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Biomedical subjects

R J Reiter

Publications and source records attributed to R J Reiter.

At least 55 records · Page 3Linked to original sources
PubMed2001

Endogenous rhythms of melatonin, total antioxidant status and superoxide dismutase activity in several tissues of chick and their inhibition by light.

Melatonin was recently shown to be a component of the antioxidative defense system of organisms due to its free radical scavenging ability and to its capacity to stimulate several antioxidant enzymes. In this report, we studied the endogenous rhythm of the antioxidant enzyme superoxide dismutase (SOD) in three different tissues (cerebral cortex, liver and lung) of chick (Gallus domesticus) (three weeks, at age and sacrificed every 2 hr). During the study the chicks were under a light:dark cycle of 12:12. Total antioxidant status of the plasma was correlated with physiological blood melatonin concentrations. Superoxide dismutase activity exhibited a marked 24 hr rhythm in cerebral cortex, lung and liver, with peak activity coincident with the melatonin and total antioxidant status peaks. The exposure of chicks to constant light for 7 days eliminated the melatonin rhythm as well as the peaks in superoxide dismutase activity and the total antioxidant status. These findings suggest that the melatonin rhythm may be related to the nighttime increase in the superoxide dismutase activity and to total antioxidant capacity of the blood.

Animals↗
PubMed2001

Melatonin, vitamin E, and estrogen reduce damage induced by kainic acid in the hippocampus: potassium-stimulated GABA release.

Melatonin, vitamin E and estrogen have been shown to exert neuroprotective effects against kainic acid (KA)-induced damage in the hippocampus. The aim of the present study was to examine the changes in potassium-evoked gamma-aminobutyric acid (GABA) release in the hippocampus of KA-treated rats and to test the possible protective effects of melatonin, vitamin E or estrogen. Following the treatment of mice with KA, a marked reduction in potassium-evoked [3H]GABA release was observed. Melatonin or estrogen prevented the reduction in potassium-evoked GABA release due to kainate administration. Vitamin E also exhibited some protective effect, but it was less than that provided by melatonin or estrogen. Melatonin, estrogen and, to a lesser extent, vitamin E reduce the physiological toxicity of KA. Since KA is believed to cause neuronal alterations via oxidative processes, it is assumed that the free radical scavenging and oxidative properties of melatonin, estrogen and vitamin E account for the protective effects of these agents.

Animals↗
PubMed2001

Effect of melatonin on cell growth, metabolic activity, and cell cycle distribution.

We have recently demonstrated that the pineal secretory product melatonin inhibits the key transcriptional regulator nuclear factor-kappa B (NF-kappa B). As the activation of NF-kappa B is known to regulate the expression of cellular genes associated with cell cycle progression, cell growth, and differentiation, we investigated the effect of melatonin treatment on several cellular processes. These include cell viability, metabolic activity, and cell cycle phase distribution. Human embryonic kidney (293S) cells were treated with melatonin at concentrations of 0.02, 0.2, or 2 mM. When cell viability was measured 24, 48, and 72 hr after continuous exposure to melatonin using the trypan blue dye exclusion method, no significant cell death was observed. Even after exposure to 2 mM melatonin for 72 hr, cell viability remained at 98%. In contrast, another antioxidant compound, pyrrolidine dithiocarbomate (PDTC), at a 2 mM concentration reduced cell viability to 80.7+/-2.1% as early as 24 hr compared with untreated controls (P<0.05). When the metabolic activity was determined at 24, 48, and 72 hr using the colorimetric MTT assay, no significant changes in metabolic activity were observed. Even if the cells were treated with 10 mM melatonin for 72 hr, the metabolic activity was similar to that of the control cells. When cell cycle analysis was performed by flow cytometry, no marked difference in cell cycle distribution was observed. Melatonin at a concentration of 2 mM, however, did slightly alter the cell cycle (percentage of S phase cells) at 48 hr. This study revealed that when 293S cells are treated with concentrations of melatonin up to 2 mM, no significant alterations in three important cellular functions occurred. Exogenously added melatonin appeared to have a limited influence on the normal functioning of the cells even when the exposure continued for 72 hr.

