Magnesium Sulfate Treatment Reverses Seizure Susceptibility and Decreases Neuroinflammation in a Rat Model of Severe Preeclampsia

Abstract

Eclampsia, defined as unexplained seizure in a woman with preeclampsia, is a life-threatening complication of pregnancy with unclear etiology. Magnesium sulfate (MgSO4) is the leading eclamptic seizure prophylactic, yet its mechanism of action remains unclear. Here, we hypothesized severe preeclampsia is a state of increased seizure susceptibility due to blood-brain barrier (BBB) disruption and neuroinflammation that lowers seizure threshold. Further, MgSO4 decreases seizure susceptibility by protecting the BBB and preventing neuroinflammation. To model severe preeclampsia, placental ischemia (reduced uteroplacental perfusion pressure; RUPP) was combined with a high cholesterol diet (HC) to cause maternal endothelial dysfunction. RUPP+HC rats developed symptoms associated with severe preeclampsia, including hypertension, oxidative stress, endothelial dysfunction and fetal and placental growth restriction. Seizure threshold was determined by quantifying the amount of pentylenetetrazole (PTZ; mg/kg) required to elicit seizure in RUPP+HC±MgSO4 and compared to normal pregnant controls (n = 6/group; gestational day 20). RUPP+HC rats were more sensitive to PTZ with seizure threshold being ∼65% lower vs. control (12.4±1.7 vs. 36.7±3.9 mg/kg PTZ; p<0.05) that was reversed by MgSO4 (45.7±8.7 mg/kg PTZ; p<0.05 vs. RUPP+HC). BBB permeability to sodium fluorescein, measured in-vivo (n = 5–7/group), was increased in RUPP+HC vs. control rats, with more tracer passing into the brain (15.9±1.0 vs. 12.2±0.3 counts/gram ×1000; p<0.05) and was unaffected by MgSO4 (15.6±1.0 counts/gram ×1000; p<0.05 vs. controls). In addition, RUPP+HC rats were in a state of neuroinflammation, indicated by 35±2% of microglia being active compared to 9±2% in normal pregnancy (p<0.01; n = 3–8/group). MgSO4 treatment reversed neuroinflammation, reducing microglial activation to 6±2% (p<0.01 vs. RUPP+HC). Overall, RUPP+HC rats were in a state of augmented seizure susceptibility potentially due to increased BBB permeability and neuroinflammation. MgSO4 treatment reversed this, increasing seizure threshold and decreasing neuroinflammation, without affecting BBB permeability. Thus, reducing neuroinflammation may be one mechanism by which MgSO4 prevents eclampsia during severe preeclampsia.

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

“…We have previously used pentylenetetrazol treatment to induce eclampsia-like seizures in pregnant rats treated with low-dose LPS. 41 Johnson et al 42 combined reduced uteroplacental perfusion pressure with a highcholesterol diet to develop an eclampsia model. In the present study, we successfully induced eclampsia-like seizures using electrical stimulation in the hippocampus of PE rats.…”

Epidemiología y manifestaciones neurológicas asociadas a eclampsia en un hospital de referencia del Perú. Serie de casos

“…Las manifestaciones visuales y auditivas mostraron frecuencias concordantes con otros estudios (12) (27,2% y 12,1%); estas son producidas por la estimulación anormal de grupos neuronales en áreas occipitales y temporales, zonas preferentemente afectadas por edema en los casos de PRES (16)(17)(18) . Debemos recordar que la afectación cerebral en la preeclampsia involucra no solo edema cerebral sino también neuroinflamación, lo que agrava y perpetúa el edema cerebral; adicionalmente existe una disminución del umbral convulsivo por la internalización de los receptores inhibitorios y la disminución de los receptores ácido d-amino-butírico (GABA) (16,19,20) . La eclampsia, por tanto, dentro de la fisiopatología de la PRES constituiría la estimulación anormal de grupos neuronales en áreas motoras.…”

Eclampsia: Still a major problem in rural KwaZulu-Natal Province, South Africa

“…[3] Lowering of sustained severe acute hypertension in pregnancy therefore warrants judicious use of rapid-acting antihypertensive agents as immediate management. [4][5][6][7][8] It is plausible that some health professionals are of the view that magnesium sulphate may have antihypertensive properties and that acute lowering of high blood pressure may cause hypotension. If magnesium sulphate has antihypertensive properties, this is probably based on its sedative effects.…”

“…If magnesium sulphate has antihypertensive properties, this is probably based on its sedative effects. [6][7][8] Failure to prescribe rapid-acting antihypertensives immediately and not performing prerequisite investigations are factors indicating that clinical protocols are not being followed. Recently, severe hypertension in pregnancy has been reported to be associated with posterior reversible encephalopathy syndrome (PRES).…”

“…It has been suggested that the use of rapid-acting antihypertensives and magnesium sulphate given promptly may facilitate recovery from PRES, the most common cause of which is severe preeclampsia and eclampsia. [6][7][8] The study identified that the majority of cases of eclampsia occurred in teenagers and primigravidae <24 years of age. This is consistent with similar findings of the SMR.…”