Showing papers by "Dun Xian Tan published in 2003"

The chemistry of melatonin's interaction with reactive species

Abstract: Melatonin has been shown to be an effective antioxidant in a number of experimental models both in vitro and in vivo. Considering the data available, it is now clear that the indoleamine is involved in antioxidative mechanisms more complex than originally envisaged. These range from the direct radical scavenging of a variety of radicals and reactive species to the control and/or modulation of a number of processes which may trigger a redox imbalance between antioxidant and prooxidant species. This review focuses on the direct radical scavenging activity of melatonin and provides a summary of the mechanisms of the reactions between the indoleamine and reactive species in pure chemical solutions. These actions likely account for at least some of the protective actions of melatonin under conditions of high oxidative stress.

Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans.

Abstract: This brief resume enumerates the multiple actions of melatonin as an antioxidant. This indoleamine is produced in the vertebrate pineal gland, the retina and possibly some other organs. Additionally, however, it is found in invertebrates, bacteria, unicellular organisms as well as in plants, all of which do not have a pineal gland. Melatonin's functions as an antioxidant include: a), direct free radical scavenging, b), stimulation of antioxidative enzymes, c), increasing the efficiency of mitochondrial oxidative phosphorylation and reducing electron leakage (thereby lowering free radical generation), and 3), augmenting the efficiency of other antioxidants. There may be other functions of melatonin, yet undiscovered, which enhance its ability to protect against molecular damage by oxygen and nitrogen-based toxic reactants. Numerous in vitro and in vivo studies have documented the ability of both physiological and pharmacological concentrations to melatonin to protect against free radical destruction. Furthermore, clinical tests utilizing melatonin have proven highly successful; because of the positive outcomes of these studies, melatonin's use in disease states and processes where free radical damage is involved should be increased.

Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin

Abstract: 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.

Melatonin: A novel protective agent against oxidative injury of the ischemic/reperfused heart

Abstract: This brief review summarizes the recently obtained evidence which illustrates the beneficial effects of the endogenously produced antioxidant, melatonin, in reducing tissue damage and reversing cardiac pathophysiology in models of experimental ischemia/reperfusion. The report also describes the actions of other antioxidants, especially vitamin E and antioxidative enzymes, in altering the degree of ischemia/reperfusion damage in the heart. Based on the data available, melatonin seems to have advantages over other antioxidants tested in terms of ameliorating the hypoxia and reoxygenation-induced damage. While the bulk of the studies that have used melatonin to overcome cardiac injury following transient arterial occlusion and subsequent reperfusion have used pharmacological doses to achieve protection, two recent reports have further shown that merely reducing endogenous circulating concentrations of melatonin (by surgical removal of a source of melatonin, i.e. the pineal gland) exaggerates the degree of injury and reduces survival of animals as a result of induced ischemia/reperfusion of the heart. These findings are consistent with observations in other organs where the loss of physiological concentrations of melatonin results in increased oxidative damage during hypoxia and reoxygenation. These findings have implications for the elderly since in the aged endogenous levels of melatonin are naturally reduced thereby possibly predisposing them to more severe cardiac damage during a heart attack. To date, the bulk of the studies relating to the protective actions of melatonin in reducing cardiac ischemia/reperfusion injury have used the rat as the experimental model. Considering the high efficacy of melatonin in limiting ischemia/reperfusion damage as well as melatonin's low toxicity, the studies should be expanded to include other species and models of cardiac ischemia/reperfusion. The results of these investigations would help to clarify the potential importance of the use of melatonin in situations of oxidative damage to the heart in humans.

Antioxidant properties of the melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK): scavenging of free radicals and prevention of protein destruction

