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Published on: February 15, 2021
Ticlopidine induces cardiotoxicity in zebrafish embryos through AHR-mediated oxidative stress signaling pathway
Rong Xu1, Yong Huang2, Chen Lu2
1Medical College of Soochow University, Suzhou 215123, Jiangsu, P.R.China; The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi, P.R.China.
Insights
Ticlopidine causes developmental and cardiac toxicity in zebrafish embryos, indicated by abnormalities and increased oxidative stress. This suggests potential risks that require further investigation for safe clinical use.
Area of Science:
- Developmental Toxicology
- Cardiovascular Pharmacology
- Zebrafish Embryology
Background:
- Ticlopidine is used clinically to prevent thromboembolic diseases by inhibiting platelet aggregation.
- Previous reports suggest ticlopidine may have teratogenic effects on the heart, but the mechanism is unclear.
- Zebrafish embryos serve as a valuable model for studying drug toxicity and developmental effects.
Purpose of the Study:
- To investigate the developmental and cardiac toxicity of ticlopidine using zebrafish embryos.
- To elucidate the molecular mechanism underlying ticlopidine-induced cardiotoxicity.
Main Methods:
- Zebrafish embryos were exposed to varying concentrations of ticlopidine (6, 7.5, and 9 mg/L).
- Observed developmental abnormalities, cardiac function parameters (heart rate, SV-BA distance), and mortality.
- Analyzed gene expression related to heart development and apoptosis, and measured oxidative stress levels.
- Investigated the role of oxidative stress using an aromatic hydrocarbon receptor (AHR) inhibitor (CH223191).
Main Results:
- Ticlopidine exposure resulted in significant developmental abnormalities, including body curvature, edema, and reduced vitelline sac absorption.
- Cardiac toxicity was evident through decreased heart rate, increased SV-BA distance, and elevated mortality.
- Ticlopidine exposure upregulated apoptotic gene expression and embryonic oxidative stress, leading to reduced cardiomyocyte proliferation.
- Inhibition of AHR signaling with CH223191 protected against ticlopidine-induced cardiotoxicity, implicating oxidative stress.
Conclusions:
- Ticlopidine exhibits significant developmental and cardiotoxicity in zebrafish embryos.
- Increased oxidative stress appears to be a key molecular mechanism driving ticlopidine-induced cardiotoxicity.
- Further research is needed to assess these potential risks in human clinical practice for safe drug usage.
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.
