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PubMed1977

L-Dopa peroxidase activity of human erythrocyte catalase.

The human red cell hemolysate was found to have 3-(3',4'-dihydroxphenyl)-L-alanine (L-dopa) peroxidase activity. During the purification of glutathione peroxidase and catalase by ammonium sulfate precipitation, ion exchange chromatography. Sephadex gel filtration, and preparative polyacrylamide disc electrophoresis, the L-dopa peroxidase activity was found to be associated with catalase. Both sodium azide, 8 mM, and 3-amino-1,2,4-triazole, 50 mM, besides inhibiting catalase, inhibited the L-dopa peroxidase activity in each fraction. Ethylenediamine tetraacetic acid (EDTA), 4 mM, had no effect on catalase or L-dopa peroxidase activity, indicating that the oxidation of L-dopa is not a nonenzymatic process mediated by metal ions. Although the electrophoretic mobility of catalase, L-dopa peroxidase, and glutathione peroxidase are similar, a homogeneous preparation of glutathione peroxidase was free of L-dopa peroxidase activity. L-Dopa peroxidase in human red cells was co-purified with catalase.

Azides↗

PubMed1977

[Results of determination of plasma methoxydopa in parkinsonian patients with or without dyskinesia induced by L-Dopa].

Horary plasmatic dosages of Dopa and metabolites in 30 treated parkinsonian patients have shown that, within the group of patients treated with L-Dopa combined with an extracerebral decarboxylase inhibitor, highly significant by increased plasmatic O-methyl-dopa levels can be found in patients with dyskinesias compared with those without dyskinesias. On the contrary, in these two subgroups of patients, plasmatic Dopa levels are not significantly different. By comparing some favoured Dopa and O-methyl-dopa levels between these two subgroups of patients, it seems more likely, that the elevated plasmatic O-methyl-dopa levels are due to an progressive accumulation on of its compound than to an excessive formation from Dopa.

Aged↗

PubMed1978

Mass spectrometric measurement of catecholamine turnover in rat hypothalamus after long-term L-dopa infusion.

To test the effect of L-dopa on norepinephrine turnover in rat hypothalamus, we gave steady-state, long-term (19-hour) infusions of L-dopa to conscious, restrained rats. After 19 hours, infusions were switched to identical doses of 2,5,6-trideutero-L-dopa (D3-L-dopa) and production of D3-dopamine and D3-norepinephrine was followed at intervals thereafter. Animals were sacrificed and their hypothalami were dissected and divided into left and right halves. Using gas chromatography-mass spectrometry, we measured isotopic enrichment with one side of the hypothalamus and, after the addition of deuterated internal standards, determined total concentration of dopamine and norepinephrine in the other half of the same hypothalamus. Maximal steady-state enrichment by a given dose of D3-L-dopa was determined by 19-hour infusions of D3-L-dopa alone. Results show that total dopamine production is proportional to dopa dose. Norepinephrine synthesis, on the other hand, proceeds at a constant rate that is independent of dopa dose or dopamine concentration and which is similar to the endogenous rate reported by others using tracer techniques.

Animals↗

PubMed1981

[Biochemical evaluation of the effectiveness of antiparkinson preparations containing L-DOPA].

The content of adrenaline, noradrenaline, DOPA, and dopamine in the daily portion of the urine was examined in 26 patients with parkinsonism who took for many years L-DOPA which was then replaced by the drugs synemet and nacom containing, in addition to DOPA, a specific inhibitor of peripheral DOPA-decarboxylase (MK-486). As control 10 healthy subjects and 37 non-treated parkinsonic patients were examined. Advantages of the drugs synemet and nacom over L-DOPA are noted. These advantages manifest themselves in the form of favourable changes of the mediator balance in the presence of positive clinical effect and possibility of reducing the L-DOPA dose by administering those drugs. No substantial changes of biochemical parameters were revealed in the patients treated with synemet and nacom. A correlation between the hypersecretion of adrenaline and noradrenaline in the patients with parkinsonism treated with L-DOPA-containing drugs and the development of cerebral side effects (hyperkinesias, psychic disturbances) was discovered. Possible mechanisms of the development of the cerebral side effects in patients treated with DOPA-containing drugs are discussed, and necessity of combined therapy is stressed.

