Jinying Yang

Increased neuronal seizure activity correlates with excessive systemic inflammation in a rat model of severe preeclampsia.

Preeclampsia (PE), one of the most common disorders of pregnancy, is characterized by hypertension and albuminuria. In severe cases, PE results in eclampsia-like seizures. Studies have suggested that severe PE is related to an exaggerated systemic inflammatory response, which may increase sensitivity to seizures. In the current study, we investigated whether the seizure activity of neurons was enhanced under excessive systemic inflammation. We also sought to determine whether MgSO4 could reduce the effects of systemic inflammation on seizure activity after electrical stimulation in a lipopolysaccharide (LPS)-induced model of PE. In addition to pregnancy outcomes, we analyzed biochemical parameters to ascertain whether our PE model was successful. Enzyme-linked immunosorbent assay analysis revealed that the levels of inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1β) were significantly higher in the LPS-treated rats than in the untreated rats. After electrical stimulation, behavioral assessments showed that the LPS-treated rats that were not treated with MgSO4 had the shortest latency period to develop a seizure and the longest seizure duration. The electroencephalographic (EEG) recordings in the hippocampus demonstrated that this group also had the highest EEG amplitude. MgSO4 treatment significantly decreased both TNF-α and IL-1β concentrations, increased the latency to develop a seizure, decreased the seizure duration and shortened the EEG amplitude. These results suggest that neuronal seizure activity and systemic inflammation are increased in severe PE. In addition, MgSO4 treatment reduced systemic inflammation and seizure severity. We conclude that excessive systemic inflammation in PE promotes eclampsia seizures, which can be attenuated by MgSO4 treatment.

Magnesium Sulfate Provides Neuroprotection in Eclampsia-Like Seizure Model by Ameliorating Neuroinflammation and Brain Edema

Eclampsia is a hypertensive disorder of pregnancy that is defined by the new onset of grand mal seizures on the basis of preeclampsia and a leading cause of maternal and fetal mortality worldwide. Presently, magnesium sulfate (MgSO4) is the most effective treatment, but the mechanism by which MgSO4 prevents eclampsia has yet to be fully elucidated. We previously showed that systemic inflammation decreases the seizure threshold in a rat eclampsia-like model, and MgSO4 treatment can decrease systemic inflammation. Here, we hypothesized that MgSO4 plays a neuroprotective role in eclampsia by reducing neuroinflammation and brain edema. Pregnant Sprague–Dawley rats were given an intraperitoneal injection of pentylenetetrazol following a tail vein injection of lipopolysaccharide to establish the eclampsia-like seizure model. Seizure activity was assessed by behavioral testing. Neuronal loss in the hippocampal CA1 region (CA1) was detected by Nissl staining. Cerebrospinal fluid levels of S100-B and ferritin, indicators of neuroinflammation, were detected by enzyme-linked immunosorbent assay, and ionized calcium binder adapter molecule 1 (Iba-1, a marker for microglia) and glial fibrillary acid protein (GFAP, a marker for astrocytes) expression in the CA1 area was determined by immunofluorescence staining. Brain edema was measured. Our results revealed that MgSO4 effectively attenuated seizure severity and CA1 neuronal loss. In addition, MgSO4 significantly reduced cerebrospinal fluid levels of S100-B and ferritin, Iba-1 and GFAP activation in the CA1 area, and brain edema. Our results indicate that MgSO4 plays a neuroprotective role against eclampsia-like seizure by reducing neuroinflammation and brain edema.

Cyclosporin A significantly improves preeclampsia signs and suppresses inflammation in a rat model.

Preeclampsia is associated with an increased inflammatory response. Immune suppression might be an effective treatment. The aim of this study was to examine whether Cyclosporin A (CsA), an immunosuppressant, improves clinical characteristics of preeclampsia and suppresses inflammation in a lipopolysaccharide (LPS) induced preeclampsia rat model. Pregnant rats were randomly divided into 4 groups: group 1 (PE) rats each received LPS via tail vein on gestational day (GD) 14; group 2 (PE+CsA5) rats were pretreated with LPS (1.0 μg/kg) on GD 14 and were then treated with CsA (5mg/kg, ip) on GDs 16, 17 and 18; group 3 (PE+CsA10) rats were pretreated with LPS (1.0 μg/kg) on GD 14 and were then treated with CsA (10mg/kg, ip) on GDs 16, 17 and 18; group 4 (pregnant control, PC) rats were treated with the vehicle (saline) used for groups 1, 2 and 3. Systolic blood pressure, urinary albumin, biometric parameters and the levels of serum cytokines were measured on day 20. CsA treatment significantly reduced LPS-induced systolic blood pressure and the mean 24-h urinary albumin excretion. Pro-inflammatory cytokines IL-6, IL-17, IFN-γ and TNF-α were increased in the LPS treatment group but were reduced in (LPS+CsA) group (P<0.05). Anti-inflammatory cytokine IL-4 was decreased in the LPS group but was increased in (LPS+CsA) group (P<0.05). Cyclosporine A improved preeclampsia signs and attenuated inflammatory responses in the LPS induced preeclampsia rat model which suggests that immunosuppressant might be an alternative management option for preeclampsia.

