title: 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.
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
authors.forename: Abbie Chapman
authors.initials: AC
authors.lastname: Johnson
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Tremble
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
authors.forename: Siu-Lung
authors.initials: SL
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors.forename: Janae
authors.initials: J
authors.lastname: Moseley
authors.affiliation: Department of Pharmacology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors.forename: Babbette
authors.initials: B
authors.lastname: LaMarca
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Nagle
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America; Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Vermont College of Medicine, Burlington, Vermont, United States of America; Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont, United States of America.
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Cipolla
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D003292:Convulsants / Q000627:therapeutic use; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004461:Eclampsia / Q000517:prevention & control*; D005260:Female; D007249:Inflammation / Q000517:prevention & control*; D008278:Magnesium Sulfate / Q000494:pharmacology / Q000627:therapeutic use*; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D010433:Pentylenetetrazole / Q000627:therapeutic use; D010539:Permeability / Q000187:drug effects; D011225:Pre-Eclampsia / Q000473:pathology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D012720:Severity of Illness Index
chemical_list: D003292:Convulsants; D008278:Magnesium Sulfate; D010433:Pentylenetetrazole