Dopamine Quinone Formation Research Articles

Dopamine decreases LPS-induced expression of proinflammatory cytokines in microglial cells through the formation of dopamine quinone in the mouse striatum.

Dopamine decreases LPS-induced expression of proinflammatory cytokines in microglial cells through the formation of dopamine quinone in the mouse striatum.

Dopamine inhibits the expression of proinflammatory cytokines of microglial cells through the formation of dopamine quinone in the mouse striatum

We previously reported that dopamine (DA) attenuated lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines through the formation of DA quinone (DAQ) in murine microglial cell line BV-2 and primary murine microglial cells. To reveal whether DA inhibits the expression of proinflammatory cytokines of microglial cells through the formation of DAQ in the central nervous system (CNS), in this study, we examined the effect of DAQ on LPS-induced mRNA expression of proinflammatory cytokines in C57BL/6 mouse brain under two experimental conditions: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration and l-dopa/carbidopa administration. Acute MPTP administration reduced the number of tyrosine hydroxylase-positive cells in the substantia nigra, and decreased the level of quinoprotein, an indicator of DAQ formation, in the striatum. Real-time RT-PCR analysis revealed that intraperitoneal administration of LPS increased the mRNA levels of proinflammatory cytokines, including tumor-necrosis factor-α and interleukin-1β, in the striatum. These increases were enhanced in MPTP-treated mice. On the other hand, l-dopa/carbidopa administration increased the level of quinoprotein, attenuated the LPS-induced mRNA expression of proinflammatory cytokines, and reduced the LPS-induced increase in the number of microglial cells in the striatum. These results suggest that DA attenuate the expression of proinflammatory cytokines in microglia through the formation of DAQ in the CNS.

Dopamine attenuates lipopolysaccharide-induced expression of proinflammatory cytokines by inhibiting the nuclear translocation of NF-κB p65 through the formation of dopamine quinone in microglia.

Many reports have indicated that dopamine has immunomodulatory effects on peripheral immune cells. The purpose of this study was to reveal the immunomodulatory effect of dopamine on the expression of proinflammatory cytokines in microglial cells, which are the immune cells of the central nervous system. In murine microglial cell line BV-2 cells, pretreatment with dopamine for 24 h attenuated the lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines such as tumor-necrosis factor-α, interleukin-1β, and interleukin-6. Neither (5R)-8-chloro-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol; hydrochloride (SCH-23390) nor sulpiride, which are dopamine D1-like and D2-like receptor antagonists, respectively, affected the attenuation of LPS-induced expression of cytokines by dopamine. In addition, pretreatment with neither (−)-(6aR,12bR)-4,6,6a,7,8,12b-Hexahydro-7-methylindolo[4,3-a]phenanthridin (CY208-243) nor bromocriptine, dopamine D1-like and D2-like receptor agonists, respectively, was effective in doing so. However, N-acetylcysteine (NAC), which inhibits dopamine oxidation to dopamine quinone, did inhibit this attenuated expression. Dopamine increased the level of quinoproteins, and this increase was inhibited by NAC. Western blot and immunocytochemical analyses revealed that dopamine inhibited LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB) p65. Dopamine also attenuated the expression of cytokines and the nuclear translocation of NF-κB p65 induced by LPS in mouse microglial cells in primary culture. These results suggest that dopamine attenuated LPS-induced expression of cytokines by inhibiting the nuclear translocation of NF-κB p65 through the formation of dopamine quinone in microglial cells.

Synthesis and anti-tyrosinase mechanism of the substituted vanillyl cinnamate analogues

