RT Journal Article
SR Electronic
T1 COMT inhibitor tolcapone represses the migration and invasion of trophoblast and results in preeclampsia-like phenotypes in mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.03.17.530517
DO 10.1101/2023.03.17.530517
A1 Chen, Lu
A1 Pang, Menglan
A1 Jie, Qiuling
A1 Sun, Fei
A1 Huang, Liping
A1 Ma, Yanlin
A1 Yue, Xiaojing
YR 2023
UL http://biorxiv.org/content/early/2023/03/20/2023.03.17.530517.abstract
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