Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China.
Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
J Appl Toxicol. 2024 Feb;44(2):175-183. doi: 10.1002/jat.4530. Epub 2023 Aug 22.
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.
氯氮平（CLZ）是治疗难治性精神分裂症最常开的药物，但与显著的心血管毒性相关。本研究旨在使用斑马鱼作为模型动物来研究 CLZ 引起的心血管毒性。为此，将发育至受精后 80 小时的斑马鱼暴露于不同浓度的 CLZ 溶液中 24 小时，然后观察卵黄囊水肿、心包水肿和血液凝固情况，以及 SV-BA 距离增加，表现为心动过缓，同时使用未处理的胚胎作为对照，测量心脏射血分数降低。同时，使用 RNA 测序研究 CLZ 诱导的心血管毒性的可能分子机制。结果表明，与对照组相比，实验组共有 5888 个差异表达基因（DEGs），基因本体（GO）和京都基因与基因组百科全书（KEGG）功能富集分析表明，DEGs 主要富集在与离子通道相关的途径中。这些发现可能为 CLZ 诱导的心血管毒性的分子机制的后续深入研究提供新的见解和方向。