This study aimed to synthesize and screen tyrosinase inhibitors for delay fruit browning. A series of vanillyl cinnamate analogues were designed and synthesized by simple processes, and the inhibitory effects of all the synthesized derivatives on mushroom tyrosinase were evaluated. In the enzymatic activity test, compounds 21, 22, and 26 had significant (P < 0.05) effect on mushroom tyrosinase at a preliminary screening dose (1 mg/mL in vitro). IC50 analysis showed that the IC50 values of compounds 21, 22 and 26 were 268.5 μM, 213.2 μM and 413.5 μM, respectively. In the cytotoxicity evaluation, Cell Counting Kit-8 (CCK-8) assay showed that compounds 21, 22 and 26 had no significant effect on the proliferation of hepatocyte L02 and B16 melanoma cells at the dosage of 25–200 μM. Inhibition of tyrosinase activity and melanin content in B16 melanoma cells investigations indicated that compounds 21, 22 and 26 inhibited both cellular tyrosinase activity and melanin content dose-dependently and more strongly than the reference standard arbutin. The UV–visible spectra showed compound 22 inhibits the formation of dopamine quinone, further the molecular docking analysis of compound 22 with tyrosinase (PDB: 2Y9X) indicated that compound 22 interacted with the amino acid residues of tyrosinase. The results of anti-browning test showed that compounds 21, 22 and 26 had significant tyrosinase inhibition and anti-browning effects on fresh-cut apple slices at 4 °C in 48 h. Compound 22 could be used as novel tyrosinase inhibitor to delay fruit browning.

L-3,4-dihydroxyphenylalanine (l-DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha-synuclein mouse models of Parkinson's disease.

Treatment with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (l-DOPA) provides symptomatic relief arising from DA denervation in Parkinson's disease. Mounting evidence that DA autooxidation to neurotoxic quinones is involved in Parkinson's disease pathogenesis has raised concern about potentiation of oxidative stress by l-DOPA. The rate of DA quinone formation increases in the presence of excess redox-active iron (Fe), which is a pathological hallmark of Parkinson's disease. Conversely, l-DOPA has pH-dependent Fe-chelating properties, and may act to 'redox silence' Fe and partially allay DA autoxidation. We examined the effects of l-DOPA in three murine models of parkinsonian neurodegeneration: early-life Fe overexposure in wild-type mice, transgenic human (h)A53T mutant α-synuclein (α-syn) over-expression, and a combined 'multi-hit' model of Fe-overload in hA53T mice. We found that l-DOPA was neuroprotective and prevented age-related Fe accumulation in the substantia nigra pars compacta (SNc), similar to the mild-affinity Fe chelator clioquinol. Chronic l-DOPA treatment showed no evidence of increased oxidative stress in wild-type midbrain and normalized motor performance, when excess Fe was present. Similarly, l-DOPA also did not exacerbate protein oxidation levels in hA53T mice, with or without excess nigral Fe, and showed evidence of neuroprotection. The effects of l-DOPA in Fe-fed hA53T mice were somewhat muted, suggesting that Fe-chelation alone is insufficient to attenuate neuron loss in an animal model also recapitulating altered DA metabolism. In summary, we found no evidence in any of our model systems that l-DOPA treatment accentuated neurodegeneration, suggesting DA replacement therapy does not contribute to oxidative stress in the Parkinson's disease brain.

Inhibition potential of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites on the in vitro monoamine oxidase (MAO)-catalyzed deamination of the neurotransmitters serotonin and dopamine

Neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA) is still controversially discussed. Formation of reactive oxygen species e.g. based on elevated dopamine (DA) concentrations and DA quinone formation is discussed among others. Inhibition potential of MDMA metabolites regarding neurotransmitter degradation by catechol-O-methyltransferase and sulfotransferase was described previously. Their influence on monoamine oxidase (MAO) - the major DA degradation pathway-has not yet been studied in humans. Therefore the inhibition potential of MDMA and its metabolites on the deamination of the neurotransmitters DA and serotonin (5-HT) by MAO-A and B using recombinant human enzymes in vitro should be investigated. In initial studies, MDMA and MDA showed relevant inhibition (>30%) toward MAO A for 5-HT and DA. No relevant effects toward MAO B were observed. Further investigation on MAO-A revealed MDMA as a competitive inhibitor of 5-HT and DA deamination with Ki 24.5±7.1 μM and 18.6±4.3 μM respectively and MDA as a mixed-type inhibitor with Ki 7.8±2.6 μM and 8.4±3.2 μM respectively. Although prediction of in vivo relevance needs to be done with care, relevant inhibitory effects at expected plasma concentrations after recreational MDMA consumption seems unlikely based on the obtained data.

