnology, Inc, F1A, Building 5, No. 88 Jiangling Road, Binjiang Zone, Hangzhou City, Zhejiang Province, 310051, PR China.
Eur J Pharmacol. 2020 Dec 15;889:173292. doi: 10.1016/j.ejphar.2020.173292. Epub 2020 Jul 12.
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.
用于药物筛选的传统哺乳动物缺血性中风模型在技术上具有挑战性，费力且耗时。在本研究中，我们使用波纳替尼作为诱导剂，开发并表征了一种斑马鱼缺血性中风模型。这种斑马鱼缺血性中风具有脑血管内皮损伤、血栓形成、血流减少、炎症和细胞凋亡以及运动能力下降等特征。该斑马鱼缺血性中风模型用6种已知的人类缺血性中风治疗药物（阿司匹林、氯吡格雷、脑心通胶囊、依达拉奉、醒脑静注射液、舒血宁注射液）进行了验证。新血管生成相关基因（vegfaa）和血管内皮生长因子受体基因（VEGFR）、神经发育相关基因（mbp和α1-微管蛋白）、脑源性神经营养因子（BDNF）和胶质细胞源性神经营养因子（GDNF）的mRNA水平显著下调；而凋亡相关基因（caspase-3、caspase-7、caspase-9和bax/bcl-2）以及炎症因子基因（IL-1β、IL-6、IL-10、TNF-α和NF-κB）在该模型中显著上调。这些结果表明，波纳替尼诱导的斑马鱼缺血性中风的病理生理学与人类缺血性中风患者相似，这种整体动物模型可用于研究缺血性中风复杂的细胞和分子发病机制，并快速鉴定治疗药物。
