Poster Presentation ESA-SRB-APEG-NZSE 2022

Investigation of ticagrelor as a potential therapeutic to delay preterm birth using a pipeline of in vitro, ex vivo and in vivo models of preterm birth (#388)

Bridget M Arman 1 2 , Natalie K Binder 1 2 , Natasha M de Alwis 1 2 , Sally Beard 1 2 , Stephen Tong 1 3 , Tu'uhevaha J Kaitu'u-Lino 1 3 , Natalie J Hannan 1 2
  1. Mercy Perinatal, Heidelberg, Victoria, Australia
  2. Department of Obstetrics and Gynaecology, University of Melbourne, Therapeutics Discovery and Vascular Function in Pregnancy Group, Heidelberg, Victoria, Australia
  3. Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Victoria, Australia

Preterm birth is still the leading cause of death in infants; hence there is an urgent need to find new drugs to delay preterm delivery. One approach to therapeutic development is repurposing existing drugs. Ticagrelor is an antiplatelet agent used for cardiovascular events but we have previously found that it can relax vascular smooth muscle. We hypothesised that ticagrelor may have similar relaxant effects on the myometrium (outer uterine muscular layer). Here, we assessed the effect of ticagrelor on myometrial contractility and key inflammatory markers (central to preterm labour pathophysiology) in our pipeline of human and mouse models of preterm birth.

Human myometrial tissue (non-labouring; collected at caesarean-section) was used in tissue bath experiments (DMT myograph) to measure the effect of ticagrelor on spontaneous contractions. To assess ticagrelor’s prolonged effects on contraction, human myometrial cells were embedded in collagen gel and treated with pro-inflammatory mediators, tumour necrosis factor (TNF) and lipopolysaccharide (LPS), +/- ticagrelor for 48 hours. TNF and LPS were used to evoke an inflammatory response in cultured myometrial cells co-treated with ticagrelor; altered mRNA expression of pro-inflammatory cytokines was measured via qPCR. Preterm birth was induced in mice using LPS on gestational day 16.5 to determine whether ticagrelor delayed delivery.

Ticagrelor did not reduce ex vivo myometrial contractility (n=3) or TNF/LPS-induced contraction in myometrial collagen contraction assays (n=3) when compared with vehicle control treatment. Ticagrelor did not reduce mRNA expression of pro-inflammatory cytokines interleukin (IL)-1B, IL-6 and CXCL8 in cultured myometrial cells (n=3). Preliminary findings showed that ticagrelor could not delay LPS-induced preterm birth in mice (20mg/kg, n=3; 40mg/kg, n=2).

Our pipeline of drug assessment rigorously evaluated ticagrelor. Collectively these data demonstrate ticagrelor does not reduce human myometrial contractions or inflammation, or prevent preterm delivery in mice. This suggests ticagrelor is not a promising preterm birth therapeutic candidate.