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PubMed2006

Tamoxifen effect on L-DOPA induced response complications in parkinsonian rats and primates.

The contribution of striatal protein kinase C (PKC) isoform changes in levodopa (L-DOPA) induced motor response complications in parkinsonian rats was investigated and the ability of tamoxifen, an antiestrogen with a partial PKC antagonist property, to prevent these response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats as well as in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated cynomologous monkeys was studied. Following treatment of adult male rats with L-DOPA twice daily for 3 weeks, protein levels of left (lesioned) and right (intact) striatal PKC isoforms were measured. Western blot analysis showed increased protein expression of both the novel PKC epsilon isoform and the atypical PKC lambda isoform ipsilateral to the lesion (174+/-17% for epsilon, 140+/-9% for lambda, of intact striatum in 6-OHDA lesioned plus chronic L-DOPA treated animals) in acute L-DOPA treated rats. No enhancement was observed in PKC immunoreactivity for other isoforms. Tamoxifen (5.0 mg/kg p.o.) significantly attenuated the L-DOPA induced augmentation of protein expression of PKC epsilon and PKC lambda, but had no effect on immunoreactivity for other PKC isoforms. In chronic L-DOPA treated parkinsonian rats, tamoxifen prevented (5.0 mg/kg p.o.) as well as ameliorated (5.0 mg/kg p.o.) the characteristic shortening in duration of motor response to L-DOPA challenge. In MPTP lesioned primates, similar to the ameliorative effect seen in rats, tamoxifen (1 and 3 mg/kg p.o) reduced the appearance of L-DOPA induced dyskinesia by 61% and 55% respectively (p<0.05). These results suggest that changes in specific striatal PKC isoforms contribute to the pathogenesis of L-DOPA induced motor complications and further that drugs able to selectively inhibit these signaling kinases might provide adjunctive benefit in the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Sodium nitroprusside stimulates L-DOPA release from striatal tissue through nitric oxide and cGMP.

The effects of the nitric oxide (NO) donor, sodium nitroprusside, on L-DOPA and dopamine release from striatal tissue were evaluated using a static incubation system in which the striatal tissue released between three and six times more L-DOPA than DA, although the DA content was four times higher than that of L-DOPA. Sodium nitroprusside stimulated L-DOPA release in a time- and concentration-dependent (25, 50 and 100 microM) manner. This effect was not due to an increase in L-DOPA synthesis because sodium nitroprusside did not modify the tyrosine hydroxylase activity of striatal tissue. DA release was also stimulated by sodium nitroprusside but it required a higher concentration (500 microM) and longer incubation (60 min). Neither basal nor sodium nitroprusside-stimulated L-DOPA release was influenced by Ca(2+) deprivation (EGTA 5 mM) and/or the presence of nitrendipine (1 microM), a blocker Ca(2+) channel, in the incubation medium. However, cGMP (1 mM) increased L-DOPA release, and the soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ) (5 microM), partially blunted the stimulatory effect of sodium nitroprusside 100 microM. In addition, the presence of certain scavengers of free radicals, such as uric acid (300 microM) or melatonin (300 microM) but not of superoxide dismutase (1000 UI/ml) or salicylic acid (300 microM), completely blocked sodium nitroprusside (100 microM)-induced L-DOPA release. These results show that NO stimulates L-DOPA release from striatal tissue by an apparently Ca(2+)-independent mechanism, mediated by cGMP but also by peroxynitrite.

Animals↗
PubMed2000

Effects of dopamine metabolites on locomotor activities and on the binding of dopamine: relevance to the side effects of L-dopa.