Adjuvants, Immunologic↗
PubMed2001

Melatonin suppresses homocysteine enhancement of serotonin-induced vasoconstriction in the human umbilical artery.

Hyperhomocysteinemia is a major and independent risk factor for vascular disease. Oxidative stress is a possible mechanism for homocysteine (Hcy)-induced endothelial dysfunction. Herein, we evaluated the antioxidant property of melatonin as related to the vasospastic effect of Hcy on the human umbilical artery. Helical strips of human umbilical arteries with intact endothelium were obtained at elective Caesarean delivery between 37 and 39 wks of gestation. Changes in 5-hydroxytryptamine (5-HT)-induced vasoconstriction were measured. Arterial strips were treated with FeSO4 (10 microM) and Hcy (10 or 100 microM) or pre-treated with a hydroxyl radical (.OH) scavenger (mannitol, 20 mM), a cyclooxygenase inhibitor (indomethacin, 20 microM), nitric oxide (NO) synthesis inhibitor (L-NG-monomethylarginine, LNMA, 200 microM), or melatonin (1 or 10 microM). Hcy potentiated 5-HT-induced constriction in a concentration-dependent manner. Pre-treatment with mannitol significantly suppressed the vasospastic effect of Hcy. LNMA augmented the vasospastic effect of Hcy, but indomethacin did not. Melatonin significantly suppressed the vasospastic effect of Hcy in a concentration-dependent manner. These findings suggest that Hcy potentiates 5-HT-induced vasoconstriction in the human umbilical artery, possibly by suppressing bioavailable NO. Melatonin protects against the vasospastic effect of Hcy, most likely by scavenging.OH arising from Hcy autooxidation.

Antioxidants↗
PubMed2001

Role of extracellular calcium on the regulation of melatonin synthesis in the Syrian hamster pineal gland.

The role of extracellular calcium on the induction of cyclic AMP production, N-acetyltransferase (NAT) activity and melatonin synthesis, induced by forskolin, was investigated in Syrian hamster pineal glands. Pineals were removed from hamsters killed either in the first half of the normal dark period or late in the dark period. Forskolin immediately increased NAT activity and melatonin levels only when the glands were collected late in the dark period, while in the first half of the dark phase, hamster pineals responded to forskolin with an increase of NAT activity and melatonin production only after 6 hr of incubation. The absence of calcium prevented the induction of melatonin synthesis by forskolin only when glands were collected early in the dark phase and incubated for 6 hr. In the second half of the normal dark period removal of calcium markedly decreased NAT activity and melatonin levels in glands incubated with forskolin for either 4 or 6 hr. However, the absence of extracellular calcium had no significant effect on the induction of cyclic AMP production by forskolin in pineals collected either early in the dark period or late in the dark phase. These data indicate that at least part of the action of extracellular calcium is indirect and that it affects steps in the induction of melatonin synthesis beyond the accumulation of cAMP.

Animals↗
PubMed2001

Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin.

Free radicals have been implicated in the pathogenesis of neonatal asphyxia and its complications. This study measured a product of lipid peroxidation, malondialdehyde, and the nitrite/nitrate levels in the serum of 20 asphyxiated newborns before and after treatment with the antioxidant melatonin given within the first 6 hr of life. Ten asphyxiated newborns received a total of 80 mg of melatonin (8 doses of 10 mg each separated by 2-hr intervals) orally. One blood sample was collected before melatonin administration and two additional blood samples (at 12 and 24 hr) were collected after giving melatonin. A third group of healthy newborn children served as controls. Serum malondialdehyde and nitrite+nitrate concentrations in newborns with asphyxia before treatment were significantly higher than those in infants without asphyxia. In the asphyxiated newborns given melatonin, there were significant reductions in malondialdehyde and nitrite/nitrate levels at both 12 and 24 hr. Three of the 10 asphyxiated children not given melatonin died within 72 hr after birth; none of the 10 asphyxiated newborns given melatonin died. The results indicate that the melatonin may be beneficial in the treatment of newborn infants with asphyxia. The protective actions of melatonin in this study may relate to the antioxidant properties of the indole as well as to the ability of melatonin to increase the efficiency of mitochondrial electron transport.

