PT  - JOURNAL ARTICLE
AU  - Chen, Lu
AU  - Pang, Menglan
AU  - Jie, Qiuling
AU  - Sun, Fei
AU  - Huang, Liping
AU  - Ma, Yanlin
AU  - Yue, Xiaojing
TI  - COMT inhibitor tolcapone represses the migration and invasion of trophoblast and results in preeclampsia-like phenotypes in mice
AID  - 10.1101/2023.03.17.530517
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.03.17.530517
4099  - http://biorxiv.org/content/early/2023/03/20/2023.03.17.530517.short
4100  - http://biorxiv.org/content/early/2023/03/20/2023.03.17.530517.full
AB  - Pregnancy in young onset Parkinson’s disease (YOPD) does not often occur, yet the medication in this condition is critical for maternal and fetal health. Tolcapone is an effective antiparkinsonian drug whereas the safety studies on mother and fetus are rather limited. In this study, we aimed to investigate the effects of tolcapone on mother and developing fetus in different gestations. Tolcapone was administrated to pregnant mice at the dose of 60 mg/kg/day (H-Tol) or 30 mg/kg/day (L-Tol), in the early gestation or the mid-gestation. We demonstrated that tolcapone in early gestation caused abortion and delayed fetus development in a dose-dependent manner. Taking tolcapone in mid-gestation barely caused embryo lethality, however, the mice developed preeclampsia-like phenotypes, including maternal hypertension, proteinuria and fetal growth restriction. The histomorphology analysis of placentas from tolcapone treated mice exhibited abnormalities in trophoblast layer and the hampered trophoblast invasion in decidua. In mechanistic study, we revealed that tolcapone inhibited the invasion and migration of trophoblast in vitro, with the changes in protein expressions of Snail, Twist and E-cadherin. In conclusion, tolcapone causes embryo lethality and growth restriction in early gestation, while in mid-gestation tolcapone causes preeclampsia-like phenotypes in mice with defective trophoblast invasion. Our study provides novel insight in understanding the effects of tolcapone in pregnancy.Competing Interest StatementThe authors have declared no competing interest.YOPDyoung onset Parkinson’s diseasePDParkinson’s diseaseCOMTcatechol O-methyltransferaseToltolcaponeH-Tolhigh-dose tolcaponeL-Tollow-dose tolcaponeJZjunction zoneLZlabyrinth zoneSPspongiotrophoblastSBPsystolic blood pressureCK8cytokeratin 8α-SMAα-smooth muscle actinEMTepithelial–mesenchymal transition