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PubMed1995

pGlu-L-Dopa-Pro: a tripeptide prodrug targeting the intestinal peptide transporter for absorption and tissue enzymes for conversion.

PURPOSE: The purpose of this study is to investigate the characteristics of pGlu-L-Dopa-Pro as a prodrug of L-Dopa. METHODS: pGlu-L-Dopa-Pro and L-Dopa-Pro were synthesized using the standard procedures of peptide synthesis. The conversion of pGlu-L-Dopa-Pro to L-Dopa was studied using pyroglutamyl aminopeptidase I and prolidase. With rats as the animal model, the stability of pGlu-L-Dopa-Pro in intestinal homogenates was determined, then the transport characteristics of pGlu-L-Dopa-Pro were studied using in-situ perfusion and Ussing chambers. RESULTS: pGlu-L-Dopa-Pro, relatively stable in intestinal homogenates and intestinal fluid, had a dimensionless permeability of 1.8 at 0.04 mM. Its intestinal permeability was significantly inhibited by 20 mM captopril, by a mixture of dipeptides, 80 mM Gly-Gly and 5 mM Gly-Pro, and by 2 mM cephradine. Further, in Ussing chambers, its mucosal to serosal permeability decreased dramatically with concentration. Conversion studies showed that pGlu-L-Dopa-Pro was degraded by pyroglutamyl aminopeptidase I, an enzyme releasing the N-terminal pyroglutamic acid, with Vmax and Km of 0.6 mumole/min/g protein and 21 mM, respectively, and that L-Dopa-Pro was degraded by prolidase with Vmax and Km of 44 mumole/min/g protein and 0.48 mM, respectively. CONCLUSIONS: This tripeptide, a potential prodrug of L-Dopa, is absorbed by the intestinal peptide transporter, is relatively stable in the gut wall, and is converted to L-Dopa by peptidases with the cleavage by pyroglutamyl aminopeptidase I to L-Dopa-Pro as the rate limiting step.

Amino Acid Sequence↗
PubMed1999

Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson's disease A 3D [(18)F]dopa-PET study.

We have studied focal changes in dopaminergic function throughout the brain volume in early and advanced Parkinson's disease by applying statistical parametric mapping (SPM) to 3D [(18)F]dopa-PET. Data from seven early hemi-Parkinson's disease and seven advanced bilateral Parkinson's disease patients were compared with that from 12 normal controls. Parametric images of [(18)F]dopa influx rate constant (K(i)(o)) were generated for each subject from dynamic 3D [(18)F]dopa datasets and transformed into standard stereotactic space. Significant changes in mean voxel [(18)F]dopa K(i)(o) values between the normal control group and each Parkinson's disease group were localized with SPM. Conventional region of interest analysis was also applied to comparable regions on the untransformed image datasets. In early left hemi-Parkinson's disease, significant extrastriatal increases in [(18)F]dopa K(i)(o) were observed in the left anterior cingulate gyrus and the dorsal midbrain region (P < 0.05, corrected) along with decreases in striatal [(18)F]dopa K(i)(o). In advanced Parkinson's disease, significant extrastriatal decreases in [(18)F]dopa K(i)(o) were observed in the ventral and dorsal midbrain regions (P < 0.05, corrected). No significant changes in [(18)F]dopa K(i)(o) were observed in the anterior cingulate region. In a direct comparison between the early and late Parkinson's disease groups, we observed relative [(18)F]dopa K(i)(o) reductions in ventral and dorsal midbrain, and dorsal pontine regions along with striatal [(18)F]dopa K(i)(o) reductions. Similiar results were found with a region of interest approach, on non-transformed data, except for the focal midbrain [(18)F]dopa K(i)(o) increase seen in early Parkinson's disease. In conclusion, using SPM with [(18)F]dopa-PET, we have objectively localized changes in extrastriatal, pre-synaptic dopaminergic function in Parkinson's disease. The significance of the increased dopaminergic activity of anterior cingulate in early Parkinson's disease remains unclear, but may be compensatory. The [(18)F]dopa signal in dorsal midbrain and pontine regions suggests that [(18)F]dopa is taken up by serotonergic and noradrenergic neurons which also degenerate in advanced Parkinson's disease. This suggests, therefore, that Parkinson's disease is a monoaminergic neurodegenerative disorder.