Dopamine inhibits lipopolysaccharide-induced nitric oxide production through the formation of dopamine quinone in murine microglia BV-2 cells

Dopamine (DA) has been suggested to modulate functions of glial cells including microglial cells. To reveal the regulatory role of DA in microglial function, in the present study, we investigated the effect of DA on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in murine microglial cell line BV-2. Pretreatment with DA for 24 h concentration-dependently attenuated LPS-induced NO production in BV-2 cells. The inhibitory effect of DA on LPS-induced NO production was not inhibited by SCH-23390 and sulpiride, D1-like and D2-like DA receptor antagonists, respectively. In addition, pretreatment with (−)-(6aR,12bR)-4,6,6a,7,8,12b-Hexahydro-7-methylindolo[4,3-a]phenanthridin (CY 208–243) and bromocriptine, D1-like and D2-like DA receptor agonists, respectively, did not affect the LPS-induced NO production. N-Acetylcysteine, which inhibits DA oxidation, completely inhibited the effect of DA. Tyrosinase, which catalyzes the oxidation of DA to DA quionone (DAQ), accelerated the inhibitory effect of DA on LPS-induced NO production. These results suggest that DA attenuates LPS-induced NO production through the formation of DAQ in BV-2 cells.

Cyclooxygenase-Independent Neuroprotective Effects of Aspirin Against Dopamine Quinone-Induced Neurotoxicity

Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property.

Protective effects of baicalein against excess L-DOPA-induced dopamine quinone neurotoxicity

Objectives: Baicalein, a flavonoid derived from the root of Scutelaria baicalensis Georgi, possesses anti-oxidative properties including reactive oxygen species scavenging and lipid peroxidation inhibiting activities. The present study was undertaken to investigate the neuroprotective effect of baicalein against dopamine (DA) neurotoxicity induced by exposure to a synthetic DA precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), in cultured dopaminergic CATH.a cells.Methods and results: Exposure to L-DOPA for 24 hours reduced the number of viable cells and enhanced protein-bound quinone (quinoprotein) formation in the cell. Both effects were prevented by simultaneous treatment with baicalein. In addition, baicalein prevented the formation of DA semiquinone radicals from DA in an in vitro cell-free system. Long-term baicalein treatment for 96 hours also protected against excess L-DOPA-induced cell death, and also increased glutathione (GSH) levels in CATH.a cells.Discussion: Our results indicate that baicalein has neuroprotective properties against excess L-DOPA-induced DA neurotoxicity through the suppression of DA quinone formation. Furthermore, the long-term treatment of baicalein upregulates intracellular GSH contents, which may also exert neuroprotective effects against oxidative stress-induced neuronal damage.

Quinoprotein Adducts Accumulate in the Substantia Nigra of Aged Rats and Correlate with Dopamine-Induced Toxicity in SH-SY5Y Cells

Parkinson's disease (PD) is an age-dependent neurodegenerative disorder characterized by dopaminergic neuron loss in substantia nigra. Previous studies have implicated a role of dopamine oxidation in PD. Dopamine oxidation leads to the formation of dopamine quinone, which generates reactive oxygen species and covalently modifies cysteinyl proteins to form quinoprotein adduct. We compared quinoprotein adduct formation and lipid peroxidation in different brain regions of young and old rats. We found a prominent age-dependent accumulation of quinoprotein adducts in the substantia nigra, while no significant change of lipid peroxidation was detected in any brain regions of 2- to 15-month old rats. To determine whether quinoprotein adduct formation correlates with dopamine-induced cytotoxicity, we analyzed dopamine treated SH-SY5Y cells and found a strong correlation between quinoprotein adduct formation and cytotoxicity. Together, our results indicate that quinoprotein adduct formation may play a role in the age-dependent selective vulnerability of dopaminergic neurons in PD.

