Maternal Progesterone Treatment Reduces Maternal Inflammation-Induced Fetal Brain Injury in a Mouse Model of Preterm Bir
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MATERNAL FETAL MEDICINE/BIOLOGY: ORIGINAL ARTICLE
Maternal Progesterone Treatment Reduces Maternal Inflammation-Induced Fetal Brain Injury in a Mouse Model of Preterm Birth Yuval Ginsberg 1 Ron Beloosesky 1
&
Ola Gutziet 1 & Salim Hadad 1 & Michael Y. Divon 2 & Nizar Khatib 1 & Ofer Fainaru 1 & Zeev Weiner 1 &
Received: 20 May 2020 / Accepted: 22 July 2020 # Society for Reproductive Investigation 2020
Abstract Maternal natural vaginal progesterone (nVP) administration has been shown to reduce the risk of preterm birth (PTB). The largest randomized trial of nVP for PTB (OPPTIMUM) noted a sonographic reduction in neonatal brain injury following nVP treatment. We investigated the neuroinflammatory protective effect of maternal nVP in a mouse model for maternal inflammation. Pregnant mice (n = 24) were randomized to nVP (1 mg/day) or vehicle from days 13–16 of gestation. At days 15 and 16, lipopolysaccharide (30 μg) or saline were administered. Mice were sacrificed 4 h following the last injection. Fetal brains and placentas were collected. Levels of NF-κB, nNOS, IL-6, and TNFα were determined by Western blot. Maternal lipopolysaccharide significantly increased fetal brain levels of IL-6 (0.33 ± 0.02 vs. 0.11 ± 0.01 u), TNFα (0.3 ± 0.02 vs. 0.10 ± 0.01 u), NF-κB (0.32 ± 0.01 vs. 0.17 ± 0.01 u), and nNOS (0.24 ± 0.04 vs. 0.08 ± 0.01 u), and reduced the total glutathione levels (0.014 ± 0.001 vs. 0.026 ± 0.001 pmol/μl; p < 0.01) compared with control. Maternal nVP significantly reduced fetal brain levels of IL-6 (0.14 ± 0.01 vs. 0.33 ± 0.02 u), TNFα (0.2 ± 0.06 vs. 0.3 ± 0.02 u), NF-κB (0.16 ± 0.01 vs 0.32 ± 0.01 u), and nNOS (0.14 ± 0.01 vs 0.24 ± 0.04 u), and prevented the reduction of fetal brain total glutathione levels (0.022 ± 0.001 vs. 0.014 ± 0.001 pmol/μl; p < 0.01) to levels similar to controls. A similar pattern was demonstrated in the placenta. Maternal nVP for PTB may protect the fetal brain from inflammation-induced brain injury by inhibiting specific inflammatory and oxidative pathways in both brain and placenta. Keywords Maternal inflammation . Fetal brain injury . Oxidative stress . Progesterone . Preterm birth
Abbreviations ASQ Ages and Stages Questionnaire CP Cerebral palsy Yuval Ginsberg and Ola Gutziet contributed equally to this work. This study was presented at the 38th Annual Meeting of the Society for Maternal-Fetal Medicine (SMFM). * Yuval Ginsberg [email protected] 1
Department of Obstetrics and Gynecology,Rambam Health Care Campus, 8 Ha’alya St., 38302 Haifa, Israel
2
Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, Lenox Hill Hospital, Northwell Health, New York City, NY, USA
iNOS IP IV IL-6 IL-1β LPS Mg N F κB nNOS NO NS nVP PTB SC TBI TNFα
Inducible nitric oxide synthase Intraperitoneal Intravenous Interleukin-6 Interleukin-1β Lipopolysaccharide Magnesium sulfate Nuclear factor kappa-light-chain-enhancer of activated B cells Neural nitric oxide synthase Nitric oxide Normal saline Natural vaginal progesterone Preterm birth Subcutaneous Trau
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