Carbidopa↗

PubMed1999

Comparison between the decrease of dopamine transporter and that of L-DOPA uptake for detection of early to advanced stage of Parkinson's disease in animal models.

Early diagnosis of Parkinson's disease (PD) is important for the potential application of neuroprotective therapies. The purpose of this study was to assess the detection of the early changes of PD by either imaging the dopamine transporter (DAT) or uptake of L-3,4-dihydroxyphenylalanine (L-DOPA). An early to advanced stage model of PD was induced in rats by stereotaxic injection of 1-10 microg 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta. Using adjacent sections of the same animals, the binding of [I-125]beta-CIT, which labels DAT and the uptake of [C-14]L-DOPA, were evaluated 4 weeks after induction of the lesion. Any decrease in dopaminergic neurons was evaluated by in situ hybridization histochemistry (ISH) by detection of DAT mRNA-positive neurons. In addition, the expression levels of DAT, dopa decarboxylase (DDC), and vesicular monoamine transporter (VMAT2) in each neuron were studied with ISH. Our results show a decrease in both [I-125]beta-CIT binding and [C-14]L-DOPA uptake in parallel with a decrease in DA neurons from early to advanced stage models of PD. The decrease in [C-14]L-DOPA uptake was smaller than that in [I-125]beta-CIT binding in the same animal (P < 0.0001). Expression levels of DAT, DDC, and VMAT2 mRNAs were also decreased with the progression of the disease. Although ISH failed to detect the origin of the discrepancy between [I-125]beta-CIT and [C-14]L-DOPA levels, it was concluded that [C-14]L-DOPA levels underestimated the decrease of dopaminergic neurons and that [I-125]beta-CIT levels more precisely reflected the decrease.

Animals↗

PubMed2000

Opposite effects of glutamate antagonists and antiparkinsonian drugs on the activities of DOPA decarboxylase and 5-HTP decarboxylase in the rat brain.

This study measured the activities of L-DOPA and 5-HTP decarboxylase (DDC and 5-HTPDC) in the substantia nigra and corpus striatum of reserpine-treated rats. Acute injection of the NMDA receptor antagonists CGP 40116 (5 mg/kg) and HA 966 (5 mg/kg), and to a lesser extent eliprodil (10 mg/kg), greatly elevated DDC in both structures, whilst having no effect on (nigra) or inhibiting (striatum) 5-HTPDC. L-DOPA (25 mg/kg) on its own inhibited both enzymes in either brain region. The weak NMDA receptor-channel blockers (and antiparkinsonian drugs) budipine (10 mg/kg), memantine (40 mg/kg) and amantadine (40 mg/kg) strongly increased DDC, whilst not affecting or decreasing 5-HTPDC activity in nigra and striatum. The L-DOPA-induced suppression of DDC was mostly reversed by all three antiparkinsonian drugs, whilst L-DOPA-induced inhibition of 5-HTPDC was only reversed by CGP 40116 (striatum only). It is concluded that glutamate exerts a differential physiological influence on the biosynthesis of dopamine and 5-HT in the brain, by tonically suppressing DDC and tonically stimulating 5-HTPDC. The L-DOPA-induced reduction in DDC may help to explain the eventual loss of efficacy of L-DOPA therapy in parkinsonian patients. It is suggested, however, that it may be possible to extend the lifetime of L-DOPA therapy with drugs which potentiate the activity of DDC, such as budipine and the 1-aminoadamantanes.

Animals↗

PubMed2003

L-DOPA supply to the neuro retina activates dopaminergic communication at the early stages of embryonic development.

