Dopamine 3-O-sulphate, an end product of L-dopa metabolism in Parkinson patients

Jenner, William N.; Rose, F. A.

doi:10.1038/252237a0

Cited by 45 publications

(14 citation statements)

References 8 publications

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“…Because the formation of dopamine O-sul fate, the major plasma metabolite of L-DOPA in hu mans (Goodall and Alton, 1972;Jenner and Rose, 1974), depends on AAAD, blockade of this enzyme with peripherally acting carbidopa increases the availability of L-DOPA in the circulation of patients undergoing treatment (Doller et a!., 1978). Simi larly, most PET studies with e8p]PDOPA require carbidopa.…”

Section: Fractionationmentioning

confidence: 99%

Pharmacokinetics of Plasma 6-[¹⁸F]Fluoro-l-3,4-Dihydroxyphenylalanine ([¹⁸F]FDOPA) in Humans

Cumming

Léger

Kuwabara

et al. 1993

J Cereb Blood Flow Metab

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Summary: Like native DOPA, [18Fl-6-fluoro-L-3 ,4-dihydroxyphenylalanine ([18F1FDOPA) is subject to methylation and decarboxylation. To determine the rates of formation and elimination of [18F1FDOPA metabolites, plasma from human subjects undergoing positron emis sion tomographic (PET) studies was analyzed by high performance liquid chromatography (HPLC). In addition to the principal metabolite O-methyl-[18F1FDOPA (OMe [18F1FDOPA), two decarboxylated metabolites were de tected in plasma from carbidopa pretreated subjects. The concentrations of each metabolite during 90 min following tracer injection could be described as a function of the concentration of [18F1FDOPA, and two rate constants; ko, the rate of formation, and k_ I ' the rate of clearance. Plasma metabolite time series generated from total plasma activity curves and measured rate constants wereThe labeled amino acid 6-[lsP]fluoro-L-3,4-dihydroxyphenylalanine (esp]PDOPA) is employed as a tracer of the enzyme aromatic amino acid de carboxylase (AAAD) in positron emission tomogra phy (PET) studies of the human brain (Garnett et aI. , 1983; CaIne et aI. , 1985; Gjedde et aI., 1991; Kuwabara et aI. , 1992 668in close agreement with the actual concentrations deter mined by HPLC fractionation. Population means for ko (0.011 ± 0.002 min-I ) and L I (0.010 ± 0. 003 min-I ) were used to generate "simulated" plasma curves. The measured and generated plasma curves were used as in puts for estimation of partition and decarboxylation co efficients of [18F1FDOPA in brain. The use of generated input functions from normal population means of transfer coefficients did not introduce a systematic error into the estimate of the enzyme activity. However, the high vari ability of these estimates in patients precludes the use of this technique as an alterative to individual HPLC mea surements.ery. In carbidopa-pretreated subjects, circulating eSp]PDOPA is rapidly metabolized by catechol O-methyltransferase (COMT) to O-Methyl [lsp]PDOPA (OMe-esP]PDOPA), which pene trates the blood-brain barrier more readily then the parent compound (Reith et aI. , 1990). Kinetic mod els for the estimation of cerebral AAAD activity therefore require the fractionation of plasma in or der to determine the relative amounts of esp] PDOPA and its principal metabolite (Gjedde et aI. , 1991; Huang et aI. , 1991). However, the pharma cokinetics of eSp]PDOPA with respect to minor plasma metabolites has not previously been de scribed.Time series for the plasma concentrations of eSp]PDOPA and its metabolites can be fitted to lin ear differential equations described the respective coefficients of formation (ko) and clearance (k _ I) of a metabolite (Gjedde et aI. , 1991). The present study consists in a retrospective reanalysis of 28 PET studies, in which the coefficients were deter-

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Section: Fractionationmentioning

confidence: 99%

Pharmacokinetics of Plasma 6-[¹⁸F]Fluoro-l-3,4-Dihydroxyphenylalanine ([¹⁸F]FDOPA) in Humans

Cumming

Léger

Kuwabara

et al. 1993

J Cereb Blood Flow Metab

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“…Levodopa (L-DOPA) crosses the blood-brain barrier, to be converted to dopamine, and thus reestablishing dopaminergic effects. After dopamine biotransformation, the metabolically inert dopamine 3-O-sulphate is the predominant sulphate conjugate that is excreted in the urine of parkinsonian patients (Jenner and Rose 1974). Analysis by gas chromatography-mass spectrometry (GC-MS) showed that the urinary excretion of 5-and 6-hydroxydopamine (5-OHDA and 6-OHDA) in L-DOPA-treated parkinsonian patients was significantly higher than in Parkinson's disease patients not treated with L-DOPA (Andrew et al 1993).…”

Section: Discussionmentioning

confidence: 98%

Protective effect of resveratrol against 6-hydroxydopamine-induced impairment of renal p-aminohippurate transport

