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  • 1
    Electronic Resource
    Electronic Resource
    Modification of Dopamine Transporter Function: Effect of Reactive Oxygen Species and Dopamine (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 67 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Dopamine can oxidize to form reactive oxygen species and quinones, and we have previously shown that dopamine quinones bind covalently to cysteinyl residues on striatal proteins. The dopamine transporter is one of the proteins at risk for this modification, because it has a high affinity for dopamine and contains several cysteinyl residues. Therefore, we tested whether dopamine transport in rat striatal synaptosomes could be affected by generators of reactive oxygen species, including dopamine. Uptake of [3H]dopamine (250 nM) was inhibited by ascorbate (0.85 mM; −44%), and this inhibition was prevented by the iron chelator diethylenetriaminepentaacetic acid (1 mM), suggesting that ascorbate was acting as a prooxidant in the presence of iron. Preincubation with xanthine (500 µM) and xanthine oxidase (50 mU/ml) also reduced [3H]dopamine uptake (−76%). Preincubation with dopamine (100 µM) caused a 60% inhibition of subsequent [3H]dopamine uptake. This dopamine-induced inhibition was attenuated by diethylenetriaminepentaacetic acid (1 mM), which can prevent iron-catalyzed oxidation of dopamine during the preincubation, but was unaffected by the monoamine oxidase inhibitor pargyline (10 µM). None of these incubations caused a loss of membrane integrity as indicated by lactate dehydrogenase release. These findings suggest that reactive oxygen species and possibly dopamine quinones can modify dopamine transport function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.67020593.x
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  • 2
    Electronic Resource
    Electronic Resource
    Identification of Catechol-Protein Conjugates in Neostriatal Slices Incubated with [3H]Dopamine: Impact of Ascorbic Acid and Glutathione (1994)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 63 (1994), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: There is evidence to suggest that degeneration of dopaminergic neurons in Parkinson's disease and certain other conditions results from the action of reactive species generated during the oxidation of dopamine. We, therefore, have begun to explore the conditions under which such reactive species are formed. Tissue slices prepared from rat neostriatum were incubated in a standard Krebs bicarbonate buffer for up to 120 min. In the presence of [3H]dopamine (0.01–100 µM), binding of tritium to the acid-insoluble protein fraction was detected. Binding was attenuated by the addition of ascorbate (0.085–0.85 mM) or glutathione (0.01–1.0 mM) to the buffer. Acid hydrolysis of the protein revealed the presence of cysteinyl-dopamine and cysteinyl-dihydroxyphenylacetic acid residues. These results suggest that dopamine oxidizes to form reactive metabolites, presumably quinones, that then bind to nucleophilic sulfhydryl groups on protein cysteinyl residues. The findings further suggest that the extent to which reactive metabolites are formed is determined in part by the balance between the availability of dopamine and the antioxidant environment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1994.63031126.x
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  • 3
    Electronic Resource
    Electronic Resource
    Estimating Hydroxyl Radical Content in Rat Brain Using Systemic and Intraventricular Salicylate: Impact of Methamphetamine (1995)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 64 (1995), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Free radicals have been implicated in the etiology of many neurodegenerative conditions. Yet, because these species are highly reactive and thus short-lived it has been difficult to test these hypotheses. We adapted a method in which hydroxyl radicals are trapped by salicylate in vivo, resulting in the stable and quantifiable products, 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA. After systemic (100 mg/kg i.p.) or intraventricular (4 µmol) administration of salicylate, the amount of DHBA in striatal tissue correlated with tissue levels of salicylate. After systemic salicylate, the ratio of total DHBA to salicylate in neostriatum was at least 10-fold higher than that observed after central salicylate. In addition, systemic salicylate resulted in considerably higher concentrations of 2,3- and 2,5-DHBA in plasma than in brain. Therefore, a large portion of the DHBA present in brain after systemic salicylate may have been formed in the periphery. A neurotoxic regimen of methamphetamine increased the concentration of DHBA in neostriatum after either central or systemic administration of salicylate. The increase in 2,3-DHBA after the central administration of salicylate was significant at 2 h, but not at 4 h, after the last dose of methamphetamine. These results suggest that (1) when assessing specific events in brain, it is preferable to administer salicylate centrally, and (2) neurotoxic doses of methamphetamine increase the hydroxyl radical content in brain in a time-dependent manner.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1995.64041819.x
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  • 4
    Electronic Resource
    Electronic Resource
