Experimental Preeclampsia Research Articles

Thrombin in Pregnancy and Preeclampsia: Expression, Localization, and Vasoactivity in Brain and Microvessels From Rats.

Thrombin is a coagulation factor increased in pregnancy and further increased in preeclampsia (PE), a hypertensive disorder. Thrombin is also expressed in the brain and may have a nonhemostatic role. We characterized thrombin expression and vasoactivity in brain cerebral parenchymal arterioles (PAs) in rat models of pregnancy and PE. PAs were isolated and pressurized from nonpregnant (NP) and late-pregnant (LP) rats and rats with experimental preeclampsia (ePE). Reactivity to thrombin (1-50 U/mL) was measured in the absence and presence of inhibition of cyclooxygenase and nitric oxide synthase. Plasma levels of prothrombin, thrombin-antithrombin (TAT), tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1) and cerebrospinal fluid levels of TAT were compared using enzyme-linked immunosorbent assay. Expression of protease-activated receptor types 1 and 2 in PAs were measured by Western blot and immunohistochemistry. Neuronal thrombin expression was quantified in brains from all groups by immunohistochemistry. Prothrombin and TAT were elevated in ePE plasma compared with NP and LP. TAT was detected in cerebrospinal fluid from all groups and significantly elevated in LP (NP: 0.137 ± 0.014 ng/mL, LP: 0.241 ± 0.015 ng/mL, ePE: 0.192 ± 0.028 ng/mL; P < 0.05). Thrombin caused modest vasoconstriction in PAs from all groups regardless of cyclooxygenase or nitric oxide synthase inhibition. PAR1 and PAR2 were found in PAs from all groups colocalized to smooth muscle. Thrombin expression in central neurons was decreased in both LP and ePE groups compared with NP. These findings suggest a role for thrombin and other hemostatic changes during pregnancy and PE beyond coagulation.

Prior Exposure to Experimental Preeclampsia Increases Atherosclerotic Plaque Inflammation in Atherogenic Mice-Brief Report.

Women with a history of preeclampsia have evidence of premature atherosclerosis and increased risk of myocardial infarction and stroke compared with women who had a normotensive pregnancy. Whether this is due to common risk factors or a direct impact of prior preeclampsia exposure has never been tested in a mouse atherosclerosis model. Pregnant LDLR-KO (low-density lipoprotein receptor knockout; n=35) female mice were randomized in midgestation to sFlt1 (soluble fms-like tyrosine kinase 1)-expressing adenovirus or identical control adenovirus. Postpartum, mice were fed high-fat diet for 8 weeks to induce atherogenesis. Comparison between the control and preeclampsia models was made for metabolic parameters, atherosclerosis burden and composition by histology, plaque inflammation by flow cytometry, and aortic cytokines and inflammatory markers using a cytokine array. In pregnant LDLR-KO mice, sFlt1 adenovirus significantly induced serum sFlt1, blood pressure, renal endotheliosis, and decreased pup viability. After 8 weeks of postpartum high fat feeding, body weight, fasting glucose, plasma cholesterol, HDL (high-density lipoprotein), and LDL (low-density lipoprotein) were not significantly different between groups with no change in aortic root plaque size, lipid content, or necrotic core area. Flow cytometry demonstrated significantly increased CD45+ aortic arch leukocytes and CD3+T cells and aortic lysate contained more CCL (CC motif chemokine ligand) 22 and fetuin A and decreased expression of IGFBP6 (insulin-like growth factor-binding protein 6) and CCL21 in preeclampsia-exposed mice compared with controls. In atherogenic LDLR-KO mice, exposure to sFlt1-induced preeclampsia during pregnancy increases future atherosclerotic plaque inflammation, supporting the concept that preeclampsia directly exacerbates atherosclerotic inflammation independent of preexisting risk factors. This mechanism may contribute to ischemic vascular disease in women after preeclampsia pregnancy.

