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PubMed1995

3,4-dihydroxyphenylalanine (DOPA) decarboxylase deficiency and resultant high levels of plasma DOPA and dopamine in unfavorable neuroblastoma.

Neuroblastoma (NB) is a tumor which arises from neural crest cells. In the developing neural crest cells, the induction of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase is more delayed than that of tyrosine hydroxylase and dopamine-beta-hydroxylase. If NB cells are arrested in an early stage of neural crest development, the induction of DOPA decarboxylase is insufficient and the accumulation and secretion of DOPA can be caused. The biochemically immature phenotype is thought to represent the undifferentiated characteristics of the cells and might correlate with the grade of malignancy. To investigate whether the hypothesis is clinically applicable or not, we have measured plasma DOPA, dopamine and urinary catecholamine metabolites in NB patients. The levels of plasma DOPA, dopamine, urinary homovanillic acid (HVA) and vanillactic acid (VLA) were significantly higher in patients with unfavorable NBs and the higher plasma DOPA level was significantly associated with the patients' age (> 1 year old), tumor stage (III, IV) and DNA diploidy. Serial determination of plasma DOPA was a good monitor of the disease course. These results are compatible with the hypothesis on DOPA decarboxylase deficiency and DOPA secretion in undifferentiated, unfavorable NBs. In conclusion, the plasma DOPA can be used to predict patients' prognosis as well as to follow up patients with NB.

Biomarkers, Tumor↗
PubMed1991

Dopa-responsive dystonia: [18F]dopa positron emission tomography.

The syndrome of dopa-responsive dystonia comprises a minority of patients with dystonia, yet it is of considerable diagnostic importance because patients respond dramatically to L-dopa therapy. Benefits from this treatment are lasting, and the problems associated with long-term L-dopa therapy in patients with Parkinson's disease are generally absent. It has been suggested that this condition is due to a defect in the dopamine synthetic pathway, which is bypassed when patients are treated with L-dopa. We have studied [18F]dopa uptake in 6 patients with classic dopa-responsive dystonia (5 familial patients and 1 sporadic patient), aged 18 to 66 years. Data have been analyzed according to a graphic approach, calculating an influx constant for each region studied. We have also studied a seventh, clinically atypical, patient with juvenile dystonia-parkinsonism. Similar data have been calculated for a group of 10 healthy control subjects and 10 patients with Parkinson's disease. The 6 patients with typical dopa-responsive dystonia had a modest but significant reduction in the uptake of tracer into both caudate and putamen, which indicates a defect in the decarboxylation, vesicular uptake, and storage of [18F]dopa. This argues against the proposition that dopa-responsive dystonia is due to an inherited defect of tyrosine hydroxylase alone. In the atypical patient, however, we found a greater reduction of [18F]dopa uptake into both caudate and putamen, comparable with that in patients with Parkinson's disease.

Adolescent↗
PubMed1992

Regional brain kinetics of 6-fluoro-(beta-11C)-L-dopa and (beta-11C)-L-dopa following COMT inhibition. A study in vivo using positron emission tomography.

The regional brain kinetics of (beta-11C)-L-dopa and 6-fluoro-(beta-11C)-L-dopa was measured in six Rhesus monkeys using positron emission tomography (PET). Radioactivity accumulated specifically in the striatal region and the increase in L-dopa-derived radioactivity utilization with time was calculated using surrounding brain as a reference area, this being devoid of dopaminergic activity. The rate constant for selective striatal utilization i.e. grossly decarboxylation was 0.0110 +/- 0.0007 (S.D) and 0.0057 +/- 0.0006 min-1 for (beta-11C)-L-dopa and 6-fluoro-(beta-11C)-L-dopa, respectively. After pretreatment of the monkeys with the peripherally and centrally active catecholamine-O-methyl transferase (COMT) inhibitor Ro 40-7592 10 mg/kg, the decarboxylation rate remained unchanged (0.0112 +/- 0.0015 min-1) for (beta-11C)-L-dopa, whereas an increase in rate was measured for 6-fluoro-(beta-11C)-L-dopa (0.0092 +/- 0.0015 min-1). Differences in the distribution of radiolabelled metabolites i.e. the corresponding O-methyl-L-dopa in the reference area is most probably the reason for the difference in calculated decarboxylation rate seen between the radiotracers. The higher decarboxylation rate measured for 6-fluoro-(beta-11C)-L-dopa after blockade of COMT shows that the radiolabelled metabolites i.e. 6-fluoro-O-methyl-(beta-11C)-L-dopa significantly contributes to background radioactivity.

