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PubMed1980

Effects of 3,4-dihydroxyphenylpyruvic acid and L-glutamic acid on some pharmacokinetic parameters of L-dopa in the rat.

In the rat, various oral doses of 3,4-dihydroxyphenylpyruvic acid (DHPPA) administered simultaneously with L-dopa were shown to elevate the serum L-dopa and cerebral dopamine concentrations dose-dependently. With increasing DHPPA: L-dopa ratio the L-dopa-sparing effect became greater. Although oral and intravenous doses of DHPPA showed that it was readily converted to L-dopa in the serum, only small amounts of dopamine (DA) were detected in the brain. The high 3-O-methyldopa concentrations, measured in the serum after DHPPA administration, might be responsible for the failure of the L-dopa formed to pass the blood-brain barrier. Concomitant administration of L-dopa and glutamic acid gave significantly higher L-dopa values in the serum and DA and homovanillic acid values in the brain than did the same dose of L-dopa alone. This indicates that the transamination of L-dopa can also be effected by coadministration of L-dopa and an amino group donor in vivo.

Animals↗

PubMed2005

Increased divalent metal transporter 1 expression might be associated with the neurotoxicity of L-DOPA.

Based on the available data, we speculated that changes in brain iron metabolism induced by L-DOPA might be associated with the neurotoxicity of L-DOPA. To investigate this possibility, the effects of L-DOPA on the expression of iron influx proteins [transferrin receptor (TfR) and divalent metal transporter 1 (DMT1)], iron efflux protein (ferroportin 1), and iron uptake in C6 glioma cells were determined in this study using Northern blot and Western blot analysis and the calcein method. The findings showed that treatment of C6 cells with different concentrations of L-DOPA (0-100 microM) did not affect the expression of mRNA and protein of TfR and DMT1 with iron-responsive element (+IRE) and protein of ferroportin 1. However, a significant increase in the expression of DMT1(-IRE) mRNA and protein was found in cells treated, respectively, with 10 and 30 microM L-DOPA (mRNA) and 1, 5, 10 and 30 microM L-DOPA (protein). The increase in DMT(-IRE) protein induced by L-DOPA treatment was in parallel with the increase in DMT(-IRE) mRNA. The levels of DMT1(-IRE) mRNA and protein peaked in the cells treated with 10 microM L-DOPA and then decreased progressively with increasing concentrations of L-DOPA. Further study demonstrated that treatment of the cells with 10 microM L-DOPA induced a significant increase in ferrous uptake by C6 glioma cells. The findings suggested that the increased DMT1(-IRE) expression might be partly associated with the neurotoxicity of L-DOPA. Clinical relevance of the findings needs to be investigated further.

Animals↗

PubMed2003

L-DOPA treatment modulates nicotinic receptors in monkey striatum.

Nicotinic acetylcholine receptor (nAChR) activation is well known to stimulate dopamine release in the striatum. This phenomenon may be physiologically significant in the control of motor function, as well as in pathological conditions such as Parkinson's disease. An understanding of the mechanisms that influence nAChR expression and function is therefore important. Because the dopamine precursor l-DOPA is the most commonly used therapeutic agent for Parkinson's disease, we investigated the effects of l-DOPA treatment on striatal nAChR expression in unlesioned and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In unlesioned animals, l-DOPA (15 mg/kg) administered twice daily for 2 weeks decreased both 125I-epibatidine and [125I]iodo-3-[2(S)-azetidinylmethoxy]pyridine (A-85380) binding sites in the caudate and putamen, but did not affect 125I-alpha-CtxMII sites. alpha-CtxMII inhibition of striatal 125I-epibatidine and [125I]A-85380 binding with alpha-CtxMII suggest that there are both high- (Ki < 0.2 nM) and low-affinity (Ki > 100 nM) alpha-CtxMII-sensitive sites, as well as alpha-CtxMII-resistant sites, and that l-DOPA treatment influences only the low-affinity alpha-CtxMII-sensitive subtype. The l-DOPA effect was selective for striatal nAChRs with no change in cortical sites. Monkeys with severe nigrostriatal damage did not exhibit l-DOPA-induced declines in striatal nAChRs, suggesting that l-DOPA primarily affects nAChRs associated with dopaminergic terminals. In summary, these data show that l-DOPA treatment decreases nAChR expression, in contrast with the well established up-regulation of these sites by chronic nicotine exposure. Furthermore, they demonstrate preferential l-DOPA regulation of a novel low-affinity alpha-CtxMII-sensitive site. These declines in nAChRs with l-DOPA may be relevant to both the therapeutic and side effect profiles of l-DOPA therapy in Parkinson's disease.