Epicatechin effect in an experimental pre-eclampsia model

Epicatechin effect in an experimental pre-eclampsia model Cecilia del Carmen Tufiño Martínez, Luis Jonathan Soto Ramírez, Betzabel Reyes Rodríguez, Damián Arturo Madrigal Aguilar, Rosa Amalia Bobadilla Lugo.Escuela Superior de Medicina del Instituto Politécnico Nacional (Salvador Díaz Mirón esq. Plan de San Luis S/N, Miguel Hidalgo, Casco de Santo Tomas, 11340 Ciudad de México, CDMX)Preclampsia (PE) is a pregnancy specific disorder characterized by de novo development of hypertension and proteinuria. Both the pathophysiology and the treatment of this disease are not clearly established. Epicatechin is a natural product that has shown beneficial effects in several conditions including hypertensive as well as having recognized antioxidant capacity. The objective of this work was to evaluate if the Epicatechin can reduce blood pressure and vascular contractility in an experimental model of preclampsia. For this purpose, 250g ± 50 pregnant female Wistar rats at term were divided into control and with subrenal aortic coarctation or PE, and treated: a) Vehicle, b) epicatechin (10 mg/Kg/day) p.o. during the first two weeks or c) epicatechin (10 mg/Kg/day) p.o. during the last two weeks of gestation. Blood pressure and weight were recorded, and a glucose tolerance curve was performed. The animals were sacrificed at term (day 20) to assess vascular contractility in aortic rings using a conventional isolated organ device. The results showed that rats with PE have an increase in systolic blood pressure, blood glucose and vascular contractility (abdominal aorta) compared to rats with normal pregnancy. Epicatechin administration during the 1st and 2nd week decrease systolic blood pressure, and the contractile response to phenylephrine and angiotensin II in the abdominal segment but not in the thoracic segment of the aorta of preclamptic rats. We conclude that preventive epicatechin treatment improves systolic blood pressure increase observed in the preclampsia model. However, results suggest epicatechin effect is more relevant on resistance than conductance vessels. Funding: Consejo Nacional de Ciencia y Tecnología (CONACyT) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Worsened Stroke Outcome in a Model of Preeclampsia is Associated With Poor Collateral Flow and Oxidative Stress.

Preeclampsia increases the incidence of maternal stroke, a devastating condition that is on the rise. We investigated stroke outcome in a model of experimental preeclampsia with and without treatment with clinically relevant doses of magnesium sulfate (experimental preeclampsia+MgSO4) compared to normal late-pregnant and nonpregnant rats. Transient middle cerebral artery occlusion was used to induce focal stroke for either 1.5 or 3 hours. Infarct volume and hemorrhagic transformation were determined as measures of stroke outcome. Changes in core middle cerebral artery and collateral flow were measured by dual laser Doppler. The relationship between middle cerebral artery perfusion deficit and infarction was used as a measure of ischemic tolerance. Oxidative stress and endothelial dysfunction were measured by 3-nitrotyrosine and 8-isoprostane, in brain and serum, respectively. Late-pregnant animals had robust collateral flow and greater ischemic tolerance of brain tissue, whereas experimental preeclampsia had greater infarction that was related to poor collateral flow, endothelial dysfunction, and oxidative stress. Importantly, pregnancy appeared preventative of hemorrhagic transformation as it occurred only in nonpregnant animals. MgSO4 did not provide benefit to experimental preeclampsia animals for infarction. Stroke outcome was worse in a model of preeclampsia. As preeclampsia increases the risk of future stroke and cardiovascular disease, it is worth understanding the influence of preeclampsia on the material brain and factors that might potentiate injury both during the index pregnancy and years postpartum.

PS-BPB04-7: PRO-ANGIOGENIC EFFECTS OF LSKL, A THROMBOSPONDIN-1 INHIBITOR, IN HUMAN AND EXPERIMENTAL MODELS OF PREECLAMPSIA

