Melatonin prevents preterm labor due to LPS and improves offspring

DOMÍNGUEZ RUBIO, AP; SALAZAR, AI; CELLA, M; MARTTÍNEZ PATETTA, RE; BARIANI, MV; ROSENSTEIN, RE; FRANCHI, AM

Hamburgo

Congreso; Joint International Congress of the American Society for Reproductive Immunology (ASRI) and the European Society for Reproductive Inmunology (ESRI); 2012

American Society for Reproductive Immunology (ASRI) and the European Society for Reproductive Inmunology (ESRI)

Preterm delivery is the leading cause of neonatal mortality and promotes delayed physical and cognitive development in children. A large body of evidence suggests that intra-amniotic infection may be a significant, and potentially preventable, cause of preterm birth.We have developed a mouse model of inflammation-associated preterm delivery to mimic, as closely as possible, the clinical consequences of preterm infections. We obtained 100% incidence of preterm birth with minimal fatal effects on mothers (5%) administrating two doses of LPS (i.p. 0.4 mg/kg at 11 and 13 h) on day 15 of pregnancy.The macroscopic observation of the fetal brain from mothers treated with LPS revealed brain injury.We have also demonstrated that uterine nitric oxide (NO) and prostaglandins (PG) synthesis are augmented by the LPS treatment, that also increases inducible NO Synthase (iNOS) and cyclooxygenase 2 (COX-2) protein levels, whereas nNOS, eNOS and COX-1 remained unchanged.Melatonin, a potent endogenous antioxidant, may contribute to the maintenance of pregnancy by stimulating progesterone production, while inhibiting the synthesis of prostaglandins and uterine contractility. Melatonin crosses the placenta to enter the fetal circulation.Four doses of melatonin (i.p. 10 mg/kg at 9, 11, 13 and 15 h on day 15 of pregnancy) prevented preterm birth in 80% of cases and confer protection for the fetuses.Uterine PGs production was measured and we observed that melatonin blocks the increase in PGF2alpha and COX-2 protein levels induced by LPS. On the other hand, melatonin was also able to inhibit the increase of NO synthesis and iNOS protein levels induced by the endotoxin.Fetuses born alive and had no changes comparing to the control animals. Maternal treatment with LPS and melatonin did not affect newborn mouse weight during the first month of life and confers protection from LPS-induced fetal brain injury.These results suggest that melatonin could be a useful tool to prevent preterm labor and improve offspring.