Animals↗
PubMed1994

3-O-methyl-DOPA is not involved in the development of behavioral supersensitivity after repeated L-dopa administration in 6-OHDA lesioned rats.

The underlying cause of long-term complications of L-DOPA therapy in Parkinson's disease is largely unknown. Recently, centrally and peripherally acting catechol-O-methyltransferase (COMT) inhibitors became available. These drugs are capable of inhibiting the generation of 3-O-methyl-DOPA (3-OMD), a major metabolite of L-dopa developing considerable plasma levels during L-dopa therapy. The use of these drugs offers the opportunity to study the involvement of 3-OMD in the development of behavioral supersensitivity following repeated doses of L-dopa over 11 days in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic system. Repeated daily administration of L-dopa/Carbidopa produced continuous increase of contralateral rotations to both L-dopa/Carbidopa and to challenge doses of apomorphine. This increase was not influenced by peripherally and peripherally plus centrally acting COMT inhibitors, OR-462 and OR-486, respectively, administered simultaneously with L-dopa/Carbidopa. Both COMT inhibitors suppressed the L-dopa induced increase of 3-OMD plasma levels, OR-486 being more effective than OR-462. This indicates that 3-OMD is not involved in the development of behavioral supersensitivity following repeated L-dopa treatment in rats with unilateral 6-OHDA lesion of the nigrostriatal system.

Animals↗
PubMed2002

Behavioral activity and stereotypy in rats induced by L-DOPA metabolites: a possible role in the adverse effects of chronic L-DOPA treatment of Parkinson's disease.

L-3,4-Dihydroxyphenylalanine (L-DOPA) is a common and effective treatment for Parkinson's disease, but dyskinesia continues to be a serious adverse effect with chronic use. Evidence suggests that L-DOPA induces increases in dopamine, which then binds to supersensitive dopamine receptors, resulting in dyskinesia. We have shown previously that L-DOPA directly causes stereotypy in rats, suggesting that chronic L-DOPA-induced dyskinesia is also caused by L-DOPA itself. This raises the possibility that other L-DOPA metabolites have a role in dyskinesia. We examined the behavioral effects of five L-DOPA metabolites (3-methoxytyramine, 3-MT; 3,4-dihydroxyphenylalanine, DOPAC; dopamine; homovanillic acid, and 3-o-methyl-DOPA) in rats. A unilateral, intracerebroventricular injection of 3-MT (10-200 microg, 40 microl) over 30 min, dose-dependently increased behavioral activity and stereotypy. This effect was suppressed by the dopamine D1/5-receptor antagonist SCH 23390, but not by the dopamine D2/3/4-receptor antagonist sulpiride. Dopamine denervation resulted in behavioral supersensitivity to 3-MT. Neither dopamine nor DOPAC levels increased in the striatum after 3-MT administration, as measured using in vivo voltammetry. The behavioral changes paralleled a rise in 3-MT in the contralateral striatum. DOPAC also caused behavioral changes and stereotypy, but to a smaller degree than 3-MT. Dopamine-denervated rats did not exhibit a supersensitive response to DOPAC, however. Other L-DOPA metabolites did not cause behavioral effects. These data suggest that 3-MT directly induced dopamine-D1/5-receptor-mediated behavioral changes in rats, and that 3-MT may have a role in dyskinesia due to chronic L-DOPA treatment in Parkinson's disease patients.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1981

A specific radioenzymatic assay for dihydroxyphenylalanine (DOPA). Plasma dopa may be the precursor of urine free dopamine.