    Enzymatic Oxidation of Dopamine: The Role of Prostaglandin H Synthase (1995)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 64 (1995), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: An enzyme responsible for the oxidation of dopamine and formation of neuromelanin in brain has not been identified. Prostaglandin H synthase is prominent in brain and possesses peroxidase activity that may cooxidize dopamine to reactive dopamine quinones. This study examined the ability of purified prostaglandin H synthase to catalyze the oxidation of dopamine in vitro. Dopamine oxidation was determined by monitoring the formation of aminochrome and by examining catechol-modified residues on protein present in the reaction mixture. Aminochrome was formed from dopamine in the presence of prostaglandin H synthase, and the reaction rate was dependent on the concentration of substrate and enzyme in the reaction mixture. Both arachidonic acid and hydrogen peroxide could serve as substrates for the prostaglandin H synthase-catalyzed oxidation of dopamine. Indomethacin blocked the reaction when arachidonic acid was used as a substrate, but not when hydrogen peroxide was used. Enzymatically oxidized dopamine covalently bound to protein, as indicated by the presence of cysteinyl-dopamine residues. Binding was significantly reduced in the absence of enzyme or in the presence of antioxidants. These results suggest that the peroxidase activity of prostaglandin H synthase is responsible for catalyzing the oxidation of dopamine to reactive dopamine quinones. It is possible that prostaglandin H synthase is responsible for the oxidation of dopamine and formation of neuromelanin in vivo, which may have implications for the development of Parkinson's disease. Furthermore, drugs such as aspirin that modulate the activity of this enzyme may provide a potential therapeutic approach for the prevention of Parkinson's disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1995.64020919.x
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  • 5
    Electronic Resource
    Electronic Resource
    Peroxynitrite- and Nitrite-Induced Oxidation of Dopamine : Implications for Nitric Oxide in Dopaminergic Cell Loss (1999)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 73 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : Increased nitric oxide (NO) production has been implicated in many examples of neuronal injury such as the selective neurotoxicity of methamphetamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to dopaminergic cells, presumably through the generation of the potent oxidant peroxynitrite (ONOO). Dopamine (DA) is a reactive molecule that, when oxidized to DA quinone, can bind to and inactivate proteins through the sulfhydryl group of the amino acid cysteine. In this study, we sought to determine if ONOO could oxidize DA and participate in this process of protein modification. We measured the oxidation of the catecholamine by following the binding of [3H]DA to the sulfhydryl-rich protein alcohol dehydrogenase. Results showed that ONOO oxidized DA in a concentration- and pH-dependent manner. We confirmed that the resulting DA-protein conjugates were predominantly 5-cysteinyl-DA residues. In addition, it was observed that ONOO decomposition products such as nitrite were also effective at oxidizing DA. These data suggest that the generation of NO and subsequent formation of ONOO or nitrite may contribute to the selective vulnerability of dopaminergic neurons through the oxidation of DA and modification of protein.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0732546.x
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  • 6
    Electronic Resource
    Electronic Resource
    Inhibition of Glutamate Transport in Synaptosomes by Dopamine Oxidation and Reactive Oxygen Species (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 69 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Dopamine can form reactive oxygen species and other reactive metabolites that can modify proteins and other cellular constituents. In this study, we tested the effect of dopamine oxidation products, other generators of reactive oxygen species, and a sulfhydryl modifier on the function of glutamate transporter proteins. We also compared any effects with those on the dopamine transporter, a protein whose function we had previously shown to be inhibited by dopamine oxidation. Preincubation with the generators of reactive oxygen species, ascorbate (0.85 mM) or xanthine (500 µM) plus xanthine oxidase (25 mU/ml), inhibited the uptake of [3H]glutamate (10 µM) into rat striatal synaptosomes (−54 and −74%, respectively). The sulfhydryl-modifying agent N-ethylmaleimide (50–500 µM) also led to a dose-dependent inhibition of [3H]glutamate uptake. Preincubation with dopamine (100 µM) under oxidizing conditions inhibited [3H]glutamate uptake by 25%. Exposure of synaptosomes to increasing amounts of dopamine quinone by enzymatically oxidizing dopamine with tyrosinase (2–50 U/ml) further inhibited [3H]glutamate uptake, an effect prevented by the addition of glutathione. The effects of free radical generators and dopamine oxidation on [3H]glutamate uptake were similar to the effects on [3H]dopamine uptake (250 nM). Our findings suggest that reactive oxygen species and dopamine oxidation products can modify glutamate transport function, which may have implications for neurodegenerative processes such as ischemia, methamphetamine-induced toxicity, and Parkinson's disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.69031185.x
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  • 7
    Electronic Resource
    Electronic Resource