DOPA decarboxylase (DDC; aromatic-l-amino acid decarboxylase; EC 4.1.1.28) is absent in retinas from 6-day-old chicken embryos (E6) but is expressed in retina of E8 embryos, in the presumptive outer plexiform layer. Thereafter, DDC appears in cell bodies of presumptive amacrine cells. The dopamine (DA) content of E9/10 and E15/16 retinas, pre-incubated with l-DOPA for 1 h, increased 250- and 600-fold, respectively, showing that DDC is active since early in development. Intercellular communication, measured by endogenous cyclic AMP accumulation, was observed when retinas from E9/10 to E15/16 were pre-incubated for 1 h with 1 mm l-DOPA, washed and followed by incubation in the presence of 0.5 mm 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor. Cyclic AMP accumulation was prevented when pre-incubation with l-DOPA was carried out in the presence of carbidopa. Moreover, the accumulation of cyclic AMP was inhibited by SCH 23390 (2 micro m). The incubation of retinas in medium previously conditioned by retina-pigmented epithelium (RPE) also increased its cyclic AMP content with the characteristics described for l-DOPA. Our results show that dopaminergic communication takes place in the embryonic retina, before tyrosine hydroxylase expression, provided l-DOPA is supplied to the tissue. It also shows that RPE is a potential source of l-DOPA early in development.

Animals↗

PubMed1980

Induction of translatable mRNA for dopa decarboxylase in Drosophila: an early response to ecdysterone.

Ecdysteroid titer and dopa decarboxylase (aromatic-L-amino-acid carboxy-lyase, EC 4.1.1.28) activity were determined throughout the life cycle of Drosophila melanogaster. Five peaks in the amount of hormone were observed, which preceeded five dopa decarboxylase peaks by times ranging from 5 to 58 hr. Late in the third instar the hormone and enzyme maxima are nearly coincident. The increase in enzyme activity observed at this time is paralleled by an increase in translatable dopa decarboxylase mRNA. To obtain evidence that ecdysterone induces the appearance of this mRNA we made use of the temperature-sensitive ecd1 mutant. Garen et al. [Garen, A., Kauvar, L. & Lepesant, J.-A. (1977) Proc. Natl, Acad. Sci. USA 74, 5099-5103] have shown that when third instar mutant larvae are kept at 29 degrees C, the ecdysteroid titer remains low. In such larvae we show that the normal increase in dopa decarboxylase activity fails to appear, and no translatable dopa decarboxylase mRNA can be detected. Exogenous feeding of ecdysterone to these larvae results in a rapid synthesis of dopa decarboxylase in the epidermal cells. In addition, a parallel increase in translatable dopa decarboxylase mRNA occurs, which may be a primary response of these target cells to ecdysterone.

Animals↗

PubMed1993

Striatal L-dopa decarboxylase activity in Parkinson's disease in vivo: implications for the regulation of dopamine synthesis.

L-DOPA is a large neutral amino acid subject to transport out of, as well as into, brain tissue. Competition between dopamine synthesis and L-DOPA egress from striatum must favor L-DOPA egress if decarboxylation declines relatively more than transport in Parkinson's disease. To test this hypothesis, we injected patients with Parkinson's disease with a radiolabeled analogue of L-DOPA and recorded regional brain radioactivity as a function of time by means of positron emission tomography. We simultaneously estimated the activity of the decarboxylating enzyme and the amino acid transport. In the striatum of patients, we found the L-DOPA decarboxylase activity to be reduced in the head of the caudate nucleus and the putamen. However, the rate of egress of the DOPA analogue was unaffected by the disease and thus inhibited dopamine synthesis more than predicted in the absence of L-DOPA egress.

Corpus Striatum↗

PubMed1993

Chronic administration does not alter the pharmacokinetic profile of L-dopa in the rat.

Chronic administration of L-dopa (200 mg kg-1 day-1 for 12 months) plus carbidopa (25 mg kg-1 day-1) or carbidopa (25 mg kg-1 day-1) alone did not alter the t1/2, AUC0-infinity k10, k12, k21, CLp or Vdss of L-dopa following intra-aortic (i.a.) administration (50 mg kg-1) alone or after carbidopa (25 mg kg-1, i.p.) pretreatment, or the t1/2, AUC0-infinity, tmax or the bioavailability (F) of L-dopa (50 mg kg-1) administered orally, alone or after acute pretreatment with carbidopa (25 mg kg-1 i.p.). The peripheral metabolism of L-dopa was unaltered by chronic administration of L-dopa plus carbidopa or carbidopa alone as measured by unaltered AUC0-360 min for 3-O-methyldopa, dopamine, DOPAC or homovanillic acid in the plasma of rats following acute administration of L-dopa (50 mg kg-1, p.o. or i.a.) alone or following pretreatment with carbidopa, and unaltered hepatic dopa decarboxylase activity.

