Zhejiang Center for Drugs and Cosmetics Evaluation, Zhejiang Province Food and Drug Administration, Hangzhou 310012, China.
Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou 310053, China.
Molecules. 2016 Feb 23;21(3):190. doi: 10.3390/molecules21030190.
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.
七叶皂苷钠（SA）是一种广泛应用的三萜皂苷类药物，来源于欧洲七叶树的种子，具有血管活性和器官保护作用，可通过口服或注射在临床上使用。迄今为止，使用常规模型（体内或体外）未报告 SA 的毒性或不良反应，但这些模型不足以预测其药理学和毒理学作用的所有方面。在这项研究中，我们利用透明斑马鱼幼虫（Danio rerio），通过卵黄囊微注射评估了 SA 在 1/10 MNLC、1/3 MNLC、MNLC 和 LC10 剂量下的心血管毒性。在 SA 处理后 48 小时，使用特定的表型终点评估斑马鱼的定性和定量心脏毒性：心率、心律、心脏畸形、心包水肿、循环异常、血栓形成和出血。结果表明，SA 在 1/10 MNLC 及以上剂量可诱导明显的心脏和心包畸形，而 1/3 MNLC 及以上剂量可诱导显著的心脏功能障碍（心率和循环减少/缺失），与未处理或载体处理的对照组相比。在 MNLC 和 LC10 处理的所有斑马鱼中，超过 50%至 100%的斑马鱼出现这种心脏毒性表现。我们的研究结果首次揭示了 SA 的潜在心脏毒性，表明在其临床应用中需要更加注意其风险。这种省时、省钱的斑马鱼心脏毒性检测方法对于在药物研发过程中快速预测化合物毒性非常有效和可靠。
