New Ideas for the Prevention and Treatment of Preeclampsia and Their Molecular Inspirations

Abstract

Preeclampsia (PE) is a pregnancy-specific disorder affecting 4-10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main symptoms generally appear after week 20 of gestation, scientific studies indicate that the mechanism underpinning PE is initiated at the beginning of gestation. It is known that the pathomechanism of preeclampsia is strongly related to inflammation and oxidative stress, which influence placentation and provoke endothelial dysfunction in the mother. However, as of yet, no "key players" regulating all these processes have been discovered. This might be why current therapeutic strategies intended for prevention or treatment are not fully effective, and the only effective method to stop the disease is the premature induction of delivery, mostly by caesarean section. Therefore, there is a need for further research into new pharmacological strategies for the treatment and prevention of preeclampsia. This review presents new preventive methods and therapies for PE not yet recommended by obstetrical and gynaecological societies. As many of these therapies are in preclinical studies or under evaluation in clinical trials, this paper reports the molecular targets of the tested agents or methods.

Keywords: anti-inflammatory agents; antioxidants; antithrombin III; apheresis; metformin; nitric oxide; nuclear factor kappa B; peptides; polyphenols; preeclampsia; probiotics; proton pump inhibitors; short interfering RNA; soluble fms-like tyrosine kinase 1; statins; vitamins.

Figure 1

The groups of agents adopted for the prevention and treatment of preeclampsia and their molecular inspirations, i.e.,: NFĸB inhibitors: aspirin, hydroxychloroquine, metformin, proton pump inhibitors, statins, sulfasalazine; inflammation inhibitors: aspirin, eculizumab, metformin, mesenchymal cells and their exosomes, probiotics, statins, sulfasalazine, vitamin D; oxidative stress inhibitors: aspirin, polyphenols, vitamin C, vitamin D, vitamin E; coagulation regulators: aspirin, antithrombin, hydroxychloroquine, mesenchymal cells and their exosomes; sFlt1 level regulators: apheresis, chimera of elastin like-polypeptide with vascular endothelial growth factor type A or type B, small interfering RNA particles; vessel construction regulators: aspirin, hydroxychloroquine, metformin, L-arginine, L-citrulline, proton pump inhibitors, statins, sulfasalazine. Legend: abbreviations: AA—arachidonic acid; ARG—arginine; AT1-AA—angiotensin II type 1 receptor autoantibody; ATR1—angiotensin II receptor type 1; C3a—complement component 3a; C5a—complement component 5a; COX—cyclooxygenase; ET1—endothelin 1; FVa—active coagulation factor Va; FVIIa—active coagulation factor VII; FXa—active coagulation factor Xa; ICAM 1—intracellular adhesion molecule type 1; IL6—interleukin 6; IL8—interleukin 8; NFĸB—nuclear factor kappa B; NO—nitric oxide; PAI-1—plasminogen activator inhibitor 1; PlGF—placenta growth factor; ROS—reactive oxygen species; sENG—soluble endoglin; sFlt1—soluble fms-like tyrosine kinase 1; TF—tissue factor; TGFβ—tumour growth factor beta; THX—thromboxane; TNFα—tumour necrosis factor alpha; VCAM 1—vascular adhesion molecule type 1, VEGFR1—vascular endothelial growth factor receptor type 1; VEGFR2—vascular endothelial growth factor receptor type 2; symbols: process activation; process inhibition; the direction of common relationships between the analysed factors.