Ticlopidine induces cardiotoxicity in zebrafish embryos through AHR-mediated oxidative stress signaling pathway.

Abstract

Ticlopidine has inhibitory effects on platelet aggregation via ADP (adenosine diphosphate), platelet release reaction and depolymerization. In clinical practice, it is commonly used to prevent heart, cerebrovascular and other thromboembolic diseases. However, ticlopidine has also been reported to have teratogenic effects on the heart, though its specific molecular mechanism remains unclear. In this study, zebrafish embryos were used as model organisms to examine the toxicity effect of ticlopidine. Zebrafish embryos exposed to 6, 7.5, and 9 mg/L ticlopidine solutions manifested several abnormalities, including body curvature, smaller eyes, slower absorption of the vitella sac, pericardial edema, slower heart rate, increased mortality, longer venous sinus - arterial ball (SV-BA) distance, and increased oxidative stress, which indicated developmental and cardiac toxicity. Abnormal expression of key genes related to heart development was observed, and the level of apoptotic gene expression was up-regulated. Further experiments revealed up-regulation of embryonic oxidative stress following ticlopidine exposure, leading to a decrease in cardiomyocyte proliferation. Conversely, the aromatic hydrocarbon receptor (AHR) inhibitor CH223191 protected embryos from the cardiotoxicity effect of ticlopidine, confirming further the role of up-regulated oxidative stress as the molecular mechanism of ticlopidine-induced cardiotoxicity in zebrafish. In conclusion, ticlopidine exposure leads to developmental and cardiotoxicity in zebrafish embryos. Therefore, further studies are warranted to ascertain such potential harms of ticlopidine in humans, which are vital in providing guidance in the safe use of drugs in clinical practice.

• Authors: Rong Xu, Yong Huang, Chen Lu, Weiming Lv, Shihua Hong, Shuqin Zeng, Wenyan Xia, Li Guo, Huiqiang Lu, Yijian Chen
• Journal: Ecotoxicology and environmental safety (Ecotoxicol Environ Saf) Vol. 230 Pg. 113138 (Jan 15 2022) ISSN: 1090-2414 [Electronic] Netherlands
• PMID: 34995907 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.