title: Melatonin modulates neonatal brain inflammation through endoplasmic reticulum stress, autophagy, and miR-34a/silent information regulator 1 pathway.
abstract: Maternal infection/inflammation represents one of the most important factors involved in the etiology of brain injury in newborns. We investigated the modulating effect of prenatal melatonin on the neonatal brain inflammation process resulting from maternal intraperitoneal (i.p.) lipopolysaccharide (LPS) injections. LPS (300 μg/kg) was administered to pregnant rats at gestational days 19 and 20. Melatonin (5 mg/kg) was administered i.p. at the same time as LPS. Melatonin counteracted the LPS sensitization to a second ibotenate-induced excitotoxic insult performed on postnatal day (PND) 4. As melatonin succeeded in reducing microglial activation in neonatal brain at PND1, pathways previously implicated in brain inflammation regulation, such as endoplasmic reticulum (ER) stress, autophagy and silent information regulator 1 (SIRT1), a melatonin target, were assessed at the same time-point in our experimental groups. Results showed that maternal LPS administrations resulted in an increase in CHOP and Hsp70 protein expression and eIF2α phosphorylation, indicative of activation of the unfolded protein response consequent to ER stress, and a slighter decrease in the autophagy process, determined by reduced lipidated LC3 and increased p62 expression. LPS-induced inflammation also reduced brain SIRT1 expression and affected the expression of miR-34a, miR146a, and miR-126. All these effects were blocked by melatonin. Cleaved-caspase-3 apoptosis pathway did not seem to be implicated in the noxious effect of LPS on the PND1 brain. We conclude that melatonin is effective in reducing maternal LPS-induced neonatal inflammation and related brain injury. Its role as a prophylactic/therapeutic drug deserves to be investigated by clinical studies.
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carloni
authors.affiliation: Department of Neonatal and Pediatric Intensive Care, CHRU de Tours, Tours, France.|INSERM U930, Université François Rabelais de Tours, Tours, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Favrais
authors.affiliation: Department of Neonatal and Pediatric Intensive Care, CHRU de Tours, Tours, France.|INSERM U930, Université François Rabelais de Tours, Tours, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Saliba
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Albertini
authors.affiliation: INSERM U930, Université François Rabelais de Tours, Tours, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.affiliation: Department of Molecular and Developmental Medicine, Policlinico Le Scotte, University of Siena, Siena, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Longini
authors.affiliation: PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Department of Molecular and Developmental Medicine, Policlinico Le Scotte, University of Siena, Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Buonocore
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy. walter.balduini@uniurb.it.
authors.forename: Walter
authors.initials: W
authors.lastname: Balduini
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000187:drug effects*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008550:Melatonin / Q000494:pharmacology*; D035683:MicroRNAs / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D008070:Lipopolysaccharides; C560944:MIRN34 microRNA, rat; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D008550:Melatonin
keywords: autophagy; endoplasmic reticulum stress; inflammation; melatonin; miRNA; neonatal brain injury; silent information regulator 1