1 A sensitive radioenzymatic assay was developed, in which DOPA is enzymatically decarboxylated to dopamine and the latter converted to [3H]-methoxytyramine in the presence of [3H]-S-adenosyl-L-methionine and catechol-o-methyltransferase. 2 The assay was specific for DOPA, and was sensitive to 50 pg/ml. 3 Endogenous DOPA was found to be present in the plasma of eight human volunteers at a concentration of 10.46 +/- 2.42 nmol/l. 4 Simultaneous urine collections in the same subjects showed a free dopamine excretion of 68.88 +/- 17.70 nmol/h. There was significant correlation (P less than 0.01) between plasma DOPA concentration and urine free dopamine excretion (r = 0.84). 5 After the oral administration of 250 mg levodopa, plasma DOPA and urine dopamine both increased by a similar proportion (98 +/- 8.4-fold, and 93.4 +/- 6.9-fold respectively). These compare with an increase in plasma dopamine of only 26 +/- 15-fold (P less than 0.01). 6 Following the orale dose DOPA, the increase in plasma DOPA, but not plasma dopamine, could account for the increase in urine dopamine. The calculated clearance of plasma DOPA by renal decarboxylation to dopamine was 114 +/- 20 ml/min. 7 This is not significantly different from the apparent clearance of endogenous DOPA by renal decarboxylation to dopamine, and suggests that there is adequate renal decarboxylase activity for DOPA to be the precursor for renal dopamine formation.

Catechol O-Methyltransferase↗
PubMed1983

Chronic L-dopa administration decreases striatal accumulation of dopamine from exogenous L-dopa in rats with intact nigrostriatal projections.

To examine whether chronic administration of L-dopa can affect its own utilization in striatum, rats were injected once daily for 30 days with L-dopa and carbidopa or with saline. On day 31, saline and L-dopa animals were sacrificed 1, 2, or 3 hours after L-dopa injection. In rats given long-term L-dopa, the elevations in striatal dopamine concentrations induced by L-dopa administration were smaller and of shorter duration than those in controls. Such changes did not occur in animals pretreated with L-dopa for only 10 days. Results suggest that prolonged L-dopa therapy may decrease striatal accumulation of dopamine from exogenous L-dopa even when the nigrostriatal projections are intact. Therefore, it is possible that declining efficacy of L-dopa in parkinsonism may be due to effects of the drug itself and not only to disease progression.

Animals↗
PubMed1990

L-dopa methyl ester antagonizes competitively L-dopa-induced facilitation of noradrenaline release from rat hypothalamic slices.

In rat hypothalamic slices, antagonism by L-DOPA methyl ester and (-)-propranolol against L-DOPA-induced facilitation of endogenous noradrenaline (NA) release was characterized under the inhibition of dopadecarboxylase. L-DOPA at 10 nM to 1 microM facilitated the evoked NA release in a concentration-dependent manner. L-DOPA methyl ester (3, 10 and 30 nM) progressively shifted the concentration-release curve for L-DOPA to the right: Schild plots gave a straight line with a slope of 1.00 and pA2 was 8.9. This antagonistic action was not mimicked by L-phenylalanine, a substrate for L-DOPA transport system. In contrast, 10 and 100 nM propranolol concentration-dependently reduced the maximal effect of L-DOPA without rightward shift of the concentration-release curve. L-DOPA methyl ester is a potent competitive antagonist for the action of L-DOPA, and the recognition site of L-DOPA differs from presynaptic beta-adrenoceptors.

Animals↗
PubMed1971

Decrease of the 3,4-dihydroxyphenylalanine (DOPA) decarboxylase activities in human erythrocytes and mouse tissues after administration of DOPA.

