BACKGROUND: Preeclampsia is a serious complication of pregnancy, and a leading cause of maternal and neonatal death. Aspirin is the only preventative therapy currently available - but has limited efficacy. Previously, we identified that the new generation antiplatelet agents, clopidogrel, prasugrel and ticagrelor could mitigate multiple aspects of preeclampsia pathogenesis (unpublished) - particularly enhancing antioxidant pathways in the placenta at term. Here, we test the safety/toxicity of clopidogrel, prasugrel and ticagrelor on first trimester placenta, and investigate whether they upregulate antioxidant gene expression at this important stage of early placental development.
METHODS: Primary cytotrophoblast cells (cells unique to the placenta) were isolated from first trimester placental samples collected at surgical terminations of pregnancy (9-13 weeks gestation). Cells were treated with: 100µM Aspirin, 1-100µM clopidogrel, 1-100µM prasugrel, or 5-25µM Ticagrelor under 5% oxygen for 48h. Cell viability was measured via MTS assay. Expression of antioxidant genes Heme oxygenase 1 (HMOX1), Glutamate-Cysteine Ligase Catalytic subunit (GCLC), Thioredoxin (TXN), and NAD(P)H dehydrogenase [quinone 1] (NQO1) were assessed via qPCR.
RESULTS: Cytotrophoblast cell viability was not altered with aspirin treatment, or any dose of prasugrel and ticagrelor. However, the highest dose of clopidogrel (100µM) significantly reduced cell viability, hence was excluded from further analysis - lower doses had no effect (n=5). Preliminary data (n=3) demonstrates that 10µM prasugrel and 25µM ticagrelor treatments increased expression of antioxidant gene GCLC, with trending increase in HMOX1 expression. Treatment with aspirin and clopidogrel did not demonstrate altered antioxidant gene expression.
CONCLUSION: Preliminary studies demonstrate that the new generation antiplatelet agents prasugrel and ticagrelor may increase antioxidant gene expression in the first trimester placenta. Further investigations will examine whether these agents might also improve first trimester placental growth and angiogenesis. This would add important preclinical evidence to support the safety of these antiplatelet agents in early pregnancy, and demonstrate their potential to enhance early placental development - key features of an effective therapy to prevent preeclampsia.