Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation

Tan, Dun Xian; Manchester, Lucien C.; Reíter, Russel J.; Plummer, Benjamin F.; Limson, Janice; Weintraub, Susan E; Qi, Wenbo

doi:10.1016/s0891-5849(00)00435-4

Cited by 424 publications

(347 citation statements)

References 34 publications

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“…Thus, it is necessary that use of antioxidants that penetrates the bloodbrain barrier such as melatonin [24]. Melatonin displays important antioxidant properties based on its free radical scavenger ability [46,48,52,53] and, in contrast to conventional antioxidants, rapidly crosses the blood-brain barrier after systemic administration and reaches every neuronal compartment [41]. Melatonin also regulates the expression and activity of the redox enzymes [9,16].…”

Section: Discussionmentioning

confidence: 99%

“…Experiments in vivo and in vitro have shown that melatonin promotes mitochondrial phosphorylation and ATP synthesis interacting with the electron transport chain complexes I and IV [5,[37][38][39]. These effects are related to the antioxidant role of melatonin, since it scavenges hydrogen peroxide [53] and increases mitochondrial GSH levels, counteracting the oxidative stress-induced mitochondrial damage [37]. These data, with those reporting an effect of melatonin on mitochondrial inner membrane fluidity [22], further support that mitochondria are an important target for melatonin action [2,5].…”

Section: Discussionmentioning

confidence: 99%

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Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion

Khaldy

Escames

León

et al. 2003

Neurobiology of Aging

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Previous studies showed a synergistic effect of melatonin and deprenyl against dopamine (DA) autoxidation in vitro. Since oxidative stress is implicated in Parkinson's disease (PD), we explored the effects of melatonin plus deprenyl administration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in C57/Bl6 mice. Melatonin, but not deprenyl prevents the inhibition of mitochondrial complex I and the oxidative damage in nigrostriatal neurons induced by MPTP. With the dose used deprenyl recovers 50% DA levels and tyrosine hydroxylase activity depressed by the neurotoxin, normalizing locomotor activity of mice. Melatonin, which was unable to counteract MPTP-induced DA depletion and inhibition of tyrosine hydroxylase activity, potentiates the effect of deprenyl on catecholamine turnover and mice ambulatory activity. These results suggest a dissociation of complex I inhibition from DA depletion in this model of Parkinson's disease. The data also support that a combination of melatonin, which improves mitochondrial electron transport chain and reduces oxidative damage, and deprenyl, which promotes the specific function of the rescued neurons, i.e. DA turnover, may be a promising strategy for the treatment of PD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion

Khaldy

Escames

León

et al. 2003

Neurobiology of Aging

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“…Melatonin (N-acetyl-5-metyoxytr yptamine), a secretory product of the pineal gland, is a powerful endogenous antioxidant, regulates circadian rhythms, sleep and immune system activity, behaves as a free radical scavenger [4] , eliminates oxygen free radicals and reactive intermediates [5][6][7][8][9] . Both in vitro and in vivo experiments have shown that melatonin can protect cells, tissues, and organs against oxidative damage induced by a variety of free-radical-generating agents and processes, such as safrole, lipopolysaccharide (LPS), carbon tetrachloride (CCl 4 ), ischemia-reperfusion, amyloid-protein, and ionizing radiation [10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Melatonin ameliorates experimental hepatic fibrosis induced by carbon tetrachloride in rats

