Melatonin, the neurohormone of the pineal gland, is also produced by various other tissues and cells. It acts via G protein-coupled receptors expressed in various areas of the central nervous system and in peripheral tissues. Parallel signaling mechanisms lead to cell-specific control and recruitment of downstream factors, including various kinases, transcription factors and ion channels. Additional actions via nuclear receptors and other binding sites are likely. By virtue of high receptor density in the circadian pacemaker, melatonin is involved in the phasing of circadian rhythms and sleep promotion. Additionally, it exerts effects on peripheral oscillators, including phase coupling of parallel cellular clocks based on alternate use of core oscillator proteins. Direct central and peripheral actions concern the up- or downregulation of various proteins, among which inducible and neuronal NO synthases seem to be of particular importance for antagonizing inflammation and excitotoxicity. The methoxyindole is also synthesized in several peripheral tissues, so that the total content of tissue melatonin exceeds by far the amounts in the circulation. Emerging fields in melatonin research concern receptor polymorphism in relation to various diseases, the control of sleep, the metabolic syndrome, weight control, diabetes type 2 and insulin resistance, and mitochondrial effects. Control of electron flux, prevention of bottlenecks in the respiratory chain and electron leakage contribute to the avoidance of damage by free radicals and seem to be important in neuroprotection, inflammatory diseases and, presumably, aging. Newly discovered influences on sirtuins and downstream factors indicate that melatonin has a role in mitochondrial biogenesis.

Melatonin was found to be a potent free radical scavenger in 1993. Since then over 800 publications have directly or indirectly confirmed this observation. Melatonin scavenges a variety of reactive oxygen and nitrogen species including hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide and peroxynitrite anion. Based on the analyses of structure-activity relationships, the indole moiety of the melatonin molecule is the reactive center of interaction with oxidants due to its high resonance stability and very low activation energy barrier towards the free radical reactions. However, the methoxy and amide side chains also contribute significantly to melatonin's antioxidant capacity. The N-C=O structure in the C3 amide side chain is the functional group. The carbonyl group in the structure of N-C=O is key for melatonin to scavenge the second reactive species and the nitrogen in the N-C=O structure is necessary for melatonin to form the new five membered ring after melatonin's interaction with a reactive species. The methoxy group in C5 appears to keep melatonin from exhibiting prooxidative activity. If the methoxy group is replaced by a hydroxyl group, under some in vitro conditions, the antioxidant capacity of this molecule may be enhanced. However, the cost of this change are decreased lipophility and increased prooxidative potential. Therefore, in in vivo studies the antioxidant efficacy of melatonin appears to be superior to its hydroxylated counterpart. The mechanisms of melatonin's interaction with reactive species probably involves donation of an electron to form the melatoninyl cation radical or through an radical addition at the site C3. Other possibilities include hydrogen donation from the nitrogen atom or substitution at position C2, C4 and C7 and nitrosation. Melatonin also has the ability to repair damaged biomolecules as shown by the fact that it converts the guanosine radical to guanosine by electron transfer. Unlike the classical antioxidants, melatonin is devoid of prooxidative activity and all known intermediates generated by the interaction of melatonin with reactive species are also free radical scavengers. This phenomenon is defined as the free radical scavenging cascade reaction of the melatonin family. Due to this cascade, one melatonin molecule has the potential to scavenge up to 4 or more reactive species. This makes melatonin very effective as an antioxidant. Under in vivo conditions, melatonin is often several times more potent than vitamin C and E in protecting tissues from oxidative injury when compared at an equivalent dosage (micromol/kg). Future research in the field of melatonin as a free radical scavenger might be focused on: 1), signal transduction and antioxidant enzyme gene expression induced by melatonin and its metabolites, 2), melatonin levels in tissues and in cells, 3), melatonin structure modifications, 4), melatonin and its metabolites in plants and, 5), clinical trials using melatonin to treat free radical related diseases such as Alzheimer's, Parkinson's, s...

Melatonin has been shown to protect against oxidative stress in various, highly divergent experimental systems. There are many reasons for its remarkable protective potential. Signaling effects comprise the upregulation of antioxidant enzymes, such as superoxide dismutases, peroxidases, and enzymes of glutathione supply, down-regulation of prooxidant enzymes, such as nitric oxide synthases and lipoxygenases, and presumably also the control of quinone reductase 2. Other mechanisms are based on direct interactions with several reactive oxygen and nitrogen species. Among these reactions, the capacity of easily undergoing single-electron transfer reactions is of particular importance. Electron donation by melatonin is not only an aspect of direct radical scavenging, but additionally represents the basis for formation of the protective metabolites AFMK (N1-ace-tyl-N2-formyl-5-methoxykynuramine) and AMK (N1-acetyl-5-methoxykynuramine). Recent investigations on mitochondrial metabolism indicate that melatonin as well as AMK are capable of supporting the electron flux through the respiratory chain, of preventing the breakdown of the mitochondrial membrane potential, and of decreasing electron leakage, thereby reducing the formation of superoxide anions. Radical avoidance is a new line of investigation, which exceeds mitochondrial actions and also comprises antiexcitatory effects and contributions to the maintenance of internal circadian phase relationships.

The presence of melatonin in plants is universal. Evidence has confirmed that a major portion of the melatonin is synthesized by plants themselves even though a homologue of the classic arylalkylamine N-acetyltransferase (AANAT) has not been identified as yet in plants. Thus, the serotonin N-acetylating enzyme in plants may differ greatly from the animal AANAT with regard to sequence and structure. This would imply multiple evolutionary origins of enzymes with these catalytic properties. A primary function of melatonin in plants is to serve as the first line of defence against internal and environmental oxidative stressors. The much higher melatonin levels in plants compared with those found in animals are thought to be a compensatory response by plants which lack means of mobility, unlike animals, as a means of coping with harsh environments. Importantly, remarkably high melatonin concentrations have been measured in popular beverages (coffee, tea, wine, and beer) and crops (corn, rice, wheat, barley, and oats). Billions of people worldwide consume these products daily. The beneficial effects of melatonin on human health derived from the consumption of these products must be considered. Evidence also indicates that melatonin has an ability to increase the production of crops. The mechanisms may involve the roles of melatonin in preservation of chlorophyll, promotion of photosynthesis, and stimulation of root development. Transgenic plants with enhanced melatonin content could probably lead to breakthroughs to increase crop production in agriculture and to improve the general health of humans.

Melatonin, a derivative of an essential amino acid, tryptophan, was first identified in bovine pineal tissue and subsequently it has been portrayed exclusively as a hormone. Recently accumulated evidence has challenged this concept. Melatonin is present in the earliest life forms and is found in all organisms including bacteria, algae, fungi, plants, insects, and vertebrates including humans. Several characteristics of melatonin distinguish it from a classic hormone such as its direct, non-receptor-mediated free radical scavenging activity. As melatonin is also ingested in foodstuffs such as vegetables, fruits, rice, wheat and herbal medicines, from the nutritional point of view, melatonin can also be classified as a vitamin. It seems likely that melatonin initially evolved as an antioxidant, becoming a vitamin in the food chain, and in multicellular organisms, where it is produced, it has acquired autocoid, paracoid and hormonal properties.