Department of Biopharmacy, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland; Independent Laboratory of Behavioral Studies, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland.
Department of Biopharmacy, Medical University of Lublin, 4a Chodzki Street, 20-093 Lublin, Poland.
Biomed Pharmacother. 2022 Apr;148:112695. doi: 10.1016/j.biopha.2022.112695. Epub 2022 Feb 11.
Cardiotoxicity remains the most common reason for failure during drug development. Recently, the zebrafish (Danio rerio) model has emerged for the evaluation of drug-dependent cardiotoxicity and for the identification of cardioprotective molecules. However, it remains unknown how closely the zebrafish-based results may be translated to humans. To tackle this issue, we established embryonic zebrafish models of doxorubicin-, adrenaline- and terfenadine-induced cardiotoxicity with unified dosing regimen which eventually enabled head-to-head comparison of the drugs. Subsequently, we determined whether human cardioprotective medications - dexrazoxane, metoprolol, carvedilol and valsartan - are able to manage heart dysfunction in zebrafish. Our results indicated that doxorubicin, adrenaline and terfenadine elicited overt signs of cardiotoxicity in fish, and we further showed that the blockade of the renin-angiotensin system and, to a lesser extent, β-adrenergic system, ameliorated the heart disease in zebrafish. From the drug development standpoint, our work opens the possibility to determine the cardiovascular properties of tested compounds using the rapid and affordable zebrafish model.
心脏毒性仍然是药物开发过程中失败的最常见原因。最近，斑马鱼（Danio rerio）模型已被用于评估药物依赖性心脏毒性和鉴定心脏保护分子。然而，斑马鱼模型的结果与人类的相关性如何，目前仍不清楚。为了解决这个问题，我们建立了统一的给药方案诱导的多柔比星、肾上腺素和特非那定致心脏毒性的胚胎斑马鱼模型，最终实现了药物的直接比较。随后，我们确定了人类心脏保护药物 - 右雷佐生、美托洛尔、卡维地洛和缬沙坦 - 是否能够改善斑马鱼的心脏功能障碍。我们的结果表明，多柔比星、肾上腺素和特非那定在鱼类中引起了明显的心脏毒性迹象，我们进一步表明，肾素-血管紧张素系统的阻断，以及在较小程度上β-肾上腺素能系统的阻断，改善了斑马鱼的心脏病。从药物开发的角度来看，我们的工作为使用快速且经济实惠的斑马鱼模型来确定受试化合物的心血管特性开辟了可能性。