Biological Transport↗
PubMed1971

Modification of the cardiovascular effects of L-dopa by decarboxylase inhibitors.

Intravenously infused L-dopa (0.3 mg/kg per min) produced hypertension and cardiac arrhythmias in halothane anesthetized dogs. Biochemical studies showed that the heart, kidney, and brain of these animals accumulated significant amounts of catecholamines formed from the administered precursor. Pretreatment of dogs with an extracerebral inhibitor of dopa decarboxylase [D,L-alpha-hydrazino-alpha-methyl-beta-(3.4-dihydroxyphenyl) propionic acid] prevented the development of hypertension and arrhythmias with infusion of L-dopa. Instead, these animals developed significant hypotension. The heart and kidney of these animals accumulated markedly reduced amounts of catecholamines formed from L-dopa compared with dogs receiving L-dopa alone: the amount of catecholamines accumulated in brain was unchanged. L-dopa, after extracerebral decarboxylase inhibition, appeared to produce hypotension by reducing peripheral vascular resistance without altering sympathetic nerve function. During hypotension, cardiac output was not altered and arterial pressure in perfused hindlimbs fell, even though flow was maintained. The pressor response to intravenous injections of norepinephrine and dopamine was unchanged. Hindlimb arterial pressure response to direct electrical stimulation of the lumbar sympathetic trunk was also unchanged. Pretreatment with a drug which inhibits brain as well as extracerebral dopa decarboxylase [D,L-seryl-2,3,4-trihydroxybenzylhydrazine hydrochloride] abolished all effects of L-dopa on blood pressure. In these animals, there was a marked reduction of catecholamine formation from L-dopa in the brain as well as the heart and kidney. It appears that L-dopa produces opposite effects on blood pressure depending on the site of accumulation of its metabolic products, dopamine and norepinephrine. If L-dopa is rapidly decarboxylated to catecholamines in peripheral organs, hypertension and cardiac arrhythmias occur. If peripheral dopa decarboxylase is selectively inhibited, a centrally mediated hypotensive effect, probably secondary to the accumulation of catecholamines in the brain, becomes apparent. If dopa decarboxylase is inhibited in the brain in addition to extracerebral organs, L-dopa has no effect on blood pressure.

Animals↗
PubMed1992

Plasma dopa responses during stress: dependence on sympathoneural activity and tyrosine hydroxylation.

Dihydroxyphenylalanine (dopa), the precursor of all the endogenous catecholamines, circulates in plasma at a concentration higher than that of the sympathetic neurotransmitter, norepinephrine (NE). Sources of dopa in plasma and the meaning of plasma dopa levels in terms of sympathoneural function have been unclear. Plasma concentrations of dopa, the catecholamines NE, epinephrine and dopamine, the deaminated catechol metabolites dihydroxyphenylglycol and dihydroxyphenylacetic acid, and the O-methylated metabolites methoxyhydroxyphenylglycol and homovanillic acid were measured during immobilization stress in conscious rats. Animals were pretreated with chlorisondamine to block ganglionic neurotransmission or with alpha-methyl-para-tyrosine to inhibit tyrosine hydroxylation. Immobilization produced rapid, sustained increases in plasma levels of dopa, catecholamines and catecholamine metabolites. Chlorisondamine decreased base-line plasma dopa and NE levels and abolished the increases in plasma dopa and NE levels during immobilization. alpha-Methyl-para-tyrosine administration produced sustained decreases in plasma dopa levels and markedly attenuated immobilization-induced increases in plasma dopa levels. Bilateral adrenalectomy augmented base-line plasma levels of dopa and NE and augmented dopa and NE responses during immobilization. The results indicate that during immobilization stress, increased postganglionic sympathoneural outflow stimulates the synthesis of dopa in sympathetic neurones and enhances release of dopa into the circulation. The data generally support the view that changes in plasma dopa levels during stress reflect in vivo changes in the rate of catecholamine biosynthesis in sympathetic nerve terminals.