Choline Supplementation During Pregnancy Protects Against Gestational Lipopolysaccharide-Induced Inflammatory Responses.

Objectives: To estimate the effects and mechanisms of choline, an essential nutrient and a selective α7 nicotinic acetylcholine receptor (α7nAChR) agonist, on the prevention of symptoms and the effects on the cholinergic anti-inflammatory pathways (CAP) in a lipopolysaccharide (LPS)-induced inflammatory response in a rat model. Methods: Inflammation was induced by LPS treatment (1.0 μg LPS/kg body weight) on gestational day (GD) 14. Nonpregnant and pregnant Sprague Dawley rats were placed on a normal choline diet (1.1 g/kg) or supplemented choline diet (5.0 g/kg) from GDs 1 to 20. Systolic blood pressure (SBP), urinary albumin, and pregnancy outcomes were recorded. On GD 20, serum and placentas were assayed for cytokines. Western blots were used to determine the expression of placenta α7nAChR and components of the α7nAChR-CAP, including nuclear factor-κB (NF-κB) and protein kinase B (AKT). Immunohistochemistry was used to localize placental sites for the p65 subunit of NF-κB. Results: Lipopolysaccharide significantly increased SBP and urinary albumin and decreased pregnancy outcomes, and these effects were partially reversed by higher choline treatment. Choline supplementation also significantly attenuated the LPS-induced increase in serum and placental inflammatory cytokines, decreased the expression of placental α7nAChR, lowered the activation of NF-κB signaling in placenta mononuclear cells, and inhibited placental AKT phosphorylation. Conclusion: This study confirms that LPS induces inflammatory conditions in pregnant rats and shows that choline supplementation protects against the inflammatory symptoms through its action on α7nAChR and CAP. These observations have important implications for the prevention and treatment of inflammatory responses associated with pregnancy.

174. Evaluation of sFlt-1/PlGF ratio for improving clinical management of pre-eclampsia: Experience in a tertiary hospital

Introduction Management of pregnant women with gestational hypertension (GH) varies according to the severity of the disease. An imbalance of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), is involved in pre-eclampsia (PE) pathogenesis. An elevated ratio(>110) is highly predictive of PE, whereas the diagnosis of PE can be ruled out within one week for low ratio( Objective The main objective of this study was to assess whether the cutoff value in late pregnancy (>34 weeks) help to management the preeclampsia. Methods We performed an observational study to evaluate serum sFlt-1/PlGF ratio (Roche Diagnostics Cobas e411 system) for differential diagnosis and the severity of disease from 2018 February to April (three months). Thirty-seven women with singleton pregnancies diagnosis withsuspected preeclampsia were enrolled. Serum sFlt-1 and PlGF were measured when they admitted (>34 weeks). The sFlt-1, PlGF, and the maternal clinical data were obtained. Results Among the 37 patients included, 25 had a sFlt-1/PlGF ratio lower than 38; only one diagnosis with PE leading to a negative predictive value of 96%. Two patients diagnosed with clinical PE as the ratio higher than 110. For the rest 10 patients had a sFlt-1/PlGF ratio between 38 and 110, four of them diagnosis with clinical PE. There were five patients with thrombocytopenia, the sFlt-1/PlGF ratio were all lower than 38 and rule out for HELLP. All patients were delivered without adverse maternal and neonatal outcomes. Discussion The serum sFlt-1/PlGF ratio showed highly value of differential diagnosis for ruling out PE. In our data, four of ten patients had a sFlt-1/PlGF ratio between 38 and 110 diagnosed with clinical PE, the cutoff value may be considering more clinical experience. Using these biomarkers in routine management of PE may improve clinical management of suspect patients. It need more clinical experience in future.