Journal
CARDIOVASCULAR TOXICOLOGY
Volume 21, Issue 5, Pages 399-409Publisher
HUMANA PRESS INC
DOI: 10.1007/s12012-021-09632-7
Keywords
Clozapine; Cardiotoxicity; Danio rerio; Oxidative stress; Development
Categories
Funding
- Mount Taishan Scholar Program of Shandong Province [tspd20181211]
- International Science and Technology Cooperation Project of Shandong Academy of Sciences [2019GHPY13]
- Project for the Integration of Science, Education and Industry, major innovation project of Shandong Academy of Sciences [2020KJC-ZD10]
- Project of Shandong Province Higher Educational Science and Technology Program [J18KA154]
- Outstanding youth fund of the Shandong Academy of Sciences
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The study on clozapine-induced cardiotoxicity in zebrafish embryos revealed that clozapine exposure led to dose-dependent mortality, morphological abnormalities, slower heart rate, disturbed rhythm, oxidative stress, and upregulation of inflammatory cytokines. These findings provide experimental explanations for myocarditis and pericarditis induced by clozapine in clinics and may aid in finding effective solutions to reduce its cardiotoxicity.
Clozapine is one of the antipsychotic drugs for treating schizophrenia, but its cardiotoxicity was the primary obstacle for its clinical use, due to the unknown mechanism of clozapine-induced cardiotoxicity. In this study, we studied the cardiotoxicity of clozapine by employing zebrafish embryos. Acute clozapine exposure showed dose-dependent mortality with the LC50 at 59.36 mu mol L-1 and 49.60 mu mol L-1 when determined at 48 and 72 h post exposure, respectively. Morphological abnormalities like pericardial edema, incompletely heart looping, and bradycardia were detected after clozapine exposure in a time- and dose-dependent manner. Clozapine treatment also resulted in a slower heart rate and disturbed rhythm in zebrafish embryos. Also, oxidative stress was observed after clozapine exposure by measurement of ROS (reactive oxygen species), MDA (a lipid peroxidation marker), antioxidant enzyme activities, and oxidative stress-related gene expression. The elevation of inflammation coincided with oxidative stress by the assay of inflammation-related genes expression accompanied by clozapine incubation. Collectively, the data indicate that clozapine might achieve cardiotoxic effect in zebrafish larva through increasing oxidative stress, attenuation in antioxidant defense, and up-regulation of inflammatory cytokines. The data could provide experimental explanations for myocarditis and pericarditis induced by clozapine in clinics, and help find an effective solution to reduce its cardiotoxicity.
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