Abstract: In numerous experimental systems, the neurohormone melatonin has been shown to protect against oxidative stress, an effect which appears to be the result of a combination of different actions. In this study, we have investigated the possible contribution to radical scavenging by substituted kynuramines formed from melatonin via pyrrole ring cleavage. N1-Acetyl-5-methoxykynuramine (AMK), a metabolite deriving from melatonin by mechanisms involving free radicals, exhibits potent antioxidant properties exceeding those of its direct precursor N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and its analog N1-acetylkynuramine (AK). Scavenging of hydroxyl radicals was demonstrated by competition with ABTS in a Fenton reaction system at pH 5 and by competition with DMSO in a hemin-catalyzed H2O2 system at pH 8. Under catalysis by hemin, oxidation of AMK was accompanied by the emission of chemiluminescence. AMK was a potent reductant of ABTS cation radicals, but, in the absence of catalysts, a poor scavenger of superoxide anions. In accordance with the latter observation, AMK was fairly stable in a pH 8 H2O2 system devoid of hemin. Contrary to AFMK, AMK was easily oxidized in a reaction mixture generating carbonate radicals. In an oxidative protein destruction assay based on peroxyl radical formation, AMK proved to be highly protective. No prooxidant properties of AMK were detected in a sensitive biological test system based on light emission by the bioluminescent dinoflagellate Lingulodinium polyedrum. AMK may contribute to the antioxidant properties of the indolic precursor melatonin.

Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical.

Abstract: Melatonin and classic antioxidants possess the capacity to scavenge ABTSb+ with IC50s of 4, 11, 15.5, 15.5, 17 and 21 microm for melatonin, glutathione, vitamin C, trolox, NADH and NADPH, respectively. In terms of scavenging ABTSb+, melatonin exhibits a different profile than that of the classic antioxidants. Classic antioxidants scavenge one or less ABTSb+, while each melatonin molecule can scavenge more than one ABTSb+, probably with a maximum of four. Classic antioxidants do not synergize when combined in terms of scavenging ABTSb+. However, a synergistic action is observed when melatonin is combined with any of the classic antioxidants. Cyclic voltammetry indicates that melatonin donates an electron at the potential of 715 mV. The scavenging mechanism of melatonin on ABTSb+ may involve multiple-electron donations via intermediates through a stepwise process. Intermediates including the melatoninyl cation radical, the melatoninyl neutral radical and cyclic 3-hydroxymelatonin (cyclic 3-OHM) and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) seem to participate in these reactions. More interestingly, the pH of the solution dramatically modifies the ABTSb+ scavenging capacity of melatonin while pH changes have no measurable influence on the scavenging activity of classic antioxidants. An acidic pH markedly reduces the ABTSb+ scavenging capacity of melatonin while an increased pH promotes the interaction of melatonin and ABTSb+. The major melatonin metabolites that develop when melatonin interacts with ABTSb+ are cyclic 3-OHM and AFMK. Cyclic 3-OHM is the intermediate between melatonin and AFMK, and cyclic 3-OHM also has the ability to scavenge ABTSb+. Melatonin and the metabolites which are generated via the interaction of melatonin with ABTSb+, i.e. the melatoninyl cation radical, melatoninyl neutral radical and cyclic 3-OHM, all scavenge ABTSb+. This unique cascade action of melatonin, in terms of scavenging, increases its efficiency to neutralized ABTSb+; this contrasts with the effects of the classic antioxidants.

Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and α‐lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: a study of their individual and synergistic actions

Abstract: DNA damage generated by oxygen-derived free radicals is related to mutagenesis, carcinogenesis and aging. In the last several years, hundreds of publications have confirmed that melatonin is a potent endogenous free radical scavenger. In the present in vitro study, we have examined the efficacy of three polyphenolic antioxidants, i.e. xanthurenic acid, resveratrol (3,4',5-trihydroxy-trans-stilbene) and (-)-epigallocatechin-3-gallate (EGCG) and two classical non-polyphenolic antioxidants, i.e. vitamin C (ascorbic acid) and alpha-lipoic acid (LA, 1,2-dithiolane-3-pentanoic acid) in inhibiting *OH-induced oxidative DNA damage. We compared the efficacy of these five antioxidants with the effectiveness of melatonin (N-acetyl-5-methoxytryptamine) and we also investigated the possible synergistic effects of melatonin with the other five molecules. Using high performance liquid chromatography (HPLC), the formation of 8-hydroxy-2-deoxyguanosine (8-OH-dG) in purified calf thymus DNA treated with the Fenton reagents, chromium(III) (as CrCl3) plus hydrogen peroxide (H2O2) (Cr(III)/H2O2), was measured in the presence or absence of the antioxidants alone or in combination with melatonin. 8-OH-dG is considered a biomarker of oxidative DNA damage. Among the antioxidants tested, melatonin was the most effective of these with an IC50 = 3.6 +/- 0.1 micro m. For the other antioxidants the IC50 values were as follows: xanthurenic acid (IC50 = 7.9 +/- 0.3), resveratrol (IC50 = 10.9 +/- 0.3), EGCG (IC50 = 5.7 +/- 0.3), vitamin C (IC50 = 16.9 +/- 0.5) and LA (IC50 = 38.8 +/- 0.7). These values differ from that of melatonin with a P < 0.01. Melatonin (1 micro M) reversed the pro-oxidant effect of resveratrol (0.5 micro M) and vitamin C (0.5 micro M), had an antagonistic effect when used in combination with EGCG (1 micro M) and it exhibited synergism in combination with vitamin C (0.5 micro M) and with LA (5 micro M).

