Melatonin and its metabolites as anti-nitrosating and anti-nitrating agents

Abstract

Although basal and moderately elevated levels of nitric oxide are physiologically necessary and beneficial, excessive upregulations of this signaling molecule can be a cause of damage and cellular dysfunctions. In the presence of increased amounts of superoxide anions (•O2 -) and carbon dioxide, peroxynitrite (ONOO -) and the peroxynitrite-CO2 adduct (ONOOCO2 -) generate hydroxyl (•OH), nitrogen dioxide (•NO2) and carbonate (•CO3 -) radicals, which damage biomolecules by oxidation/peroxidation, nitration and nitrosation reactions. Nitrosation also occurs with all three NO congeners (NO + , •NO, and HNO = protonated NO -), with •NO especially in combination with electron/hydrogen-abstracting compounds, or with N2O3.3-Nitrotyrosine, found in low-density lipoprotein particles (LDL), atherosclerotic plaques, ion channels, receptors, transporters, enzymes and respirasomal subunits, is associated with numerous dysfunctions. Damage to the mitochondrial electron transport chain (ETC) is of particular significance and involves nitration, nitrosation and oxidation of proteins, cardiolipin peroxidation, and binding of •NO to ETC irons. Resulting bottlenecks of electron flux cause enhanced electron leakage which leads to elevated •O2 -. In combination with high •NO, •O2initiates a vicious cycle by generating more peroxynitrite that leads to further blockades and electron dissipation. Mitochondrial dysfunction, as induced via the •NO/peroxynitrite pathway, is of utmost importance in inflammatory diseases, especially sepsis, but also relevant to neurodegenerative and various other disorders. It may contribute to processes of aging.Melatonin, hormone of the pineal gland and product of other organs, interacts directly with reactive nitrogen species, but, more importantly, has antiinflammatory properties and downregulates inducible and neuronal NO synthases (iNOS, nNOS). It does not block moderately elevated •NO formation, but rather blunts excessive rises as occurring in sepsis and breaks the vicious cycle of mitochondrial electron leakage. The melatonin metabolite N 1 -acetyl-5-methoxykynuramine (AMK) forms stable nitrosation products and efficiently inhibits iNOS and nNOS, in conjunction with other antiinflammatory properties.

Gene regulation by melatonin linked to epigenetic phenomena

“…Melatonin exhibits its beneficial potential in a variety of ways: i) it and its metabolites are direct scavengers of ROS (Bonnefont-Rousselot et al, 2011;Galano et al, 2011;Peyrot and Ducrocq, 2008;Reiter et al, 2009a). In this sense, melatonin might be considered similar to other antioxidants such as vitamins C and E; however, melatonin is a terminal/suicidal antioxidant which means it never exhibits prooxidant activity and does not consume GSH; ii) melatonin also scavenges RNS which is an important step in preventing the harmful consequences of nitrooxidative stress (Hardeland, 2011;Korkmaz and Manchester, 2011;Peyrot and Ducrocq, 2008;Reiter et al, in press;Tan et al, 2007). Among the various candidates with RNS scavenging/decomposition properties are metalloporphyrins, ebselen, desferrioxamine, mercaptoalkylguanidines, amidine derivatives and several marketed drugs including cabergoline, nebivolol, and acetaminophen, none of which has yet offered promising outcomes; iii) melatonin induces antioxidant enzyme gene expression by epigenetically inducing Nrf2 at the transcriptional level.…”

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

“…60 Excessive NO production can be cytotoxic, the result of NO's reaction with reactive oxygen and nitrogen species, leading to peroxynitrite anion formation, protein tyrosine nitration, hydroxyl radical production 61 and mitochondrial dysfunction. 62 NADPH oxidase has been shown to be one of the most powerful prooxidants in both the vasculature and the kidney. NADPH oxidase contributes importantly to renal cortical oxidative stress, inflammation, renal damage and dysfunction and increased in arterial pressure.…”

Melatonin and Synthetic Melatonergic Agonists: Actions and Metabolism in the Central Nervous System

“…refs. [2,4,9,37,45,72,132,141,[188][189][190][191][192][193][194][195][196][197][198][199][200][201][202][203][204][205]. In this place, it should be only mentioned that neuroprotection comprises a plethora of actions, to an extent that can be only expected from a highly pleiotropic agent like melatonin (1) [2].…”

“…Their relative contributions obviously differ with regard to the various forms of antiexcitatory actions and also depend on CNS areas, but the attenuation of neuronal excitation seems to be a general feature of elevated melatonin (1) levels. In particular, the following effects have been described: modulation of GABA and glutamate receptors [132,133], secondary effects by decreases of cytosolic Ca 2+ via GABA c [134] or metabotropic mGlu 3 receptors [135], interference with neuronal NO synthase (including actions of the melatonin metabolite AMK, 10) [4,45,[136][137][138], changes in K + currents [139], and potentiation of strychninesensitive glycine-induced currents [140]. Although the specific relevance of these antiexcitatory actions varies between CNS regions, the rather consistently observed attenuation of neuronal excitation by melatonin (1) contributes to the avoidance or reduction of excitotoxicity, free radical formation and neuronal apoptosis [2,141].…”

“…This leads to reductions in the activities of BH4-dependent enzymes, such as aromatic amino acid hydroxylases, e.g., tryptophan hydroxylase, [42] and NO synthases [43,135], independently of NOS downregulations known from melatonin (1) and its other metabolite, AMK (10) (Fig. (2)) [44,45]. Nacetylserotonin (2) was recently shown to potently activate the TrkB receptor [46], a protein otherwise implicated in the transmission of brain-derived neurotrophic factor (BDNF) signaling.…”