Involvement of the weak metabolic function in cardiovascular toxicity induced by idebenone in zebrafish

Abstract

Idebenone (IDE) is a commonly used psychotropic drug in the clinic. However, the cardiovascular toxicity of IDE has not been reported previously. Therefore, we evaluated the safety of IDE and preliminarily elucidated the mechanism of cardiovascular toxicity induced by IDE using zebrafish as the model organism. In this study, wild-type AB zebrafish, and transgenic zebrafish Tg(cmcl2:EGFP) with green fluorescence-labelled cardiomyocytes were used as the research objects. We evaluated the effects of IDE on the sinus venosus-bulbus arteriosus (SV-BA) distance, ejection fraction, ventricular short-axis shortening rate, blood flow rate, and the staining area and intensity of cardiac erythrocytes. The toxic mechanism of IDE was elucidated using transcriptomics and Quantitative real-time PCR (qRT-PCR). We found that high concentrations of IDE could cause acute poisoning of some zebrafish within a short period (6 h), mainly characterized by severe cardiac venous stasis. IDE decreased the blood flow and reduced the red blood cell stained area in the heart region of some zebrafish. The results of transcriptome analysis and qRT-PCR showed that the expression of genes related to drug metabolism and lipid metabolism was significantly down-regulated in zebrafish with IDE-induced cardiovascular toxicity. We believe that IDE may be more likely to cause acute cardiovascular toxicity in organisms with weak metabolic enzyme function. The present study investigated the mechanism of the toxic effects of IDE using a zebrafish model and laid the foundation for a more comprehensive understanding of the cardiovascular toxicity of IDE.