Introduction: Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by blood pressure above 140/90 mmHg. It accounts for 10% of all pregnancies and is responsible for 25% of preterm births and low birth weight. To date, no medications can treat or prevent PE. We identified an activation of the anti-angiogenic protein thrombospondin-1 (THBS1) in human and experimental preeclampsia. THBS1 is also a main activator of TGF-β. We postulate that THBS1-mediated TGF-β activation may contribute to impair placental angiogenesis during PE. Objective: We aimed to test the effects of LSKL, an inhibitor of THBS1-mediated TGF-β activation, on angiogenesis in placentas of a mouse model of PE and in human placental endothelial cells. Methods: Peptide LSKL or its control peptide SLLK (280 μM in 0.5 ml saline, s.c.) was administered at gestational day (GD) 14.5 in heterozygous transgenic mice overexpressing human renin and human angiotensinogen and controls (C57BL/6). Placentas (n = 12/group) were removed at GD 18.5. Protein expression of TGF-β1, TGF-β2, total and phosphorylated SMAD2 were assessed by western blot of placental lysates. Placental angiogenesis was assessed by CD31+ immunohistochemistry in placental sections. CD31+ endothelial cells were extracted by magnetic sorting from human placentas (n = 4) of healthy pregnancies. Cells (2–5 passages) were treated with LSKL or SLLK (30 μM) under hypoxia (0.5% vs. 8% O2) or thrombin (10 u/mL) exposure (4 hours). THBS1 expression in placental endothelial cells was assessed by immunofluorescence. Cell angiogenesis was quantified by the number of closed tubes formed on matrigel (per 15,000 cells, 4 hours). Results: Maternal LSKL treatment significantly reduced the expression of TGF-β2 (P &lt; 0.01) and SMAD2 phosphorylation (P &lt; 0.05) while improving angiogenesis (P &lt; 0.05) in placentas of transgenic preeclamptic mouse compared to controls. In human placental endothelial cells, both thrombin (P &lt; 0.05) and hypoxia (P &lt; 0.05) significantly increased THBS1 expression. Thrombin (P &lt; 0.01) and hypoxia (P &lt; 0.05) significantly impaired cell angiogenesis on matrigel (P &lt; 0.01), which was prevented by LSKL treatment (P &lt; 0.01). In human cells, LSKL similarly reduced TGB-β2 (p &lt; 0.05) and phospho-SMAD2 (P &lt; 0.05) expressions under thrombin and hypoxia cell exposure. Conclusion: Our results describe a significant pro-angiogenic effect of LSKL treatment by regulating THBS1 and TGF-β2 mechanisms in human and experimental models of PE.

Study of the effect of acetylsalicylic acid and a selective arginase II inhibitor KUD 975 on the correction of hemostatic disorders in experimental preeclampsia

Introduction: The disruption of the functional state of the vascular endothelium is among the main causes of pre­eclampsia, which is one of the most common causes of maternal and perinatal mortality. It can be enhanced by the humoral factors secreted by the activated platelets. The use of acetylsalicylic acid is an effective way to prevent pre­eclampsia. However, its ability to activate eNOS is a prerequisite for researching its ability to correct the disorders in developing preeclampsia, including by reducing the platelet activity. In this case its effect can be enhanced through increasing the bioavailability of L-arginine by using a selective arginase II inhibitor KUD 975. These facts were the prerequisite for conducting this study.&#x0D; Materials and methods: The study was conducted on 180 female Wistar rats weighing 250–300 g. Acetylsalicylic acid was used at a dose of 7 mg/kg/day and 10 mg/kg/day, KUD 975 – at a dose of 1 mg/kg/day and 3 mg/kg/day. Adenosine diphosphate (ADP, 6.5 microns), arachidonic acid (ASPI, 0.5 mM), and collagen (3.2 mcg/ml) were used as aggregation inducers.&#x0D; Results and discussion: ADMA-like preeclampsia simulation led to an increase in platelet aggregation ability when using all aggregation inducers. This is evidenced by an increase in a degree, rate of aggregation, and a shortened time of thrombus formation. The use of acetylsalicylic acid and a selective arginase II inhibitor KUD 975 led to a decrease in the aggregation ability of platelets and an increase in thrombosis time, while the combined administration of the studied agents showed a more pronounced effect.&#x0D; Conclusion: The data obtained while performing a series of experiments strongly indicate a promising outlook for using acetylsalicylic acid and a selective arginase II inhibitor KUD 975 in order to correct emerging disorders in preeclampsia.

Cerebral Blood Flow Autoregulation in Offspring From Experimentally Preeclamptic Rats and the Effect of Age.

Preeclampsia is a hypertensive disorder of pregnancy that causes significant, long term cardiovascular effects for both the mother and offspring. A previous study demonstrated that middle cerebral arteries in offspring from an experimental rat model of preeclampsia were smaller, stiffer, and did not enlarge over the course of maturation, suggesting potential hemodynamic alterations in these offspring. Here we investigated the effect of experimental preeclampsia on cerebral blood flow autoregulation in juvenile and adult offspring that were born from normal pregnant or experimentally preeclamptic rats. Relative cerebral blood flow was measured using laser Doppler flowmetry, and cerebral blood flow autoregulation curves were constructed by raising blood pressure and controlled hemorrhage to lower blood pressure. Immunohistochemistry was used to assess middle cerebral artery size. Heart rate and blood pressure were measured in awake adult offspring using implanted radiotelemetry. Serum epinephrine was measured using enzyme-linked immunosorbent assay. Offspring from both groups showed maturation of cerebral blood flow autoregulation as offspring aged from juvenile to adulthood as demonstrated by the wider autoregulatory plateau. Experimental preeclampsia did not affect cerebral blood flow autoregulation in juvenile offspring, and it had no effect on cerebral blood flow autoregulation in adult offspring over the lower range of blood pressures. However, experimental preeclampsia caused a right shift in the upper range of blood pressures in adult offspring (compared to normal pregnant). Structurally, middle cerebral arteries from normal pregnant offspring demonstrated growth with aging, while middle cerebral arteries from experimentally preeclamptic offspring did not, and by adulthood normal pregnant offspring had significantly larger middle cerebral arteries. Middle cerebral artery lumen diameters did not significantly change as offspring aged. Serum epinephrine was elevated in juvenile experimentally preeclamptic offspring, and a greater degree of hemorrhage was required to induce hypotension, suggesting increased sympathetic activity. Finally, despite no evidence of increased sympathetic activity, adult experimentally preeclamptic offspring were found to have persistently higher heart rate. These results demonstrate a significant effect of experimental preeclampsia on the upper range of autoregulation and cerebrovascular structure in juvenile and adult offspring that could have an important influence on brain perfusion under conditions of hypo and/or hypertension.