Animals↗

PubMed1973

An analysis of six patients with Parkinson's disease who have been unresponsive to L-dopa therapy.

Six patients diagnosed as Parkinson's disease on a clinical basis alone are described, and their response to L-dopa and to alpha methyl dopa hydrazine (MK 486) and L-dopa. They are compared with 239 other patients with Parkinson's disease treated in the same time period. These six patients were unusual in that they did not have a clinical response to L-dopa, nor did they develop dyskinesias on L-dopa or on L-dopa with MK 486, although they showed high blood levels of L-dopa and high homovanillic acid levels in the spinal fluid. Unresponsiveness to L-dopa is attributed to a specific brain mechanism and not to problems of transport of L-dopa to the brain or to abnormal peripheral metabolism of L-dopa. The term `motor unresponsiveness to L-dopa' may be useful to describe such patients who may eventually be shown to be suffering from diseases other than Parkinsonism.

Aged↗

PubMed1998

Uptake and intracellular fate of L-DOPA in a human intestinal epithelial cell line: Caco-2.

The aim of the present study was to examine the kinetic characteristics of the L-3,4-dihydroxyphenylalanine (L-DOPA) transporter and the fate of newly formed dopamine in Caco-2 cells. In the presence of 50 microM benserazide (an inhibitor of aromatic L-amino acid decarboxylase), L-DOPA was rapidly accumulated in Caco-2 cells. At equilibrium (30 min of incubation) the intracellular L-DOPA concentration was 10.2 +/- 0.1 microM at a medium concentration of 0.5 microM. In saturation experiments the accumulation of L-DOPA was saturable with a Michaelis-Menten constant (Km) of 60 +/- 10 microM and a maximal reaction velocity (Vmax) of 6.6 +/- 0.3 nmol . mg protein-1 . 6 min-1; at 4 degrees C the amount of L-DOPA accumulated in the cells was nonsaturable. When cells were incubated with increasing concentrations of L-DOPA (10-100 microM) in the absence of benserazide, a substantial amount of the L-DOPA that was taken up was decarboxylated to dopamine, with an apparent Km of 27.2 microM. In experiments performed in cells cultured in polycarbonate filters, the accumulation of L-DOPA in the presence of benserazide was greater when the substrate was applied from the basolateral cell border than when it was applied from the apical cell border. In the absence of benserazide, L-DOPA applied from the basolateral cell border resulted in a nonlinear formation of dopamine (Km = 43 +/- 7 microM, Vmax = 23.7 +/- 1.2 nmol . mg protein-1 . 6 min-1). The amount of dopamine leaving the cell through the apical cell border was lower than the amount that escaped through the basolateral cell border, and the process was saturable (Km = 623 +/- 238 microM, Vmax = 0.19 +/- 0.02 nmol . mg protein-1 . 6 min-1). In conclusion, the data presented here show that Caco-2 cells are endowed with an efficient L-DOPA uptake system, and intracellular L-DOPA was found to be rapidly converted to dopamine, some of which diffuses out of the cell. The utilization of Caco-2 cells cultured on polycarbonate filters probably provides a better way to look at processes such as the outward transfer of intracellular molecules, namely, the outward transfer of newly formed dopamine.