Cojocel

Thomson

2004

Arch Toxicol

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In the present study, the effects of resveratrol on 6-hydroxydopamine (6-OHDA)-induced p-aminohippurate (PAH) transport impairment were investigated in vitro using rat renal cortical slices. Cisplatin and cephaloridine (CPH), known nephrotoxins, were used as positive controls. In one series of experiments, renal cortical slices were incubated in a cisplatin-containing medium or a cisplatin-free medium. In another series of experiments, renal cortical slices were incubated in a CPH-containing medium, in a CPH- and probenecid-containing medium, or in a CPH-free medium. Subsequently, for each series of experiments kidney slices were incubated in a media containing PAH or tetraethylammonium. In a further series of experiments, renal cortical slices were incubated in a 6-OHDA-containing medium and in a 6-OHDA-free medium. In another series of experiments, renal cortical slices were incubated in a medium containing 50 micro M 6-OHDA, in a 6-OHDA- and resveratrol-containing medium or in a 6-OHDA- and resveratrol-free medium. Subsequently, for each series of experiments kidney slices were incubated in media containing PAH. The results of this study in which slices were incubated in 6-OHDA-containing media indicate that 6-OHDA induced a time- and concentration-dependent decrease in PAH accumulation by renal cortical slices. Resveratrol inhibited the 6-OHDA-induced time-dependent decrease of PAH accumulation in a concentration-dependent manner. Therefore, 6-OHDA causes functional injuries of renal proximal tubule cell membrane, thus leading to impairment of transport processes across the cell membrane and to nephrotoxicity. Resveratrol has a nephroprotective effect.

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“…In PD patient's brain, neurons of the nigra progressively degenerate, and this loss of neurons in nigra can cause reduced amount of DA available for neurotransmission [56]. Reductions of DA content in brain tissue from patients with PD have been documented in a variety of studies [57–59]. Dopamine synthesis can be promoted by TH through hydroxylation of tyrosine to L-DOPAThese results support that thicremonone could be an effective compound for neurodegenerative disease, and this effect can protect the brain against PD risk.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of thiacremonone on MPTP-induced dopaminergic neurodegeneration through inhibition of p38 activation

et al. 2016

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Neuroinflammation is implicated for dopaminergic neurodegeneration. Sulfur compounds extracted from garlic have been shown to have anti-inflammatory properties. Previously, we have investigated that thiacremonone, a sulfur compound isolated from garlic has anti-inflammatory effects on several inflammatory disease models. To investigate the protective effect of thiacremonone against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment and dopaminergic neurodegeneration, 8 week old ICR mice were given thiacremonone (10 mg/kg) in drinking water for 1 month and received intraperitoneal injection of MPTP (15 mg/kg, four times with 2 h interval) during the last 7 days of treatment. Our data showed that thiacremonone decreased MPTP-induced behavioral impairments (Rotarod test, Pole test, and Gait test), dopamine depletion and microglia and astrocytes activations as well as neuroinflammation. Higher activation of p38 was found in the substantia nigra and striatum after MPTP injection, but p38 activation was reduced in thiacremonone treated group. In an in vitro study, thiacremonone (1, 2, and 5 μg/ml) effectively decreased MPP+ (0.5 mM)-induced glial activation, inflammatory mediators generation and dopaminergic neurodegeneration in cultured astrocytes and microglial BV-2 cells. Moreover, treatment of p38 MAPK inhibitor SB203580 (10 μM) further inhibited thiacremonone induced reduction of neurodegeneration and neuroinflammation. These results indicated that the anti-inflammatory compound, thiacremonone, inhibited neuroinflammation and dopaminergic neurodegeneration through inhibition of p38 activation.

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Dopamine 3-O-sulphate, an end product of L-dopa metabolism in Parkinson patients

Cited by 45 publications

References 8 publications

Pharmacokinetics of Plasma 6-[¹⁸F]Fluoro-l-3,4-Dihydroxyphenylalanine ([¹⁸F]FDOPA) in Humans

Pharmacokinetics of Plasma 6-[¹⁸F]Fluoro-l-3,4-Dihydroxyphenylalanine ([¹⁸F]FDOPA) in Humans

Protective effect of resveratrol against 6-hydroxydopamine-induced impairment of renal p-aminohippurate transport

Inhibitory effect of thiacremonone on MPTP-induced dopaminergic neurodegeneration through inhibition of p38 activation

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Dopamine 3-O-sulphate, an end product of L-dopa metabolism in Parkinson patients

Cited by 45 publications

References 8 publications

Pharmacokinetics of Plasma 6-[18F]Fluoro-l-3,4-Dihydroxyphenylalanine ([18F]FDOPA) in Humans

Pharmacokinetics of Plasma 6-[18F]Fluoro-l-3,4-Dihydroxyphenylalanine ([18F]FDOPA) in Humans

Protective effect of resveratrol against 6-hydroxydopamine-induced impairment of renal p-aminohippurate transport

Inhibitory effect of thiacremonone on MPTP-induced dopaminergic neurodegeneration through inhibition of p38 activation

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Pharmacokinetics of Plasma 6-[¹⁸F]Fluoro-l-3,4-Dihydroxyphenylalanine ([¹⁸F]FDOPA) in Humans

Pharmacokinetics of Plasma 6-[¹⁸F]Fluoro-l-3,4-Dihydroxyphenylalanine ([¹⁸F]FDOPA) in Humans