The effect of antiparkinsonian drugs on oxidative stress induced pathological [3H]dopamine efflux after in vitro rotenone exposure in rat striatal slices

An in vitro model of mitochondrial dysfunction with subsequent oxidative stress was elaborated and utilized to study the effect of drugs, currently used for the treatment of Parkinson's disease, on pathological H(2)O(2)-evoked [(3)H]dopamine efflux and the formation of toxic dopamine metabolites in rat striatal slices. 60 min rotenone (0.1-10 muM) pretreatment decreased dopamine content and [(3)H]dopamine uptake, as well as ATP level and energy charge of the slices. In addition, a robust potentiation of H(2)O(2)-evoked [(3)H]dopamine efflux and the formation of dopamine quinone in the effluent was detected. l-DOPA (200 muM) markedly elevated resting but not 100 muM H(2)O(2)-evoked and electrically-induced [(3)H]dopamine efflux. Furthermore, l-DOPA promoted the formation of dopamine quinone. Ropinirole (100 nM) did not affect resting and H(2)O(2)-evoked [(3)H]dopamine efflux and inhibited the electrically evoked release only in untreated slices. l-deprenyl, at concentration of 0.01 muM potentiated, whilst between 1 and 50 muM diminished H(2)O(2)-evoked [(3)H]dopamine efflux. Rasagiline (0.01-50 muM) slightly inhibited H(2)O(2)-evoked [(3)H]dopamine efflux, and it was able to prevent the generation of dopamine quinone. Neither of the drugs was able to suppress both the pathological H(2)O(2)-evoked [(3)H]dopamine efflux and the formation of dopamine quinone with simultaneous augmentation of electrically evoked [(3)H]dopamine release what should be a future concept of antiparkinsonian drug-design.

Anti-Inflammatory Agents in Parkinsons Disease

Parkinsons disease (PD) is a frequent neurological disorder of the basal ganglia, which is characterized by the progressive loss of dopaminergic neurons mainly in the substantia nigra pars compacta (SNpc). Recently, increasing evidence from human and animal studies has suggested that neuroinflammation is a cause or rather a consequence of neurodegeneration. Activated microglia, as well as to a lesser extent reactive astrocytes, are found in the area associated with cell loss, possibly contributing to the inflammatory process by the release of pro-inflammatory prostaglandins or cytokines. Further deleterious factors released by activated microglia or astrocytes are reactive oxygen species. Although dopamine replacement can alleviate symptoms of the disorder, there is no proven therapy to halt the underlying progressive degeneration of dopamine-containing neurons. Furthermore, growing experimental evidence demonstrates that inhibition of the inflammatory response can, in part, prevent degeneration of nigrostriatal dopamine-containing neurons in several animal models of PD, It has been revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) have neuroprotective properties based not only on their cyclooxygenase-inhibitory action, but also on other properties including their inhibitory effects on the synthesis of nitric oxide radicals. NSAIDs inhibit prostaglandin H synthase, thus suppressing dopamine oxidation and subsequent dopamine quinone formation. This study suggests that inhibition of inflammation may become a promising therapeutic intervention for PD. Keywords: Parkinson's disease (PD), neuroinflammation, activated microglia, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-1, COX-2, Minocycline, quinine

Preventing effects of a novel anti-parkinsonian agent zonisamide on dopamine quinone formation

The neurotoxicity of dopamine (DA) quinones as dopaminergic neuron-specific oxidative stress is considered to play a role in the pathogenesis and/or progression of Parkinson's disease (PD), since DA quinones conjugate with several key PD pathogenic molecules ( e.g., tyrosine hydroxylase, α-synuclein and parkin) to form protein-bound quinone (quinoprotein) and consequently inhibit their functions. Zonisamide (ZNS) is used as an anti-epileptic agent but also improved the cardinal symptoms of PD in recent clinical trials in Japan. To evaluate the effects of ZNS on excess cytosolic free DA-induced quinone toxicity, we examined changes in DA quinone-related indices after ZNS treatment both in in vitro cell-free system and in cultured cells. Co-incubation of DA and ZNS in a cell-free system caused conversion of DA to stable melanin via formation of DA-semiquinone radicals and DA chrome. Long-term (5 days) treatment with ZNS decreased quinoprotein and increased DA/DOPA chromes in dopaminergic CATH.a cells. ZNS significantly inhibited quinoprotein formation induced by treatment with tetrahydrobiopterin and ketanserin that elevate cytosolic free DA in the cells. Our results suggest that the novel anti-parkinsonian agent ZNS possesses preventing effects against DA quinone formation induced by excess amount of cytosolic DA outside the synaptic vesicles.