Aromatic-L-Amino-Acid Decarboxylases↗

PubMed1978

L-dopa absorption and the pituitary-hypothalamic axis.

Administration of oral L-dopa is often used as a neuropharmacological probe to evaluate the pituitary hypothalamic axis. The effect of gastrointestinal absorption of L-dopa on the changes in plasma GH, PRL, and body temperature which occur after ingestion of this amino acid is unknown. Plasma L-dopa, GH, PRL, and rectal and skin temperatures were measured in 14 male volunteers after oral administration of 1.0 g measured in 24 men after random administration of L-dopa and a placebo. L-Dopa levels rose to 1.85 +/- 1.33 microgram/ml (mean +/- SD), but maximum plasma levels occurred at variable times from 30-230 min after drug administration. Plasma GH levels increased to 23.7 +/- 14.7 ng/ml, while PRL levels fell to 46.7 +/- 12.3% of the mean basal values. Rectal temperature decreased significantly in 3 of the men after L-dopa ingestion. Plasma GH levels after L-dopa correlated with the absorption of the drug (P less than 0.05) and inversely with the basal level of GH before L-dopa administration. There was no correlation between the basal PRL level or basal body temperature and the magnitude of the fall in PRL or body temperature after L-dopa administration. The variability of responses in GH, PRL, and body temperature after oral L-dopa ingestion is not the result of differences in absorption in the amino acid alone, and indicate either that there is a different sensitivity in the mechanisms that stimulate GH secretion and lower plasma PRL and body temperature, or that L-dopa acts at different sites to bring about each of these changes.

Adolescent↗

PubMed1979

The effects of L-dopa on in vitro and in vivo calcitonin release from medullary thyroid carcinoma.

The in vivo and in vitro effects of the dopamine precursor L-dopa on basal and stimulated calcitonin release from medullary thyroid carcinoma have been studied. In six studies of five patients, including 7- to 8-h control and test periods, oral L-dopa depressed basal calcitonin secretion by an average of 35%; the peak effects occurred within 30 min of drug administration and lasted for as long as 4 h. In seven of eight patients with medullary thyroid carcinoma (three infused with calcium and five with pentagastrin), L-dopa inhibited to varying degrees peak levels of stimulated calcitonin release and total calcitonin secretion; basal calcitonin levels, where directly tested, also again generally fell after L-dopa by an average of 50%. In a short term organ culture system using medullary thyroid carcinoma tissues, calcitonin secretion into the medium was linear with time for 2 h and could be stimulated by dibutyryl cAMP and pentagastrin. L-Dopa, in concentrations from 0.5--3.0 mM, inhibited basal calcitonin secretion (ranging from 25--55%). Addition of the L-dopa decarboxylase inhibitor, alpha-methyldopa, abolished the inhibitory effects of L-dopa. Another L-dopa decarboxylase inhibitor, carbidopa, stimulated calcitonin secretion in vitro; this effect may be independent of the L-dopa decarboxylase-inhibiting properties of this drug since alpha-methyldopa alone did not stimulate calcitonin secretion. It is concluded that the amine precursor L-dopa inhibits calcitonin release in patients with medullary thyroid carcinoma; the in vitro studies suggest that a portion of this effect may involve direct metabolism of L-dopa to dopamine in the tumor tissue itself. The importance of considering the uptake of amine precursors and the subsequent metabolism of these compounds as a modulating site for peptide hormone release from peripheral endocrine tissues is stressed.

Calcitonin↗

PubMed1999

Lack of a pharmacokinetic interaction at steady state between ropinirole and L-dopa in patients with Parkinson's disease.

