Chemical and Physical Properties and Potential Mechanisms: Melatonin as a Broad Spectrum Antioxidant and Free Radical Scavenger

Abstract

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...

Regulatory roles of serotonin and melatonin in abiotic stress tolerance in plants

“…The high resonance stability, electroreactivity and low activation energy barriers make melatonin a potent free radical scavenger. 32, 33 The side chains also have a significant contribution in the antioxidative properties of the molecule. Carbonyl moiety present in the functional group (NÀ ÀCHO ) of C3 amide side chain has a key role in the quenching of more than one reactive oxygen species.…”

“…Melatonin also shows damage repairing ability since it can repair molecules that have been oxidized. 33 At low concentrations ROS function as secondary messengers in signal transduction and are required for growth, but at high endogenous concentrations they can be detrimental to plants due to oxidative burst. 40,41 In order to protect themselves from the adverse effects of ROS, plant cells have a non-enzymatic and enzymatic detoxification system.…”

Melatonin, Oxidative Stress, and the Aging Brain

“…An unresolved issue is whether melatonin acts as an antioxidant directly or acts by promotion of key pathways involved in the disposition of free radicals [94]. The evidence for a direct effect rests on the fact that melatonin can act as a powerful free radical scavenger in isolated cell-free systems [95,96]. However, it has also been reported that melatonin can act as a pro-oxidant in such systems [52,97].…”

Efeito de diferentes concentrações de melatonina em espermatozoides de carneiros sobre estresse oxidativo após criopreservação

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