Antioxidants↗
PubMed2001

Melatonin in plants.

Once thought to be exclusively a molecule of the animal kingdom, melatonin has now been found to exist in plants as well. Among a number of actions, melatonin is a direct free radical scavenger and an indirect antioxidant. Melatonin directly detoxifies the hydroxyl radical (OH), hydrogen peroxide, nitric oxide, peroxynitrite anion, peroxynitrous acid, and hypochlorous acid. The products from each of these reactions have been identified in pure chemical systems and in at least one case in vivo; the interaction product of melatonin with the OH, ie., cyclic 3-hydroxymelatonin, is found in the urine of humans and rats. Some of the products that are produced when melatonin detoxifies reactive species are also highly efficient scavengers. As a result, a cascade of scavenging reactions may enhance the antioxidant capacity of melatonin. Additionally, melatonin increases the activity of several antioxidative enzymes, thereby improving its ability to protect macromolecules from oxidative stress. Melatonin is endogenously produced and is also consumed in edible plants. In animal experiments, feeding melatonin-containing foods raised blood levels of the indole. Because physiologic concentrations of melatonin in the blood are known to correlate with the total antioxidant capacity of the serum, consuming food-stuffs containing melatonin may be helpful in lowering oxidative stress.

Absorption↗
PubMed2001

Melatonin attenuates estradiol-induced oxidative damage to DNA: relevance for cancer prevention.

Estrogens exert pro-oxidative effects and have been shown to damage DNA, potentially leading to cancer. Melatonin is a well-known antioxidant, free radical scavenger, and oncostatic agent. Changes in the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), an index of DNA damage, and the levels of malondialdehyde + 4-hydroxyalkenals, an index of lipid peroxidation, were measured in kidneys, liver, and testes from hamsters treated with E2 (75 mg/kg body wt) and were collected 3 or 5 hr later. Other animals were treated with melatonin (15 mg/kg body wt, 30 min before and 120 min after E2 treatment) or were given both compounds. Additionally, lipid peroxidation was measured in liver homogenates exposed to ferrous sulfate (15 microM) in vitro. E2 treatment caused an increase in 8-oxodGuo levels in kidneys collected 5 hr after E2 administration, and in liver 3 hr after estrogen treatment. Melatonin completely prevented E2-induced DNA damage in both organs. Melatonin alone or when given with E2 and examined 3 hr later decreased the base level of 8-oxodGuo in testes. A tendency for a reduction in in vivo lipid peroxidation was observed after treatment of hamsters with either melatonin, E2, or both compounds, with a statistically significant decrease being measured in the liver following E2 administration. In vitro exposure to iron significantly enhanced lipid peroxidation in hepatic homogenates from untreated, melatonin-treated, or E2-injected hamsters; in the hepatic homogenates of hamsters given both E2 and melatonin, ferrous sulfate failed to augment lipid peroxidation. Our results confirm the dual actions of estrogens relative to oxidative damage, i.e., estrogen increases oxidative destruction of DNA while reducing lipid peroxidation. Melatonin had antioxidative actions in reducing oxidative damage to both DNA and to membrane lipids. Melatonin completely prevented the damaging action of E2 on DNA and synergized with the steroid to reduce lipid peroxidation.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2001

Effects of melatonin treatment in septic newborns.

