Melatonin prevents experimental preterm labor and increases offspring survival

Abstract

Preterm delivery is the leading cause of neonatal mortality and contributes to delayed physical and cognitive development in children. At present, there is no efficient therapy to prevent preterm labor. A large body of evidence suggests that intra-amniotic infections may be a significant and potentially preventable cause of preterm birth. This work assessed the effect of melatonin in a murine model of inflammation-associated preterm delivery which mimics central features of preterm infection in humans. For this purpose, preterm labor was induced in BALB/c mice by intraperitoneal injections of bacterial lipopolysaccharide (LPS) at 10.00 hr (10 μg LPS) and 13.00 hr (20 μg LPS) on day 15 of pregnancy. On day 14 of pregnancy, a pellet of melatonin (25 mg) had been subcutaneously implanted into a group of animals. In the absence of melatonin, a 100% incidence of preterm birth was observed in LPS-treated animals, and the fetuses showed widespread damage. By comparison, treatment with melatonin prevented preterm birth in 50% of the cases, and all pups from melatonin-treated females were born alive and their body weight did not differ from control animals. Melatonin significantly prevented the LPS-induced rises in uterine prostaglandin (PG) E2 , PGF2α, and cyclooxygenase-2 protein levels. In addition, melatonin prevented the LPS-induced increase in uterine nitric oxide (NO) production, inducible NO synthase protein, and tumor necrosis factor-alpha (TNFα) levels. Collectively, our results suggest that melatonin could be a new therapeutic tool to prevent preterm labor and to increase offspring survival.

Developmental Programming of Adult Disease: Reprogramming by Melatonin?

“…Administration of melatonin was reported to restore redox balance to alleviate maternal hyperthermia-induced embryo death [52]. Additionally, melatonin prevented preterm labor and increased offspring survival in a mouse model of lipopolysaccharide (LPS)-induced inflammation [53]. In a continuous light exposure-induced melatonin deficiency pregnant rat model, offspring developed intrauterine growth retardation and disrupted circadian, which were prevented by maternal melatonin treatment [54].…”

Role of the endocannabinoid system in the mechanisms involved in the LPS-induced preterm labor

“…Indeed, it seems that this relationship varies greatly depending on the tissue as well as the studied species. In our model, LPS increased uterine PG and cyclooxygenase levels (Cella et al 2010, Domínguez Rubio et al 2014. Here, we show that the in vitro blockade of CB1 receptor decreased the uterine PGF2a levels in control and LPS-treated mice.…”

“…administration of LPS on day 15 of pregnancy. Exposure to bacterial endotoxin produces 100% of preterm birth with low incidence of maternal mortality (Cella et al 2010, Domínguez Rubio et al 2014.…”

Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury

“…As previously reported, virgin female mice were mated with fertile males of the same strain. ( 17 ) The timing of pregnancy was determined by visual inspection of the vaginal plug, which was defined as day 0.5 of pregnancy. ( 17 ) Normal term labor occurs on day 19.5 of gestation (G19.5), under our animal facility conditions.…”

“…( 17 ) The timing of pregnancy was determined by visual inspection of the vaginal plug, which was defined as day 0.5 of pregnancy. ( 17 ) Normal term labor occurs on day 19.5 of gestation (G19.5), under our animal facility conditions. Approximately 50%-saturated hydrogen water (H 2 water) was a kind gift from Blue Mercury, Inc. (Tokyo, Japan).…”