Administration, Oral↗

PubMedDate not supplied

3,4-dihydroxyphenylalanine (DOPA) metabolism in screening-detected and non-screening-detected neuroblastoma.

To investigate the possible clinical application of the hypothesis that insufficient induction of 3,4-dihydroxyphenylalanine decarboxylase (DDC) causes accumulation and secretion of 3,4-dihydroxyphenylalanine (DOPA) in unfavorable neuroblastomas, we measured plasma DOPA in 28 neuroblastoma patients. Abnormally high levels were demonstrated in patients with neuroblastoma, and the levels in patients with clinical manifestations (median, 44,800 pg/ml; range, 17,700 to 220,000 pg/ml; n = 6) were significantly higher than those in patients detected by screening (median, 5825 pg/ml; range 2890 to 33,300 pg/ml; n = 22) (P = 0.0004). The catecholamine secretion profiles of the two groups were different, and it was suggested that the relative deficiency of DDC caused DOPA secretion in patients in the former group, whose prognosis was unfavorable, except in one case. In both groups, serial determination of plasma DOPA was a good monitor of the disease course. The higher plasma DOPA level (>9400 pg/ml) was significantly correlated with the patients' age (>1 year old) (P = 0.019), tumor stage (III, IV) (P = 0.029), and DNA diploidy (P = 0.018). These results are consistent with previous studies that demonstrated plasma DOPA was a useful marker in the diagnosis and follow-up of neuroblastoma. The results also indicate that higher plasma DOPA levels are associated with the unfavorable characteristics of neuroblastoma, which seem to support the hypothesis on DDC deficiency in unfavorable neuroblastoma.

Catecholamines↗

PubMed1983

Effects of dibutyryl cyclic adenosine 3':5'-monophosphate on the growth of cultured human small-cell lung carcinoma and the specific cellular activity of L-dopa decarboxylase.

High activity of L-dopa decarboxylase separates small (oat)-cell from non-small-cell lung cancer in cell culture. The present study investigates relationships between the specific cellular activity of this enzyme and: (a) cell growth kinetics of an established line (O-H-1) of human small cell lung carcinoma, and (b) responses of these cells to treatment with cyclic adenosine 3':5'-monophosphate and sodium butyrate. The O-H-1 cells, as for most other established small-cell lines, grow as suspended cell aggregates. During growth, the specific cellular activity of L-dopa decarboxylase parallels levels for [3H]thymidine labeling index and the ratio of cells in G2-M to those in G1-G0 phases of the cell cycle. Each of these parameters is 2- to 3-fold higher during exponential versus stationary growth. Continuous treatment with dibutyryl cyclic adenosine 3':5'-monophosphate (dcAMP; 0.1 or 1 mM) and 1 mM theophylline produces simultaneous cessation of cell growth and an increase in cellular L-dopa decarboxylase activity. During this period, analyses of DNA histograms reveal an increase in the number of cells in the G2-M phase; the rate of increase in the ratio of G2-M to G1-Go cells paralleled the rate of increase in specific activity of the enzyme. The effects of the dcAMP were promptly reversible; release of the apparent G2-M block preceded regrowth of the cells and was accompanied by a return of L-dopa decarboxylase activity to base-line levels. The changes in enzyme activity were specific for cyclic adenosine 3':5'-monophosphate; another cyclic adenosine 3':5'-monophosphate analogue, 8-bromo adenosine cyclic 3':5'-monophosphate yielded similar increases in L-dopa decarboxylase to those seen with dcAMP, while 0.01 to 1 mM butyrate alone produced the inhibition of cell growth but no changes in specific activity of L-dopa decarboxylase or percentage of cells in the different phases of the cell cycle. We conclude that the specific activity of L-dopa decarboxylase, a key neuroendocrine marker for cultured small-cell lung carcinoma, is highest during proliferative growth and/or when these cells are in the G2M phase of the cell cycle. The differential effects of dcAMP and sodium butyrate offer potential for exploring neuroendocrine differentiation in this important lung cancer and related endocrine neoplasms.

