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 (1mg/day) or vehicle from days 13-16 of gestation. At days 15 and 16, lipopolysaccharide (30μg) or saline were administered. Mice were sacrificed 4h 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 ± 0.01u), TNFα (0.3 ± 0.02 vs. 0.10 ± 0.01u), NF-κB (0.32 ± 0.01 vs. 0.17 ± 0.01u), and nNOS (0.24 ± 0.04 vs. 0.08 ± 0.01u), and reduced the total glutathione levels (0.014 ± 0.001 vs. 0.026 ± 0.001pmol/μl; p < 0.01) compared with control. Maternal nVP significantly reduced fetal brain levels of IL-6 (0.14 ± 0.01 vs. 0.33 ± 0.02u), TNFα (0.2 ± 0.06 vs. 0.3 ± 0.02u), NF-κB (0.16 ± 0.01 vs 0.32 ± 0.01u), and nNOS (0.14 ± 0.01 vs 0.24 ± 0.04u), and prevented the reduction of fetal brain total glutathione levels (0.022 ± 0.001 vs. 0.014 ± 0.001pmol/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.
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