Free radicals have been implicated in the pathogenesis of neonatal sepsis and its complications. This study was conducted to determine the changes in the clinical status and the serum levels of lipid peroxidation products [malondialdehyde (MDA) and 4-hydroxylalkenals (4-HDA)] in 10 septic newborns treated with the antioxidant melatonin given within the first 12 h after diagnosis. Ten other septic newborns in a comparable state were used as "septic" controls, while 10 healthy newborns served as normal controls. A total of 20 mg melatonin was administered orally in two doses of 10 mg each, with a 1-h interval. One blood sample was collected before melatonin administration and two additional blood samples (at 1 and 4 h) were collected after melatonin administration to assess serum levels of lipid peroxidation products. Serum MDA + 4-HDA concentrations in newborns with sepsis were significantly higher than those in healthy infants without sepsis; in contrast, in septic newborns treated with melatonin there was a significant reduction (p < 0.05) of MDA + 4-HDA to the levels in the normal controls at both 1 and 4 h (p < 0.05). Melatonin also improved the clinical outcome of the septic newborns as judged by measurement of sepsis-related serum parameters after 24 and 48 h. Three of 10 septic children who were not treated with melatonin died within 72 h after diagnosis of sepsis; none of the 10 septic newborns treated with melatonin died. To our knowledge, this is the first study where melatonin was given to human newborns.

Apgar Score↗
PubMed2001

Characterization of nocturnal ultradian rhythms of melatonin in children with growth hormone-dependent and independent growth delay.

To assess the existence of a possible nocturnal ultradian rhythm of melatonin in children, we analyzed 28 pediatric patients (mean age, 9.08 +/- 2.2 yr) with GH-dependent and GH-independent growth delay. Plasma melatonin was measured by RIA in children sampled every 30 min between 2100-0900 h. Statistical analysis consisted of cluster analysis to examine the presence of peaks and troughs. The pattern of melatonin levels was related to the cause of growth delay, although the means of the nocturnal concentrations of melatonin were similar in all children. Interestingly, children with a GH deficit showed a nearly normal melatonin profile, whereas children with normal GH values but abnormal growth displayed atypical profiles of melatonin. The results also prove the existence of an ultradian rhythm of melatonin in most of the patients studied. The ultradian rhythm of melatonin in children was characterized by irregular interburst intervals, thus differing from the rhythm previously described in adults that had an almost constant pulse frequency. Moreover, the existence of low and high melatonin producers was revealed in the study, a feature unrelated to the cause of growth delay. The group of children with a GH deficit showed the lowest values of integrated melatonin production and of the area of peaks and troughs. These results prove that children exhibit an ultradian rhythm of melatonin like that in adults. Whereas it is not clear whether the episodic production of melatonin is required for its biological actions, the existence of irregular pulses may reflect endocrine influences at this age and/or the immaturity of the intrinsic pulse generator.

Adult↗
PubMed2001

Individual and synergistic antioxidative actions of melatonin: studies with vitamin E, vitamin C, glutathione and desferrioxamine (desferoxamine) in rat liver homogenates.

The pharmacological effects of melatonin, vitamin E, vitamin C, glutathione and desferrioxamine (desferoxamine) alone and in combination on iron-induced membrane lipid damage in rat liver homogenates were examined by estimating levels of malondialdehyde and 4-hydroxyalkenals (MDA+4-HDA). Individually, melatonin (2.5-1600 microM), vitamin E (0.5-50 microM), glutathione (100-7000 microM) and desferrioxamine (1-8 microM) inhibited lipid peroxidation in a concentration-dependent manner. Vitamin C had both a pro-oxidative (25-2000 microM) and an antioxidative (2600-5000 microM) effect. The IC50 (concentration that reduces damage by 50%) values were 4, 10, 426, 2290 and 4325 microM for vitamin E, desferrioxamine, melatonin, glutathione and vitamin C, respectively. The synergistic actions of melatonin with vitamin C, vitamin E, and glutathione were systematically investigated. When melatonin was combined with vitamin E, glutathione, or vitamin C, the protective effects against iron-induced lipid peroxidation were dramatically enhanced. Even though melatonin was added at very low concentrations, it still showed synergistic effects with other antioxidants at certain concentrations. Furthermore, melatonin not only reversed the pro-oxidative effects of vitamin C, but its efficacy in reducing lipid peroxidation was improved when it was combined with pro-oxidative concentrations of vitamin C. The results provide new information in terms of the possible pharmacological use of the combination of melatonin and classical antioxidants to treat free radical-related conditions.