Changes in the Deformability and Resistance of Erythrocyte Membranes under the Action of Gamma-Aminobutyric Acid Derivatives in the Offspring of Rats with Experimental Preeclampsia

INTRODUCTION: Preeclampsia is a severe complication of pregnancy associated with the negative consequences for the mother and child. Such complications can be a reduction in the resistance of erythrocyte membranes to damaging agents and alteration of rheological properties of the blood in offspring. Promising compounds for the correction of these negative consequences of preeclampsia are gamma-aminobutyric acid (GABA) derivatives, which showed membraneprotective, antioxidant, and antihypoxic effects in previous studies.&#x0D; AIM: To evaluate the effect of GABA derivatives Succicard (4-phenylpiracetam and ethane-1,2-dicarboxylic acid, 2:1), Salifen (4-amino-3-phenylbutanoic acid and 2-hydroxybenzoic acid, 2:1), and Phenibut (aminophenylbutyric acid) on the deformability and resistance of erythrocyte membranes in 8- and 14-month-old offspring of rats with experimental preeclampsia (EP).&#x0D; MATERIALS AND METHODS: The study involved offspring (male and female) of white non-inbred female rats with a normal pregnancy and EP that was modeled by replacement of drinking water with a 1.8% sodium chloride solution during gestation (121 days). For 30 days (from day 40 to day 70 of life), pup rats intragastrically received Succicard (22 mg/kg), Salifen (7.5 mg/kg), and Phenibut (25 mg/kg), along with a comparison drug Pantogam (calcium gopantenate) (50 mg/day) once a day. The offspring of the positive and negative control groups were injected with distilled water in a similar mode. In offspring aged 8 and 14 months, the resistance of erythrocyte membranes to the action of hydrochloric acid and their deformability were determined.&#x0D; RESULTS: In 8-month-old male offspring of rats with EP, a shorter time of achievement of half the maximal amplitude of erythrogram was noted in acid hemolysis relative to the positive control group, and the erythrocyte elongation index was reduced. Relative to the negative control group, Succicard, Salifen, Phenibut, and Pantogam promoted the prolongation of hemolysis and the erythrocyte elongation index in 8-month-old male rats in the experimental groups. In 14-month-old male and female rats of different ages, no statistically significant differences were found between the groups.&#x0D; CONCLUSION: Changes in the stiffness and strength of erythrocyte membranes were noted only in male offspring of rats with EP. Succicard, Salifen, Phenibut, and Pantogam produced membrane-protective effects on the erythrocytes of 8-month-old male rats of the experimental groups.

Influence of GABA derivatives on the DNA damage of placenta and fetuses’s brain at experimental preeclampsia

Influence of GABA derivatives on the DNA damage of placenta and fetuses’s brain at experimental preeclampsia

Effect of early and late pharmacological correction with GABA derivatives on cognitive disorders in offspring of rats with experimental preeclampsia