Aromatic-L-Amino-Acid Decarboxylases↗

PubMed1997

L-DOPA modulates striatal dopaminergic function in vivo: evidence from PET investigations in nonhuman primates.

Significant increases in striatal L-[11C]DOPA retention were observed in adult female rhesus monkeys with positron emission tomography (PET) following administration of drugs that increase cerebral L-DOPA concentrations. The monkeys were scanned twice: at baseline (using 10-50 micrograms of tracer substance) and during continuous administration of L-DOPA (3 or 15 mg/kg/h) and 6-R-Erythro-4,5,6,7-tetrahydrobiopterin (6R-BH4) (5 mg/kg/h) and during combined administration of both drugs. PET scans of L-[11C]DOPA distribution were obtained in GE2048-15B or GE4096-15WB Plus positron tomographs. In all studies the specific striatal L-[11C]DOPA influx rate increased by an average of 17-20%. These increases were significantly higher than the retest variability obtained with saline infusions under identical experimental conditions. In individual monkeys the magnitude of increase in the striatal L-[11C]DOPA influx rate varied from no effect of the drug infusion to a 45% increase. Taken together, the results of this study demonstrate that L-DOPA in itself can affect dopaminergic neurotransmission in vivo and also adds further evidence that the neuromodulatory effects of the amino acid are predominantly autoreceptor antagonist-like. The findings most likely have importance for the further understanding of the dopaminergic system in neurodegenerative and psychiatric disorders.

Animals↗

PubMed1982

3-O-methyldopa blocks dopa metabolism in rat corpus striatum.

3-O-Methyldopa (OMD) given to rats inhibits striatal uptake and utilization of L-dopa. Thus, the accumulation of L-dopa, dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in OMD-pretreated rats after L-dopa injection is significantly lower compared with control rats. This effect of OMD is dose-dependent. OMD inhibits L-dopa accumulation in the striatum after inhibition of aromatic amino acid decarboxylase activity with 3-hydroxybenzylhydrazine-HCL. This effect is not mediated through inhibition of firing in dopaminergic neurons, since the accumulation of dopamine in the striatum after gamma-butyrolactone injection was also significantly reduced by OMD. It is suggested that OMD competes with L-dopa and tyrosine uptake into the brain. These findings are in line with clinical observations which indicate that high plasma levels of OMD in parkinsonian patients are associated with poor response to L-dopa. The data presented here indicate that use of catechol-O-methyltransferase inhibitors with L-dopa may be of value in the treatment of parkinsonian patients.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Immunocytochemical localization of L-dopa and dopamine in the brain of the chicken (Gallus domesticus).

A light microscopic immunocytochemical study, with antisera against dihydroxyphenylalanine (L-DOPA) and dopamine (DA), revealed the dopaergic and dopaminergic systems in the brain of the chicken (Gallus domesticus). L-DOPA- and DA-immunoreactive (ir) elements are similarly distributed throughout the entire brain. Virtually all regions of the brain contained a dense innervation by L-DOPA- and DA-immunopositive varicose fibers. The neuronal cell bodies immunoreactive for the two monoamines were confined to more restricted regions, the hypothalamus, the midbrain and the brainstem. In the hypothalamus, DA- and L-DOPA-ir neurons were subdivided into a medial periventricular and a lateral group. The medial group starts at the level of the anterior commissure, in the ventral part of the nucleus periventricularis hypothalami, and continues in a more dorsal periventricular position caudally into the dorsal tuberal hypothalamic region. Densely labeled cerebrospinal fluid contacting cells can be observed in the paraventricular organ. The lateral group consists of immunopositive neurons loosely arranged in the lateral hypothalamic area and in the nucleus mamillaris lateralis. Most of the dopaminergic cell groups, identified in the hypothalamus of mammals, could be observed in the chicken, with the exception of the tuberoinfundibular group. The majority of L-DOPA- and DA-ir perikarya is, however, situated in the mesencephalic tegmentum, in the area ventralis of Tsai and in the nucleus tegmenti pedunculo-pontinus, pars compacta, the avian homologues of, respectively, the ventral tegmental area and the substantia nigra of mammals. In the pons, dense groups of cells are found in the locus coeruleus and in the nucleus subcoeruleus ventralis and dorsalis. A few labeled cells appear in and around the nucleus olivaris superior in the most caudal part of the metencephalic tegmentum. In the medulla oblongata, L-DOPA- and DA-ir cells can be seen at the level of the nucleus of the solitary tract and in a ventrolateral complex. A comparison with tyrosine hydroxylase (TH) immunocytochemistry revealed TH-immunopositive neurons greatly outnumbering the cells exhibiting DA and L-DOPA immunoreactivity. These results are discussed in relation to catecholaminergic systems previously reported in avian species and in the mammalian brain.

