Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care

Abstract

Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in dark conditions and regulates the circadian rhythm of the organism. Its intrinsic properties, including high cell permeability, the ability to easily cross both the blood-brain and placenta barriers, and its role as an endogenous reservoir of free radical scavengers (with indirect extra activities), confer it beneficial uses as an adjuvant in the biomedical field. Melatonin can exert its effects by acting through specific cellular receptors on the plasma membrane, similar to other hormones, or through receptor-independent mechanisms that involve complex molecular cross talk with other players. There is increasing evidence regarding the extraordinary beneficial effects of melatonin, also via exogenous administration. Here, we summarize molecular pathways in which melatonin is considered a master regulator, with attention to cell death and inflammation mechanisms from basic, translational and clinical points of view in the context of newborn care.

Fig. 1. Mechanisms of action of melatonin.

Melatonin can exert its effects by acting through receptor-independent mechanisms, which involve the direct interaction of melatonin and other molecules, and they are mainly related to its antioxidant and radical scavenging action (a). As any other hormone, melatonin can also act through specific cellular receptors, by membrane melatonin receptors, called MT1 and MT2, which are seven transmembrane-spanning proteins belonging to the G-protein-coupled receptor (GPCR) superfamily, by the cytosolic enzyme QR2 (also called MT3), or through the nuclear receptors RZR/ROR (b)

Fig. 2. Antiapoptotic mechanisms operated by melatonin.

Endogenous levels of melatonin and exogenous administration confer to injured cells protection from many cell death forms including apoptosis, necroptosis, mPTP-driven cell death, and autophagy. Melatonin is high cell permeable and its beneficial effects are mediated by both MT1/2-dependent and MT1/2-independent mechanisms. Once in the cytoplasm it blocks the Ripk3 cascade, Drp1 activation, and Bax-dependent cytochrome c (Cyt. C) release caused by external insults; as a result, the cell receives pro-survival signals. Melatonin localizes also in mitochondria where PEPT1/2 and GLUT channels are postulated to be new transporters of this hormone in the organelle. In mitochondria, melatonin modulates mitochondrial permeability transition pore (mPTP) opening and counteracts oxidative stress

Fig. 3. Anti-inflammatory effects of melatonin.

Melatonin is mainly reported to possess anti-inflammatory properties by inhibiting inflammasome activation, thus inhibiting caspase-1 activation, cytokines release, and pyroptosis. In addition, melatonin can also inhibit the expression of the cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS) by inhibiting nuclear NF-κB traslocation

Fig. 4. Clinical trial of melatonin in newborn care.

Melatonin clinical trial in full term infants (blue), in preterm pathologies (purple) or both (green). In yellow are reported studies of pharmacokinetic. HIE hypoxic–ischemic encephalopathy, IUGR intrauterine growth retardation, CLD chronic lung disease, PVL periventricular leukomalcia