[1]张 凤,韩利文,张 云,等.氯氮平通过诱导斑马鱼胚胎心脏细胞凋亡引起心脏毒性[J].中国药理学通报,2018,(08):1088-1093.[doi:10.3969/j.issn.1001-1978.2018.08.012]
 ZHANG Feng,HAN Li-wen,ZHANG Yun,et al.Clozapine induced cardiotoxicity in zebrafish embryos through apoptosis[J].Chinese Pharmacological Bulletin,2018,(08):1088-1093.[doi:10.3969/j.issn.1001-1978.2018.08.012]
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氯氮平通过诱导斑马鱼胚胎心脏细胞凋亡引起心脏毒性()
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《中国药理学通报》[ISSN:/CN:]

卷:
期数:
2018年08期
页码:
1088-1093
栏目:
论著
出版日期:
2018-08-26

文章信息/Info

Title:
Clozapine induced cardiotoxicity in zebrafish embryos through apoptosis
文章编号:
1001-1978(2018)08-1088-06
作者:
张 凤12韩利文2张 云2韩 建2侯海荣2王希敏2刘可春2田青平1何秋霞2
1.山西医科大学药学院,山西 太原 030001; 2.齐鲁工业大学(山东省科学院),山东省科学院生物研究所,山东省生物检测技术工程实验室,山东省生物传感器重点实验室,山东省科学院药物筛选重点实验室,山东 济南 250014
Author(s):
ZHANG Feng12HAN Li-wen2ZHANG Yun2HAN Jian2HOU Hai-rong2WANG Xi-min2LIU Ke-chun2TIAN Qing-ping1HE Qiu-xia2
1.School of Pharmacy, Shanxi Medical University, Taiyuan 030001,China; 2.Biology Institute,Qilu University of Technology(Shandong Academy of Sciences), Shandong Provincial Engineering Laboratory for Biological Testing Technology, Key Laboratory for Biosensor of Shandong Province, Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, Jinan 250014, China
关键词:
氯氮平 心脏毒性 斑马鱼胚胎 细胞凋亡 Bcl-2/Bax caspase
Keywords:
clozapine cardiotoxicity zebrafish embryos cell apoptosis Bcl-2/Bax caspase
分类号:
R-332; R322.11; R329.25; R971.41
DOI:
10.3969/j.issn.1001-1978.2018.08.012
文献标志码:
A
摘要:
目的 观察氯氮平对斑马鱼胚胎心脏的毒性,研究其毒性作用的机制。方法 以24 hpf(hours post fertilization)斑马鱼胚胎为研究模型,以不同浓度的氯氮平(12.5、25、37.5、50、62.5 μmol·L-1)进行处理,于处理24、48、72 h后观察斑马鱼的死亡率、心率和心脏形态变化。采用吖啶橙染色初步考察氯氮平产生心脏毒性的作用机制; 利用实时定量PCR检测与凋亡相关的基因Bcl-2、Bax、caspase-9、caspase-3的表达。结果 氯氮平可引起斑马鱼出现体长明显缩短、心包水肿、心脏变小、心率下降等现象,这些具有剂量依赖性。吖啶橙染色结果显示,氯氮平可剂量依赖性地诱导斑马鱼心脏细胞发生凋亡。给药处理72 h后,斑马鱼胚胎细胞抗凋亡基因Bcl-2的表达水平降低,促凋亡基因Bax的表达明显升高,Bcl-2/Bax表达比值明显下降; caspase-9和caspase-3表达均明显增加。结论 氯氮平可导致斑马鱼胚胎产生心脏毒性,其毒性作用可能与其诱导胚胎细胞发生凋亡有关。
Abstract:
Aim To observe the toxic effects of clozapine on zebrafish embryos and investigate the possible mechanisms underlying its cardiac toxicity.Methods Zebrafish of 24 hpf(hours post fertilization)were exposed to different concentrations of clozapine.After treatment for 24, 48 and 72 h, the heart rates of the zebrafish embryos were examined and morphological changes of the heart were determined.The mechanism of clozapine induced cardiac toxicity was preliminarily explored by means of acridine orange(AO)staining.The mRNA levels of Bcl-2,Bax,caspase-9,caspase-3 were detected by real-time PCR analysis.Results Clozapine induced the decrease of body length, formation of pericardial edema, and decrease of heart rates of the embryos in a time and dose-dependent manner.AO staining showed that clozapine induced cell apoptosis of the cardiomyocytes.Real-time PCR analysis showed that the anti-apoptotic gene Bcl-2 was down-regulated and pro-apoptosis gene Bax was up-regulated at 72 h post treatment, resulting in the decreased expression ratio of Bcl-2/Bax.In addition, caspase-9 and caspase-3 were induced significantly by clozapine.Conclusion Clozapine caused cardiac toxicity in zebrafish embryos by inducing cell apoptosis.

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备注/Memo

备注/Memo:
收稿日期:2018-03-16,修回日期:2018-04-24
基金项目: 国家自然科学基金资助项目(No 31400979); 山东省重点研发计划(No 2016GSF121039); 山东省科学院杰出青年人才计划(No SDASJQ2017HQX)
作者简介:张 凤(1992-),女,硕士生,研究方向:基于斑马鱼模型的心脏毒性评价技术,E-mail:zhangfeng1992_vip@163.com;
何秋霞(1980-),女,博士,副研究员,研究方向:斑马鱼心血管模型构建与应用,通讯作者,E-mail: heqx@sdas.org;
田青平(1966-),女,博士,教授,研究方向:药物制剂及应用,通讯作者,E-mail: tianqp123456@163.com
更新日期/Last Update: 2018-07-26