Human erythrocytes have been found to contain appreciable amounts of DOPA decarboxylase (EC 4.1.1.26) activity. The enzyme activity in erythrocytes from patients with Parkinson's disease who were treated with DOPA was significantly lower than that of untreated patients and of normal individuals. Administration of the drug to mice led to a marked decrease of DOPA decarboxylase in liver and kidney, but not of the brain enzyme. The findings thus indicate that administration of DOPA leads to a decrease in peripheral DOPA decarboxylase, an effect that is expected to be of benefit in DOPA therapy of patients with Parkinson's disease. Peripheral DOPA decarboxylase concentration also decreases in mice after short periods of fasting; the findings suggest that the peripheral enzyme activities may be affected by various nutritional and perhaps hormonal influences, which may be partially responsible for the observed fluctuations in the motor abilities of Parkinsonian patients receiving constant doses of the drug. Study of DOPA decarboxylase activity in erythrocytes may be useful in following changes in patients receiving DOPA therapy and may also be of general interest and value in investigations of catecholamine metabolism in man.

Age Factors↗
PubMed1988

The effect of carbidopa on plasma and muscle levels of L-dopa, dopamine, and their metabolites following L-dopa administration to rats.

Administration of L-dopa (L-3,4-dihydroxyphenylalanine) (200 mg/kg p.o.) to rats produced elevated plasma and muscle concentrations of both L-dopa and 3-O-methyldopa (3-OMD). This effect was potentiated by simultaneous administration of carbidopa (25 mg/kg p.o.). Both L-dopa and 3-OMD accumulated in muscle after administration of L-dopa with or without carbidopa. Elevated dopamine levels were detected in both muscle and plasma after treatment with L-dopa alone. Concurrent administration of carbidopa only diminished dopamine levels in plasma, and the duration of raised dopamine levels in muscle was increased. Carbidopa administration had no effect on the elevated plasma concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) caused by L-dopa administration. In muscle, carbidopa treatment tended to prolong the duration of raised metabolite levels. Muscle appears to accumulate L-dopa at a site where decarboxylation is not totally prevented by concurrent carbidopa administration, and where dopamine is not degraded as actively as in other tissues. The muscle sink for L-dopa may influence the plasma profile of the amino acid, which has implications for the therapeutic response to L-dopa in Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Dopa-sensitive and dopa-resistant gait parameters in Parkinson's disease.

Quantitative analysis of gait was performed in 20 parkinsonians before and 1 h after the acute administration of L-Dopa in order to discriminate between the Dopa-sensitive and the Dopa-resistant kinematic gait parameters. The stride length and the kinematic parameters (swing velocity, peak velocity) related to the energy were Dopa-sensitive. The improvement of the bent forward posture by L-Dopa may explain the stride length increase. Temporal parameters (stride and swing duration, stride duration variability), related to rhythm, were Dopa-resistant. Experimental data argue for the importance of force control in maintaining the posture. The stride length variability, possibly related to the variability of force production shown to exist in parkinsonians was not significantly improved by L-Dopa. In Parkinson's disease different hypotheses might explain the inexorable aggravation of gait disorders along the course of the disease: (1) an advancing disorder of coordination between postural control and locomotion, (2) if some gait parameters like stride length and kinematic parameters are Dopa-sensitive, the others are Dopa-resistant and thus may involve other mechanisms than dopamine deficiency.

Aged↗
PubMed1991

Effect of dopa-loading on glutathione metabolising enzymes and tyrosinase in relation to 5-S-cysteinyl-dopa genesis in cultured B-16 melanoma cells.

The effect of DOPA and glutathione (GSH) on enzyme systems for 5-S-cysteinyl-DOPA (5SCD) genesis in murine melanoma cells cultured in tyrosine- and cystine-free medium were studied. DOPA at its optimum concentration (10(-5) M) when added alone did not alter tyrosinase, glutathione-S-transferase or gamma-glutamyl transpeptidase activities. In the presence of GSH at its optimum concentration (10(-5) M), DOPA loading did not cause any significant changes in tyrosinase or glutathione-S-transferase (GST) activities. This indicates that the higher 5SCD levels observed in the medium because of DOPA loading in the GSH dependent system results from increased substrate availability rather than the increased enzyme activity. An acute drop in 5SCD at DOPA concentrations above 10(-5) M observed in the GSH dependent system may be due to the inhibition of tyrosinase at high substrate concentrations (10(-4) M). Conversely, in the presence of DOPA, when GSH was increased, the resultant higher production of 5SCD could be explained by the increased activity of GST. When added alone, GSH (10(-5) M) caused a significant increase in GST (approximately 125%) and gamma-GTP (approximately 50%) activities. A drop in 5SCD in the medium when GSH was added beyond its optimum concentration (10(-5) M) in the DOPA-dependent system could be due to competitive inhibition of gamma-GTP by GSH. The data demonstrate that 5SCD genesis may be enhanced due to the accumulation of cytotoxic melanin precursors such as DOPA/DOPA quinone. The relative quantities of GSH at the sites of DOPA quinone formation and the levels of its metabolising enzymes can influence the type of product formed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

