Analysis of N1-acetyl-N2-formyl-5-methoxykynuramine/N1-acetyl-5-methoxy-kynuramine formation from melatonin in mice

Niu, Sida; Li, Feng; Tan, Dun Xian; Zhang, Lirong; Idle, Jeffrey R.; Gonzalez, Frank J.; Ma, Xiaochao

doi:10.1111/j.1600-079x.2010.00771.x

Cited by 15 publications

(16 citation statements)

References 36 publications

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“…This result is supported by previous studies which showed that melatonin maintained or attenuated the reduction of neurogenesis after irradiation [28, 54] or pinealectomy [30]. In addition, N 1 ‐acetyl‐N 2 ‐formyl‐5‐methoxykynuramine, a melatonin metabolite, which is also an antioxidant [55, 56], significantly ameliorated a radiation‐induced impairment in spatial memory and a reduction in immature and proliferating neurons in the dentate gyrus based on DCX and Ki‐67 immunohistochemistry [29].…”

Section: Discussionsupporting

confidence: 80%

Melatonin improves d‐galactose‐induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression

Yoo

Kim

Lee

et al. 2011

Journal of Pineal Research

116

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Melatonin (N-acetyl-5-methoxytryptamine) has multiple functions. In this study, we investigated the effects of melatonin on memory, cell proliferation, and neuroblast differentiation in the dentate gyrus of a mouse model of D-galactose-induced aging. D-galactose was subcutaneously administered to 7-wk-old mice for 10 wk, and age-matched mice were used as controls. Seven weeks after D-galactose administration, vehicle (water) or melatonin (6 mg/L in water) was administered ad libitum to the mice for 3 wk. The administration of D-galactose significantly increased the escape latency compared with that in the control mice on days 1-3. In addition, cells in the subgranular zone and in the granule cell layer of the dentate gyrus showed severe damage (cytoplasmic condensation) in the D-galactose-treated mice. However, melatonin supplementation to these mice for 3 wk significantly ameliorated the D-galactose-induced increase in escape latency and neuronal damage compared with the vehicle-treated group. The administration of melatonin also significantly restored the D-galactose-induced reduction of proliferating cells (Ki67-positive cells) and differentiating neuroblasts (doublecortin-positive neuroblasts) in the dentate gyrus. Furthermore, the administration of melatonin significantly increased Ser133-phosphorylated cyclic AMP response element binding protein in the dentate gyrus. The administration of melatonin significantly reduced D-galactose-induced lipid peroxidation in the dentate gyrus. These results suggest that melatonin may be helpful in reducing age-related phenomena in the brain.

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Section: Discussionsupporting

confidence: 80%

Melatonin improves d‐galactose‐induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression

Yoo

Kim

Lee

et al. 2011

Journal of Pineal Research

116

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“…A recent study by Niu et al. raised some questions about the notion that AFMK and AMK are major melatonin metabolites. In their study, AFMK and AMK were not detected in several mouse tissues, including liver, brain, and eyes.…”

Section: Antioxidant Capacity Of Melatonin's Metabolitesmentioning

confidence: 99%

Melatonin: a well‐documented antioxidant with conditional pro‐oxidant actions

Zhang

2014

Journal of Pineal Research

705

565

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Melatonin (N-acetyl-5-methoxytryptamine), an indoleamine produced in many organs including the pineal gland, was initially characterized as a hormone primarily involved in circadian regulation of physiological and neuroendocrine function. Subsequent studies found that melatonin and its metabolic derivatives possess strong free radical scavenging properties. These metabolites are potent antioxidants against both ROS (reactive oxygen species) and RNS (reactive nitrogen species). The mechanisms by which melatonin and its metabolites protect against free radicals and oxidative stress include direct scavenging of radicals and radical products, induction of the expression of antioxidant enzymes, reduction of the activation of pro-oxidant enzymes, and maintenance of mitochondrial homeostasis. In both in vitro and in vivo studies, melatonin has been shown to reduce oxidative damage to lipids, proteins and DNA under a very wide set of conditions where toxic derivatives of oxygen are known to be produced. Although the vast majority of studies proved the antioxidant capacity of melatonin and its derivatives, a few studies using cultured cells found that melatonin promoted the generation of ROS at pharmacological concentrations (lM to mM range) in several tumor and nontumor cells; thus, melatonin functioned as a conditional pro-oxidant. Mechanistically, melatonin may stimulate ROS production through its interaction with calmodulin. Also, melatonin may interact with mitochondrial complex III or mitochondrial transition pore to promote ROS production. Whether melatonin functions as a pro-oxidant under in vivo conditions is not well documented; thus, whether the reported in vitro pro-oxidant actions come into play in live organisms remains to be established.

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“…The original assumption of a significant catabolism via the kynuramine route [234] has not received experimental support under normal, healthy conditions [279]. Perhaps, this pathway gains relevance under conditions of immune stimulation and/or brain inflammation, but the details remain to be identified.…”

Section: Resultsmentioning

confidence: 98%

“…Later, AFMK (9) was shown to be formed in macrophages, keratinocytes and nonvertebrate organisms [44]. However, a recent metabolomic study did not find substantial amounts of them in the murine brain [279]. Instead, a new, hydroxylated AMK metabolite and a glucuronide conjugate of this substance were discovered.…”

Section: Ramelteon (12) M-i (13)mentioning

confidence: 97%

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

Hardeland¹,

Pöeggeler²

2012

CNSAMC

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The CNS is both source and target of melatonin. This methoxyindole formed in the pineal gland is also produced in other CNS regions and additionally enters the brain by uptake from the circulation as well as via the pineal recess. The mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN), not only controls the pineal, but also receives a feedback information on darkness. Two G protein-coupled melatonin receptors, MT1 and MT2, are responsible for the transduction of many melatonergic actions. High receptor densities are especially found in the SCN, but their presence at lower expression levels in other areas is functionally important. Various metabolites and analogs are formed in the CNS, such as N-acetylserotonin, 5-methoxytryptamine, 5-methoxytryptophol, 5-methoxylated kynuramines, and even 6-sulfatoxymelatonin. The chronobiological effects of melatonin go beyond the resetting of a single circadian oscillator. They contribute to phase relationships between oscillatory subsets and are required for robust rhythm amplitudes. CNS effects of melatonin comprise sleep initiation, antiexcitatory, antiepileptic, antinociceptive, anxiolytic, proneurotrophic, antiinflammatory, antioxidant and other neuroprotective actions. The role as a sleep-promoting compound, which is limited by its short half-life in the circulation, has led to the development of controlled-release formulations and of various synthetic agonists, such as ramelteon, agomelatine, tasimelteon, TIK-301, UCM765 and UCM924. Their differences concerning receptor affinities, preferences for receptor subtypes, and pharmacokinetics are discussed, as well as additional antidepressive actions of agomelatine and TIK-301 based on properties as antagonists of the serotonergic 5-HT2C receptor. Indirect antidepressive effects by melatonergic drugs are largely explained by circadian readjustments.

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Analysis of N1-acetyl-N2-formyl-5-methoxykynuramine/N1-acetyl-5-methoxy-kynuramine formation from melatonin in mice

Cited by 15 publications

References 36 publications

Melatonin improves d‐galactose‐induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression

Melatonin improves d‐galactose‐induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression

Melatonin: a well‐documented antioxidant with conditional pro‐oxidant actions

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

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