BACKGROUND: Preeclampsia is a serious complication of pregnancy which augments the risk of cognitive disorders in the offspring at different stages of life. Presently, there are no methods with proven effectiveness for correction of post-hypoxic disorders in children of mothers with preeclampsia. AIM: To assess the cognitive functions of the offspring of rats with experimental preeclampsia (EP) through early (40th to 70th day of life) and late (24th to 25th month of life) pharmacological correction with gamma aminobutyric acid (GABA) derivatives: Succicard, Salifen, Phenibut, and the drug of comparisonPantogam. MATERIALS AND METHODS: EP was modeled by replacing drinking water with 1.8% sodium chloride solution in rats from the first day of pregnancy to delivery. In the offspring, short-term and long-term memory was studied at the age of 34, 1819, and 2526 months in the Novel object recognition test and Barnes Maze test. The functioning of the GABAergic and dopaminergic systems (which play an essential role in the development of memory) was evaluated by cases of convulsions after administering corazol at a dose of 20 mg/kg intraperitoneally (model of corazol kindling) and by haloperidol-induced catalepsy (haloperidol at a dose of 0.3 mg/kg intraperitoneally), respectively. RESULTS: Early and late pharmacological correction with GABA derivativessuccicard, Salifen, Phenibut, and comparison drug, Pantogamneutralized the negative effect of EP on the function of GABAergic and dopaminergic systems in the offspring of the experimental groups. Therapy with Succicard in puberty and long-term periods of life contributed to the improvement of short-term and long-term memory in the offspring of rats with EP. Thus, it could be reasonable enough to develop a drug against cognitive disorders in children of mothers with preeclampsia. CONCLUSION: In the offspring of rats with EP, short-term and long-term disorders of memory in the functioning of the GABAergic and dopaminergic systems were noted in the early and late stages of the individual development. Pharmacological correction with GABA derivatives improves cognitive processes and the functioning of neurotransmitter systems in the offspring of rats with complicated pregnancy. The highest effectiveness was demonstrated by succicard, and was comparable with or superior to the Pantogam (standard drug).

Antenatal Mesenchymal Stromal Cell Extracellular Vesicle Therapy Prevents Preeclamptic Lung Injury in Mice.

In preeclamptic pregnancies, a variety of intrauterine alterations lead to abnormal placentation, release of inflammatory and/or antiangiogenic factors, and subsequent fetal growth restriction with significant potential to cause a primary insult to the developing fetal lung. Thus, modulation of the maternal intrauterine environment may be a key therapeutic avenue to prevent preeclampsia-associated developmental lung injury. Abiologic therapy of interest is mesenchymal stromal cell-derived extracellular vesicles (MEx), which we have previously shown to ameliorate preeclamptic physiology through intrauterine immunomodulation. To evaluate the therapeutic potential of MEx to improve developmental lung injury in experimental preeclampsia, using the heme oxygenase-1-null mouse (Hmox1-/-) model, preeclamptic pregnant dams were administered intravenous antenatal MEx treatment during each week of pregnancy followed by analysis of fetal and postnatal lung tissues, amniotic fluid protein profiles, and lung explant and amniotic fluid cocultures in comparison with controland untreated preeclamptic pregnancies. We first identified that a preeclamptic intrauterine environment had a significant adverse impact on fetal lung development, including alterations in fetal lung developmental gene profiles in addition to postnatal alveolar and bronchial changes. Amniotic fluid proteomic analysis and fetal lung explant and amniotic fluid cocultures further demonstrated that maternally administered MEx altered the expression of multiple inflammatory mediators in the preeclamptic intrauterine compartment, resulting in the normalization of fetal lung branching morphogenesis and developmental gene expression. Our evaluation of fetal and postnatal parameters overall suggests that antenatal MEx treatment may provide a highly valuable preventative therapeutic modality for amelioration of lung development in preeclamptic disease.

Abnormal development of cerebral arteries and veins in offspring of experimentally preeclamptic rats: Potential role in perinatal stroke

Preeclampsia, a hypertensive disorder of pregnancy, complicates up to 10 % of all pregnancies and increases the risk for perinatal stroke in offspring. The mechanism of this increase is unknown, but may involve vascular dysfunction. The goal of this study was to evaluate the effect of experimental preeclampsia (ePE) on cerebrovascular function in offspring to eludciate a possible mechanism for this association. Dams were fed a high cholesterol diet beginning on day 7 of gestation to induce experimental preeclampsia. Middle cerebral arteries (MCA) and the Vein of Galen (VoG) were isolated from pups from ePE dams and compared to pups from normal pregnant (NP) dams at postnatal days 16, 23, and 30 and studied pressurized in an arteriograph chamber. Markers of inflammation and oxidative stress were measured in serum. Our results suggest altered structure and function in both MCA and VoG of ePE pups. We also found evidence of systemic inflammation and oxidative stress in ePE pups. These findings provide a potential link between preeclampsia and the occurrence or severity of perinatal stroke.