The O-methylated derivative of L-DOPA, 3-O-methyl-L-DOPA, fails to inhibit neuronal and non-neuronal aromatic L-amino acid decarboxylase.

The present study examined whether the O-methylated derivative of L-DOPA, 3-O-methyl-L-DOPA (3-OM-L-DOPA), inhibits neuronal (brain) and non-neuronal (liver and kidney) aromatic L-amino acid decarboxylase (AADC) activity. The incubation of brain, liver and kidney homogenates with 3-OM-L-DOPA (5 mM) did not result in the formation of 3-methoxytyramine, the compound expected to result from the decarboxylation of 3-OM-L-DOPA. Incubation of tissue homogenates with L-DOPA resulted in a concentration-dependent formation of dopamine, revealing K(m) values (in mM) of similar magnitude for brain (0.8), liver (1.6) and kidney (1.0). Both benserazide and L-5-hydroxytryptophan (L-5-HTP) were found to produce concentration dependent decreases in AADC activity with K(i) values in the microM range. By contrast, 3-OM-L95% reduction) in liver and kidney AADC activity accompanied by a marked decrease (49% reduction) in brain AADC activity. By contrast, the administration of 30 mg/kg (p.o.) 3-OM-L-DOPA, which generates levels in brain, liver and kidney six-fold those in L-DOPA-treated rats, was found to change neither neuronal nor non-neuronal AADC activity. In conclusion, 3-OM-L-DOPA fails to interact with neuronal and non-neuronal AADC, either as substrate or inhibitor.

5-Hydroxytryptophan↗
PubMed2003

Blockade of A2A receptors plus l-DOPA after nigrostriatal lesion results in GAD67 mRNA changes different from l-DOPA alone in the rat globus pallidus and substantia nigra reticulata.

Studies in animal models of Parkinson's disease (PD) suggest the potential utility of adenosine A(2A) antagonists in the treatment of this disease. In the present study, unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats received chronic intermittent treatment with the adenosine A(2A) antagonist SCH58261 (5 mg/kg) plus l-DOPA (3 mg/kg) or l-DOPA (6 mg/kg) alone, at doses producing the same intensity of contralateral turning on first administration. Three days after discontinuation of treatments, GABA synthesizing enzyme glutamic acid decarboxylase (GAD67) mRNA was evaluated at cellular level in the globus pallidus (GP) and substantia nigra pars reticulata (SNr) by in situ hybridization. 6-OHDA lesion significantly increased GAD67 mRNA levels in both the GP and SNr ipsilateral to the lesion. Chronic l-DOPA (6 mg/kg), in contrast to SCH58261 plus l-DOPA (3 mg/kg), produced a sensitized contralateral turning indicative of dyskinetic potential and further increased GAD67 mRNA in the GP. In the SNr, a significant decrease in GAD67 mRNA was observed after either treatments. However, while l-DOPA (6 mg/kg) decreased SNr GAD67 mRNA below the intact side, SCH58261 plus l-DOPA (3 mg/kg) brought GAD67 mRNA to the same level of the intact SNr. l-DOPA (3 mg/kg) or SCH58261 (5 mg/kg) alone failed to modify GAD67 mRNA. Results suggest that an increase in GAD67 mRNA in GP and a decrease in SNr might underlie dyskinetic movements induced by chronic l-DOPA. In contrast, the lack of GAD67 mRNA changes in the GP and a less marked inhibition of SNr might correlate with the absence of dyskinetic potential observed after SCH58261 plus l-DOPA.

