Melatonin protects against pro-oxidant enzymes and reduces lipid peroxidation in distinct membranes induced by the hydroxyl and ascorbyl radicals and by peroxynitrite (original) (raw)
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Cell Biochemistry and Biophysics, 2001
Melatonin (N-acetyl-5-methoxytryptamine), an endogenously produced indole found throughout the animal kingdom, was recently reported, using a variety of techniques, to be a scavenger of a number of reactive oxygen and reactive nitrogen species both in vitro and in vivo. Initially, melatonin was discovered to directly scavenge the high toxic hydroxyl radical (•OH). The methods used to prove the interaction of melatonin with the •OH included the generation of the radical using Fenton reagents or the ultraviolet photolysis of hydrogen peroxide (H 2 O 2) with the use of spin-trapping agents, followed by electron spin resonance (ESR) spectroscopy, pulse radiolysis followed by ESR, and several spectrofluorometric and chemical (salicylate trapping in vivo) methodologies. One product of the reaction of melatonin with the •OH was identified as cyclic 3-hydroxymelatonin (3-OHM) using high-performance liquid chromatography with electrochemical (HPLC-EC) detection, electron ionization mass spectrometry (EIMS), proton nuclear magnetic resonance (1 H NMR) and COSY 1 H NMR. Cyclic 3-OHM appears in the urine of humans and other mammals and in rat urine its concentration increases when melatonin is given exogenously or after an imposed oxidative stress (exposure to ionizing radiation). Urinary cyclic 3-OHM levels are believed to be a biomarker (footprint molecule) of in vivo •OH production and its scavenging by melatonin. Although the data are less complete, besides the •OH, melatonin in cell-free systems has been shown to directly scavenge H 2 O 2 , singlet oxygen (1 O 2) and nitric oxide (NO•), with little or no ability to scavenge the superoxide anion radical (O 2 •-). In vitro, melatonin also directly detoxifies the peroxynitrite anion (ONOO-) and/or peroxynitrous acid (ONOOH), or the activated form of this molecule, ONOOH*; the product of the latter interaction is proposed to be 6-OHM. How these in vitro findings relate to the in vivo antioxidant actions of melatonin remains to be established. The ability of melatonin to scavenge the lipid peroxyl radical (LOO•) is debated. The weight of the evidence is that melatonin is probably not a classic chain-breaking antioxidant, since its ability to scavenge the LOO• seems weak. Its ability to reduce lipid peroxidation may stem from its function as a preventive antioxidant (scavenging initiating radicals), or yet unidentified actions. In sum, in vitro melatonin acts as a direct free radical scavenger with the ability to
Actions of melatonin in the reduction of oxidative stress
Journal of Biomedical Science, 2000
Melatonin was discovered to be a direct free radical scavenger less than 10 years ago. Besides its ability to directly neutralize a number of free radicals and reactive oxygen and nitrogen species, it stimulates several antioxidative enzymes which increase its efficiency as an antioxidant. In terms of direct free radical scavenging, melatonin interacts with the highly toxic hydroxyl radical with a rate constant equivalent to that of other highly efficient hydroxyl radical scavengers. Additionally, melatonin reportedly neutralizes hydrogen peroxide, singlet oxygen, peroxynitrite anion, nitric oxide and hypochlorous acid. The following antioxidative enzymes are also stimulated by melatonin: superoxide dismutase, glutathione peroxidase and glutathione reductase. Melatonin has been widely used as a protective agent against a wide variety of processes and agents that damage tissues via free radical mechanisms.
Melatonin: Action as antioxidant and potential applications in human disease and aging
Toxicology, 2010
This review aims at describing the beneficial properties of melatonin related to its antioxidant effects. Oxidative stress, i.e., an imbalance between the production of reactive oxygen species and antioxidant defences, is involved in several pathological conditions such as cardiovascular or neurological disease, and in aging. Therefore, research for antioxidants has developed. However, classical antioxidants often failed to exhibit beneficial effects, especially in metabolic diseases. Melatonin has been shown as a specific antioxidant due to its amphiphilic feature that allows it to cross physiological barriers, thereby reducing oxidative damage in both lipid and aqueous cell environments. Studies on the antioxidant action of melatonin are reported, with a special mention to water gamma radiolysis as a method to produce oxygen-derived free radicals, and on structure-activity relationships of melatonin derivatives. Mass spectrometry-based techniques have been developed to identify melatonin oxidation products. Besides its ability to scavenge several radical species, melatonin regulates the activity of antioxidant enzymes (indirect antioxidant properties). Efficient detection methods confirmed the presence of melatonin in several plant products. Therapeutic potential of melatonin relies either on increasing melatonin dietary intake or on supplementation with supraphysiological dosages. Clinical trials showed that melatonin could be efficient in preventing cell damage, as well under acute (sepsis, asphyxia in newborns) as under chronic (metabolic and neurodegenerative diseases, cancer, inflammation, aging). Its global action on oxidative stress, together with its rhythmicity that plays a role in several metabolic functions, lead melatonin to be of great interest for future clinical research in order to improve public health. gen species (RNS) can also be involved in cell damage, such as nitric oxide ( • NO) that is produced by the NO-synthases, and that reacts with O 2 •− to form peroxynitrite (ONOO − ), an effi-0300-483X/$ -see front matter
A Review of Biological and Pharmacological Actions of Melatonin: Oxidant and Prooxidant Properties
Melatonin as an indole amine exists in most of mammals and produced by various organs. It involved in circadian regulation of physiological and neuroendocrine function. Also it modulates diverse physiological functions such as sleep and sexual behavior. During the last decade, melatonin has been shown to possess potent free radical scavenger properties against reactive oxygen species (ROS). Moreover, by induction of the expression of antioxidant enzymes and reduction of the activation of pro-oxidant enzymes, melatonin indirectly could protect cells against a variety of free radical-related diseases. Besides, melatonin has been shown to promote the generation of ROS at pharmacological concentrations in in-vitro studies. Although melatonin could potentially be useful but safety, efficacy remains uncertain. In the present report, we review the studies which document the influence of melatonin on the various oxidative stress associated diseases .We also analyze the possible mechanisms by which melatonin induce ROS formation.