Adrenalectomy↗
PubMed1995

[Effectiveness of slow release L-DOPA/benserazide in treatment of end-of-dose akinesia in Parkinson disease].

In an open label study 63 patients with idiopathic Parkinson's disease suffering from end-of-dose akinesia were switched from a treatment with a L-DOPA standard formulation to a combined therapy of L-DOPA standard in the morning and L-DOPA slow release (levodopa, benserazide, Madopar Depot) at the remaining single doses. Substitution of L-DOPA standard by L-DOPA slow release took on average 2-4 weeks. Patients were subsequently treated for 6 months. Due to a lower bioavailability of the slow release formulation--the latter is based on the "hydrodynamically balanced system" (HBS)--, the patients remained initially on their time schedule of drug intake but received a higher dose of L-DOPA slow release compared to the preceding L-DOPA standard therapy. In 20 centers 37 men and 26 women were included into the study. 27 males and 20 females completed the 6 month treatment period. Before switching, the patients received 438 +/- 213 mg a day L-DOPA standard, after conversion, the average dose was 617 +/- 323 mg L-DOPA slow release and 107 +/- 95 mg L-DOPA standard a day. Fluctuations during the day and at night which were rated according to a newly developed clinical 5-point rating scale were significantly improved by the treatment regimen from 2.8 +/- 0.9 to 1.4 +/- 1.2. Additionally, parkinsonian symptoms were significantly reduced during the ON-phase as there was a significant decrease of the Webster rating score from 12.0 +/- 4.6 to 7.1 +/- 4.0. Quality of life as measured by subjective ratings of the patients improved. The tolerability of the new formulation of L-DOPA was rated to be good in 51.1% and very good in 48.9%. The results of this open label study suggest that the combination of L-DOPA standard in the morning and L-DOPA slow release formulation at the following time points can be an efficient therapy in parkinsonian patients who suffer form L-DOPA related end-of-dose motor akinesia.

Adult↗
PubMed1991

Brain kinetics of L-[beta-11C]dopa in humans studied by positron emission tomography.

The in vivo dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) labelled with 11C in the beta position has been used for positron emission tomography studies of L-DOPA utilization in the brain. The brain uptake and kinetics of L-[11C]DOPA-derived radioactivity were studied in healthy male volunteers, and the specific utilization, i.e. decarboxylation rate of L-[11C]DOPA in different brain areas, was quantified using a brain region devoid of specific L-[11C]DOPA utilization as reference. Total uptake of L-[11C]DOPA-derived radioactivity measured in the brain varied two- to three-fold between subjects, with highest radioactivity in the striatal region. Specific utilization of L-[11C]DOPA radioactivity in the striatal region and in the prefrontal cortex varied twofold between subjects. No specific utilization was observed in other regions of the brain. The uptake of radioactivity in the brain increased dose-dependently with the simultaneous administration of unlabelled L-DOPA up to 10 mg. On the other hand, a decrease in brain radioactivity uptake was measured after pretreatment with 1 mg/kg oral L-DOPA, indicating competition for transport across the blood-brain barrier. Benserazide 0.5 mg/kg orally increased somewhat the radioactivity uptake to the brain. None of these pharmacological perturbations demonstrated any clearcut effect on specific utilization of L-[11C]DOPA. Thus, 11C-labelled L-DOPA is introduced as an alternative to the well-established L-6-[18F]fluoro-DOPA methodology in clinical studies on brain L-DOPA uptake and dopamine synthesis.

