Serotonin Acts as a Radical Scavenger and Is Oxidized to a Dimer During the Respiratory Burst of Activated Microglia

Huether, Gerald; Fettkötter, Inga; Keilhoff, Gerburg; Wolf, Gerald

doi:10.1046/j.1471-4159.1997.69052096.x

Cited by 49 publications

(32 citation statements)

References 38 publications

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“…Although pyrrole-ring cleavage represents a classic pathway of tryptophan catabolism, this is not generally the case with the oxidation of other indoles. That investigation demonstrated for the first time the formation of kynuramines from an indoleamine, whereas non-acetylated compounds like serotononin are predominantly catabolized by MAO A, as discussed above, and 5-hydroxylated indoles, such as serotonin and NAS frequently form dimers in non-enzymatic redox reactions [10,56].…”

Section: The Kynuramine Pathwaymentioning

confidence: 77%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

112

110

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Abstract:The metabolism of melatonin in the central nervous system is of interest for several reasons. Melatonin enters the brain either via the pineal recess or by uptake from the blood. It has been assumed to be also formed in some brain areas. Neuroprotection by melatonin has been demonstrated in numerous model systems, and various attempts have been undertaken to counteract neurodegeneration by melatonin treatment. Several concurrent pathways lead to different products. Cytochrome P 450 subforms have been demonstrated in the brain. They either demethylate melatonin to Nacetylserotonin, or produce 6-hydroxymelatonin, which is mostly sulfated already in the CNS. Melatonin is deacetylated, at least in pineal gland and retina, to 5-methoxytryptamine. N 1 -acetyl-N 2 -formyl-5-methoxykynuramine is formed by pyrrole-ring cleavage, by myeloperoxidase, indoleamine 2,3-dioxygenase and various non-enzymatic oxidants. Its product, N 1 -acetyl-5-methoxykynuramine, is of interest as a scavenger of reactive oxygen and nitrogen species, mitochondrial modulator, downregulator of cyclooxygenase-2, inhibitor of cyclooxygenase, neuronal and inducible NO synthases. Contrary to other nitrosated aromates, the nitrosated kynuramine metabolite, 3-acetamidomethyl-6-methoxycinnolinone, does not re-donate NO. Various other products are formed from melatonin and its metabolites by interaction with reactive oxygen and nitrogen species. The relative contribution of the various pathways to melatonin catabolism seems to be influenced by microglia activation, oxidative stress and brain levels of melatonin, which may be strongly changed in experiments on neuroprotection. Many of the melatonin metabolites, which may appear in elevated concentrations after melatonin administration, possess biological or pharmacological properties, including N-acetylserotonin, 5-methoxytryptamine and some of its derivatives, and especially the 5-methoxylated kynuramines.

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Section: The Kynuramine Pathwaymentioning

confidence: 77%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

112

110

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“…For the HPLC assay, 100 M serotonin was incubated with 3 mM H 2 O 2 and 500 nM A␤-heme in 50 mM Hepes, pH 7.2. At specific time intervals, the oxidation products of serotonin were analyzed by injecting 23.5 l from the reaction mixture into RP-HPLC on a 300-ϫ 3.9-mm column of Bond-Clone-C18 (Phenomenex) by using as mobile-phase 10% methanol, pH 3 (48). Serotonin or oxidation products were analyzed with a UV-online detector set at 280 nm.…”

Section: Preparation Of Hemementioning

confidence: 99%

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Atamna¹,

Boyle²

2006

Proc. Natl. Acad. Sci. U.S.A.

269

279

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Amyloid-␤ peptide (A␤) is the toxic agent in Alzheimer's disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive A␤ binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD. We demonstrated that HD triggers the release of oxidants (e.g., H 2O2) from mitochondria due to the loss of complex IV, which contains heme-a. Now we add more evidence that A␤ binding to regulatory heme in vivo is the mechanism by which A␤ causes HD. Heme binds to A␤, thus preventing A␤ aggregation by forming an A␤-heme complex in a cell-free system. We suggest that this complex depletes regulatory heme, which would explain the increase in heme synthesis and iron uptake we observe in human neuroblastoma cells. The A␤-heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H 2O2. Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of A␤ to heme supports a unifying mechanism by which excessive A␤ induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive A␤ for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.curcumin ͉ heme deficiency ͉ mitochondria ͉ regulatory heme ͉ serotonin

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“…Activation of immune and inflammatory response favors production of reactive oxygen species (ROS) by various mechanisms (Adibhalta et al, 2008;Adibhatla and Hatcher, 2006;Fialkow et al, 2007;Guzik et al, 2003;Im et al, 2006; Winterbourn, 2002). Another mechanism which is a source of ROS in the course of depression is deficiency of monoamines-important free radical scavengers (Heuther et al, 1997;Pandey et al, 1992). On the other hand, increased metabolism of monoamines is another pathway of ROS generation in depression (Fridovich, 1983).…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients

Gałecki

Szemraj

Bieńkiewicz

et al. 2009

Human Psychopharmacology

119

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The obtained results indicate a significant decrease in the activity of SOD1, CAT and GSHP-x, as well as in MDA concentration after the combined therapy. Also a significant TAS increase was observed after the combined therapy. The study demonstrated that combined therapy with fluoxetine and ASA is characterized by the same efficacy and clinical safety as fluoxetine monotherapy, resulting additionally in improvement of oxidative stress parameters in the patients treated for depression.

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Serotonin Acts as a Radical Scavenger and Is Oxidized to a Dimer During the Respiratory Burst of Activated Microglia

Cited by 49 publications

References 38 publications

Melatonin Metabolism in the Central Nervous System

Melatonin Metabolism in the Central Nervous System

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients

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