Animals↗
PubMed2001

Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence.

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 (H202) 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 (1H NMR) and COSY 1H 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 H2O2, singlet oxygen (1O2) and nitric oxide (NO*), with little or no ability to scavenge the superoxide anion radical (O2*-) 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 detoxify both reactive oxygen and reactive nitrogen species; in vivo, it is an effective pharmacological agent in reducing oxidative damage under conditions in which excessive free radical generation is believed to be involved.

Animals↗
PubMed2001

Gastric toxicity and mucosal ulceration induced by oxygen-derived reactive species: protection by melatonin.

Uncontrolled hydrochloric acid secretion and ulceration of the stomach mucosa due to various factors are serious global problems. Although the mechanism of acid secretion from the parietal cell is now well understood, the processes involved in gastric ulceration are still not clear. Among various causes of gastric ulceration, lesions caused by stress, alcohol consumption, Helicobacter pylori infection and due to use of nonsteroidal antiinflammatory drugs have been shown to be mediated largely through the generation of reactive oxygen species, especially the hydroxyl radical. A number of excellent drugs have proven useful in controlling hyperacidity and ulceration but their long-term use is associated with disturbing side-effects. Hence, the search is still on to find a compound possessing antisecretory, antiulcer and antioxidant properties which will serve as a therapeutic agent to reduce gastric hyperacidity and ulcers. This article describes the role of reactive oxygen species in gastric ulceration, drugs controlling them with their merits and demerits and, the role of melatonin, a pineal secretory product, in protecting against gastric lesions. In experimental studies, melatonin has been shown to be effective in reducing mucosal breakdown and ulcer formation in a wide variety of situations. Additionally, the low toxicity of melatonin supports further investigation of this molecule as a gastroprotective agent. Finally, we include a commentary on how melatonin research with respect to gastric pathophysiology can move forward with a view of eventually using this indole as a therapeutic agent to control gastric ulceration in humans.

Animals↗
PubMed2001

Indole-3-propionic acid, a melatonin-related molecule, protects hepatic microsomal membranes from iron-induced oxidative damage: relevance to cancer reduction.

Excessive free iron and the associated oxidative damage are commonly related to carcinogenesis. Among the antioxidants known to protect against iron-induced oxidative abuse and carcinogenesis, melatonin and other indole compounds recently have received considerable attention. Indole-3-propionic acid (IPA), a deamination product of tryptophan, with a structure similar to that of melatonin, is present in biological fluids and is an effective free radical scavenger. The aim of the study was to examine the effect of IPA on experimentally induced oxidative changes in rat hepatic microsomal membranes. Microsomes were preincubated in presence of IPA (10, 3, 2, 1, 0.3, 0.1, 0.01 or 0.001 mM) and, then, incubated with FeCl(3) (0.2 mM), ADP (1.7 mM) and NADPH (0.2 mM) to induce oxidative damage. Alterations in membrane fluidity (the inverse of membrane rigidity) were estimated by fluorescence spectroscopy and lipid peroxidation by measuring concentrations of malondialdehyde+4-hydroxyalkenals (MDA+4-HDA). IPA, when used in concentrations of 10, 3 or 2 mM, increased membrane fluidity, although at these concentrations it did not influence lipid peroxidation significantly. The decrease in membrane fluidity due to Fe(3+) was completely prevented by preincubation in the presence of IPA at concentrations of 10, 3, 2 or 1 mM. The enhanced lipid peroxidation due to Fe(3+) was prevented by IPA only at the highest concentration (10 mM). It is concluded that Fe(3+)-induced rigidity and, to a lesser extent, lipid peroxidation in microsomal membranes may be reduced by IPA. However, IPA in high concentrations increase membrane fluidity. Besides melatonin, IPA may be used as a pharmacological agent to protect against iron-induced oxidative damage to membranes and, potentially, against carcinogenesis.