Adult↗
PubMed2005

Apical and basolateral 4F2hc and the amino acid exchange of L-DOPA in renal LLC-PK1 cells.

The present study aimed to examine the presence and define the role of 4F2hc, a glycoprotein associated with the LAT2 amino acid transporter, in L-DOPA handling by LLC-PK1 cells. For this purpose we have measured the activity of the apical and basolateral inward and outward transport of [14C] L-DOPA in cell monolayers and examined the influence of 4F2hc antisense oligonucleotides on [14C] L-DOPA handling. The basal-to-apical transepithelial flux of [14C] L-DOPA progressively increased with incubation time and was similar to the apical-to-basal transepithelial flux. The spontaneous and the L-DOPA-stimulated apical fractional outflow of [14C] L-DOPA were identical to that through the basal cell side. The L-DOPA-induced fractional outflow of [14C] L-DOPA through the apical or basal cell side was accompanied by marked decreases in intracellular levels of [14C] L-DOPA. In cells treated with an antisense oligonucleotide complementary to 4F2hc mRNA for 72 h, [14C] L-DOPA inward transport and 4F2hc expression were markedly reduced. Treatment with the 4F2hc antisense oligonucleotide markedly decreased the spontaneous fractional outflow of [14C] L-DOPA through the apical or the basal cell side. It is likely that the Na+-independent and pH-sensitive uptake of L-DOPA include the hetero amino acid exchanger LAT2/4F2hc, which facilitates the trans-stimulation of L-DOPA and its outward transfer at both the apical and basal cell sides.

Amino Acid Transport Systems↗
PubMed1991

Chronic L-dopa treatment in the unilateral 6-OHDA rat: evidence for behavioral sensitization and biochemical tolerance.

Two separate experiments were conducted to assess the behavioral and biochemical effects of chronic L-dihydroxyphenylalanine (L-DOPA) treatment in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this animal model, contralateral rotation provides the behavioral indicator response for L-DOPA activation of the dopamine denervated striatum. Following 30 daily L-DOPA treatments, a subthreshold dose (10 mg/kg) for rotation became suprathreshold and the contralateral rotation induced by a suprathreshold dose (20 mg/kg) became exaggerated. This motoric sensitization to L-DOPA was not reversed by a three-day period of L-DOPA withdrawal. In contrast with the emergence of behavioral sensitization to L-DOPA, biochemical measurements showed that the increase of dopamine metabolite concentrations (DOPAC and HVA) induced by acute L-DOPA treatment became attenuated with chronic treatment. This finding suggests that chronic L-DOPA treatment produces a partial tolerance in the conversion of L-DOPA to extracellular dopamine. The emergence of L-DOPA sensitization-over-stimulation effects was hypothesized to reflect the combined effects of dopamine receptor priming and Pavlovian drug conditioning and to contribute to the emergence of dyskinetic effects of L-DOPA therapy. The partial tolerance observed for dopamine metabolites was hypothesized to represent a decreased conversion of L-DOPA to dopamine which with long-term treatment could progress to an eventual wearing-off effect of L-DOPA therapy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Some interactions of L-DOPA and its related compounds with glutamate receptors.

