Is Melatonin the Cornucopia of the 21st Century?

Abstract

Melatonin, an indoleamine hormone produced and secreted at night by pinealocytes and extra-pineal cells, plays an important role in timing circadian rhythms (24-h internal clock) and regulating the sleep/wake cycle in humans. However, in recent years melatonin has gained much attention mainly because of its demonstrated powerful lipophilic antioxidant and free radical scavenging action. Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant. Melatonin-induced signal transduction through melatonin receptors promotes the expression of antioxidant enzymes as well as inflammation-related genes. Melatonin also exerts an immunomodulatory action through the stimulation of high-affinity receptors expressed in immunocompetent cells. Here, we reviewed the efficacy, safety and side effects of melatonin supplementation in treating oxidative stress- and/or inflammation-related disorders, such as obesity, cardiovascular diseases, immune disorders, infectious diseases, cancer, neurodegenerative diseases, as well as osteoporosis and infertility.

Keywords: anti-inflammatory action; anti-obesogenic properties; anti-tumoral activity; bone mass protection; cardiovascular protection; fertility amelioration; free radical scavenging; immunomodulation; neuroprotection; sleep–wake cycle regulation.

Figure 1

Melatonin biosynthesis and intracellular signal-transduction pathways activated by stimulation of melatonin specific receptors. The picture shows: (figure top left) the intracerebral site of melatonin biosynthesis, that is the pineal gland, the melatonin biosynthetic pathway, and the influence of light and photoperiod change on melatonin biosynthesis; (figure bottom left) mitochondrial melatonin biosynthesis and local action: melatonin is synthesized within mitochondrial matrix, but it can also enter the mitochondria through a specific transporter; melatonin activates specific MT1 and MT2 receptors on mitochondrial outer membrane, also in an autocrine way, inhibits MPTP and ROS production, and stimulates ETC and UCP; (figure right) melatonin interaction with its specific MT1 and MT2 receptors and RZR/ROR orphan nuclear receptors, and activation of different metabolic pathways. AAAD, aromatic L-amino acid decarboxylase; AC, adenylate cyclase; AFMK, N1-acetyl-N2-formyl-S-methoxykynuramine (melatonin metabolite); ASMT, N-acetylserotonin O-methyltransferase; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; DAG, diacylglycerol; ETC, electron transfer chain; GC, guanylate cyclase; IP3, inositol triphosphate; MPTP, mitochondrial permeability transition pore; MT1-MT3, melatonin specific receptor 1, 2, 3; PLC, phospholipase C; QR-2, quinone reductase 2; ROS, reactive oxygen species; RZR/ROR, retinoid Z receptor/retinoid acid receptor-related orphan receptor; SNAT, serotonin N-acetyltransferase; TPH, tryptophan hydroxylase; UCP, uncoupling protein.

Figure 2

Pleiotropic actions of melatonin in human body.