PUBLICATION
Clozapine Induced Developmental and Cardiac Toxicity on Zebrafish Embryos by Elevating Oxidative Stress
- Authors
- Zhang, F., Han, L., Wang, J., Shu, M., Liu, K., Zhang, Y., Hsiao, C., Tian, Q., He, Q.
- ID
- ZDB-PUB-210126-7
- Date
- 2021
- Source
- Cardiovascular Toxicology 21(5): 399-409 (Journal)
- Registered Authors
- Hsiao, Chung-Der
- Keywords
- Cardiotoxicity, Clozapine, Danio rerio, Development, Oxidative stress
- MeSH Terms
-
- Animals
- Antipsychotic Agents/toxicity*
- Cardiotoxicity
- Clozapine/toxicity*
- Cytokines/genetics
- Cytokines/metabolism
- Embryonic Development/drug effects
- Gene Expression Regulation
- Heart Diseases/chemically induced*
- Heart Diseases/genetics
- Heart Diseases/metabolism
- Heart Diseases/physiopathology
- Heart Rate/drug effects
- Lipid Peroxidation/drug effects
- Oxidative Stress/drug effects*
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 33486714 Full text @ Cardiovasc. Toxicol.
Citation
Zhang, F., Han, L., Wang, J., Shu, M., Liu, K., Zhang, Y., Hsiao, C., Tian, Q., He, Q. (2021) Clozapine Induced Developmental and Cardiac Toxicity on Zebrafish Embryos by Elevating Oxidative Stress. Cardiovascular Toxicology. 21(5):399-409.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping