596: Ethyl pyruvate: A novel approach to protect the fetus against antenatal inflammatory damage

Abstract

In pregnancies complicated by inflammation, activation of RAGE signaling pathways may be responsible for poor fetal and neonatal outcomes including stillbirth and neonatal brain injury. Ethyl pyruvate (EP) improved survival in murine models of endotoxemia via RAGE inhibition, and was already shown to be safe in humans. We investigated the effect of maternal administration of EP on neonatal growth and neurodevelopmental outcome using a genetically engineered over-expressing RAGETg murine model of in-utero inflammation. Saline or endotoxin (LPS, 5 or 10 μg/dam) were given intra-peritoneal (i.p.) on day 15 (d0=sperm plug), in mice randomly assigned to the following groups: 1) RAGETg and 2) Wild-type (WT) (n=9-30 pups/group) as controls. EP (40 mg/kg) was administered i.p. 2 hours later. Doses were chosen based on prior experiments demonstrating live birth. Pups underwent post-natal daily behavioral testing (i.e. cliff aversion, forelimb grasp, negative geotaxis) from birth to day 14 of life. Using immunohistochemistry (IHC), we assessed cortical neuronal density in animals sacrificed on day 20 of life. 1) In-utero exposure to EP did not increase post-natal mortality rate; 2) Compared to control, weight gain was inhibited in WT receiving LPS5 (p=0.02), which was ameliorated by EP (p=0.0001); 3) WT and RAGETg mice exposed to LPS demonstrated delay in achieving behavioral milestones, an effect reversed by EP (p<0.001, Figure); 4) WT and RAGETg mice showed improved neurobehavioral battery with EP independent of fetal gender; 5) EP protected against LPS-induced cortical neuronal loss (p=0.001) by IHC. We report a novel neuroprotective effect of EP from perinatal inflammatory insult.