L-DOPA is probably a transmitter and/or modulator in the central nervous system (1). L-DOPA methyl ester (DOPA ME) is a competitive L-DOPA antagonist. However, it remains to be clarified whether there exist L-DOPAergic receptors. In Xenopus laevis oocytes injected with rat brain poly(A)+ RNA, L-DOPA induced small inward currents with ED50 of 2.2 mM at a holding potential of -70 mV. The currents were abolished by kynurenic acid or CNQX. Similar L-DOPA-currents were seen in oocytes co-injected with AMPA receptors, GluRs1,2,3 and 4. In brain membrane preparations, L-DOPA inhibited specific binding of [3H]-AMPA with IC50 of 260 microM. This inhibition was not modified by 200 microM ascorbic acid, an antioxidant. L-DOPA did not inhibit binding of [3H]-ligands of MK-801, kainate, DCKA and CGP39653. DOPA ME and L-DOPA cyclohexyl ester, a novel, potent and competitive antagonist (2), inhibited specific binding of [3H]-MK-801 with respective IC50 of 1 and 0.68 mM, but elicited no effect on that of the other [3H]-ligands. With low affinities, L-DOPA acts on AMPA receptors, while competitive antagonists act on NMDA ion channel domain. L-DOPAergic agonist and antagonist may not interact on ionotropic glutamate receptors. DOPA ME-sensitive L-DOPA recognition sites (1) seem to differ from glutamate receptors.

2-Amino-5-phosphonovalerate↗
PubMed1996

Sodium benzoate differentially blocks circling induced by D-and L-dopa in the hemi-parkinsonian rat.

D-3,4-Dihydroxyphenylalanine (D-dopa) and L-3,4-dihydroxyphenylalanine (L-dopa) induced circling in rats with a unilateral 6-hydroxydopamine lesion of substantia nigra with similar potency. D-Dopa is not a substrate for aromatic L-amino acid decarboxylase, the enzyme which metabolizes L-dopa to dopamine. This raises the question of how D-dopa has behavioral effect. Two pathways have been suggested to result in conversion of D-dopa to L-dopa, one involving oxidation of D-dopa to dihydroxyphenylpyruvic acid (DHPPA) by D-amino acid oxidase, the other involving transamination of D-dopa to DHPPA. Here we show that sodium benzoate, an inhibitor of D-amino acid oxidase, blocks D-dopa-induced circling while having no effect on circling induced by L-dopa. The results suggest that conversion of D-dopa to L-dopa via DHPPA is highly dependent on oxidase activity and that sodium benzoate effectively inhibits this process in vivo in rat.

Amino Acid Oxidoreductases↗
PubMed1998

The protein oxidation product 3,4-dihydroxyphenylalanine (DOPA) mediates oxidative DNA damage.

A major product of hydroxy-radical addition to tyrosine is 3, 4-dihydroxyphenylalanine (DOPA) which has reducing properties. Protein-bound DOPA (PB-DOPA) has been shown to be a major component of the stable reducing species formed during protein oxidation under several conditions. The aim of the present work was to investigate whether DOPA, and especially PB-DOPA, can mediate oxidative damage to DNA. We chose to generate PB-DOPA using mushroom tyrosinase, which catalyses the hydroxylation of tyrosine residues in protein. This permitted us to study the reactions of PB-DOPA in the virtual absence of other protein-bound oxidation products. The formation of two oxidation products of DNA, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodG) and 5-hydroxy-2'-deoxycytidine (5OHdC), were studied with a novel HPLC using gradient elution and an electrochemical detection method, which allowed the detection of both DNA modifications in a single experiment. We found that exposure of calf thymus DNA to DOPA or PB-DOPA resulted in the formation of 8oxodG and 5OHdC, with the former predominating. The formation of these DNA oxidation products by either DOPA or PB-DOPA depended on the presence of oxygen, and also on the presence and on the concentration of transition metal ions, with copper being more effective than iron. The yields of 8oxodG and 5OHdC increased with DOPA concentration in proteins. Thus PB-DOPA was able to promote further radical-generating events, which then transferred damage to other biomolecules such as DNA.

Basidiomycota↗
PubMed1989

Continuous oral administration of L-dihydroxyphenylalanine (L-DOPA) solution to patients with advanced Parkinson's disease.