L-dopa is the major treatment for Parkinson's disease (PD), but its efficacy is limited by the presence of dyskinesia. The dyskinesia develops over a period of exposure to L-dopa and is related to the dosage, therefore, the cause may involve inductive changes that produce toxic levels of metabolites, interfering with dopamine (DA) neurotransmission. Chronic L-dopa induces catechol-O-methyltransferase (COMT) and methionine adenosyl transferase (MAT), enzymes involved in the methylation of catecholamines (CA). In addition, high levels of 3-O-methyl-dopa have been reported in the plasma of dyskinetic PD patients, treated with L-dopa, as compared to non-dyskinetic patients, therefore, the methyl metabolites of CA may be increased during L-dopa therapy and may be involved in the dyskinesia. Since large amounts of DA are produced from L-dopa, and DA is extensively methylated, the methyl metabolites of DA, 3-methoxytyramine (3-MT) and 3,4-dimethoxyphenylethylamine (DIMPEA), may be also involved. The first step in knowing this, is to assess the behavioral and DA-receptor activities of 3-MT and DIMPEA. In the rat, the intraventricular injection of 0.5 micromol of DIMPEA increased the total distance traveled (TD) by over 100%, the number of movement (NM) made by 40% and the time spent moving (MT) by about 36%. Identical doses of 3-MT decreased the TD by 42%, NM by 22% and MT by 39%. DIMPEA (1 mM) increased the binding of DA with brain membranes by 44.7%, whereas 3-MT decreased it by 15.8%. The results show that 3-MT and DIMPEA are behaviorally active, and in parallel, they interact with the binding sites for DA, consequently, they may contribute to the side effects of L-dopa. L-dopa produces high levels of DA and induces MAT and COMT. It is proposed, therefore, that DA will be methylated to 3-MT and 3-MT to DIMPEA. At threshold level each product will inhibit, allosterically, its enzyme of methylation, causing sequential and rhythmic up and down regulation of its concentration. At peak levels these hydrophobic metabolites will modulate the actions of DA on synaptic membranes, causing abnormal movements, at times, resembling the "on-off effects".

Animals↗
PubMed1999

The NMDA antagonist, MK-801, alters L-DOPA-induced air-stepping in neonatal rats.

Administration of L-DOPA (sc) to neonatal rats suspended in harnesses induces coordinated stepping of all four limbs (diagonal progression; L-DOPA-induced air-stepping) by 5 days of age. Because NMDA also induces locomotion in several species, NMDA receptor activation may be required for L-DOPA to elicit coordinated air-stepping. The purpose of the present experiment was to determine if the NMDA receptor antagonist, MK-801, would block L-DOPA-induced air-stepping in developing rats. Neonatal rats administered MK-801 alone rarely air-stepped with the forelimbs or hindlimbs in a coordinated fashion, whereas those treated with L-DOPA alone primarily stepped with all four limbs using a diagonal progression pattern during the session. In contrast, the number of limbs that stepped during the session was gradually altered in 5- to 20-day-old rats treated with MK-801 + L-DOPA. Gaits of those rats progressed from diagonal progression to extension of the forelimbs beneath the chin with hindlimb alternation, to forelimb extension without hindlimb activity. Twenty-day-olds treated with MK-801 + L-DOPA subsequently became completely inactive when the forelimbs dropped from their elevated position beneath the chin. In addition to the sequence just described, 15-day-old rats treated with the lowest concentration of MK-801 + L-DOPA occasionally stepped with one pair of homolateral limbs or stepped with the hindlimbs in near synchrony while the forelimbs either stepped in alternation, were extended beneath the chin or groomed the face. Because limb participation during L-DOPA-induced air-stepping was altered in neonatal rats pretreated with MK-801, NMDA receptor activation may be important for locomotor coordination (gait).

Animals↗
PubMed2002

Increases in striatal preproenkephalin gene expression are associated with nigrostriatal damage but not L-DOPA-induced dyskinesias in the squirrel monkey.

Changes in preproenkephalin expression in the caudate and putamen have been linked to the development of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in primate models of Parkinson's disease, although not all investigators have been able to confirm this association. Because nigrostriatal damage per se is associated with increases in striatal preproenkephalin mRNA levels, it is difficult to know if changes in transcript levels are a result of lesioning or concurrent L-DOPA treatment and resulting dyskinesias. To circumvent these difficulties, we measured striatal preproenkephalin mRNA levels in monkeys with L-DOPA-induced dyskinesias both with and without lesions of the nigrostriatal system. The latter model is not confounded by morphological and biochemical changes resulting from nigrostriatal damage. Monkeys were gavaged with L-DOPA (15 mg/kg) twice daily for a 2-week period and killed 3 days after treatment. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment alone resulted in an increase in preproenkephalin mRNA levels as previously shown. However, striatal transcript levels were similarly elevated in dyskinetic MPTP-lesioned animals treated with L-DOPA. In unlesioned animals, preproenkephalin mRNA levels were also similar in control and L-DOPA-treated dyskinetic monkeys. Because drug-induced changes in mRNA may not be sustained for a prolonged period after treatment, a second series of experiments were done in which animals were killed 3-4 h after the last dose of L-DOPA, but the results were similar to those obtained after 3 days. These data show that, while elevations in striatal preproenkephalin mRNA levels are associated with nigrostriatal damage, they are not linked to the development of L-DOPA-induced dyskinesias. These results thus question the importance of preproenkephalin mRNA in the pathogenesis of this disabling complication of L-DOPA therapy in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Entacapone and selegiline with L-dopa in patients with Parkinson's disease: an interaction study.

