Melatonin Suppresses Toll Like Receptor 4-Dependent Caspase-3 Signaling Activation Coupled with Reduced Production of Proinflammatory Mediators in Hypoxic Microglia

Abstract

Microglia activation and associated inflammatory response play pivotal roles in the pathogenesis of different neurodegenerative diseases including neonatal hypoxic brain injury. Here we show that caspase3 expression was upregulated in activated microglia after hypoxic exposure, and remarkably, the cell viability remained unaffected alluding to the possibility of a non-apoptotic role of caspase3 in activated microglia. Chemical inhibition of caspase3 suppressed microglia activation as evident by an obvious reduction in expression of proinflammatory mediators and NF-κB signaling activation. Hypoxia induced caspase3 activation was TLR4 dependent as supported by the fact that caspase3 activation was hindered in cells with TLR4 knockdown. Interestingly, melatonin treatment significantly suppressed caspase3 activation. More importantly, melatonin also inhibited the increase in TLR4 protein and mRNA expression in hypoxic microglia. Inhibition of TLR4 expression by melatonin was also found in microglia of postnatal rats subjected to hypoxic exposure. Taken together, it is concluded that melatonin could inhibit TLR4 expression in hypoxic microglia followed by suppression of caspase3 activation leading to decrease in production of proinflammatory mediators.

SIRT1 Mediates Melatonin’s Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence

“…The detailed comprehension of melatonin's mechanisms of action is hence of paramount importance. So far, studies on the protective activity of the hormone in hypoxia have mainly focused on direct neuronal effects, whereas evidence regarding melatonin's involvement in the modulation of inflammatory responses [49], as also shown by our data, prompted us to turn our attention to the effects on microglia that indirectly influence neurons. Microglia are, in fact early responders to hypoxic insults and can deeply affect neuronal vulnerability [50].…”

Oral Supplementation of Sodium Butyrate Attenuates the Progression of Non-Alcoholic Steatohepatitis

“…Furthermore, the expression of Mtr1a, shown before to be highly dependent upon the presence of melatonin [19], was also significantly higher in the livers of FFC+SoB-fed mice, but not in those of FFC-fed mice. The results of studies of others also suggest that melatonin may decrease Tlr4 expression, and subsequently the induction of dependent signaling cascades including NFκB and iNOS, and that these changes in Tlr4 expression may be independent of Myd88 [49][50][51]. Supporting the hypothesis that SoB alters melatonin synthesis in the small intestine, the incubation of everted sacs with SoB was associated with an increase in melatonin levels and a decrease in pAANAT (Thr29), the latter suggested to play a role in the inactivation of AANAT through proteasomal degradation [29].…”

Molecular Analysis of Fetal and Adult Primary Human Liver Sinusoidal Endothelial Cells: A Comparison to Other Endothelial Cells

“…Moreover, several pathways related to the degradation of serotonin, dopamine and melatonin, are hypoactive due to a decrease in the expression of two main enzymes, namely aryl sulfotransferase and mono-amine oxidase. This leads to relatively higher levels of these products, specifically in LSECs and to a decrease in angiogenesis [ 39 , 40 ] and a decrease in pro-inflammatory cytokines [ 41 ].…”