In six patients with advanced Parkinson's disease (PD), we have characterized the clinical responses and serum levels of DOPA and 3-O-methyldopa in response to continuous i.v., nasogastroduodenal (NGD), and oral (p.o.) administration of L-DOPA solution with concomitant suppression of peripheral decarboxylase activity by carbidopa. When compared to therapy with L-DOPA/carbidopa tablets, all patients experienced increased "on" and decreased "off" time with continuous L-DOPA intake. This improvement in mobility was accompanied by increases in duration and severity of dyskinesias. Serum levels of DOPA and 3-O-methyldopa were linearly related in ultrafiltered serum water compared to perchloric acid-treated serum samples, suggesting little protein binding. DOPA serum levels at which patients first turned "on" and those after several hours of continuous i.v. infusion clustered over a narrow range and were not predictable based on i.v. infusion rates, in spite of concomitant carbidopa intake. Continuous p.o. intake of L-DOPA solution produced serum levels of both DOPA and 3-O-methyldopa that were generally steady over the day and predictable based on L-DOPA intake rate. We conclude that "continuous" intake of L-DOPA solution orally, while cumbersome to and demanding of patients, can produce stable DOPA serum levels and approximate the improvement seen with continuous i.v. infusion. In our study, the apparent volume of distribution of L-DOPA was predictable with p.o. intake but not with i.v. administration of L-DOPA solution.

Administration, Oral↗
PubMedDate not supplied

Levetiracetam Interferes With the L-dopa priming process in MPTP-lesioned drug-naive marmosets.

OBJECTIVE: Levetiracetam (LEV; Keppra, UCB Pharma) has been shown to reduce established l-3,4 dihydroxyphenylalanine (l-dopa)-induced dyskinesia. This study investigated whether LEV can modify induction of dyskinesia by l-dopa or the process of priming. METHODS: Drug-naive MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) -lesioned marmosets were treated for 21 days with l-dopa/LEV or l-dopa alone. Subsequently, the animals were left untreated for 1 week and then both groups were challenged with a single dose of l-dopa alone on day 29. Behavior was assessed by automated activity counts and by post hoc analysis of videotapes using validated rating scales. RESULTS: LEV had no significant effect on the appearance of dyskinesia when administered de novo in combination with l-dopa. However, after a week of drug holiday, the 2 groups exhibited a different response to an acute l-dopa challenge. Thus, animals previously treated with l-dopa alone exhibited a similar level of dyskinesia to that seen on day 21 of the repeated treatment phase of the study. However, animals previously treated with l-dopa/LEV demonstrated significantly reduced dyskinesia compared with day 21 of the repeated treatment phase of the study. CONCLUSIONS: LEV does not modify the onset of dyskinesia following de novo treatment with l-dopa. However, concomitant treatment with l-dopa/LEV reduces the level of dyskinesia induced by l-dopa following a drug holiday. Thus, prior treatment with LEV appears to modify the mechanisms responsible for the maintenance of l-dopa-induced dyskinesia.

Analysis of Variance↗
PubMedDate not supplied

Pergolide mesylate, a dopaminergic receptor agonist, applied with L-DOPA enhances serum antioxidant enzyme activity in Parkinson disease.

The aim of this study was to compare patients with Parkinson disease (PD) patients treated with pergolide mesylate (PM), a dopaminergic receptor agonist, together with L-DOPA and those these treated with L-DOPA alone on the concentration of free radicals (FR), glutathione, and the activity of superoxide dismutase (SOD) and catalase in the serum. The study was carried out using 16 age-matched control subjects, 16 PD patients treated with L-DOPA at a dose of 1 to 1.5 g daily, and 16 PD patients treated with L-DOPA 1 to 1.5 g daily with PM 0.75 to 1.25 mg daily. The mean duration of treatment of PD was 6 years (range, 2-8 years) with l-DOPA, and 2 years with PM + L-DOPA or L-DOPA alone. Although there was no significant difference in lipid peroxidation products among the 3 groups, patients treated with L-DOPA showed high levels of FR as determined by dichlorofluorescein. Although catalase and SOD activities were elevated in both groups of PD patients, additional treatment with PM further enhanced catalase activity compared with those treated with l-DOPA alone. Interestingly, patients treated with PM + L-DOPA showed a significantly increased level of glutathione compared with those treated with L-DOPA alone. Collectively, these data suggest that PM + L-DOPA is a more efficient therapy in maintaining an antioxidative defense in PD patients compared with treatment with L-DOPA alone.