Both the catechol-O-methyltransferase (COMT) inhibitor entacapone and the monoamine oxidase B (MAO-B) inhibitor selegiline are L-dopa extenders. Both are used, often simultaneously, as adjuncts to L-dopa/dopa decarboxylase (DDC) inhibitor treatment of Parkinson's disease (PD). Their possible interactions have not been previously studied in a double-blind manner.We studied clinical response, tolerability, haemodynamics and cardiac rhythm in 16 PD patients with end-of-dose-type motor fluctuations. The patients' individual L-dopa/DDC inhibitor treatment was stabilized before the experimental treatments. This was followed by three consecutive, randomized, double-blind 2-week treatment periods with entacapone (200mg with each L-dopa dose), selegiline (10mg o.d.) or both entacapone and selegiline with the L-dopa/DDC inhibitor medication. Clinical efficacy (L-dopa test with repeated motor and dyskinesia scoring) and safety (orthostatic test, 24-h ambulatory ECG, haematological and clinical chemistry variables and adverse events) evaluations were performed before each treatment (control) and at the end of each treatment period.All three treatments, entacapone, selegiline, and entacapone+selegiline as adjunct to L-dopa/DDC inhibitor improved (p<0.05) clinical disability compared to L-dopa only but they did not differ significantly from each other. Dyskinesias increased with all the treatments, statistically significantly (p<0.01) with entacapone+selegiline. No significant differences in haemodynamics were observed between control and any of the experimental treatments, or between the experimental treatments in the orthostatic test. One patient already had symptomatic orthostatism before experimental treatments (control). In two other patients orthostatism emerged after the introduction of selegiline, and in one after every experimental treatment. Twenty-four-hour ECG did not show any differences in supraventricular or ventricular extrasystoles or heart rate between treatments. No statistically significant differences were observed in adverse events or in haematology and clinical chemistry variables. One patient treated with entacapone+selegiline discontinued the study due to dizziness and insomnia. Our results suggest that co-administration of entacapone with L-dopa/DDC inhibitor, with or without selegiline, improves clinical disability, is safe, but may also enhance dopamine-related adverse events to some extent in PD patients with end-of-dose type motor fluctuations.

Journal Article↗
PubMed2002

Imaging and therapeutics: the role of neuronal transport in the regional specificity of L-DOPA accumulation in brain.

PURPOSE: To investigate the in vitro regional accumulation of L-3,4-dihydroxyphenylalanine (L-DOPA) in brain tissue. PROCEDURE: Neuronal membrane transport of L-DOPA was investigated in rat and squirrel monkey brain tissue. The kinetics of L-DOPA regional transport was characterized, and the effect of amino acids on transport was evaluated using isolated nerve terminals from striatum and cerebral cortex. RESULTS: When L-DOPA uptake was measured in modified Krebs-Ringer medium, transport occurred in both synaptosome preparations. In the presence of dilute protein-free plasma, uptake of L-DOPA was significantly present in striatal nerve terminals (P < 0.005), but was completely inhibited in terminals isolated from the cortex. L-DOPA transport in striatal synaptosomes was primarily inhibited by large neutral aromatic L-amino acids, in contrast to that in cortical synaptosomes that was mainly affected by large neutral aliphatic L-amino acids. A saturable component of influx was detected in both synaptosome preparations, where kinetic analysis revealed that the relative affinity of L-DOPA was greater for the carrier in the striatum than in the cortex. Based on the distribution of neuronal cell types within the two regions and the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioning in squirrel monkeys, the striatal specific accumulation of L-DOPA likely occurs within dopaminergic terminals. CONCLUSIONS: These results demonstrate that the in vivo regional specificity of L-DOPA localization in brain tissue is primarily controlled by neuronal transport.