Change in physical performance indicators of the progenies of rats with experimental preeclampsia in early and late pharmacological correction by GABA derivatives

Change in physical performance indicators of the progenies of rats with experimental preeclampsia in early and late pharmacological correction by GABA derivatives

EFFECT OF THE GABA DERIVATIVE SUCCICARD ON THE LIPID AND CARBOHYDRATE METABOLISM IN THE OFFSPRING OF RATS WITH EXPERIMENTAL PREECLAMPSIA IN EARLY AND LATE ONTOGENY

Maternal preeclampsia can bring about metabolic disorders in the offspring at different stages of ontogeny. Up to date, no ways of preventive pharmacological correction of lipid and carbohydrate metabolism disorders developing in different periods of ontogeny in the children born to mothers with this pregnancy complication, have been developed.The aim of the experiment was to study the effect of the gamma-aminobutyric acid derivative succicard (22 mg/kg) and its reference drug pantogam (50 mg) administered per os in the course of treatment in puberty (from 40 to 70 days after birth), on the parameters of lipid and carbohydrate metabolism in the offspring of the rats with experimental preeclampsia, in different periods of ontogeny.Materials and methods. To assess the activity of lipid and carbohydrate metabolism in the offspring, an oral glucose tolerance test was performed at 40 days, 3, 6, 12 and 18 months of age. The level of glycosylated hemoglobin was measured at the age of 6, 12, and 18 months, and the concentrations of total cholesterol, high-density lipoprotein cholesterol and triglycerides were tested at 40 days, 3, 6, 12, and 18 months of age.Results. The offspring of the rats with experimental preeclampsia, were found out to have lipid and carbohydrate metabolism disturbances during early (40 days and 3 months of age) and late (6, 12, and 18 months of age) ontogeny. In comparison with the offspring of healthy females, these disturbances were manifested by significantly higher levels of glucose revealed during the oral glucose tolerance test, by high glycosylated hemoglobin in males, and with elevated concentration of total cholesterol and triglycerides and a low level of high-density lipoprotein cholesterol in the negative control rats. Both the gamma-aminobutyric acid derivative succicard and its reference drug pantogam, reduced the negative effect of experimental preeclampsia on lipid and carbohydrate metabolism in the offspring in late ontogeny (6, 12 and 18 months of age). The effectiveness of succicard was either higher or comparable with pantogam.Conclusion. Thus, the negative impact manifestations of experimental preeclampsia on lipid and carbohydrate metabolism, are revealed in the offspring in early (40 days and 3 months) and late (6, 12 and 18 months of age) ontogeny. The gamma-aminobutyric acid derivative succicard reduces the negative effect of experimental preeclampsia. Based on this finding, the drug implies the possibility of the development of a safe and highly effective medicine for preventive correction of lipid and carbohydrate metabolism disorders in the children born to mothers with preeclampsia.

CORRECTION OF MORPHOFUNCTIONAL DISORDERS IN EXPERIMENTAL PREECLAMPSY BY COMBINED USE OF TRIMETAZIDINE AND PURIFIED MICRONIZED FLAVONOID FRACTION AS WELL AS THEIR COMBINATIONS WITH METHYLAMPSY

The aimof the experiment was to determine the effectiveness of the combined use of trimetazidine and a purified micronized flavonoid fraction, as well as their combinations with methyldopa, in comparison with monotherapy with the same drugs in the correction of morphofunctional disorders arising in the conditions of experimental preeclampsia. An integrated/multimethodology approach is the most effective way of treatment for preeclampsia. Therefore, an urgent task of modern pharmacology is to study the effectiveness of new drugs when used in combinations, as well as the drugs included in the standards for treatment.Materials and methods. The study was carried out at the Research Institute of Pharmacology of Living Systems of Belgorod State National Research University. The experiment was performed on 200 female Wistar rats, weighing 250–300 g, in which an ADMA-like model of preeclampsia had been reproduced. To assess the degree of correction of emerging morphological and functional disorders, the following parameters were involved: blood pressure, a coefficient of endothelial dysfunction, microcirculation in the placenta, proteinuria, fluid contents in the greater omentum, morphometric indicators of placental tissues and fetal height and weight parameters.Results. The combined use of trimetazidine (Preductal® MB) 6 mg/kg and a purified micronized flavonoid fraction (Detralex®) 260 mg/kg, as well as their combination with methyldopa (Dopegit®) 86 mg/kg, leads to a more pronounced decrease in the blood pressure, compared with a decrease in the coefficient of endothelial dysfunction by 2.22, 2.19 and 1.94 times, respectively, in relation to “untreated” animals. There was an increase in microcirculation indices in the placenta by 2.35, 2.21 and 2.03 times, respectively. In addition, there was an improvement in morphological parameters in the placenta and fetuses.Conclusion. The results of the study showed a greater effectiveness of the combined use of the studied drugs in experimental preeclampsia compared to their monotherapy. This indicates the prospects for the use of trimetazidine and purified micronized flavonoid fraction in the complex therapy for preeclampsia and the need for further research in this direction.