Ren¹,

Xu²,

Qiao³

2009

WJG

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AIM:To investigate the protective effects of melatonin on carbon tetrachloride (CCl 4 )-induced hepatic fibrosis in experimental rats. METHODS:All rats were randomly divided into normal control group, model control group treated with CCl 4 for 12 wk, CCl 4 + NAC group treated with CCl 4 + NAC (100 mg/kg, i.p.) for 12 wk, CCl 4 + MEL-1 group treated with CCl 4 + melatonin (2.5 mg/kg) for 12 wk, CCl 4 + MEL-2 group treated with CCl 4 + melatonin (5.0 mg/kg) for 12 wk, and CCl 4 + MEL-3 group treated with CCl 4 + melatonin (10 mg/kg). Rats in the treatment groups were injected subcutaneously with sterile CCl 4 (3 mL/kg, body weight) in a ratio of 2:3 with olive oil twice a week. Rats in normal control group received hypodermic injection of olive oil at the same dose and frequency as those in treatment groups. At the end of experiment, rats in each group were anesthetized and sacrificed. Hematoxylin and eosin (HE) staining and Van Gieson staining were used to examine changes in liver pathology. Serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and protein concentration were measured with routine laboratory methods using an autoanalyzer. Hydroxyproline (HYP) content in liver and malondialdehyde (MDA) and glutathione peroxidase (GPx) levels in liver homogenates were assayed by spectrophotometry. Serum hyaluronic acid (HA), laminin (LN), and procollagen Ⅲ N-terminal peptide (PⅢNP) were determined by radioimmunoassay. RESULTS:Pathologic grading showed that the fibrogenesis was much less severe in CCl 4 + MEL3 group than in model control group (u = 2.172, Moreover, treatment with melatonin (5, 10 mg/kg) significantly reduced the MDA content and increased the GPx activity in liver homogenates compared with model control group (MDA: 7.89 ± 1.49 noml/mg prot vs 6.29 ± 1.42 noml/mg prot and 6.25 ± 2.27 noml/mg prot, respectively, P = 0.015, P = 0.015; GPx: 49.13 ± 8.72 U/mg prot vs 57.38 ± 7.65 U/mg prot and 61.39 ± 13.15 U/mg prot, respectively, P = 0.035, P = 0.003). CONCLUSION:Melatonin can ameliorate CCl 4 -induced hepatic fibrosis in rats. The protective effect of melatonin on hepatic fibrosis may be related to its antioxidant activities.

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“…Melatonin has been reported to have antioxidant activity [25,26]. It can act directly by scavenging reactive species such as hydroxyl [47], H 2 O 2 [46], NO [48], and peroxynitrite [6,56]; or it can act indirectly by inducing antioxidant enzymes [25,38]. Extended deprivation of melatonin can lead to elevated levels of oxidative damage [37].…”

Section: Introductionmentioning

confidence: 99%

Dietary melatonin selectively reverses age-related changes in cortical cytokine mRNA levels, and their responses to an inflammatory stimulus

Sharman

Yang

et al. 2002

Neurobiology of Aging

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The basal levels of expression of mRNA of cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF-␣), in the cerebral cortex of 5 and 26 month-old male B6C3F1 mice have been compared. In addition, the responsivity of animals of differing age to an inflammatory stimulus (lipopolysaccharide, LPS) has been studied. Basal levels of both of these cytokine mRNAs were elevated in aged animals relative to the younger group. However LPS administration led to a robust increase in cytokine mRNA levels in the younger animals but in aged mice, there was either an unchanged (IL-6) or a depressed (TNF-␣) response. Administration of dietary melatonin (200 ppm) to aged mice for 6 weeks prior to sacrifice, resulted in reduction of basal levels of cytokine mRNA to values found in the younger animals. Furthermore, following administration of LPS to melatonin fed animals, cerebral cytokine mRNA levels were significantly elevated rather than being unchanged or depressed. Taken together these findings reflect a trend in the cortices of melatonin-treated aged mice, to more closely approximate the status of younger mice. For comparative purposes, parallel studies were carried out using an immunologically active organ (spleen) and a non-neural organ with a low rate of cell turnover (heart muscle). In both these tissues, basal levels of cytokine mRNAs of animals of either age were very low, and there was a marked positive response to LPS. Dietary melatonin had no effect on the responses of TNF-␣ mRNA to LPS but attenuated the reaction of splenic IL-6 mRNA, thus bringing the response closer to that of the younger mice.

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Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation

Cited by 424 publications

References 34 publications

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion

Melatonin ameliorates experimental hepatic fibrosis induced by carbon tetrachloride in rats

Dietary melatonin selectively reverses age-related changes in cortical cytokine mRNA levels, and their responses to an inflammatory stimulus

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