Journal Article↗
PubMed1986

A lymphotropic prodrug of L-dopa: synthesis, pharmacological properties, and pharmacokinetic behavior of 1,3-dihexadecanoyl-2-[(S)-2-amino-3-(3,4-dihydroxyphenyl)prop anoyl] propane-1,2,3-triol.

A glyceride derivative of L-Dopa, 1,3-dihexadecanoyl-2-[(S)-2-amino-3-(3,4-dihydroxyphenyl)propan oyl] propane-1,2,3-triol (1), was synthesized and tested as an orally administrable prodrug endowed with lymphotropic properties. In the oxotremorine and reserpine tests, 1 exhibited an anti-Parkinsonian activity of longer duration than L-Dopa. The time course of concentration of 1 in the intestinal lymph of rat was determined and compared to that of L-Dopa. The results clearly demonstrate that 1 is selectively absorbed from the intestinal tract by the lymphatic route without any chemical or enzymatic degradation. In the blood of rats and mice, 1 functions as a prodrug to release L-Dopa by hydrolysis. In comparison with L-Dopa itself, higher L-Dopa levels for a longer period of time were observed as well as much more favorable L-Dopa/dopamine ratios. Ultimately, studies using mice show that the administration of 1 brings about a prolonged increase of L-Dopa and dopamine levels in the brain, without initial transient peak in concentration observed after an equimolecular dose of L-Dopa.

Administration, Oral↗
PubMed2000

Melanin granules prevent the cytotoxic effects of L-DOPA on retinal pigment epithelial cells in vitro by regulation of NO and superoxide radicals.

Inasmuch as the nitrogen cycle elicits the direct reduction of N2 to NH3 through enzymatic reactions, and inasmuch as L-DOPA (L-dihydroxyphentlalamine), a catecholamine, can be a source of nitric oxide (NO), it is possible that melanin granules in the eye affect the generation of NO, which causes damage to the retinal pigment epithelial (RPE) cells during the oxidation of L-DOPA. In order to confirm this possibility, we analyzed the correlations of NO generation, cell growth, and superoxide dismutase (SOD) activities in two types (melanotic and amelanotic) of bovine RPE cells following exposure to L-DOPA. NO generation from L-DOPA was determined using an NO detector that is reliant on redox currents. The concentration of NO was measured in terms of diffusion currents run between a working electrode and a counter electrode, both being set in culture medium placed in a Petri dish. For the assays, L-DOPA was added to the medium at various concentrations (5, 29.9, 79.4, 152.7 or 249 microM), and 6 min after addition, an NO-trapping agent 2,4-carboxyphenyl-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide (carboxy-PTIO) was also added. The melanotic and amelanotic types of RPE cells were cultured separately in medium with L-DOPA under an atmosphere containing 20, 10 or 5% oxygen. Cell numbers were counted using a Coulter counter, and SOD activities were determined following incubation for 24, 48 or 72 hr using a modification of the luminol assay. The results obtained indicated that: (a) NO was produced from L-DOPA in a concentration-dependent manner and was trapped quantitatively by carboxy-PTIO; (b) the generation of NO was inhibited more markedly in the melanotic cell line than in the amelanotic one, suggesting an increased tolerance to L-DOPA-derived cytotoxicity in the former; and (c) the SOD activities were more affected by oxygen concentration in the melanotic cells than in the amelanotic ones. From these results, it is concluded that melanin granules in RPE cells have a role in preventing the cytotoxicity derived from L-DOPA and in regulating the generation of NO and superoxide radicals.

Animals↗
PubMed1995

NMDA antagonist effects on the development of L-dopa behavioral sensitization in rats.