What constitutes a physiological concentration of melatonin

Abstract: There seems to be a considerable amount of confusion as to what constitutes a physiological concentration of melatonin in organisms. A frequently made and often-propagated error is the assumption that melatonin concentrations throughout the body are the same as in the blood. Thus, in many reports the authors state, regardless of the fluid, tissue or organism with which they are working, that the physiological levels of melatonin are in the picomolar and low nanomolar range. A search of the literature, however, shows that melatonin in other body fluids and cells is not necessarily in equilibrium with those in the blood. This was dramatically emphasized when it was shown that in the bile [1] and the cerebrospinal fluid of the third ventricle [2, 3] melatonin concentrations are orders of magnitude higher than in the blood. These high levels are, in fact, the physiological concentrations of melatonin for these fluids. There is also evidence that melatonin levels in the follicular fluid of the human Graffian follicule [4] exceed those in the serum. Tissue concentrations also may not depend exclusively on those in the blood. While this is obviously true for cells that produce melatonin, e.g. cells of the pineal gland and retinas [5], it may also be the case with other cells. For example, some bone marrow cells contain high concentrations of melatonin [6] and there is evidence that these elements have the synthetic machinery to produce the indole [7]. Cells in the gastrointestinal tract also contain melatonin in seemingly high concentrations [8, 9]. Beyond this, a number of other tissues are now included in the list of organs that may have the potential to generate melatonin (for example, cochlea [10]; lens [11]; skin [12]; etc), and, therefore, these cells may have elevated concentrations of the indole relative to levels in the blood. Finally, if the findings of Stefulj et al. [13] are confirmed and extended with a documentation of the ability of many cells to produce melatonin, the concept of what constitutes a physiological level of the indole may again have to be revised. Within subcellular organelles as well, the concentrations of melatonin may vary. For example, Martin et al. [14] report that the levels of this indole in the mitochondria may significantly exceed those in the serum. Physiological levels vary according to the organism in which measurements are made. In the unicell Gonyaulax polyedra [15] and in yeast Saccharomyces cerevisiae [16], for example, melatonin concentrations can be exceptionally high but, nevertheless, physiological. There may be many other organisms and/or cells that, for various reasons, contain higher concentrations of melatonin than are normally found in the blood of mammals. In the published literature, it is often mentioned that, if melatonin levels exceed the picomolar or low nanomolar range, the concentrations are pharmacological. This is obviously not the case since, as summarized herein, melatonin concentrations differ in different body fluids, in different cells, in different subcellular organelles and in different organisms. This being so, hereinafter when the term physiological is used to describe a concentration of melatonin, it must be defined in reference to a specific compartment in multicellular organisms or for a given specie.

Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid-β peptide in rat brain: a comparative, in vivo study versus vitamin C and E

Abstract: To determine the efficacy of antioxidants in reducing amyloid-beta-induced oxidative stress, and the neuroinflammatory response in the central nervous system (CNS) in vivo, three injections of fibrillar amyloid-beta (fAbeta) or artificial cerebrospinal fluid (aCSF) into the CA1 region of the hippocampus of the rat were made. Concomitantly, one of the three free radical scavengers, i.e. melatonin, vitamin C, or vitamin E was also administered. Besides being a free radical scavenger, melatonin also has immunomodulatory functions. Antioxidant treatment reduced significantly oxidative stress and pro-inflammatory cytokines. There were no marked differences between melatonin, vitamin C, and vitamin E regarding their capacity to reduce nitrites and lipoperoxides. However, melatonin exhibited a superior capacity to reduce the pro-inflammatory response induced by fAbeta.

