- Oxidation of serotonin by superoxide radical: Implications to neurodegenerative brain disorders
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Many new lines of evidence implicate both superoxide anion radical (O2.-) and biogenic amine neurotransmitters in the pathological mechanisms that underlie neuronal damage caused by methamphetamine (MA), glutamate- mediated oxidative toxicity, ischemia-reperfusion, and other neurodegenerative brain disorders. In this investigation the oxidation of 5- hydroxytryptamine (5-HT, serotonin) by an O2.- -generating system (xanthine/xanthine oxidase) in buffered aqueous solution at pH 7.4 has been studied. The major product of the O2.- -mediated oxidation of 5-HT is tryptamine-4,5-dione (T-4,5-D). However, O2.- and H2O2, cogenerated by the xanthine oxidase-mediated oxidation of xanthine to uric acid, together react with trace levels of iron that contaminate buffer constituents to give a chemically ill-defined oxo-iron species. This species mediates the oxidation of 5-HT to a C(4)-centered carbocation intermediate that reacts with 5-HT to give 5,5'-dihydroxy-4,4'-bitryptamine (4,4'-D) and with uric acid to give 9-[3-(2-aminoethyl)-5-hydroxy-1H-indol-4-yl]-2,6,8-triketo- 1H,3H,7H-purine (7) as the major products. These products differ from those formed in the HO.-mediated oxidation of 5-HT under similar conditions. When the reaction is carried out in the presence of the intraneuronal nucleophile glutathione (GSH), T-4,5-D is scavenged to give 7-(S-glutathionyl)tryptamine- 4,5-dione, whereas the putative carbocation intermediate is scavenged to give 4-(S-glutathionyl)-5-hydroxytryptamine. T-4,5-D also reacts with the sulfhydryl residues of a model protein, alcohol dehydrogenase, and inhibits its activity. Previous investigators have proposed that T-4,5-D is a serotonergic neurotoxin. This raises the possibility that T-4,5-D and perhaps other putative intraneuronal metabolites formed by the O2.-/H2O2/oxo- iron-mediated oxidations of 5-HT might be endotoxins that contribute to neurodegeneration in brain regions innervated by serotonergic neurons caused by MA, ischemia-reperfusion, and other neurodegenerative brain disorders.
- Wrona, Monika Z.,Dryhurst, Glenn
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- Cytotoxic and cytoprotective effects of tryptamine-4,5-dione on neuronal cells: a double-edged sword
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Serotonin (5-hydroxytryptamine) is a putative substrate for myeloperoxidase, which may convert it into the reactive quinone tryptamine-4,5-dione (TD). In this study, we found that the viability of human SH-SY5Y neuroblastoma cells treated with 25 μM TD was increased to approximately 117%. On the other hand, the cell viability was significantly decreased by exposure to TD (150–200 μM), with an increase in intracellular reactive oxygen species (ROS). Interestingly, pre-treatment of SH-SY5Y cells with 100 μM TD prevented cell death and suppressed intracellular ROS generation evoked by the addition of hydrogen peroxide (H2O2). Expression of the phase-II antioxidant enzyme NAD(P)H: quinone oxidoreductase 1 and haem oxygenase 1 were upregulated by TD at a concentration of 50–100 μM. Nuclear factor erythroid 2-related factor 2 (Nrf2), the regulator of these enzyme, was translocated from the cytosol to the nucleus by 100 μM TD. In summary, moderate concentrations of TD may increase the self-defence capacity of neuronal cells against oxidative stress.
- Suga, Naoko,Murakami, Akira,Nakamura, Yoshimasa,Ishisaka, Akari,Kitamoto, Noritoshi,Ito, Mikiko,Kato, Yoji
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- Electrochemical oxidation of histamine and serotonin at highly boron- doped diamond electrodes
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The electrochemistry of histamine and serotonin in neutral aqueous media (pH 7.2) was investigated using polycrystalline, boron-doped diamond thin- film electrodes. Cyclic voltammetry, hydrodynamic voltammetry, and flow injection analysis (FIA) with amperometric detection were used to study the oxidation reactions. Comparison experiments were carried out using polished glassy carbon (GC) electrodes. At diamond electrodes, highly reproducible and well-defined cyclic voltammograms were obtained for histamine with a peek potential at 1.40 V vs SCE. The voltammetric signal-to-background ratios obtained at diamond were I order of magnitude higher than those obtained for GC electrodes at and above 100 μM analyte concentrations. A linear dynamic range of 3-4 orders of magnitude and a detection limit of 1 μM were observed in the voltammetric measurements. Well-defined sweep rate-dependent voltammograms were also obtained for 5-hydroxytryptamine (5-HT). The characteristics of the voltammogram indicated lack of adsorption of its oxidation products on the surface. No fouling or deactivation of the electrode was observed within the experimental time of several hours. A detection limit of 0.5 μM (signal-to-noise ratio 13.8) for histamine was obtained by use of the FIA technique with a diamond electrode. A remarkably low detection limit (10 nM) was obtained for 5-HT on diamond by the same method. Diamond electrodes exhibited a linear dynamic range from 10 nM to 100 μM for 5-HT determination and a range of 0.5-100 μM for histamine determination. The FIA response was very reproducible from film to film, and the response variability was below 7% at the actual detection limits.