This study, which used an animal model of Parkinsonism, evaluated whether the NMDA antagonist MK-801 can prevent the development of L-3-4-dihydroxyphenylalanine (L-DOPA) sensitization. In separate groups, rats with unilateral 6-hydroxydopamine (6-OHDA) lesions were treated with saline, 25 mg/kg L-DOPA methyl ester, 0.1 mg/kg MK-801, or MK-801 plus L-DOPA once per day for 13 days beginning 18 to 20 hr postoperatively, well before the onset of denervation supersensitivity. Following 14 days of withdrawal, all treatment groups were given a saline test and on the next day, an L-DOPA challenge test. Contralateral rotation, the behavioral index of denervation supersensitivity, emerged on Day 7 in both L-DOPA groups. However, on the L-DOPA challenge test, only the L-DOPA group showed enhanced contralateral rotations compared with a drug-naive group. In contrast, the MK-801 and MK-801/L-DOPA groups were indistinguishable from the drug-naive L-DOPA-treated rats. These findings indicate that although MK-801 treatment did not prevent the development of behavioral sensitization to the L-DOPA treatment, it did prevent its persistence following drug withdrawal.

Animals↗
PubMed1990

Increased spillover of dopa into arterial blood during dietary salt loading.

1. We measured urinary excretion rates of dopamine (3,4-dihydroxyphenethylamine) and dopa (3,4-dihydroxyphenylalanine) and the spillover rate of dopa into arterial blood during dietary salt loading in conscious Dahl salt-sensitive and salt-resistant rats with intact or denervated kidneys. 2. Dopa spillover was calculated from the steady-state clearance of intravenously infused L-[3H]dopa and arterial levels of endogenous dopa. 3. Daily excretion rates of dopa and dopamine increased by about sixfold during salt loading in both rat strains. Bilateral renal denervation delayed these increases and the natriuretic responses. 4. During dietary salt loading, dopa spillover increased to approximately the same extent as simultaneously measured dopamine excretion. 5. The results suggest that increases in urinary excretion of dopamine during dietary salt loading can be accounted for by increases in the release of dopa into the bloodstream and that the renal nerves contribute to the dopa and dopamine excretory responses.

Animals↗
PubMed2001

Evaluation of plasma 3,4-dihydroxyphenylacetic acid (DOPAC) and plasma 3,4-dihydroxyphenylalanine (DOPA) as tumor markers in children with neuroblastoma.

Catecholamines and their metabolites are important in the diagnosis of neuroblastoma (NB). Plasma (p-) levels of 3,4-dihydroxyphenylalanine (DOPA) are increased in most NB, probably reflecting decreased DOPA decarboxylase activity. Urine (u-) homovanillic acid (HVA), a DOPA and dopamine (DA) metabolite. is also increased in most NB. DOPAC (3,4-dihydroxyphenylacetic acid) is an important metabolite of DA in tissues with monoamine oxidase (MAO) activity. Because MAO is expressed in NB tumor cells, we studied the importance of measuring p-DOPAC and p-DOPA as compared to u-HVA and u-vanillylmandelic acid (VMA) in the diagnosis and follow-up of NB. DOPAC, DOPA, dopamine, noradrenaline, adrenaline, VMA and HVA were measured by reverse-phase HPLC with electrochemical detection in 106 children (28 with NB (13 newly diagnosed), 25 with other solid tumors, 28 hospitalized for nonneoplastic diseases, and 25 healthy children). P-DOPAC or p-DOPA concentrations were above the upper normal range in 92% of untreated NB patients, as were u-HVA or u-VMA levels. None of these tumor markers was correlated to tumor stage or survival. P-DOPA but not p-DOPAC was correlated to age in NB children. Increased values of p-DOPAC and p-DOPA were found in one patient surviving NB for 10 years. Plasma DOPAC concentrations were decreased in children hospitalized for non-NB diseases, probably reflecting reduced food intake. Plasma analyses of DOPA and DOPAC seem to be useful alternatives in the diagnosis and follow-up of NB if urine sampling is to be avoided. Plasma DOPAC may be an index of nutritional status in various diseases.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

'Priming' enhances the relationship of striatal L-dopa concentration to behavior.

