104: Metformin prevents preeclampsia in an obese mouse model of soluble FMS-like tyrosine kinase-1 induced pre-eclampsia

Abstract

We aim to assess the effect of standardized maternal anesthesia and surgery during pregnancy on the developing fetal brain in a rabbit model. Comparable to humans, the brain growth spurt in rabbits occurs in the perinatal period. STUDY DESIGN: 14 time-mated pregnant does (155 pups) underwent a laparotomy for 1.5h at day 28 of gestation (term¼31d). After induction with propofol, anesthesia was maintained with 4 vol-% sevoflurane for 2h. Maternal vital signs were continuously monitored (blood pressure, heart rate, peripheral and cerebral oxygen saturation, temperature, end-tidal CO 2 , pH, lactate). 7 does (74 pups), underwent invasive hemodynamic monitoring for 2h without sedation (sham). At term, does were delivered by cesarean section. Part of the pups underwent motoric and sensoric neurologic testing followed by euthanasia and brain histology at day 1. Other pups had daily neurodevelopment tests for 2 weeks and an extensive neurologic evaluation at 5 and 7 weeks (open field, object recognition test, T-maze and radial arm maze). RESULTS: Blood gases and vital parameters were stable during anesthesia. On postnatal day 1 surgery pups had significant lower motoric (25.0AE1.1 vs 23.2AE3.6;p¼0.004) and sensoric (16.7AE2.2 vs 15.0AE2.9;p¼0.005) neurobehavioral scores. Surgery pups were equal in weight but had smaller brains hence lower brain to body weight ratio (3.7%AE0.6 vs 3.4% AE0.6 ; p¼0.001). Neuron density was lower in multiple brain regions (e.g. hippocampus 2617AE410 vs 2053AE492 neurons/mm 2 ; p¼0.004) with lower proliferation rates and lower synaptic density. Daily testing showed delayed motoric development, e.g. hopping appearing later (6,4AE5,3 vs 12,3AE3,4 d; p¼0.011). By 7 weeks, no neurobehavioral differences were observed except for a reduced digging behavior (Table). CONCLUSION: In rabbits, 2h maternal general anesthesia and laparotomy without fetal manipulation at d28 of gestation have a measurable impact on the term neonatal neurologic function and brain morphology. Pups develop slower but by 7 weeks, most of the differences faded out to become almost unrecognizable.

Current Researches, Rationale, Plausibility, and Evidence Gaps on Metformin for the Management of Hypertensive Disorders of Pregnancy

“…In an obese mouse model of sFlt-1-induced PE, MET (300 mg/kg/day) significantly lowered mean and systolic blood pressure and reduced sFlt-1 levels in obese mice overexpressing sFlt-1, indicating the potential of MET in preventing PE in obese women (Jelliffe et al, 2019).…”

“…Recently, Brownfoot et al reported that a low-dose combination of MET and sulfasalazine reduced sFlt-1 and sENG secretion and, on the contrary, increased VEGF alpha expression in cytotrophoblast (MET: 200 μM; sulfasalazine: 200 μM) and placental explants (MET: 400 μM; sulfasalazine: 400 μM), providing a more effective treatment or prevention for PE compared to MET as a single agent ( Brownfoot et al, 2020 ). In an obese mouse model of sFlt-1–induced PE, MET (300 mg/kg/day) significantly lowered mean and systolic blood pressure and reduced sFlt-1 levels in obese mice overexpressing sFlt-1, indicating the potential of MET in preventing PE in obese women ( Jelliffe et al, 2019 ).…”