Oxidative Damage to Catalase Induced by Peroxyl Radicals: Functional Protection by Melatonin and Other Antioxidants

Abstract: Thermal decomposition by the azo initiator 2,2' azobis-(2-amidinopropane) dihydrochloride (AAPH) has been widely used as a water-soluble source of free radical initiators capable of inducing lipid peroxidation and protein damage. Here, in a lipid-free system, AAPH alone (40 mM) rapidly induced protein modification and inactivation of the enzyme catalase (EC 1.11.1.6). Using SDS-PAGE, it was shown that protein band intensity is dramatically reduced after 4 h of incubation with AAPH, leading to protein aggregation. Several antioxidants including melatonin, glutathione (GSH) and trolox prevented catalase modification when used at a 250 w M concentration whereas ascorbate was only effective at 1 mM concentration. All the antioxidants tested reduced carbonyl formation although melatonin was the most effective in this regard. Enzyme inactivation caused by AAPH was also significantly reduced by the antioxidants and again melatonin was more efficient than the other antioxidants used in this study. Results sho...

Melatonin: detoxification of oxygen and nitrogen-based toxic reactants.

Abstract: In the last decade, melatonin has been found to be highly protective against damage to macromolecules resulting from oxygen and nitrogen-based reactants. Considering this. numerous studies have examined the mechanisms whereby this indoleamine directly detoxifies these damaging agents. The evidence is compelling that melatonin scavenges several oxygen-derived reactive agents including the hydroxyl radical (OH), hydrogen peroxide (H207), singlet oxygen (’02) and hypochlorous acid (HOCI). Additionally, melatonin reportedly reacts with nitric oxide (NO), the peroxynitrite anion (ONOO“) and/or peroxynitrous acid (ONOOH) to detoxify them. In some cases the products that are formed as a consequence of melatonin’s scavenging actions have been identified. Whereas the ability of melatonin to neutralize these toxic agents likely accounts, in part, for the antioxidant activity of melatonin, it is not the only means by which melatonin serves to protect molecules from oxygen and nitrogen-based reactive metabolites.

Melatonin ameliorates neurologic damage and neurophysiologic deficits in experimental models of stroke.

Abstract: This review summarizes the numerous reports that have documented the neuroprotective actions of melatonin in experimental models of ischemia/reperfusion injury (stroke). In these investigations, which have used three species (rat, gerbil, and cat), melatonin was universally found to reduce brain damage that normally occurs as a consequence of the temporary interruption of blood flow followed by the reflow of oxygenated blood to the brain. The exogenous administration of melatonin in these experimental stroke models reduced infarct volume, lowered the frequency of apoptosis, increased the number of surviving neurons, reduced reactive gliosis, lowered the oxidation of neural lipids and oxidatively damaged DNA, induced bcl-2 gene expression (the activity of which improves cell survival), upregulated excision repair cross-complementing factor 6 (an essential gene for preferential DNA excision repair), restrained poly(ADP ribose) synthetase (which depletes cellular NAD resulting in the loss of ATP) activity, and improved neurophysiologic outcomes. Under no circumstances did melatonin exacerbate the damage associated with ischemia/reperfusion injury. As well as the beneficial pharmacologic actions of melatonin, several studies show that a relative deficiency of endogenous melatonin exaggerates neural damage due to stroke; this suggests that even physiologic concentrations of melatonin normally serve to protect the brain against damage. The primary action to explain melatonin's protective effects may relate to its ubiquitous direct and indirect antioxidative actions, although other beneficial functions of melatonin are not precluded.

