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Naomi B Morison Prince Henry's Institute, Department of Obstetrics and Gynaecology, Sydney Centre for Reproductive Health Research, Level 4 Block E, Monash Medical Centre, 246 Clayton Rd, Clayton, Victoria 3168, Australia

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Tu'uhevaha J Kaitu'u-Lino Prince Henry's Institute, Department of Obstetrics and Gynaecology, Sydney Centre for Reproductive Health Research, Level 4 Block E, Monash Medical Centre, 246 Clayton Rd, Clayton, Victoria 3168, Australia
Prince Henry's Institute, Department of Obstetrics and Gynaecology, Sydney Centre for Reproductive Health Research, Level 4 Block E, Monash Medical Centre, 246 Clayton Rd, Clayton, Victoria 3168, Australia

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Ian S Fraser Prince Henry's Institute, Department of Obstetrics and Gynaecology, Sydney Centre for Reproductive Health Research, Level 4 Block E, Monash Medical Centre, 246 Clayton Rd, Clayton, Victoria 3168, Australia

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Lois A Salamonsen Prince Henry's Institute, Department of Obstetrics and Gynaecology, Sydney Centre for Reproductive Health Research, Level 4 Block E, Monash Medical Centre, 246 Clayton Rd, Clayton, Victoria 3168, Australia

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Many women using progestogen (P)-only contraceptives experience uterine bleeding problems. In clinical trials, a single low dose of mifepristone, given to Implanon users at the beginning of a bleeding episode reduced the number of bleeding days by ∼50% compared with controls. In this study, a single dose of mifepristone was administered to etonogestrel (ENG)-exposed pseudo-pregnant mice, 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding. Control mice received vehicle alone. Mice were culled 12-, 18-, 24- and 48-h post-treatment. In the continued presence of ENG, a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair: most treated tissues were fully restored to the pre-decidualized state by 48 h post-treatment. During repair, proliferating cells (Ki67 immunostained) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands. Progesterone receptor-positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls. Oestrogen receptor-positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues. It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity: such action may be a key event in reducing the number of bleeding days observed in women using Implanon who were treated with a single dose of mifepristone.

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

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Natalie K Binder Therapeutics Discovery and Vascular Function Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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

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In brief

Preterm birth is the leading cause of perinatal morbidity and mortality; however, current therapies offer limited efficacy to delay birth and improve neonatal outcomes. This review explores the potential of repurposing drugs with known safety profiles to quench uterine contractions and inflammation, identifying promising agents for clinical trials.

Abstract

Preterm birth is the leading cause of neonatal morbidity and mortality globally. Despite extensive research into the underlying pathophysiology, rates of preterm birth have not significantly reduced. Currently, preterm labour management is based on optimising neonatal outcomes. Treatment involves administering drugs (tocolytics) to suppress uterine contractions to allow sufficient time for transfer to an appropriate facility and administration of antenatal corticosteroids for fetal lung maturation. Current tocolytics are limited as they are associated with adverse maternal and fetal effects and only delay delivery for a short period. There has been a serious lack of therapeutic development for preterm birth, and new approaches to protect against or delay preterm birth are urgently needed. Repurposing drugs for the prevention of preterm birth presents as a promising approach by reducing the time and costs associated with pharmaceutical drug development. In this review, we explore the evidence for the potential of therapies, specifically proton pump inhibitors, tumour necrosis factor inhibitors, prostaglandin receptor antagonists, aspirin, and statins, to be repurposed as preventatives and/or treatments for preterm birth. Importantly, many of these innovative approaches being explored have good safety profiles in pregnancy. We also review how delivery of these drugs can be enhanced, either through targeted delivery systems or via combination therapy approaches. We aim to present innovative strategies capable of targeting multiple aspects of the complex pathophysiology that underlie preterm birth. There is an urgent unmet need for preterm birth therapeutic development, and these strategies hold great promise for improving neonatal outcomes.

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Natalie K Binder Department of Zoology, Translational Obstetrics Group, University of Melbourne, Parkville, Victoria 3010, Australia
Department of Zoology, Translational Obstetrics Group, University of Melbourne, Parkville, Victoria 3010, Australia

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Sally A Beard Department of Zoology, Translational Obstetrics Group, University of Melbourne, Parkville, Victoria 3010, Australia

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Tu'uhevaha J Kaitu'u-Lino Department of Zoology, Translational Obstetrics Group, University of Melbourne, Parkville, Victoria 3010, Australia

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Stephen Tong Department of Zoology, Translational Obstetrics Group, University of Melbourne, Parkville, Victoria 3010, Australia

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Natalie J Hannan Department of Zoology, Translational Obstetrics Group, University of Melbourne, Parkville, Victoria 3010, Australia