Aging↗

PubMed2001

Idazoxan, an alpha-2 antagonist, and L-DOPA-induced dyskinesias in patients with Parkinson's disease.

Dyskinesia is a frequent and disabling side effect in patients with Parkinson's disease treated with chronic dopa-therapy. Preclinical data in the 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) monkey suggest that alpha-2 antagonists may reduce dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. We assessed, in a pilot randomised placebo-controlled study, the effects of single oral doses (10 mg, 20 mg, and 40 mg) of idazoxan, an alpha-2 antagonist, on motor parkinsonian disability and L-DOPA-induced dyskinesia following an acute oral challenge of L-DOPA in 18 patients with Parkinson's disease. The severity of L-DOPA-induced dyskinesia improved after 20 mg idazoxan pretreatment, while there was no concommittant deterioration in the antiparkinsonian response to L-DOPA. These results suggest that blocking alpha-2 receptors in patients with Parkinson's disease might improve L-DOPA-induced dyskinesia without the cost of a return of parkinsonian symptomatology. Further studies are required to assess whether this property could have potential therapeutic applications in the long-term management of dyskinetic patients with Parkinson's disease.

Administration, Oral↗

PubMed2006

Striatal subregional 6-[18F]fluoro-L-dopa uptake in early Parkinson's disease: a two-year follow-up study.

Thirty-one drug-naive patients with Parkinson's disease (PD) underwent 6-[18F]fluoro-L-dopa (F-dopa) positron emission tomography (PET) scan at the time of the diagnosis (baseline) and 2 years later in order to investigate F-dopa uptake in striatal and extrastriatal regions during the first years of early PD. Twenty-four healthy controls underwent one F-dopa PET scan. The regional differences in the striatal and extrastriatal regions were analyzed with statistical parametric mapping and automated region of interest analyses. Our study shows that the F-dopa uptake in unmedicated early PD is most severely decreased in the dorsal part of caudal putamen but significant decrease can be seen throughout the striatum compared with controls. During the first years of PD, there is a progressive regional decline in striatal F-dopa uptake, the dorsal part of caudal putamen being still the most severely affected region. The absolute decline is equal between the striatal subregions. This suggests that the decline of dopamine function starts from the dorsocaudal putamen, but once started, the rate of progression is equal between the subregions of the striatum. In contrast to the striatal decline, the increased cortical F-dopa uptake prevails at least during the first years of PD.

Aged↗

PubMed1997

The effect of catecholamine precursor L-dopa on sleep bruxism: a controlled clinical trial.

The putative role of the dopaminergic system in sleep bruxism (SB) was studied in a double-blind clinical trial by using low doses of short-term L-dopa in combination with benserazide. We recorded 10 patients with SB in our sleep laboratory for 3 consecutive nights. The first night was for habituation to the laboratory environment. During the second and the third nights, the patients received two doses of either L-dopa or a placebo in a crossover fashion: the first dose 1 h before bedtime and the second, 4 h after the first one. The order of administration was reversed in half the patients. The efficacy of L-dopa was analyzed by using multilevel models. L-Dopa resulted in a significant decrease in the average number of bruxism episodes per hour of sleep, as well as in a significant reduction in the average value of the root-mean-square (RMS) electromyography (EMG) level per bruxism burst. This indicates that L-dopa exerts an attenuating effect on SB. In addition, L-dopa caused a reduction in the variance in RMS values, which suggests that L-dopa normalizes the EMG activity patterns associated with SB.

Adult↗