Cognitive Dysfunction in the Offspring of Rats with Experimental Preeclampsia at the Early and Late Stages of Ontogeny and Its Correction with GABA Derivatives

We report here studies of cognitive impairments at different periods of ontogeny in the offspring of rats with experimental preeclampsia modeled by replacement of drinking water with 1.8% sodium chloride solution from day 1 to day 21 of gestation. The offspring of females with complications of pregnancy, at both the early (40 days and three months) and late (six and 12 months) stages of individual development showed decreases in working memory in the novel object recognition test, degraded formation and retention of memory traces in the conditioned passive avoidance reflex test, and more marked amnesia in response to scopolamine at a dose of 1.75 mg/kg on testing for retention of memory traces. Oral treatment of the offspring of females with experimental preeclampsia at pubertal age (from day 40 to day 70 of life) with GABA derivatives succicard, salifen, and phenibut, and reference agent pantogam, promoted decreases in cognitive deficit in animals at different periods of postnatal development.

The effect of early and late pharmacological correction with GABA derivatives of psychoemotional state of offspring of rats with experimental preeclampsia

Introduction: Preeclampsia is a serious complication of pregnancy, which increases the risk of anxiety disorders and depression in children at different stages of ontogenesis.&#x0D; Materials and methods: The psychoemotional state of 70-day-old offspring of rats with experimental preeclampsia (EP) was studied after pharmacological correction from the 40th to 70th day of offspring life with GABA derivatives – succicard (22 mg/kg), salifen (7.5 mg/kg), phenibut (25 mg/kg) and comparison drug pantogam (50 mg) – in the Open field test, the Elevated plus maze test, and the Marble burying test. The above mentioned tests, together with the Porsolt test, were performed at the age of 18 months.&#x0D; At the second step, the offspring received succicard (44 mg/kg), salifen (15 mg/kg), phenibut (50 mg/kg) and pantogam (100 mg) from the 24th to 25th month of life. After that, the animals were tested.&#x0D; Results and discussion: The EP progeny had an increased level of anxiety and depression, as well as obsessive-com­pulsive disorder.&#x0D; Early GABA derivatives exposure limited anxiety and depression in the animals aged 70 days and 18 months, with salifen limiting compulsive behavior. Late GABA derivatives “treatment” exerted anti-compulsive and antidepressant effects, with phenibut having a greater degree of anxiolytic activity. Succicard, salifen and phenibut were comparable or superior to pantogam in terms of effectiveness.&#x0D; Conclusion: EP has a negative effect on the psychoemotional state of offspring. Early and late pharmacological cor­rection with derivatives of GABA, such as succicard, salifen and phenibut, reduced anxiety, manifestations of obses­sive-compulsive disorder, and depression in offspring of the rats with EP pregnancy.

Коррекция функциональных нарушений при ADMA-подобной преэклампсии производными пептида, имитирующего α-спираль B эритропоэтина

Objective. The aim of the study is to investigate the correction of functional disorders in ADMA-like preeclampsia with derivatives of the peptide imitating erythropoietin α-helix B. Materials and methods. The study was performed in 120 white female Wistar rats weighing 250-300 g. ADMA-like preeclampsia was used as experimental preeclampsia. To assess the effectiveness of the pharmacological agents used, blood pressure, microcirculation in the placenta, and proteinuria were recorded, the content of final NO metabolites in the blood plasma was determined, and the coefficient of endothelial dysfunction was calculated. 50 μg / kg polypeptides (P-αB3 and P-αB4) were used as pharmacological agents, obtained by attaching to the original 11-amino acid peptide PHBSP [PubChem CID: 91810664], which is the amino acid chain Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser (QEQLERALNSS) of KGD group from different ends of the chain. Results. The use of the studied derivatives of peptide imitating erythropoietin α-helix B with ADMA-like preeclampsia leads to a pronounced correction of disorders. The greatest effect was observed with the introduction of the peptide with the laboratory code P-αB4. A significant decrease in systolic and diastolic pressure was noted, respectively, improved microcirculation in the placenta, restoration of the NO-synthesizing function of the endothelium, and a decrease in proteinuria. Conclusion. The results obtained indicate the prospect of further research on the effectiveness of short-chain derivatives of erythropoietin imitating its α-helix B for the correction of functional disorders in preeclampsia.