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David K Gardner Department of Zoology, Translational Obstetrics Group, University of Melbourne, Parkville, Victoria 3010, Australia

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Fetal growth restriction (FGR) is a major obstetric complication stemming from poor placental development. We have previously demonstrated that paternal obesity in mice is associated with impaired embryo development and significantly reduced fetal and placental weights. We hypothesised that the FGR observed in our rodent model of paternal diet-induced obesity is associated with alterations in metabolic, cell signalling and stress pathways. Male C57BL/6 mice were fed either a normal or high-fat diet for 10 weeks before sperm collection for IVF and subsequent embryo transfer. On embryonic day 14, placentas were collected and RNA extracted from both male and female placentas to assess mRNA expression of 24 target genes using custom RT-qPCR arrays. Peroxisome proliferator-activated receptor alpha (Ppara) and caspase-12 (Casp12) expression were significantly altered in male placentas from obese fathers compared with normal (P<0.05), but not female placentas. PPARA and CASP12 proteins were localised within the placenta to trophoblast giant cells by immunohistochemistry, and relative protein abundance was determined by western blot analysis. DNA was also extracted from the same placentas to determine methylation status. Global DNA methylation was significantly increased in female placentas from obese fathers compared with normal (P<0.05), but not male placentas. In this study, we demonstrate for the first time that paternal obesity is associated with changes in gene expression and methylation status of extraembryonic tissue in a sex-specific manner. These findings reinforce the negative consequences of paternal obesity before conception, and emphasise the need for more lifestyle advice for prospective fathers.

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Bridget M Arman B Arman, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Melbourne, Australia

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Natalie K Binder N Binder, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Heidelberg, Australia

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Natasha de Alwis N de Alwis, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Melbourne, Australia

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Sally Beard S Beard, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Melbourne, Australia

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Anjali Garg A Garg, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Melbourne, Australia

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Tu'uhevaha J Kaitu'u-Lino T Kaitu'u-Lino, Obstetrics and Gynaecology, Translational Obstetrics Group, University of Melbourne, Heidelberg, Australia

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Natalie J Hannan N Hannan, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Melbourne, Australia

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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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Naomi B Morison Prince Henry’s Institute, PO Box 5152, Clayton, Victoria, Australia, Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia and Sydney Centre for Reproductive Health Research, FPA Health, Ashfield, New South Wales 2131, Australia

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Jin Zhang Prince Henry’s Institute, PO Box 5152, Clayton, Victoria, Australia, Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia and Sydney Centre for Reproductive Health Research, FPA Health, Ashfield, New South Wales 2131, Australia

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Tu’uhevaha J Kaitu’u-Lino Prince Henry’s Institute, PO Box 5152, Clayton, Victoria, Australia, Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia and Sydney Centre for Reproductive Health Research, FPA Health, Ashfield, New South Wales 2131, Australia

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Ian S Fraser Prince Henry’s Institute, PO Box 5152, Clayton, Victoria, Australia, Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia and Sydney Centre for Reproductive Health Research, FPA Health, Ashfield, New South Wales 2131, Australia

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Lois A Salamonsen Prince Henry’s Institute, PO Box 5152, Clayton, Victoria, Australia, Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia and Sydney Centre for Reproductive Health Research, FPA Health, Ashfield, New South Wales 2131, Australia

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Breakthrough bleeding (BTB), a major side effect of long-acting progestogen (p)-only contraceptives in women, is the main reason for discontinuation of their use. To understand the mechanisms of BTB, a mouse model of endometrial breakdown and repair was adapted to evaluate the effects of long-term progestogens on the endometrium. Appropriately prepared mice received either an etonogestrel (ENG)- or levonorgestrel (LNG)-releasing subdermal implant. Forty eight hours after decidualization was induced in one uterine horn the majority of tissues were highly decidualized, designated 0 day (0d). Uteri were collected subsequently at 5-day intervals (to 45d) and both decidualized and non-decidualized horns were analysed for morphological changes, leukocyte infiltration and matrix metalloproteinase expression (MMP). In decidualized horns, large blood vessels (BV) developed and disturbance of tissue integrity was observed at 5d with substantial stromal breakdown by 10d, progressing until 25d when re-epithelialization was initiated. By 45d, the tissue was restored to its pre-decidualized state but with considerable tortuosity of the luminal epithelium. Tissue remodelling was not apparent in the non-decidualized horns before 35d, when hyperproliferation of the luminal epithelium resulted in tortuosity. Changes in morphology were similar with the two progestogens, but occurred more rapidly with LNG. Apart from macrophages, few leukocytes were present in non-decidualized horns but large infiltrates of neutrophils and uterine natural killer cells (uNK) were associated with tissue breakdown in decidualized tissue, many of these cells were MMP9-positive. MMP7 was primarily associated with tissue repair. Therefore, this model mimics some of the changes observed in endometria of women using p-only contraceptives and provides an opportunity for functional studies.