STUDY OBJECTIVE: To assess the interaction between therapeutic dosages of ropinirole and L-dopa plus a decarboxylase inhibitor administered at steady state in patients with Parkinson's disease. DESIGN. Open, 6-week, overlap trial with random allocation. PATIENTS: Thirty patients with Parkinson's disease not previously treated with dopamine agonists, of whom 28 produced evaluable pharmacokinetic data for ropinirole and 23 for L-dopa. INTERVENTION: Group A (14 patients) received L-dopa for weeks 1-5 and ropinirole in increasing increments for weeks 2-6; group B (16) received ropinirole for weeks 1-5 and L-dopa for weeks 5 and 6. MEASUREMENTS AND MAIN RESULTS: Primary end points were AUC0-8 and Cmax for ropinirole, and AUC0-8, AUC0-infinity and Cmax for L-dopa. Secondary end points were Tmax for ropinirole, and Tmax and half-life for L-dopa. Coadministration with L-dopa at steady state did not affect rate or extent of availability of ropinirole: point estimates of the geometric mean ratio for ropinirole plus L-dopa compared with ropinirole alone for both Cmax and AUC0-8 approximated to unity. The small (16%) increase in peak concentrations of L-dopa on administration with ropinirole is unlikely to be of clinical consequence, as peak concentrations of L-dopa are typically highly variable. CONCLUSION: There are no pharmacokinetic grounds for adjusting dosages of either ropinirole or L-dopa when given in combination.

Aged↗

PubMedDate not supplied

Long-term follow-up of L-dopa treatment in children with amblyopia.

PURPOSE: To assess regression of visual acuity in children who previously participated in three longitudinal studies of therapy with levodopa-carbidopa (L-dopa) plus occlusion for amblyopia. SUBJECTS AND METHODS: Thirty (91%) of 33 subjects contacted who participated in three similar 7-week, longitudinal dosing studies returned for follow-up. The three previous studies were undertaken approximately 27 (study 1), 21 (study 2), and 9 (study 3) months prior to this follow-up test session. All subjects received L-dopa for 7 weeks combined with part-time occlusion of the dominant eye after the termination of standard, occlusion only, therapy. Some subjects in study 2 received L-dopa without occlusion. Sixteen subjects with amblyopia who received occlusion only served as a control group. RESULTS: Subjects who received L-dopa plus occlusion demonstrated significant, but similar, amounts of regression of visual acuity from the end of their respective L-dopa studies to the follow-up test session. Subjects in study 1 regressed 1.3 lines, subjects in study 2 regressed 1.5 lines, and subjects in study 3 regressed 1.4 lines. The control group regressed, on average, 1.1 lines. This was similar to the overall regression found in the groups receiving L-dopa plus occlusion. Subjects in study 2 who received L-dopa without occlusion regressed 2.1 lines, significantly more than the occlusion only group or the L-dopa plus occlusion group. CONCLUSIONS: Children with amblyopia show similar amounts of regression of visual acuity after therapy with L-dopa plus occlusion and after therapy with occlusion only. Given that therapy with L-dopa plus occlusion initially improved visual acuity by approximately 1.7 lines following the termination of standard therapy, L-dopa plus occlusion may reset baseline visual acuity and lead to long-term improvement in visual acuity after recidivism.

Amblyopia↗

PubMed2004

A technique for standardized central analysis of 6-(18)F-fluoro-L-DOPA PET data from a multicenter study.