Aged↗
PubMed2005

Differential effects of l-DOPA on monoamine metabolism, cell survival and glutathione production in midbrain neuronal-enriched cultures from parkin knockout and wild-type mice.

l-DOPA is the most effective treatment for Parkinson's disease but in isolated neuronal cultures it is neurotoxic for dopamine (DA) neurones. Experiments in vivo and clinical studies have failed to show toxicity of l-DOPA in animals or patients but that does not exclude the possibility of a toxic effect of l-DOPA on patients with certain genetic risk factors. Mutations of the parkin gene are the most frequent cause of hereditary parkinsonism. Parkin null mice have a mild phenotype that could be modified by different neurotoxins. The aim of this study was to investigate whether the toxic effects of l-DOPA on DA neurones are amplified in parkin null mice. We have measured the effects of l-DOPA on cell viability, tyrosine hydroxylase (TH) expression, DA metabolism and glutathione levels of parkin knockout (PK-KO) midbrain cultures. Neuronal-enriched cultures from PK-KO mice have similar proportions of the different cell types with the exception of a significant increment of microglial cells. l-DOPA (400 microm for 24 h) reduced the number of TH-immunoreactive cells to 50% of baseline and increased twofold the percentage of apoptotic cells in cultures of wild-type (WT) animals. The PK-KO mice, however, are not only resistant to the l-DOPA-induced pro-apoptotic effects but they have an increased number of TH-immunoreactive neurones after treatment with l-DOPA, suggesting that l-DOPA is toxic for neurones of WT mice but not those of parkin null mice. MAPK and phosphatidylinositol-3 kinase signalling pathways are not involved in the differential l-DOPA effects in WT and PK-KO cultures. Intracellular levels of l-DOPA were not different in WT and parkin null mice but the intracellular and extracellular levels of DA and 3-4-dihydroxyphenylacetic acid, however, were significantly increased in parkin null animals. Furthermore, monoamine oxidase activity was significantly increased in parkin null mice, suggesting that these animals have an increased metabolism of DA. The levels of glutathione were further increased in parkin null mice than in controls both with and without treatment with l-DOPA, suggesting that a compensatory mechanism may protect DA neurones from neuronal death. This study opens new avenues for understanding the mechanisms of action of l-DOPA on DA neurones in patients with Park-2 mutations.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Phosphorylated mixed isomers of L-dopa increase melanin content in skins of Skh-2 pigmented hairless mice.

Dopa phosphates, a new class of compounds, contain phosphate-ester linkages at the 3- and/or 4- positions of the phenylalanine ring of L-dopa. Dopa phosphates have been shown to increase pigment production in the epidermis of hairless mice. Groups of Skh-2 pigmented hairless mice were treated topically with various concentrations of dopa phosphates daily for five weeks. Half of each group received suberythemal UVB radiation three times weekly for four weeks from a bank of filtered FS20 lamps. UVB and dopa phosphates alone each caused a modest increase in epidermal pigmentation. However, treatment of mice with dopa phosphates plus UVB radiation resulted in a marked increase in pigmentation, greater than with either treatment alone. The optimal concentration of dopa phosphates was 0.01% (100 micrograms/ml Tris-glycerol buffer) whether or not they were applied in conjunction with UVB radiation. Histological analyses revealed that dopa phosphates and UVB radiation each caused an increase in the number of pigmented melanocytes in the epidermis. Control groups treated with Tris-glycerol buffer alone, or buffer containing L-phenylalanine or L-dopa showed no significant changes in pigmentation. Our results indicate that dopa phosphates stimulate the production of melanin and affect the development and distribution of melanocytes in the skin of Skh-2 mice. By these criteria, dopa phosphates and UVB act in a similar manner to increase melanin content in the skin. The processes may be related to those recently observed in cultured mouse melanoma cells where dopa phosphates are incorporated into melanin, presumably following enzymatic hydrolysis by cellular phosphatases with the resultant production of L-dopa and inorganic phosphate.