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Rebecca L Jones Prince Henry’s Institute of Medical Research and Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia

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Tu’uhevaha J Kaitu’u-Lino Prince Henry’s Institute of Medical Research and Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia

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Guiying Nie Prince Henry’s Institute of Medical Research and Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia

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L Gabriel Sanchez-Partida Prince Henry’s Institute of Medical Research and Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia

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Jock K Findlay Prince Henry’s Institute of Medical Research and Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia

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Lois A Salamonsen Prince Henry’s Institute of Medical Research and Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia

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Maternal–fetal communications are critical for the establishment of pregnancy. Embryonic growth and differentiation factors produced by the oviduct and uterus play essential roles during the pre- and early post-implantation phases. Although several studies indicate roles for activin in embryonic development, gene-knockout studies have failed to identify a critical role in mammalian embryogenesis. We hypothesized that activin is produced by maternal tissues during the establishment of pregnancy, and thus maternally derived activin could compensate for the absence of embryonic activin in null homozygotes during critical developmental stages. We investigated the expression of inhibin α, activin βA, and βB subunits in the mouse oviduct and uterus during the estrous cycle and early pregnancy, and in the early conceptus. Inhibin α subunit was weakly expressed, while activin βA and βB subunits were strongly expressed in oviduct and uterus at estrous, and dramatically upregulated in the uterus on each day of pregnancy between days 3.5 and 8.5 post coitum. Prior to implantation, activin βA and βB subunits were immunolocalized to oviductal and uterine epithelial cells; following implantation they were expressed in the stroma, in a wave preceding decidualization. Later in pregnancy, activin βA and βB subunits were present in decidua basalis, trophoblast giant cells, and labyrinth zone of the developing placenta. Expression of activin βA subunit was also detected in blastocysts and early post-implantation embryos. These data are consistent with a role for maternally derived activins in the support of the pre-implantation embryo, and during gastrulation and embryogenesis.

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Tu’uhevaha J Kaitu’u-Lino Prince Henry’s Institute of Medical Research, Monash Medical Centre, PO Box 5152, Clayton 3168, Victoria, Australia and Departments of Anatomy and Cell Biology and Biochemistry and Molecular Biology, Monash University, Clayton 3168, Victoria, Australia

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Pavel Sluka Prince Henry’s Institute of Medical Research, Monash Medical Centre, PO Box 5152, Clayton 3168, Victoria, Australia and Departments of Anatomy and Cell Biology and Biochemistry and Molecular Biology, Monash University, Clayton 3168, Victoria, Australia

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Caroline F H Foo Prince Henry’s Institute of Medical Research, Monash Medical Centre, PO Box 5152, Clayton 3168, Victoria, Australia and Departments of Anatomy and Cell Biology and Biochemistry and Molecular Biology, Monash University, Clayton 3168, Victoria, Australia

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Peter G Stanton Prince Henry’s Institute of Medical Research, Monash Medical Centre, PO Box 5152, Clayton 3168, Victoria, Australia and Departments of Anatomy and Cell Biology and Biochemistry and Molecular Biology, Monash University, Clayton 3168, Victoria, Australia

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Claudin-11 and occludin are protein components in tight junctions (TJs) between Sertoli cells which are important for the maintenance of the blood–testis barrier. Barrier formation occurs during puberty, with evidence suggesting hormonal regulation of both claudin-11 and occludin. This study aimed to investigate the regulation of claudin-11 and occludin mRNA expression by testosterone (T) and FSH and their immunolocalisation at rat Sertoli cell TJs in vitro, and to correlate any steroid regulation with the functional capacity of TJs. Sertoli cells formed functional TJs within 3 days as assessed by transepithelial electrical resistance (TER). Both T and dihydrotestosterone significantly (P < 0.01) increased TER twofold and claudin-11 mRNA two- to threefold within 3 days. FSH partially stimulated TER and claudin-11 mRNA, but estradiol had no effect. T also promoted claudin-11 localisation into extensive intercellular contacts. In contrast to claudin-11, Tand FSH did not change occludin mRNA expression, however, T promoted localisation of occludin at cell contacts in a similar manner to claudin-11. Addition of flutamide to T-stimulated cells caused a twofold decrease in both TER and claudin-11 mRNA expression, and resulted in the loss of both proteins from cell contacts. This effect was reversible following flutamide removal. It is concluded that androgens i) co-regulate claudin-11 mRNA expression and TER, implicating claudin-11 in TJ formation and ii) promote the localisation of claudin-11 and occludin at Sertoli cell contacts. Hence, the ability of androgens to maintain spermatogenesis in vivo is partly via their effects on TJ proteins and regulation of the blood–testis barrier.

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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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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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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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