Zhang Feng, Han Liwen, Wang Jiazhen, Shu Minglei, Liu Kechun, Zhang Yun, Hsiao ChungDer, Tian Qingping, He Qiuxia
Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), 28789 Jingshi Dong Road, Licheng District, Jinan, 250103, Shandong, China.
School of Pharmacology, Shanxi Medical University, Xinjian Nan Road 56, Taiyuan, 030001, Shanxi, China.
Cardiovasc Toxicol. 2021 May;21(5):399-409. doi: 10.1007/s12012-021-09632-7. Epub 2021 Jan 24.
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 LC at 59.36 μmol L and 49.60 μmol L 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.
氯氮平是治疗精神分裂症的抗精神病药物之一，但其心脏毒性是其临床应用的主要障碍，因为氯氮平诱导心脏毒性的机制尚不清楚。在本研究中，我们利用斑马鱼胚胎研究了氯氮平的心脏毒性。急性氯氮平暴露显示出剂量依赖性死亡率，暴露后48小时和72小时测定的LC50分别为59.36 μmol/L和49.60 μmol/L。氯氮平暴露后，以时间和剂量依赖性方式检测到心包水肿、心脏环化不完全和心动过缓等形态学异常。氯氮平处理还导致斑马鱼胚胎心率减慢和心律紊乱。此外，通过测量活性氧（ROS）、丙二醛（脂质过氧化标志物）、抗氧化酶活性和氧化应激相关基因表达，观察到氯氮平暴露后的氧化应激。通过检测氯氮平孵育后炎症相关基因表达，炎症升高与氧化应激一致。总体而言，数据表明氯氮平可能通过增加氧化应激、削弱抗氧化防御和上调炎症细胞因子在斑马鱼幼虫中产生心脏毒性作用。这些数据可以为临床上氯氮平诱发的心肌炎和心包炎提供实验解释，并有助于找到降低其心脏毒性的有效解决方案。