Animals↗
PubMed1987

L-dopa esters as potential prodrugs: behavioural activity in experimental models of Parkinson's disease.

Intraperitoneal administration of the 2-tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2-hydroxypropyl and methyl ester prodrugs of L-dopa produced locomotor activity in reserpine-pretreated mice with equal intensity and duration to that observed following administration of L-dopa itself. Administration of the 2-(1-methoxy)propyl ester produced a more prolonged effect while the p-methoxyphenylethyl, n-propyl, phenylethyl, m-trifluoromethylbenzyl, cyclohexyl, p-chlorophenylethyl and benzyl ester prodrugs were less active than L-dopa itself. On oral administration, the ethyl and methyl ester prodrugs were more effective than L-dopa in reversing reserpine-induced akinesia in mice. The 2-tetrahydropyranylmethyl, 2-(1-methoxy)propyl, 2-hydroxypropyl, n-propyl, benzyl and phenoxyethyl ester prodrugs produced effects comparable with those of L-dopa. In contrast, the cyclohexyl, m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs were less effective than L-dopa on oral administration. Intraperitoneal administration of L-dopa and the ester prodrugs of L-dopa to rats with a prior 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB) produced contraversive circling responses. Rotation observed following administration of the n-propyl, 2-tetrahydropyranylmethyl, methyl and ethyl ester prodrugs was more intense than that observed following administration of L-dopa itself. Rotation produced by the administration of L-dopa and the cyclohexyl, 2-(1-methoxy)propyl, phenylethyl, p-chlorophenylethyl, p-methoxyphenylethyl, benzyl, 2-hydroxypropyl, phenoxyethyl and m-trifluoromethylbenzyl ester prodrugs was identical. Ester prodrugs of L-dopa may be as effective as L-dopa itself in producing motor activity but overall none of the compounds tested was markedly more potent or of longer duration than L-dopa itself.

Animals↗
PubMed1990

The effect of ferrous sulfate and pH on L-dopa absorption.

Ferrous sulfate decreases L-dopa bioavailability in humans probably as a result of binding of L-dopa by iron in the gastrointestinal tract. This study was conducted to determine if iron by binding L-dopa decreases L-dopa absorption and to investigate the effect of different pH buffers on intestinal absorption of L-dopa in the presence and absence of ferrous sulfate. A rat model developed to examine drug absorption was used. Control animals had buffered [14C]L-dopa solutions injected into two in vivo closed segments of intestine; a 5-cm duodenal and a 5-cm proximal jejunal segment. These studies were conducted using solutions buffered at pH 5.5, 6.5, 7.5, and 8.5. An identical procedure was followed for experimental animals except ferrous sulfate was injected with the buffered L-dopa solutions. Ferrous sulfate resulted in a reduction in L-dopa absorption in the buffers at all pHs in both the duodenum and jejunum. The average reduction in L-dopa absorption in the presence of iron was 22.6% in the duodenum and 23.9% in the jejunum. There was a tendency for ferrous sulfate to cause a greater reduction in L-dopa absorption as the buffer pH increased. There was also a decrease in L-dopa absorption in the higher pH buffers in the absence of iron. Despite this latter result, in the jejunum there was an increase in the percent reduction in L-dopa absorption associated with ferrous sulfate as pH increased. Although this tendency was not as consistent in the duodenum as the jejunum, the combined results are compatible with the chemical model of increased L-dopa--iron binding as pH increases.

Animals↗