Antioxidative Protection by Melatonin: Multiplicity of Mechanisms from Radical Detoxification to Radical Avoidance

Abstract

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.

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…There is also a set of compounds, including melatonin, that promote expression of mitochondrial antioxidant enzymes such as SOD or glutathione [121][122][123][124]. Mitoquinone mesylate (MitoQ) has been proposed for treatment of AD and other neurodegenerative diseases because its antioxidant activity localizes to the mitochondrial inner membrane to prevent oxidative damage [131].…”

Melatonin Metabolism in the Central Nervous System

“…In brief, AFMK is formed via pyrrole ring cleavage of melatonin by various catalysts, enzymes such as indoleamine 2,3-dioxygenase, myeloperoxidase, some other hemoperoxidases, by cytochrome c, various pseudoenzymatic catalysts, and in various reactions with reactive oxygen species, including free radicals and singlet oxygen [38,39,47,50,136,141]. AFMK can also derive, via radical reactions, from c3OHM [135].…”

“…The kynuramine pathway of melatonin and some recently discovered products. For more details on the formation of AFMK see refs [38,50,93,136], of AMK refs. [47,50], of AMMC ref.…”

“…Activated microglia could convert melatonin by two enzymes, indoleamine 2,3-dioxygenase, although its main substrate is tryptophan, not melatonin [50,51,122,132], and myeloperoxidase [27,50,111,123,157,158]. Additionally, melatonin might be oxidized to AFMK by reactive oxygen species [38,39,47,50,136,141] transiently formed in excess. Therefore, a scenario for elevated formation of 5-methoxykynuramines upon intracisternal melatonin administration [52] might include some transient effect on microglia, which may, thereafter, be stopped by AFMK.…”

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

“…Melatonin can detoxify the harmful effects of ROS by directly scavenging free radicals, and by the attenuation of radical formation. 26 It does not undergo redox cycling even under high physiological concentrations. These two properties make melatonin a unique antioxidant.…”