Ticagrelor increases peripheral 5-HT content by up-regulating the tryptophan hydroxylase 1 and down-regulating the serotonin transporter.

Ticagrelor, a reversible P2Y12 receptor antagonist, is the first-line recommended antiplatelet agent for acute coronary syndrome. Despite its widespread use, 13.8 % of patients report dyspnea, a side effect not fully understood but potentially linked to elevated levels of 5-hydroxytryptamine (5-HT, or serotonin) associated with tracheal constriction. This study investigates the impact of different doses of ticagrelor on the synthesis and metabolism of peripheral 5-HT in rats. Rats were randomly assigned to control, low-dose, medium-dose, and high-dose groups, receiving a 0.5 % carboxymethylcellulose sodium (CMCNa) suspension or varying doses of ticagrelor by gavage. Histopathological examinations indicated no significant impact of ticagrelor on the rat ileum mucosa. However, ticagrelor significantly increased ileal 5-HT levels, decreased 5-HIAA levels, and reduced 5-HT turnover. Immunohistochemistry revealed ticagrelor-induced proliferation of enterochromaffin cells. Further gene expression analysis showed that ticagrelor upregulated tryptophan hydroxylase 1 (tph1) mRNA in the ileum and downregulated serotonin transporter (sert) mRNA in enterocytes. Additionally, ticagrelor downregulated the serotonin transporter protein in platelets, significantly increasing plasma 5-HT levels and decreasing platelet 5-HT content, suggesting an inhibitory effect on platelet sert expression. Ticagrelor significantly alters peripheral 5-HT levels in rats by modulating its synthesis, transport, and metabolism.