Investigating ticagrelor in a preclinical pipeline as a novel therapeutic to prevent preterm birth

in Reproduction
Authors:
Bridget M Arman Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Australia

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https://orcid.org/0000-0003-0314-378X
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Natalie K Binder Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Australia

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Natasha de Alwis Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Australia

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Sally Beard Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Anjali Garg Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Tu’uhevaha J Kaitu’u-Lino Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Australia
Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Natalie J Hannan Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Australia

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https://orcid.org/0000-0001-8446-2250

Correspondence should be addressed to N J Hannan; Email: nhannan@unimelb.edu.au
DOI:
https://doi.org/10.1530/REP-23-0404
Volume/Issue:
Volume 167: Issue 3
Article ID:
e230404
Article Type:
Research Article
Online Publication Date:
02 Feb 2024
Copyright:
© the author(s) 2024
Restricted access
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In brief

Preterm birth is the leading cause of perinatal morbidity and mortality, and new therapies that delay preterm birth and improve neonatal outcomes are urgently needed. This study investigates whether ticagrelor inhibits uterine contractility and inflammation in preclinical in vitro, ex vivo (human) and in vivo (mouse) studies, to explore the potential of repurposing ticagrelor for the prevention of preterm birth.

Abstract

Preterm birth remains a significant global health challenge, affecting approximately 10% of pregnancies and resulting in one million deaths globally every year. Tocolytic agents, used to manage preterm labour, have considerable limitations including lack of efficacy, and adverse side effects, emphasising the urgent need for innovative solutions. Here, we explore repurposing an antiplatelet cardioprotective drug, ticagrelor, as a potential treatment to prevent preterm birth. Ticagrelor has demonstrated pleiotropic actions beyond platelet inhibition, including relaxant effects on smooth muscle cells and anti-inflammatory effects in models of diabetes and sepsis. As preterm birth is underscored by inflammatory processes triggering uterine contractions, these actions position ticagrelor as an attractive candidate for prevention or delay of preterm birth. Utilising primary human myometrial tissue, human myometrial cells, and a mouse model of preterm birth, we investigated ticagrelor’s potential as a safe and effective therapy for preterm birth. We showed that ticagrelor did not reduce the frequency or strength of spontaneous muscle contractions of ex vivo myometrial tissue nor did it reduce in vitro inflammation-induced contractility in myometrial cells. Additionally, ticagrelor did not exhibit the anticipated anti-inflammatory effects in myometrial cell culture experiments. In our mouse model of preterm birth, ticagrelor neither improved the preterm birth rate or fetal survival outcomes. Gene expression of pro-inflammatory cytokines and contraction-associated proteins in postpartum mouse uteri were unaltered by ticagrelor. In conclusion, ticagrelor is not a strong candidate to continue investigations in clinical trial for the treatment of preterm labour and prevention of preterm birth.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

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