COMT inhibitor tolcapone represses the migration and invasion of trophoblast and results in preeclampsia-like phenotypes in mice

Pregnancy in young-onset Parkinsons disease (YOPD) is rare; however, medication for this condition is critical for maternal and fetal health. Tolcapone is an effective antiparkinsonian drug. However, its safety studies on mothers and fetuses are limited. In this study, we aimed to investigate the effects of tolcapone on the mother and the developing fetus during different stages of gestation. Tolcapone was administered to pregnant mice at a dose of 60 (H-Tol) or 30 mg/kg/day (L-Tol) during early or mid-gestation. We observed that tolcapone administration during early gestation causes abortion and delays fetal development in a dose-dependent manner. During mid-gestation tolcapone barely caused embryo lethality; however, the mice developed preeclampsia-like phenotypes, including maternal hypertension, proteinuria, and fetal growth restriction. Histomorphological analysis of placentas from tolcapone treated mice revealed abnormalities in the trophoblast layer and the impaired trophoblast invasion in the decidua. Mechanistically, we revealed that tolcapone inhibits the invasion and migration of trophoblasts in vitro, with changes in the protein expression of Snail, Twist, and E-cadherin. In conclusion, tolcapone caused embryo lethality and growth restriction during early gestation, whereas it caused preeclampsia-like phenotypes in mice with defective trophoblast invasion in mid-gestation. Collectively, our study provides novel insights into the effects of tolcapone on pregnancy.