Melatonin and its derivatives cyclic 3‐hydroxymelatonin, N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine and 6‐methoxymelatonin reduce oxidative DNA damage induced by Fenton reagents

Abstract: Free radicals are generated in vivo and they oxidatively damage DNA because of their high reactivities. In the last several years, hundreds of publications have confirmed that melatonin is a potent endogenous free radical scavenger. Some of the metabolites produced as a result of these scavenging actions have been identified using pure chemical systems. This is the case with both N 1 -acetyl-N 2 -formyl-5-methoxykynuramine (AFMK), identified as a product of the scavenging reaction of H 2 O 2 by melatonin, and cyclic 3-hydroxymelatonin (C-3-OHM) which results when melatonin detoxifies two hydroxyl radicals (.OH). In the present in vitro study, we investigated the potential of two different derivatives of melatonin to scavenger free radicals. One of these derivatives is C-3-OHM, while the other is 6-methoxymelawtonin (6-MthM). We also examined the effect of two solvents, i.e., methanol and acetonitrile, in this model system As an endpoint, using high-performance liquid chromatography we measured the formation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in purified calf thymus DNA treated with the Fenton reagents, chromium(III) [Cr(III)] plus H 2 O 2 , in the presence and in the absence of these molecules. The 8-OH-dG is considered a biomarker of oxidative DNA damage. Increasing concentrations of Cr(III) (as CrCl 3 ) and H 2 O 2 was earlier found to induce progressively greater levels of 8-OH-dG in isolated calf thymus DNA because of the generation of .OH via the Fenton-type reaction. We found that C-3-OHM reduces .OH-mediated damage in a dose-dependent manner, with an IC 50 = 5.0 ± 0.2 μM; melatonin has an IC 50 = 3.6 ± 0.1 μ(M. These values differ statistically significantly with P < 0.05. In these studies, AFMK had an IC 50 = 17.8 ± 0.7 μM (P < 0.01). The 6-MthM also reduced DNA damage in a dose-dependent manner, with an IC 50 = 4.2 ± 0.2 μM; this value does not differ from the ICs for melatonin and C-3-OHM. We propose a hypothetical reaction pathway in which a mole of C-3-OHM scavenges 2 mol of .OH yielding AFMK as a final product. As AFMK is also a free radical scavenger, the action of melatonin as a free radical scavenger is a sequence of scavenging reactions in which the products are themselves scavengers, resulting in a cascade of protective reactions.

Antioxidant strategies in protection against neurodegenerative disorders

Abstract: The most common neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease and stroke; they are devastating clinical problems which lack effective treatments. Although the aetiology of these diseases is not fully understood, oxidative stress is believed to be a contributing causative factor. In addition to conventional therapies, antioxidant strategies in protection against neurodegenerative conditions have been increasingly addressed, as evidenced by an increasing number of animal studies, clinical reports and patents regarding these processes in recent years. The effectiveness of antioxidants in protecting against neurodegenerative disorders lies mainly in their ability to cross the blood–brain barrier, their potential in terms of subcellular distribution occurring in membranes, in the cytoplasm and especially in mitochondria, and their multifunctional capacity as well as their synergistic actions. The naturally occurring antioxidants with different properties collaborate as an array to...

Neurally-mediated and neurally-independent beneficial actions of melatonin in the gastrointestinal tract.

Abstract: Melatonin (N-acetyl-5-methoxytryptamine), originally discovered in the pineal gland, is now known also to be present in the gastrointestinal tract from the stomach to the colon. It is localized and likely synthesized in the enterochromaffin cells of the mucosal lining. Its functions in the gut generally seem to be protective of the mucosa from erosion and ulcer formation and to possibly influence movement of the gastrointestinal contents through the digestive system. In this brief review, we summarize the work documenting the function of melatonin in influencing bicarbonate secretion in the stomach and its role in preventing and repairing ulcers in the stomach and duodenum. Melatonin's actions in the control of bicarbonate secretion involve the central and peripheral sympathetic nervous systems and the actions are receptor mediated. Conversely, melatonin's actions in reducing ulcer formation also seemingly involve the ability of the indole to directly scavenge toxic oxygen-based reactants, e.g., the hydroxyl radical, and possibly to promote antioxidative enzyme activities. These same processes may be involved in the mechanisms by which melatonin promotes ulcer healing. Additionally, however, melatonin's effects on the healing of ulcers includes actions of blood flow in the margins of the ulcer and also on the sensory nerves. All indications are that melatonin has a variety of beneficial effects in the gastrointestinal tract. It is likely, however, that additional actions of melatonin on the digestive system will be uncovered.

Urgent search for safe and effective treatments of severe acute respiratory syndrome: is melatonin a promising candidate drug?