Therapeutic approaches to inflammation in neurodegenerative disease

According to the neuroinflammatory hypothesis of neurodegenerative diseases, drugs with an anti-inflammatory mode of action should slow the disease progression. Here we review recent advances in our understanding of one such disorder, Parkinson's disease, in which anti-inflammatory drugs are now becoming a new therapeutic focus. The involvement of inflammatory mechanisms in Parkinson's disease has been revealed through in-vitro and in-vivo experimental studies supported by pathological and epidemiological findings. Several of the demonstrated inflammatory mechanisms are shared by other neurodegenerative disorders but some Parkinson's disease-specific mechanisms have also emerged. These include inflammatory stimulation by interaction of alpha-synuclein with microglia and astrocytes and a suppressive action by nonsteroidal anti-inflammatory drugs on dopamine quinone formation. It can be anticipated that a more detailed understanding of neuroinflammatory mechanisms in Parkinson's disease will lead to new cellular and molecular targets, which may, in turn, permit design of Parkinson's disease modifying drugs. Future treatment may involve combination therapies with drugs directed at both inflammatory and non-inflammatory mechanisms.

Nonsteroidal anti-inflammatory drugs in Parkinson’s disease: possible involvement of quinone formation

It has been revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) have neuroprotective properties based not only on their cyclooxygenase-inhibitory action, but also on other properties including their inhibitory effects on the synthesis of nitric oxide radicals and agonistic action for peroxisome proliferator-activated receptor γ, in addition to some as yet unknown properties. Recently, a number of experimental and clinical studies have examined the neuroprotective effects of NSAIDs on the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease. In this article, various pharmacological effects of NSAIDs (except for their cyclooxygenase-inhibitory action) are reviewed, and possible neuroprotective effects of NSAIDs on Parkinson's disease are discussed. The neurotoxicity of dopamine quinones, or DOPA quinones, has recently received attention as a dopaminergic neuron-specific oxidative stress that is known to play a role in the pathogenesis of Parkinson’s disease and neurotoxin-induced parkinsonism. NSAIDs inhibit prostaglandin H synthase, thus suppressing dopamine oxidation and subsequent dopamine quinone formation. Therefore, this article also reviews possible suppressive effects of some NSAIDs against dopamine quinone generation.

Methamphetamine‐induced dopaminergic neurotoxicity is regulated by quinone formation‐related molecules

Recently, the neurotoxicity of dopamine (DA) quinone formation by auto-oxidation of DA has focused on dopaminergic neuron-specific oxidative stress. In the present study, we examined DA quinone formation in methamphetamine (METH)-induced dopaminergic neuronal cell death using METH-treated dopaminergic cultured CATH.a cells and METH-injected mouse brain. In CATH.a cells, METH treatment dose-dependently increased the levels of quinoprotein (protein-bound quinone) and the expression of quinone reductase in parallel with neurotoxicity. A similar increase in quinoprotein levels was seen in the striatum of METH (4 mg/kg X4, i.p., 2 h interval)-injected BALB/c mice, coinciding with reduction of DA transporters. Furthermore, pretreatment of CATH.a cells with quinone reductase inducer, butylated hydroxyanisole, significantly and dose-dependently blocked METH-induced elevation of quinoprotein, and ameliorated METH-induced cell death. We also showed the protective effect of tyrosinase, which rapidly oxidizes DA and DA quinone to form stable melanin, against METH-induced dopaminergic neurotoxicity in vitro and in vivo using tyrosinase null mice. Our results indicate that DA quinone formation plays an important role, as a dopaminergic neuron-specific neurotoxic factor, in METH-induced neurotoxicity, which is regulated by quinone formation-related molecules.