Adenosine A2 Receptor Antagonists↗
PubMed1998

Substrate specificity of human monoamine (M)-form phenol sulfotransferase: preparation and analysis of Dopa 3-O-sulfate and Dopa 4-O-sulfate.

Upon two-dimensional thin-layer separation, the sulfated L-3, 4-dihydroxyphenylalanine (L-DopaS) generated enzymatically was found to co-migrate with only one of the two ninhydrin-stained spots corresponding to the two sulfated forms (3-O-sulfate and 4-O-sulfate) of synthetic L-DopaS. To clarify precisely the identity of the enzymatically generated L-DopaS, the two sulfated forms of synthetic L-DopaS were separated and purified using high performance liquid chromatography. Purified L-Dopa 3-O-sulfate and L-Dopa 4-O-sulfate were identified by 1H-nuclear magnetic resonance (NMR) spectrometry and used as standards in the analysis of the L-DopaS generated during metabolic labeling of HepG2 human hepatoma cells or enzymatic assay using recombinant human monoamine (M)-form phenol sulfotransferase. The results obtained demonstrated unequivocally the generation of L-Dopa 3-O-sulfate, indicating the specificity of the M-form phenol sulfotransferase being for the meta-hydroxyl group of L-Dopa.

Arylsulfotransferase↗
PubMed2004

Hypertrophy of medial globus pallidus and substantia nigra reticulata in 6-hydroxydopamine-lesioned rats treated with L-DOPA: implication for L-DOPA-induced dyskinesia in Parkinson's disease.

The medial globus pallidus plays a crucial role in generation of L-DOPA-induced dyskinesia in patients with Parkinson's disease. The 6-hydroxydopamine-lesioned rat exhibiting behavioral sensitization to L-DOPA is one useful animal model for examining L-DOPA-induced dyskinesia. To determine neuropathological abnormality responsible for behavioral sensitization, the medial globus pallidus and the substantia nigra reticulata in 6-hydroxydopamine-lesioned rats treated with L-DOPA were examined. Intermittent L-DOPA treatment induced hypertrophy of the lesioned-side of medial globus pallidus and substantia nigra reticulata of 6-hydroxydopamine-lesioned rats with behavioral sensitization to L-DOPA. Additionally, coadministration of a 5-HT1A receptor agonist, 8-hydroxy-2(di-n-propylamino)tetralin with L-DOPA, alleviated the hypertrophy with improvement of the behavioral sensitization. These results suggest that hypertrophy of the medial globus pallidus and substantia nigra reticulata is associated with induction of behavioral sensitization to L-DOPA in 6-hydroxydopamine-lesioned rats. Therefore, neuropathological changes corresponding to hypertrophy might underlie L-DOPA-induced dyskinesia in patients with Parkinson's disease.

Animals↗
PubMed1993

The effect of L-dopa infusions with and without phenylalanine challenges in parkinsonian patients: plasma and ventricular CSF L-dopa levels and clinical responses.

We monitored the motor response and plasma and ventricular CSF (CSFv) concentrations of L-dopa during IV infusions of L-dopa in two patients with advanced Parkinson's disease. Concentrations of L-dopa in CSFv mirrored, but lagged behind, those in plasma. In the fasting state, the duration, but not the magnitude, of the motor response was greater with increasing plasma and CSFv levels of L-dopa. During IV infusions of L-dopa following oral administration of phenylalanine, a large neutral amino acid that shares a transport system into the brain with L-dopa, the duration of the motor response was markedly attenuated despite undiminished CSFv levels of L-dopa. These observations suggest that either L-dopa entry into CSFv and the brain are differentially affected by phenylalanine or that phenylalanine affects other steps in the motor response. These observations demonstrate that, except in the fasting state, L-dopa in CSFv is not a reliable predictor of motor response.

Amino Acids↗