Açaí (Euterpe oleracea Mart) seed extract protects against maternal vascular dysfunction, hypertension, and fetal growth restriction in experimental preeclampsia

ABSTRACT Objective To investigate whether Euterpe oleracea Mart. (açaí) seed extract (ASE) prevents maternal cardiovascular changes and intrauterine growth restriction (IUGR) in experimental preeclampsia (PE). Methods ASE administration (200 mg/kg/day) during mid to late pregnancy in a rat model of L-NAME-induced PE. Results ASE impaired the maternal hypertension and microalbuminuria as well as the lower fetal and placental weight in experimental PE. ASE also prevented the maternal vascular dysfunction and lipoperoxidation in this model. Conclusion ASE protected against maternal cardiovascular changes and IUGR in the L-NAME-induced PE. The protective effect of ASE may be partly explained by its antioxidant property.

Experimental Preeclampsia Causes Persistent Impairment of Hippocampal‐Dependent Memory and Network Function that is Exacerbated by Status Convulsions

Preeclampsia (PE) is a hypertensive disorder of pregnancy involving hyperlipidemia and widespread maternal endothelial dysfunction that can cause spontaneous seizures including status convulsions known as eclampsia. Further, PE increases the risk of cardiovascular disease and cognitive impairment later in life. This study investigated long‐lasting effects of PE without and with status convulsions on the hippocampus, a brain region involved in memory and cognition. Sprague Dawley rats that were either normal pregnant or with experimental PE (ePE) induced by a high cholesterol diet starting d7 of gestation were used. Acute status convulsions were induced on day 19 of a 22‐day gestation via multiple i.p. injections of the chemoconvulsant pentylenetetrazol or saline (no‐seizure controls). Five weeks after status convulsions, an object recognition task was used to quantify the percent of time spent investigating a novel object as a measure of long‐term memory function (n = 8/group). After which, hippocampal network function was assessed by evoking long‐term potentiation (LTP), a well‐accepted cellular model for learning and memory, in the Schaffer Collateral to CA1 (Sch‐CA1) pathway of hippocampal slices. Synaptically evoked field excitatory post‐synaptic potentials (fEPSPs) were collected from the Sch–CA1 area of the hippocampus at a rate of 0.05 Hz. A 20 min stable baseline period was established before delivering a 40 pulse theta burst stimulation (TBS). Increase in fEPSP slope 60 min after TBS was analyzed as a measure of synaptic LTP. Data are mean ± SEM and comparisons made via a two‐way ANOVA to determine the interaction between two independent variables (ePE and status convulsions) with a post‐hoc Tukey test.There were significant interactions between the effects of ePE and status convulsions on memory function (F (1, 18) = 9.469; p = 0.007) as well as LTP (F (1, 19) = 9.991; p = 0.005). Object recognition was reduced in rats that had ePE compared to those that had a normal pregnancy, as formerly ePE rats spent 55 ± 3 % of the time investigating the novel object, much less than the 73 ± 3 % in rats that had a healthy pregnancy (Fig 1). Status convulsions impaired memory in rats that had a normal pregnancy, but not in the ePE group likely due to memory already being impaired (Fig 1). Further, LTP was impaired in rats that had ePE, with the slope of fEPSPs increasing to only 132 ± 7 % of baseline in slices from ePE rats compared to 157 ± 4 % in rats that had a healthy pregnancy (Fig 2). Status convulsions impaired LTP in rats that had ePE and those that had a normal pregnancy, with the slope of fEPSPs increasing to only 114 ± 5 % of baseline in formerly ePE rats and 106 ± 5 % in rats that had seizures during normal pregnancy (Fig 2).Overall, these findings suggest that PE and eclampsia cause permanent memory dysfunction by impairing LTP in the hippocampus, and highlight the importance of seizure prevention to maternal cognitive health. Further, understanding mechanisms of impaired hippocampal plasticity after PE and/or eclampsia may lead to novel therapeutic approaches to minimize the cognitive burden associated with PE and eclampsia later in life.Support or Funding InformationNIH NINDS R01 NS045940NIH NINDS R01 NS108455Long‐term memory as measured via a novel object recognition task. **p&lt;0.01.Figure 1LTP of hippocampal slices. *p&lt;0.05 and **p&lt;0.01.Figure 2