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.
Highlights
Aesculus hippocastanum (Hippocastanaceae), the worldwide-distributed horse chestnut with excellent resistance to environmental conditions, possesses therapeutic properties of relieving tissueMolecules 2016, 21, 190; doi:10.3390/molecules21030190 www.mdpi.com/journal/moleculesMolecules 2016, 21, 190 edema, recovering vasopermeability and eliminating pressure caused by edema [1,2]
In both untreated and vehicle control groups, no morphological changes were found in the heart and pericardium of zebrafish
In groups with 1.5 μg/mL and 2.0 μg/mL of Sodium aescinate (SA), the zebrafish pericardium was enlarged, edematous and filled with turbid fluid, which appeared about four-times larger than that of control groups
Summary
Aesculus hippocastanum (Hippocastanaceae), the worldwide-distributed horse chestnut with excellent resistance to environmental conditions, possesses therapeutic properties of relieving tissueMolecules 2016, 21, 190; doi:10.3390/molecules21030190 www.mdpi.com/journal/moleculesMolecules 2016, 21, 190 edema, recovering vasopermeability and eliminating pressure caused by edema [1,2]. Aesculus hippocastanum (Hippocastanaceae), the worldwide-distributed horse chestnut with excellent resistance to environmental conditions, possesses therapeutic properties of relieving tissue. Sodium aescinate (SA) is a triterpene saponin derived from horse chestnut seeds, widely used as a dietary supplement and skin care product, as well as a pharmaceutical. As a bioactive natural product, SA has recently been used in clinical therapy for its anti-apoptotic, anti-edematous, anti-inflammatory and antioxidative effects [3,4,5]. To date, no report has concerned the side effect or toxic profile of SA, which is necessary for understanding of the pharmacologic action of SA in the clinic
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