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.

Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures

“…Although the mechanism(s) underlying hypothermia/ melatonin cooperation in reducing brain injury was not the aim of this study, it is worth recalling that, by acting via a specific cell membrane and nuclear receptors, melatonin achieves powerful neuroprotective effects via antioxidant, antiapoptotic, and anti-inflammatory processes [13,29], and by promoting neuronal and glial development [30]. Additional indirect antioxidant effects of melatonin include the upregulation of antioxidant enzymes and crucially the preservation of mitochondrial integrity [12,31].…”

“…Melatonin is a potent scavenger of reactive oxygen species with anti-inflammatory effects in conditions associated with oxidative stress as well as immunomodulatory effects in the presence of an exacerbated immune response [11,12]. When given before or immediately after hypoxia-ischemia in different models of perinatal brain injury, melatonin showed neuroprotective effects [13][14][15]. Melatonin also appeared effective in different neonatal pathological conditions, including neonatal sepsis, bronchopulmonary dysplasia, and neonatal asphyxia [16,17].…”

Interactions of Melatonin and MicroRNAs

“…In a rat scopolamine toxicity model of ADlike memory losses, melatonin reversed an increase of miR-124 and thereby corrected the level of the targeted Egr1 (early growth response protein 1) mRNA [27]. In another AD model, Aβ [25][26][27][28][29][30][31][32][33][34][35] peptide added to primary cortical neurons caused downregulation miR-132, an effect that was also reversed by melatonin. The normalization of miR-132 is insofar of importance, as this miRNA transmits anti-apoptotic and other protective properties known from melatonin [28].…”

“…In neonatal brain inflammation induced in rats by bacterial lipopolysaccharide (LPS), this pro-inflammatory agent upregulated miR-34a, but downregulated miR-146a, and miR-126. Again, these changes were corrected by melatonin, along with reduction in ER stress and autophagy as well as reversal of sirtuin 1 downregulation [29]. With some likelihood, other data on inflammation may have resulted from transfer of miRNAs.…”

Future Demands Concerning the Epigenetic Relevance of Melatonin and the Circadian System in Gerontology

“…In a rat scopolamine toxicity model of AD-like memory losses, an increase of miR-124 was observed that was reversed by melatonin, along with correction of the targeted Egr1 mRNA [106]. Lipopolysaccharide (LPS)-induced neonatal brain inflammation in rats caused changes in miR-34a, miR-146a, and miR-126, along with reduction of SIRT1 expression, effects that were reversed by melatonin [107]. Premature senescence of cardiac progenitor cells by H 2 O 2 was prevented by melatonin by maintaining the expression levels of lncRNA H19 and its derivative miR-675 [108].…”