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions were exposed to L-DOPA treatments, 25 mg kg-1 L-DOPA methyl ester/2 mg kg-1 carbidopa, or to saline. Fourteen days later, both sets of animals were tested with the L-DOPA/carbidopa treatment. The L-DOPA pre-exposed animals exhibited behavioral sensitization as indexed by a higher frequency of contralateral rotations. Although striatal L-DOPA and HVA concentrations were equivalent in the two groups, the L-DOPA treatment induced a 10 fold variation in the range of L-DOPA concentrations in the 6-OHDA striatum in both sets of animals. Importantly, significant correlations between striatal L-DOPA concentration and behavior were obtained only for the L-DOPA pre-exposed animals.

Animals↗
PubMed1990

Effect of a novel catechol-O-methyltransferase inhibitor, nitecapone, on the metabolism of L-dopa in healthy volunteers.

A new catechol-O-methyltransferase (COMT) inhibitor, nitecapone, was given in increasing doses of 0-100 mg concomitantly with L-Dopa/carbidopa (100/25 mg or 100/100 mg) to healthy male volunteers. Plasma concentrations of L-Dopa, 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), as well as the excretion of catecholamine metabolites in urine were followed to evaluate the changes in the metabolism of L-Dopa after nitecapone. Plasma concentrations of nitecapone and the soluble COMT activity in erythrocytes were also measured. The area under the plasma concentration-time curves (AUC) values for plasma nitecapone, L-Dopa and its metabolites were calculated. Nitecapone dose-dependently inhibited the soluble COMT activity in erythrocytes at 30 min after drug intake. Nitecapone slightly but significantly increased the relative bioavailability of L-Dopa. The AUC values of plasma 3-OMD decreased dose-dependently after nitecapone, and those of HVA decreased less, whereas the AUC values of DOPAC increased significantly. The elevation of the dose of carbidopa from 25 to 100 mg increased the AUC value of L-Dopa, but the effect of nitecapone was not clearly modified. Nitecapone decreased the excretion of the methylated dopamine metabolites 3-methoxytyramine (3-MT) and HVA at an L-Dopa/carbidopa dose of 100/25 mg. At a dose of 100/100 mg, the excretion of metanephrine, in addition to 3-MT and HVA, was also significantly decreased by nitecapone. The biochemical changes in L-Dopa metabolism and erythrocyte COMT activity indicate that nitecapone is an active COMT inhibitor in humans, when given orally in single doses. The changes in L-Dopa metabolism by COMT inhibitor warrant further clinical studies in Parkinson's disease.

Adult↗
PubMed1997

Clinical and pharmacokinetic evaluation of L-dopa and cabergoline cotreatment in Parkinson's disease.

Previous investigations on the mutual pharmacokinetic influence of L-dopa and dopamine agonists in Parkinson's disease (PD) have shown controversial results. Two studies of the possible clinical and pharmacokinetic interaction between L-dopa and cabergoline were performed in 10 patients with de novo PD and 12 patients with fluctuating PD. In the first study (de novo patients), cabergoline was administered at increasing dosages until the maximum dosage of 2 mg/day once a day for 8 weeks; subsequently L-dopa (250 mg/day) was added. Blood levels of cabergoline were assayed in two different days, before starting L-dopa, and 1 week thereafter. In the second 8-week study (fluctuating patients), cabergoline was added to the current L-dopa therapy (maximum dosage 4 mg/day once a day). Blood levels of L-dopa were measured in two different days, before cabergoline was added, and at the end of the study. In both studies motor performance was evaluated by means of the Unified Parkinson's Disease Rating Scale (motor examination) and the Clinical Global Impression Scale; on-off diaries of daily motor condition also were filled by fluctuating patients. In patients with de novo PD, cabergoline pharmacokinetic parameters were unmodified by the adjunct of L-dopa, except that the time to reach the peak concentration (Tmax) significantly increased after L-dopa. In patients with fluctuating PD, no modification of L-dopa pharmacokinetics was observed before and after cabergoline coadministration. Clinical evaluations confirmed that cabergoline is effective in the treatment of advanced PD as well as in the management of de novo patients.

Aged↗
PubMed1998

[3H]DOPA formed from [3H]tyrosine in living rat brain is not committed to dopamine synthesis.