Adenosine Diphosphate↗
PubMed2001

Protective role of melatonin against MPTP-induced mouse brain cell DNA fragmentation and apoptosis in vivo.

OBJECTIVES: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that induces a Parkinsonian-type syndrome in animals which is similar to Parkinson's disease in humans. MPTP toxicity partially depends on the production of free radicals which in turn play a key role in the apoptotic death of neurons. In the present study melatonin, a potent free radical scavenger with antiapoptotic properties, was given to determine whether it would reduce oxidative stress in mice treated with MPTP. MATERIALS AND METHODS: Male mice were given MPTP with or without melatonin and the brain was studied either 6h, 24h, 7 days or 15 days after the last MPTP injection. RESULTS: The results show that melatonin counteracted in vivo MPTP-induced apoptosis in midbrain neurons at 6 and 24 h after MPTP treatment, and partially prevented apoptosis at 7 and 15 days after MPTP administration. MPTP treatment also produced time-dependent cell damage, whereas melatonin reduced the percentage of damaged cells at all time points, the effect being most evident at 15 days after treatment. Moreover, melatonin counteracted MPTP-dependent DNA fragmentation in the midbrain and striatum at 7 and 15 days after drug administration. CONCLUSION: These results support a role for melatonin in protecting neurons against MPTP toxicity in vivo, and suggest that its antiapoptotic action is one of the mechanisms by which melatonin protects neuronal cells from neurotoxic insults.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Different patterns in the histology and autofluorescence of the Harderian glands of the Syrian Hamster, rat, mouse, Mongolian gerbil and guinea pig.

The purpose of this study was to compare the natural fluorescence in the Harderian glands of the Syrian hamster, rat, mouse, Mongolian gerbil and guinea pig (both sexes). For each species, 10 animals (five males and five females) were used. Histological autofluorescence studies were performed using a fluorescence microscope (450-490 nm filter). Two different types of fluorescent cells were observed in both hamster (type AFI high intensity and type AFII, low fluorescence) and rat (type AFI, low fluorescence and type AFII, high fluorescence) Harderian glands. The fluorescence was basally located in all mice cells, whereas it was observed near the epithelial cell nuclei in the Mongolian gerbil (occupying two-thirds and one-third of the cells in males and females, respectively). A high intensity of fluorescence was present throughout the acinar cells in the guinea pig. The patterns of fluorescence identified exhibited a sexual dimorphism in all species studied. These results demonstrate that the Harderian glands of the animal species examined exhibit a variety of histological autofluorescence patterns.

Animals↗
PubMed2001

Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.

This review briefly summarizes the multiple actions by which melatonin reduces the damaging effects of free radicals and reactive oxygen and nitrogen species. It is well documented that melatonin protects macromolecules from oxidative damage in all subcellular compartments. This is consistent with the protection by melatonin of lipids and proteins, as well as both nuclear and mitochondrial DNA. Melatonin achieves this widespread protection by means of its ubiquitous actions as a direct free radical scavenger and an indirect antioxidant. Thus, melatonin directly scavenges a variety of free radicals and reactive species including the hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide, peroxynitrite anion, and peroxynitrous acid. Furthermore, melatonin stimulates a number of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Additionally, melatonin experimentally enhances intracellular glutathione (another important antioxidant) levels by stimulating the rate-limiting enzyme in its synthesis, gamma-glutamylcysteine synthase. Melatonin also inhibits the proxidative enzymes nitric oxide synthase and lipoxygenase. Finally, there is evidence that melatonin stabilizes cellular membranes, thereby probably helping them resist oxidative damage. Most recently, melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce election leakage and the generation of free radicals. These multiple actions make melatonin a potentially useful agent in the treatment of neurological disorders that have oxidative damage as part of their etiological basis.

Animals↗