Table 1.

Summary of studies on pharmacological effects of plant-derived polyphenols and plant extracts in animal models of preeclampsia.

Polyphenols/Plant Extracts	Models and Doses	Effects	Ref.
Baicalin	- preeclampsia induced by L-NAME (50 mg/kg b.w./day) in female Sprague–Dawley rats (n = 60), - doses of baicalin: 50, 100, and 150 mg/kg/day, i.p. for 20 days.	- alleviating the blood pressure in a dose-dependent manner, - decreasing the apoptosis of cells of kidney and livers, - increasing the expressions of antiapoptotic protein (XIAP and Bcl-2), - reducing the urinary protein level.	[13]
Curcumin	- preeclampsia induced by LPS (injection of 0.5 μg/kg) in female Sprague–Dawley rats (n = 14), - dose of curcumin: 0.36 mg/kg (injection after LPS administration).	- decreasing the blood pressure and urinary protein level, - improving the deficient trophoblast invasion and spiral artery remodeling, - decreasing the TLR4, p65, JunB protein expressions in placenta, - decreasing the IL-6 (by 23.42%) and MCP-1 mRNA expressions (52.67%) in serum and placenta.	[18]
	- preeclampsia induced by LPS (injection of 10 μg/kg) in mice (n = 20), - dose of curcumin: 0.5 mg/kg (i.g.) for 17 gestational days.	- decreasing the systolic blood pressure and proteinuria, - increasing the number of live pups, fetal weight, placental weight, - decreasing the fetal resorption rate, - suppressing the placental expressions of TNF-α, IL-1β, IL-6, - upregulation of the phosphorylated Akt level in placenta after curcumin.	[19]
Punicalagin	- preeclampsia induced by L-NAME (50 mg/kg b.w./day) in female Sprague–Dawley rats (n = 40), - doses of punicalagin: 25, 50, or 100 mg/kg orally on days 14–21 of pregnancy.	- decreasing systolic and diastolic blood pressure and also mean arterial pressure, - increasing the expression of vascular endothelial growth factor, - downregulating vascular endothelial growth factor receptor- 1/fms-like tyrosine kinase-1.	[13]
Quercetin	- preeclampsia induced by LPS (1.0 infusion of 1.0 μg/kg) in female Sprague–Dawley rats (n = 24), - dose of quercetin: 2 mg/kg b.w.	- significant reduction of the systolic blood pressure by 15%, - decreasing the elevated changes of tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio, - suppressing the production of cytokine production in the placenta (TNF α, IL-6, and MCP-1), - reduction of lipid peroxidation by reducing the MDA level, - no difference of fetus size in group with and without supplementation of quercetin, - increasing the weight of placentas reduced by LPS.	[45]
	- preeclampsia induced by L-NAME (0.5 mg/mL in drinking water) in female Sprague–Dawley rats (n = 40), - dose of quercetin: 2.0 mg/kg b.w. by intraperitoneal infusion and acetylsalicylic acid (1.5 mg/kg b.w.) in rodent dough.	- reducing the systolic blood pressure and proteinuria (quercetin enhanced the effect of acetylsalicylic acid), - decreasing expressions of mRNA VEGF and mRNA sFlt-1, - reduction of lipid peroxidation by reducing the MDA level, - reducing of IL-6 and TNF-α levels, All effects were strongest in the group supplemented by quercetin with acetylsalicylic acid.	[46]
	- preeclampsia induced by L-NAME (50 mg/day; i.p.) in female Sprague–Dawley rats (n = 30), - dose of quercetin: 10 mg/kg b.w. i.p.	- no effect on decreasing the high blood pressure, - normalized in proteinuria.	[47]
Resveratrol	- preeclampsia induced by L-NAME (125 mg/kg b.w.; injection) in female albino Wistar mice, - dose of resweratrol: 20 mg/kg/day i.g.	- reducing the systolic blood pressure and urine protein level compared with the L-NAME group, - decreasing the expression of mRNA sFlt-1 compared with the L-NAME group, - increasing the expression of mRNA VEGF, AngI, and AngII compared with the L-NAME group, - activation of epithelial-mesenchymal transition.	[60]
	- preeclampsia induced by L-NAME (125 mg/kg b.w.; injection) in female Wistar albino rats - dose of resveratrol: 20 mg/kg per day, i.g. during the entire pregnancy.	- reducing the systolic blood pressure and levels of protein/creatinine, - anti-apoptotic effects in trophoblasts of placentas.	[62]
	- preeclampsia induced by desoxycorticosterone acetate (12.5 mg by injection) in female Wistar albino rats - dose of resweratrol: 40 mg/kg per day, i.g.	- no effect on decreasing the high blood pressure, placental and renal blood flows, - no effect on placental pathology parameters.	[63]
Salvianolic acid A	- preeclampsia induced by phosphatidyleserine/phosphatidylcholine (100 μL in suspension; i.p.) in mice - dose of salvianolic acid A: 10 μg/g and 30 μg/g, i.p.	- reducing the thrombin time similarly (as heparin), - increasing the plasma antithrombin III activity (as acetylsalicylic acid), - high-dose of salvianolic acid A more effective in decreasing blood pressure to normal level, - high-dose of salvianolic acid A more effective in decreasing proteinuria to normal level.	[73]