Tyrosine hydroxylase of catecholamine neurons catalyzes the synthesis of 3,4-dihydroxphenylalanine (DOPA), which is subsequently metabolized to dopamine by DOPA decarboxylase (DDC). However, DOPA is not committed to decarboxylation in vivo because export of DOPA from brain and metabolism of DOPA other than decarboxylation are possible. To estimate the relative magnitudes of the several fates of DOPA, the kinetics of the uptake and metabolism of L-[3H]tyrosine ([3H]Tyr, intravenous infusion) was measured in brain of rats pretreated with NSD 1015, an inhibitor of DDC. Some rats were pretreated with haloperidol before the blockade of DDC. The [3H]Tyr was incorporated into brain protein at a rate constant of 0.03 min(-1). The relative tyrosine hydroxylase activity in striatum was 0.005 min(-1) at 30 minutes after NSD 1015, 0.011 min(-1) 3 hours later, and 0.020 min(-1) after haloperidol treatment. The rate constant for the clearance of DOPA from brain (0.06 min(-1)) and earlier estimates of the rate constant of DDC activity in striatum (0.26 min(-1)) together predict that 80% of DOPA formed in normal rat striatum normally is available for dopamine synthesis. It follows that modulation of DDC activity can influence the rate of DA synthesis by affecting the relative magnitude of the several fates of DOPA in living brain.

Animals↗
PubMed2000

Effects of MAO inhibitors upon MPTP mice chronically treated with suprathreshold doses of L-dopa.

Groups of mice were administered either saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (2 X 40 mg / kg, s.c., separated by a 24-hour interval) 4-6 weeks prior to behavioural testing. At testing, all the MPTP-injected mice were repeatedly administered L-dopa (20 mg / kg, s.c., five times each week, Monday-Friday), by applying a procedure that induced a severe reduction of motor activity parameters from Day 1 to Day 25. Control (uninjected mice) received only saline and were retained only for neurochemical analysis. In each of three experiments, following the reduction of the activity-stimulating effects of L-dopa by repeated administration, a restorative effect of different monoamine oxidase (MAO) inhibitors was tested by co-administration of the test compounds (irreversible MAO-B inhibitor, reversible MAO-A inhibitors, or irreversible MAO-A / mixed MAO inhibitors) with L-dopa (20 mg / kg). In each case the MAO inhibitor was injected 60 min prior to L-dopa. L-Deprenyl (3 or 10 mg / kg, s.c.), in combination with L-dopa, reinstated locomotion and total activity, but not rearing, dose-dependently, in L-dopa-tolerant mice. The reversible MAO-A inhibitors, amiflamine and alpha-ethyltryptamine, in combination with L-dopa, reinstated locomotion and total activity, leaving rearing unaffected; Ro 41-1049 (3 mg / kg, s.c.) restored all three parameters of activity; locomotor activity was restored by all three doses (1, 3, and 10 mg / kg, s.c.). On the other hand, neither the irreversible MAO-A inhibitor, clorgyline, nor the mixed MAO inhibitor, phenelzine, produced any directly effective restorative increments. Neurochemical analysis confirmed the severe striatal dopamine depletion of MPTP-treated mice. These results demonstrate a synergistic and restorative action of combining certain MAO inhibitors, namely the reversible MAO-A inhibitors, with the suprathreshold dose of L-dopa in MPTP-treated, L-dopa-tolerant mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1976

The action of microelectrophoretically applied L-3,4-dihydroxyphenylalanine (DOPA) on single cortical neurones.

The technique of microelectrophoresis was used in order to compare the actions of L-3,4-dihydroxyphenylalanine (DOPA) and noradrenaline on single neurones in the cerebral cortices of cats and rats. DOPA could both excite and depress cortical neurones. Cells excited by DOPA were also excited by noradrenaline and cells depressed by DOPA were also depressed by noradrenaline. In the case of both excitatory and depressant responses, DOPA appeared to be less potent than noradrenaline. Responses to DOPA and noradrenaline could be antagonized by phentolamine and propranolol. Responses to acetylcholine were not affected. Responses to acetylcholine, but not responses to DOPA, were antagonized by atropine. The results indicate that locally applied DOPA may mimic the actions of noradrenaline on cortical neurones. Possible mechanisms for these effects of DOPA are discussed.

Acetylcholine↗