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Clozapine Induced Developmental and Cardiac Toxicity on Zebrafish Embryos by Elevating Oxidative Stress

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Abstract

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 μmol L−1 and 49.60 μmol 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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Funding

This work was supported by (1) Mount Taishan Scholar Program of Shandong Province (tspd20181211), (2) International Science and Technology Cooperation Project of Shandong Academy of Sciences (2019GHPY13), (3) the Project for the Integration of Science, Education and Industry, major innovation project of Shandong Academy of Sciences (2020KJC-ZD10), (4) a Project of Shandong Province Higher Educational Science and Technology Program (J18KA154) and(5) Outstanding youth fund of the Shandong Academy of Sciences.

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  1. Feng Zhang and Liwen Han contributed equally to the study.

Authors and Affiliations

  1. Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 Jingshi Dong Road, Licheng District, Jinan, 250103, Shandong, China

    Feng Zhang, Liwen Han, Jiazhen Wang, Kechun Liu, Yun Zhang & Qiuxia He

  2. School of Pharmacology, Shanxi Medical University, Xinjian Nan Road 56, Taiyuan, 030001, Shanxi, China

    Feng Zhang & Qingping Tian

  3. Shandong Artificial Intelligence Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250014, Shandong, China

    Minglei Shu

  4. Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li, Taiwan

    ChungDer Hsiao

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  1. Feng Zhang
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Correspondence to Qingping Tian or Qiuxia He.

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Zhang, F., Han, L., Wang, J. et al. Clozapine Induced Developmental and Cardiac Toxicity on Zebrafish Embryos by Elevating Oxidative Stress. Cardiovasc Toxicol 21, 399–409 (2021). https://doi.org/10.1007/s12012-021-09632-7

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