Quinone formation as dopaminergic neuron-specific oxidative stress in the pathogenesis of sporadic Parkinson's disease and neurotoxin-induced parkinsonism.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuron-specific degeneration in the substantia nigra. A number of gene mutations and deletions have been reported to play a role in the pathogenesis of familial PD. Moreover, a number of pathological and pharmacological studies on sporadic PD and dopaminergic neurotoxin-induced parkinsonism have hypothesized that mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome system all play important roles in the pathogenesis and progress of PD. However, these hypotheses do not yet fully explain the mechanisms of dopaminergic neuron-specific cell loss in PD. Recently, the neurotoxicity of dopamine quinone formation by auto-oxidation of dopamine has been shown to cause specific cell death of dopaminergic neurons in the pathogenesis of sporadic PD and dopaminergic neurotoxin-induced parkinsonism. Furthermore, this quinone formation is closely linked to other representative hypotheses in the pathogenesis of PD. In this article, we mainly review recent studies on the neurotoxicity of quinone formation as a dopaminergic neuron-specific oxidative stress and its role in the etiology of PD, in addition to several neuroprotective approaches against dopamine quinone-induced toxicity.

Combined effect of dopamine and MPP + on membrane permeability in mitochondria and cell viability in PC12 cells

The present study examined the combined effect of dopamine and 1-methyl-4-phenylpyridinium (MPP +) on the membrane permeability in isolated brain mitochondria and on cell viability in PC12 cells. MPP + increased effect of dopamine against the swelling, membrane potential, and Ca 2+ transport in isolated mitochondria, which was not inhibited by the addition of antioxidant enzymes (SOD and catalase). Dopamine or MPP + caused the decrease in transmembrane potential, increase in reactive oxygen species, depletion of GSH, and cell death in PC12 cells. Antioxidant enzymes reduced each effect of dopamine and MPP + against PC12 cells. Co-addition of dopamine and MPP + caused the decrease in the transmembrane potential and increase in the formation of reactive oxygen species in PC12 cells, in which they showed an additive effect. Dopamine plus MPP +-induced the depletion of GSH and cell death in PC12 cells were not decreased by the addition of antioxidant enzymes, rutin, diethylstilbestrol, and ascorbate. Melanin caused a cell viability loss in PC12 cells. The N-acetylcysteine, N-phenylthiourea, and 5-hydroxyindole decreased the cell death and the formation of dopamine quinone and melanin induced by co-addition of dopamine and MPP +, whereas deprenyl and chlorgyline did not show an inhibitory effect. The results suggest that co-addition of dopamine and MPP + shows an enhancing effect on the change in mitochondrial membrane permeability and cell death, which may be accomplished by toxic quinone and melanin derived from the MPP +-stimulated dopamine oxidation.

Dopamine- or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease.

Dopamine (DA)- or L-dihydroxyphenylalanine-(L-DOPA-) induced neurotoxicity is thought to be involved not only in adverse reactions induced by long-term L-DOPA therapy but also in the pathogenesis of Parkinson's disease. Numerous in vitro and in vivo studies concerning DA- or L-DOPA-induced neurotoxicity have been reported in recent decades. The reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of DA induce neuronal damage and/or apoptotic or non-apoptotic cell death; the DA-induced damage is prevented by various intrinsic and extrinsic antioxidants. DA and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells mainly due to the generation of highly reactive DA and DOPA quinones which are dopaminergic neuron-specific cytotoxic molecules. DA and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. For example, the formation of DA quinone-alpha-synuclein consequently increases cytotoxic protofibrils and the covalent modification of tyrosine hydroxylase by DA quinones. The melanin-synthetic enzyme tyrosinase in the brain may rapidly oxidize excess amounts of cytosolic DA and L-DOPA, thereby preventing slowly progressive cell damage by auto-oxidation of DA, thus maintainng DA levels. Since tyrosinase also possesses catecholamine-synthesizing activity in the absence of tyrosine hydroxylase (TH), the double-edged synthesizing and oxidizing functions of tyrosinase in the dopaminergic system suggest its potential for application in the synthesis of DA, instead of TH in the degeneration of dopaminergic neurons, and in the normalization of abnormal DA turnover in the long-term L-DOPA-treated Parkinson's disease patients.

Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson's disease.

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.