title: In Vivo Cardiotoxicity Induced by Sodium Aescinate in Zebrafish Larvae.
abstract: Sodium aescinate (SA) is a widely-applied triterpene saponin product derived from horse chestnut seeds, possessing vasoactive and organ-protective activities with oral or injection administration in the clinic. To date, no toxicity or adverse events in SA have been reported, by using routine models (in vivo or in vitro), which are insufficient to predict all aspects of its pharmacological and toxicological actions. In this study, taking advantage of transparent zebrafish larvae (Danio rerio), we evaluated cardiovascular toxicity of SA at doses of 1/10 MNLC, 1/3 MNLC, MNLC and LC10 by yolk sac microinjection. The qualitative and quantitative cardiotoxicity in zebrafish was assessed at 48 h post-SA treatment, using specific phenotypic endpoints: heart rate, heart rhythm, heart malformation, pericardial edema, circulation abnormalities, thrombosis and hemorrhage. The results showed that SA at 1/10 MNLC and above doses could induce obvious cardiac and pericardial malformations, whilst 1/3 MNLC and above doses could induce significant cardiac malfunctions (heart rate and circulation decrease/absence), as compared to untreated or vehicle-treated control groups. Such cardiotoxic manifestations occurred in more than 50% to 100% of all zebrafish treated with SA at MNLC and LC10. Our findings have uncovered the potential cardiotoxicity of SA for the first time, suggesting more attention to the risk of its clinical application. Such a time- and cost-saving zebrafish cardiotoxicity assay is very valid and reliable for rapid prediction of compound toxicity during drug research and development.
authors.affiliation: Zhejiang Center for Drugs and Cosmetics Evaluation, Zhejiang Province Food and Drug Administration, Hangzhou 310012, China. liangwind@sohu.com.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liang
authors.affiliation: Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China. wangdong.jin@hotmail.com.
authors.forename: Wangdong
authors.initials: W
authors.lastname: Jin
authors.affiliation: Experimental and Training Center, Zhejiang Pharmaceutical College, Ningbo 315100, China. hongwen_lee@sohu.com.
authors.forename: Hongwen
authors.initials: H
authors.lastname: Li
authors.affiliation: Hunter Biotechnology, Inc., Transfarland, Hangzhou 310012, China. lhc@zhunter.com.
authors.forename: Hongcui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Hunter Biotechnology, Inc., Transfarland, Hangzhou 310012, China. 10710@etransfar.com.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Zhejiang Center for Drugs and Cosmetics Evaluation, Zhejiang Province Food and Drug Administration, Hangzhou 310012, China. lvminella@hotmail.com.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Shan
authors.affiliation: Hunter Biotechnology, Inc., Transfarland, Hangzhou 310012, China. jackli@zhunter.com.|Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, Wenzhou Medical University,Wenzhou 325035, China. jackli@zhunter.com.
authors.forename: Chunqi
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China. letian.shan@hotmail.com.
authors.forename: Letian
authors.initials: L
authors.lastname: Shan
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany. efferth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D000818:Animals; D066126:Cardiotoxicity / Q000209:etiology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004625:Embryo, Nonmammalian; D006321:Heart / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D007814:Larva; D008845:Microinjections; D012503:Saponins / Q000009:adverse effects*; D013927:Thrombosis / Q000139:chemically induced / Q000473:pathology; D036401:Toxicity Tests, Chronic / Q000379:methods*; D014315:Triterpenes / Q000009:adverse effects*; D015017:Yolk Sac; D015027:Zebrafish
chemical_list: D012503:Saponins; D014315:Triterpenes; C584713:sodium aescinate
keywords: LC10; MNLC; cardiotoxicity; larvae; sodium aescinate; zebrafish