Biochimica et Biophysica Acta (BBA) - General Subjects, 2009
N 1-acetyl-N 2-formyl-5-methoxykynuramine (AFMK) 2,2′-azobis(2-methylpropionamidine) dihydrochloride (AAPH) Glutathione pro-oxidant activity Background: Melatonin is well-established as a powerful reducing agent of oxidant generated in the cell medium. We aimed to investigate how readily melatonin is oxidized by peroxyl radicals ROO⋅ generated by the thermolysis of 2,2′-azobis(2-amidinopropane) hydrochloride (AAPH) and the role of glutathione (GSH) during the reaction course. Methods: Chromatographic, mass spectroscopy, and UV-visible spectrometric techniques were used to study the oxidation of melatonin by ROO⋅ or horseradish peroxidase (HRP)/H 2 O 2. Our focus was the characterization of products and the study of features of the reaction. Results: We found that N 1-acetyl-N 2-formyl-5-methoxykynuramine (AFMK) and a monohydroxylated derivative of melatonin were the main products of the reaction between melatonin and ROO⋅. Higher pH or saturation of the medium with molecular oxygen increased the yield of AFMK but did not affect the reaction rate. Melatonin increased the depletion of intracellular GSH mediated by AAPH. Using the HRP/H 2 O 2 as the oxidant system, the addition of melatonin promoted the oxidation of GSH to GSSG. Conclusions: These results show, for the first time, that melatonin radical is able to oxidize GSH. General significance: We propose that this new property of melatonin could explain or be related to the recently reported pro-oxidant activities of melatonin.
On the in vitro antioxidative properties of melatonin
Journal of Pineal Research, 2002
Abstract:The aim of this study is to examine possible in vitro antioxidant effects of melatonin. Thus, the total in vitro antioxidant activity of melatonin was studied using a thiocyanate method. Additionally, the reducing power, the superoxide anion scavenging activity and free radical scavenging activity of melatonin were determined. Melatonin exhibited potent antioxidant activity in a linoleic acid emulsion system. The antioxidant activity increased with increasing concentrations of melatonin (50–500 μg). The 50, 100, 250 and 500 μg melatonin doses showed 41, 60, 86 and 99% inhibition of peroxidation of linoleic acid, respectively. On the other hand, a 500-μg dose of α-tocopherol showed 34% inhibition of peroxidation of linoleic acid. Like the total antioxidant activity, the reducing power of melatonin increased in a dose-dependent manner. The reducing power of melatonin was statistically significant versus control, but lower than butylated hydroxytoluene (BHT) or quercetin. Additionally, melatonin had potent superoxide radical scavenging activity and exhibited a higher superoxide radical scavenging activity than quercetin or BHT but lower than butylated hydroxyanisole (BHA). Melatonin's direct free radical scavenging actions may account, at least in part, for its ability to reduce lipid peroxidation. Melatonin may have utility in protecting stored foods from free radical-induced deterioration.
Neuroscience and Biobehavioral Reviews, 1993
Recent findings suggest that the ability of melatonin to enter all body tissues and to be metabolized, enzymatically or nonenzymatically, in any of them results in a spectrum of effects, which exceed substantially those transduced by membrane receptors. These actions comprise the formation of various bioactive compounds such as N-acetylserotonin, 5-methoxytryptamine, N,N-dimethyl-5-methoxytryptamine, 5-methoxytrytophol, cyclic 2-hydroxymelatonin, pinoline, and 5-methoxylated kynuramines. Apart from enzymatic metabolism, nonenzymatic reactions with free radicals, in particular the superoxide anion and the hydroxyl radical, represent a new and significant aspect of melatonin's biological role. Melatonin represents the most potent physiological scavenger of hydroxyl radicals found to date, and recent findings suggest an essential role of this indoleamine for protection from hydroxyl radical-induced carcinogenesis and neurodegeneration.