Abstract: Since the end of February of this year, global health is being threatened by the emergence of a new infectious disease, severe acute respiratory syndrome (SARS), caused by a novel coronavirus [1–3]. The disease was believed to have originated in the Guangdong province of China and has now spread throughout the world with a cumulative total of 5050 cases (321 deaths) from 26 countries as of April 28. It is noteworthy that the majority of deaths have been reported in Hong Kong and mainland China, in which the outbreak is still spreading and apparently not yet under control, despite intensive efforts by the governments concerned. Without doubt, the rapid identification of the new coronavirus as the cause of SARS by the international network of laboratories, coordinated by the World Health Organization, in a relatively short time (about 6 wk) after the syndrome was first recognized in Hanoi, Vietnam, is a major scientific achievement in the history of mankind. The molecular and virological data will hopefully enable the international research community to develop effective and specific diagnostic tests, antiviral agents and preventive vaccines against this emerging disease. However, the most immediate concerns to the health authorities of Hong Kong and mainland China are to contain the spread of the disease and to reduce the mortality of those SARS patients who succumb to acute respiratory failure. Besides reducing the public concern associated with the disease, having methods to control it would reduce the negative impact on the economy. While health officials are working hard to contain the spread of the disease in the hard-hit places such as China, Hong Kong [4], Singapore and Canada [5], clinicians are racing against time to find effective drugs to rescue SARS patients from serious illness and death. Not all patients are responsive to supportive management or to a combination of high dose steroids and ribavirin, which have been used widely as the first-line treatment in Hong Kong [6, 7]. Although it remains unknown whether the broad spectrum antiviral agent ribavirin is effective in inhibiting the growth of the SARS virus, many of the patients have apparently benefited from the use of high dose steroids as indicated by initial clinical reports. Steroids are mainly used to reduce the severe viral-induced inflammatory damage to the lungs of the patients. The lungs show histological changes comparable to acute respiratory distress syndrome (RDS) in those with severe disease [6, 7]. Apart from the wellknown side effects associated with steroid use, e.g., gastrointestinal bleeding as well as metabolic and psychologic disturbances, high dose steroids as an immunomodulator in the current therapy against SARS could be a double-edged sword. It is highly possible that suppression of immune defenses by steroids in individual patients who do not respond to steroids and ribavirin may do more harm than good, by putting these patients at higher risk of developing superimposed infections with other microbial pathogens; also, it subjects them to a reduced coronavirus-specific antibody production and to uncontrolled cytolytic lung damage by the SARS virus if its growth is ultimately shown to be refractory to ribavirin. Like many other acute and chronic inflammatory diseases, oxygen-derived free radicals play an important role in the pathogenesis of the acute RDS [8] triggered by the SARS virus. Reactive oxygen species can modulate a wide range of toxic oxidative reactions such as initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATPase activity, inactivation of membrane sodium channels and other oxidative modifications of proteins. They are also potential reactants capable of initiating DNA single strand breaks, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion and cell necrosis. Specifically in lungs, oxidative stress increases the surfactant peroxidation [9] and edema [10] and decreases the oxygen exchange function of alveoli [11]. Bernard et al. [12] reported that repletion of antioxidant levels with N-acetylcysteine and/or L-2-oxothiazolidine-4-carboxylate treatment shortened the duration of lung injury in patients with acute lung injury/acute RDS. The need for appropriate treatment with antiinflammatory and/or antioxidative drugs in SARS patients is apparent. Melatonin is a naturally occurring, endogenously produced and diet-contained molecule [13]. It is a potent antioxidant [14] with a significant anti-inflammatory activity as well [15]. This indoleamine also moderately stimulates the immune system which would decrease the likelihood that SARS patients would develop secondary viral or other microbiological infections. The protective effects of melatonin against viral encephalities in mice [16, 17] and viral infections in mink [18] have been documented. Moreover, the treatment of 40 newborn human infants suffering with RDS given intravenously administered melatonin (80 mg over 3 days) improved their clinical status and no death was observed; however, in another 36 RDS infants with conventional treatment only, 11% of them died and the clinical manifestations were more severe than in their melatonin-treated counterparts (E. Gitto, I. Barberi et al., unpublished observations). Animal studies have J. Pineal Res. 2003; 35:69–70 Copyright Blackwell Munksgaard, 2003 Journal of Pineal Research ISSN 0742-3098