The cardiovascular toxicity of clozapine in embryonic zebrafish and RNA sequencing-based transcriptome analysis.

Abstract

Clozapine (CLZ) is the most prescribed medication for treating refractory schizophrenia but is associated with significant cardiovascular toxicity. This study aimed to investigate the cardiovascular toxicity induced by CLZ using zebrafish as a model animal. For this purpose, zebrafish developed to 80-h post-fertilization were exposed to different CLZ concentration solutions for 24 h followed by cardiac morphological observations in yolk sac edema, pericardial edema, and blood coagulation, in addition to increased SV-BA distance, functionally manifested as bradycardia, and decreased cardiac ejection fraction using the untreated embryos as control. At the same time, RNA sequencing was used to study the possible molecular mechanism of CLZ-induced cardiovascular toxicity. The results indicated that compared to the control group, the experimental groups possessed a total of 5888 differentially expressed genes (DEGs), where gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment of analysis indicated that DEGs were mainly enriched in the pathways related to ion channels. These findings may provide new insights and directions for the subsequent in-depth study of the molecular mechanism of CLZ-induced cardiovascular toxicity.