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

Yue Liu; Ye Yuan; Qing Zhao; Zhu-Hang Han; Chun-Shuang Shi; Yu-Tian Zhang; Li-Nan Wang; Xiu-Ling Yang

doi:10.1016/j.intimp.2025.115094

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

Int Immunopharmacol. 2025 Jul 11:162:115094. doi: 10.1016/j.intimp.2025.115094. Online ahead of print.

Authors

Yue Liu¹, Ye Yuan², Qing Zhao³, Zhu-Hang Han², Chun-Shuang Shi⁴, Yu-Tian Zhang², Li-Nan Wang², Xiu-Ling Yang⁵

Affiliations

¹ Department of Pharmacy, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050000, China; Department of Pharmacy, Shijiazhuang People's Hospital, Shijiazhuang, Hebei Province 050026, China.
² Department of Pharmacy, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050000, China.
³ Department of Pharmacy, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050000, China; Pharmacy department, Bao Ding NO.1 Central Hospital, Shijiazhuang, Baoding, Hebei Province 050026, China.
⁴ School of Pharmacy, Hebei Medical University, Shijiazhuang, Hebei Province 050017, China.
⁵ Department of Pharmacy, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050000, China. Electronic address: 26700002@hebmu.edu.cn.

PMID: 40651436
DOI: 10.1016/j.intimp.2025.115094

Abstract

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.

Keywords: 5-HIAA; 5-HT; Enterochromaffin cells, platelets; Sert; Ticagrelor.