- Sarada,Rao, Tata N.,Tryk,Fujishima
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- Neurotoxicity of free-radical-mediated serotonin neurotoxin in cultured embryonic chick brain neurons
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Exposure of serotonin (5-HT) to oxygen-derived free-radical-generating system, xanthine oxidase-hypoxanthine or to a Fenton reaction results in the formation of the neurotoxin, tryptamine-4,5-dione. In cultured embryonic chick brain neurons, incubation of tryptamine-4,5-dione or its ethyl carbonate derivative resulted in a dose-dependent neurotoxicity (1-100 μM). The addition of sulfhydryl compound, glutathione at 2 or 10 μM significantly enhanced the toxicity induced by 10 μM tryptamine-4,5-dione. On the contrary, glutathione at 10 μM decreased the neurotoxic effect caused by 10 μM 5,6- and 5,7-dihydroxytryptamine in the cultured neurons. The toxicity resulted from 5,6- and 5,7-dihydroxytryptamine could be fully prevented by a 5-HT uptake inhibitor, fluoxetine. However, the toxicity caused by tryptamine-4,5-dione and glutathione conjugate could not be blocked by fluoxetine (10 or 100 μM) or by a glutathione transferase inhibitor, boric acid/serine. The results indicate a different molecular mechanism among 5-HT derived neurotoxins and suggest that tryptamine-4,5-dione and/or its glutathione conjugate would cause neuronal damage, if they are formed in vivo.
- Chen, Jin-Chung,Fine, Richard E.,Squicciarini, Joseph,Volicer, Ladislav
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- Influence of L-Cysteine on the Oxidation Chemistry of Serotonin
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L-Cysteine (CySH) intervenes in the normal electrochemically driven oxidation of 5-hydroxytryptamine (5-HT; serotonin) at physiological pH by scavenging the quinone imine proximate oxidation product of this indolic neurotransmitter to give 4-S-cysteinyl-5-hydroxytryptamine (4-S-CyS-5-HT). The latter cysteinyl conjugate is more easily electro-oxidized than 5-HT and, in the presence of free CySH, undergoes a complex series of reactions leading to 8-(2-aminoethyl)-1,2,3,5,6,9-hexahydro-5,9-dioxo-pyrrolobenzothiazine-2-carboxylic acid (20) and N--3-(2-aminoethyl)-1,4-dihydro-4-oxo-5H-indol-5-ylidene>-L-cysteine (4). CySH also reacts with another normal oxidation product of 5-HT, tryptamine-4,5-dione, to give 4 and 20. There is evidence that aberrant oxidative metabolism of 5-HT occurs in the brains of Alzheimer's Disease patients. In the event that such reactions occur in the cytoplasm of serotonergic nerve terminals or axons they would necessarily expose electrophilic intermediates and products to the intraneuronal nucleophiles CySH and GSH. The results of this study indicate that 4 and 20 might represent aberrant oxidative metabolites formed in such reactions. However, the ease of oxidation of 4-S-CyS-5-HT compared to 5-HT suggest that this conjugate is likely to be only a transient species in vivo under conditions where the neurotransmitter is oxidized.
- Wrona, Monika Z.,Singh, Satendra,Dryhurst, Glenn
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- Serotonin as a physiological substrate for myeloperoxidase and its superoxide-dependent oxidation to cytotoxic tryptamine-4,5-dione
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During inflammatory events, neutrophils and platelets interact to release a variety of mediators. Neutrophils generate superoxide and hydrogen peroxide, and also discharge the haem enzyme myeloperoxidase. Among numerous other mediators, platelets liberate serotonin (5-hydroxytryptamine), which is a classical neurotransmitter and vasoactive amine that has significant effects on inflammation and immunity. In the present study, we show that serotonin is a favoured substrate for myeloperoxidase because other physiological substrates for this enzyme, including chloride, did not affect its rate of oxidation. At low micromolar concentrations, serotonin enhanced hypochlorous acid production by both purified myeloperoxidase and neutrophils. At higher concentrations, it almost completely blocked the formation of hypochlorous acid. Serotonin was oxidized to a dimer by myeloperoxidase and hydrogen peroxide. It was also converted into tryptamine-4,5-dione, especially in the presence of superoxide. This toxic quinone was produced by stimulated neutrophils in a reaction that required myeloperoxidase. In plasma, stimulated human neutrophils oxidized serotonin to its dimer using the NADPH oxidase and myeloperoxidase. We propose that myeloperoxidase will oxidize serotonin at sites of inflammation. In doing so, it will impair its physiological functions and generate a toxicmetabolite that will exacerbate inflammatory tissue damage. Consequently, oxidation of serotonin by myeloperoxidase may profoundly influence inflammatory processes. The Authors Journal compilation
- Ximenes, Valdecir F.,Maghzal, Ghassan J.,Turner, Rufus,Kato, Yoji,Winterbourn, Christine C.,Kettle, Anthony J.
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- Oxidation Chemistry of 5-Hydroxytryptamine. 1. Mechanism and Products Formed at Micromolar Concentrations
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The oxidation of very low concentrations (+ reaction, giving a phenoxyl radical which exists in equilibrium with aryl, C(4)., and N(1). radicals.At low potentials the latter radicals can react to give dimeric products.At higher potentials, however, the primary phenoxyl radical is further oxidized (1e,1H+) to a reactive quinone imine.The quinone imine is rapidly attacked by water to give 4,5-dihydroxytryptamine (7), which is further oxidized to tryptamine-4,5-dione (B).In aqueous solution at pH 2 B is slowly attacked by water to give 4,5,7-trihydroxytryptamine, which is further oxidized (2e,2H+) to 5-hydroxytryptamine-4,7-dione (11).Compounds B and 11 then react together to give a hydroxylated tryptamine dimer.The facile oxidation of 1 give at least two neurotoxins, 7 and 9, might provide insight into the previously proposed anomolous oxidative metabolism of 1 as an underlying cause of various mental disorders.
- Wrona, Monika Z.,Dryhurst, Glenn
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p. 2817 - 2825
(2007/10/02)
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