    Dopamine Oxidation Alters Mitochondrial Respiration and Induces Permeability Transition in Brain Mitochondria (1999)
    Oxford UK : Blackwell Science Ltd
    Journal of neurochemistry 73 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : Both reactive dopamine metabolites and mitochondrial dysfunction have been implicated in the neurodegeneration of Parkinson’s disease. Dopamine metabolites, dopamine quinone and reactive oxygen species, can directly alter protein function by oxidative modifications, and several mitochondrial proteins may be targets of this oxidative damage. In this study, we examined, using isolated brain mitochondria, whether dopamine oxidation products alter mitochondrial function. We found that exposure to dopamine quinone caused a large increase in mitochondrial resting state 4 respiration. This effect was prevented by GSH but not superoxide dismutase and catalase. In contrast, exposure to dopamine and monoamine oxidase-generated hydrogen peroxide resulted in a decrease in active state 3 respiration. This inhibition was prevented by both pargyline and catalase. We also examined the effects of dopamine oxidation products on the opening of the mitochondrial permeability transition pore, which has been implicated in neuronal cell death. Dopamine oxidation to dopamine quinone caused a significant increase in swelling of brain and liver mitochondria. This was inhibited by both the pore inhibitor cyclosporin A and GSH, suggesting that swelling was due to pore opening and related to dopamine quinone formation. In contrast, dopamine and endogenous monoamine oxidase had no effect on mitochondrial swelling. These findings suggest that mitochondrial dysfunction induced by products of dopamine oxidation may be involved in neurodegenerative conditions such as Parkinson’s disease and methamphetamine-induced neurotoxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0731127.x
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  • 8
    Electronic Resource
    Electronic Resource
    Role of Endogenous Glutathione in the Oxidation of Dopamine (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Intrastriatal injection of dopamine causes the selective degeneration of tyrosine hydroxylase-containing terminals and an increase in content of cysteinylcatechols, an index of dopamine oxidation. Both of these effects can be attenuated by coadministration of antioxidants such as glutathione. Therefore, we investigated the effects of decreased endogenous glutathione on the neurotoxic potential of dopamine. We observed that pretreatment with either l-buthionine sulfoximine, a specific inhibitor of glutathione synthesis, or diethyl maleate, which forms adducts with glutathione, caused significant decreases in endogenous glutathione levels at the time of dopamine injection. Pretreatment with l-buthionine sulfoximine potentiated the formation of protein cysteinyl-dopamine after intrastriatal injection of 1.0 µmol of dopamine. We also observed that intrastriatal injection of 1.0 µmol of dopamine decreased striatal glutathione content in all pretreatment conditions. However, injection of a low dose (0.05 µmol of dopamine) caused a decrease in striatal glutathione levels only in the l-buthionine sulfoximine-pretreated rats. Diethyl maleate pretreatment was not effective in potentiating either cysteinyl-catechol formation or glutathione loss after dopamine injection. We conclude that dopamine contributes to cellular oxidative stress and that this can be exacerbated, or at least unmasked, if glutathione synthesis is compromised.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71052071.x
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  • 9
    Electronic Resource
    Electronic Resource
    Could a loss of α-synuclein function put dopaminergic neurons at risk? (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 89 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The α-synuclein gene is implicated in Parkinson's disease, the symptoms of which occur after a marked loss of substantia nigra dopamine neurons. While the function of α-synuclein is not entirely elucidated, one function appears to be as a normal regulatory protein that can bind to and inhibit tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Soluble α-synuclein levels may be diminished in Parkinson's disease substantia nigra dopamine neurons both by reduced expression and by α-synuclein aggregation as Lewy bodies and Lewy neurites form. The loss of functional α-synuclein may then result in dysregulation of tyrosine hydroxylase, dopamine transport and dopamine storage, resulting in excess cytosolic dopamine. Because dopamine and its metabolites are reactive molecules capable of generating highly reactive quinones and reactive oxygen species, a failure to package dopamine into vesicles could cause irreversible damage to cellular macromolecules and contribute to resultant neurotoxicity. This review focuses on how a loss of normal α-synuclein function may contribute to the dopamine-related loss of substantia nigra neurons during Parkinson's disease pathogenesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02423.x
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  • 10
    Electronic Resource
    Electronic Resource
    Neurochemical Responses to 6-Hydroxydopamine and L-Dopa Therapy: Implications for Parkinson's Disease (1992)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 648 (1992), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1992.tb24525.x
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