	- preeclampsia induced by phosphatidyleserine/phosphatidylcholine (100 μL in suspension; i.p.) in mice - dose of salvianolic acid A: 10 μg/g and 30 μg/g, i.p.	- high-dose of salvianolic acid A more effective in decreasing blood pressure to normal level, - high-dose of salvianolic acid A more effective in decreasing proteinuria to normal level, - lowering the expression of thrombomodulin in placenta.	[72]
Silibinin	- preeclampsia induced by L-NAME (70–80 mg/kg/day in drinking water) in female Wistar rats - dose of silibinin: 100 mg/kg/day by 10 days (by gavage).	- reducing the systolic blood pressure, - reducing the level of pro-inflammatory factors: TNF-α, IL-1β, IFN-γ, - reducing the proteinuria, - normalized the platelet count, - improving the fetal outcomes.	[81]
	- preeclampsia induced by LPS (50 mg/mouse; i.p.) in C57BL/6 mice, - dose of silibinin: 70 mg/kg by injection.	- decreasing the expression of IL-6, IL-8, MMP-9, - decreasing the expression of IL-6, IL-8, COX-2, PGE2, PGF2a.	[76]
Vitexin	- preeclampsia induced by L-NAME (0.5 mg/mL in drinking water) female Sprague–Dawley rats, - dose of vitexin: 30, 45, 60 mg/kg for 10 days.	- reducing the systolic blood pressure, - diminishing TFPI-2, HIF 1α, and VEGF in placenta, - alleviating the oxidative stress in blood and placentas, - high dosage (60 mg/kg) decreased sFlt-1, increased PlGF, - dose of 60 mg/kg more effective in low pups/placenta ratio.	[86]
Euterpe oleracea aqueous crude extract from seeds (polymeric proanthocyanidins, catechin, epicatechin)	- preeclampsia induced by L-NAME (60 mg/kg/day in drinking water) in female Wistar rats - dose of extract: 200 mg/kg in drinking water during 8 days.	- reducing the blood pressure in the second half of pregnancy, - decreasing of lipid peroxidation, - diminishing maternal microalbuminuria, - increasing in total placental mass, and fetal weight, - no effect in activities of superoxide dismutase, catalase, glutathione peroxidase, - lowering the nitrite content (NO).	[99]
Moringa oleifera - ethanolic extract from leaves (e.g., flavonoids—quercetin)	- preclampsia induced by L-NAME (50 mg/kg/day) - doses of extract: 50,100, and 200 mg/kg b.w, during 13 days of gestation.	- reducing the systolic and diastolic blood pressure (all doses) - similar preventive effect as the low-dose acetylsalicylic acid (1.35 mg/200 g b.w.), - decreasing the concentration of IL-17 (after extract at doses 50 and 100 mg/kg).	[107]
Thymus schimperion - aqueous crude extract from leaves	- preeclampsia induced by L-NAME (50 mg/kg/day) - doses of extract: 250, 500, and 1000 mg/kg/day during nine days of gestation.	- decreasing the levels of hemoglobin and hematocrit (all doses), - increasing count of platelets and total leukocyte, - the highest effect after 1000 mg/kg of extract.	[108]
Uncaria rhynchophylla - hydroethanolic extract (oxindole alkaloids: isorhynchophylline, yohimbine, 3α-dihydrocadambine, raubasine, hirsuteine, hirsutine)	- preeclampsia induced by LPS (1.0 mg/kg b.w./day; injection) in female Sprague–Dawley rats, - doses of extract: 35, 70, and 140 mg/kg b.w./day during six days.	- reducing the systolic blood pressure between 14 and 18 days of gestation (after extract at a dose of 140 mg/kg), - decreasing the level of urinary (after extract in a dose-dependent manner), - diminishing the levels of serum and placental cytokines: IL-6, IL-1b, TNF-a, IFN-g (after extract at a dose of 140 mg/kg), - diminishing the mRNA expression of pro-inflammatory cytokines in placenta, - diminishing the level of NF-jB p65 in the placenta, - higher the live fetuses (after extract at a dose of 140 mg/kg).	[118]
Vitis labrusca - hydroethanolic extract from skin of fruits (polyphenols concentration 55.5 mg g­ 1)	- hypertension induced by L-NAME (60 mg/kg/day, in drinking water, for 28 days) in male Wistar rats, - dose of extract: 100 mg/kg/day during 28 days of pregnancy.	- increasing the heart rate, - decreasing the systolic, mean, and diastolic arterial pressure after four weeks after administration of extract, - decreasing the lipid peroxidation in liver.	[124]
Vitis labrusca - hydroethanolic extract from skin of fruits (polyphenols concentration 55.5 mg g­ 1)	- hypertension induced by deoxycorticosterone acetate (12.5 mg kg −1 per week, drinking solution for 30 days); male Wistar rats, - dose of extract: 100 mg/kg/day during 13 days of pregnancy.	- increasing the heart rate, - decreasing the systolic, mean, and diastolic arterial pressure - decreasing the lipid peroxidation in liver.	[124]
Vitis vinifera grape skin extract	- hypertension induced by L-NAME (60 mg/kg/day, in drinking water, for seven days) in male Wistar rats, - dose of extract: 200 mg/kg/day for seven days.	- preventing the increasing the arterial pressure and insulin resistance.	[122]
Vitis vinifera grape skin extract	- spontaneously hypertensive rats, - dose of extract ACH09: 200 mg/kg/day in drinking water for 12 weeks.	- reducing the systolic blood pressure, - decreasing the elevated concentrations of cholesterol and triglyceride, - diminishing the formation of products of peroxidation of lipid, - no effect in catalase activity.	[123]