UNLABELLED: We have recently completed a large 6-(18)F-fluoro-L-DOPA ((18)F-DOPA) PET study comparing rates of loss of dopamine terminal function in Parkinson's disease (PD) patients taking either the dopamine agonist ropinirole or L-DOPA. This trial involved a "distributed acquisition/centralized analysis" method, in which (18)F-DOPA images were acquired at 6 different PET centers around the world and then analyzed at a single site. To our knowledge, this is the first time such a centralized approach has been employed with (18)F-DOPA PET and this descriptive basic science article outlines the methods used. METHODS: One hundred eighty-six PD patients were randomized (1:1) to ropinirole or L-DOPA therapy, and (18)F-DOPA PET was performed at baseline and again at 2 y. The primary outcome measure was the percentage change in putamen (18)F-DOPA influx rate constant (K(i)) from Patlak graphical analysis. Dynamic images were acquired and reconstructed using each center's individual protocols before being transferred to the site performing the central analysis. Once there, individual parametric K(i) images were created using a single analysis program without file formats being transformed from the original. Parametric images were then normalized to standard space and K(i) values extracted with a region of interest analysis. Significant K(i) changes were also localized at a voxel level with statistical parametric mapping. These processes required numerous checks to ensure the integrity of each dataset. RESULTS: Three hundred twenty-five (170 baseline, 155 follow-up) dynamic PET datasets were acquired, of which 12 were considered uninterpretable due to missing time frames, radiopharmaceutical problems, lack of measured attenuation correction, or excessive head movement. In those datasets suitable for central analysis, after quality control and spatial normalization of the images had been applied, putamen (18)F-DOPA signal decline was found to be significantly (one third) slower in the ropinirole group compared with that of the L-DOPA group. CONCLUSION: Paired (18)F-DOPA-PET images acquired from multiple sites can be successfully analyzed centrally to assess the efficacy of potential disease-modifying therapies in PD. However, numerous options must be considered and data checks put in place before adopting such an approach. Centralized analysis offers the potential for improved detection of outcomes due to the standardization of the analytic approach and allows the analysis of large numbers of PET studies.

Algorithms↗

PubMed1983

Dopa oxidation and tyrosine oxygenation by human melanoma tyrosinase.

A tyrosinase purified from cultured human melanoma cells was studied for dopa oxidation and tyrosine oxygenation. Km for oxidation of L-dopa was 0.5 mM, and for D-dopa 3 mM. L-tyrosine was oxygenated only in the presence of a cosubstrate. L-Dopa was superior to D-dopa, dopamine, L- and D-alpha-methyldopa, dopac, and 5,6-dihydroxyindole-2-carboxylic acid as cosubstrate. Ascorbic acid, 5-S-cysteinyldopa, and 5-OH-dopa did not function as cosubstrates. The rate of tyrosine hydroxylation was much lower than that of dopa oxidation. Tyrosine inhibits dopa oxidation, and dopa in high concentrations inhibits tyrosine hydroxylation. The cosubstrate function of dopa, the substrate functions of dopa and tyrosine, and the mutual inhibition of tyrosinase by these compounds are explained in three equations.

Catechol Oxidase↗

PubMed1996

Modeling of fluorine-18-6-fluoro-L-Dopa in humans.

UNLABELLED: Fluorine-18-6-fluoro-L-Dopa (F-Dopa) has been used successfully to evaluate striatal dopaminergic function in humans. The kinetic analysis of F-Dopa studies, however, is confounded by the presence of [18F]6-fluoro-3-O-methyl-L-Dopa (OMFD), the major metabolite of F-Dopa formed in the periphery that crosses the blood-brain barrier. We present results of compartmental analysis in subjects in whom we independently measured the kinetics of OMFD in the blood and striatum, and used this knowledge to solve for the kinetics of F-Dopa. METHODS: The kinetics of F-Dopa in striatum were measured with PET from 0 to 150 min after an intravenous bolus injection of tracer in four normal subjects and two patients suffering from Parkinson's disease. On a separate occasion, the kinetics of OMFD were determined in the plasma and striatum of the same individuals. The measured OMFD kinetics of each individual allowed us to reduce the number of compartments and rate constants which have to be solved for any compartmental analysis of the kinetics of F-Dopa. RESULTS: A two-compartmental, three rate-constant model was sufficient to describe the time course of F-Dopa and its metabolites in the striatum. The rate constant (k21) representing the decarboxylation rate of F-Dopa was 0.0124 min-1 in the normal subjects, and 0.0043 min-1 in the parkinsonian patients. CONCLUSION: The data do not support the need to include a fourth rate constant representing the egress of F-Dopamine and its metabolites. The forward transport rates for F-Dopa and OMFD from plasma to striatum are very similar in humans.

Adult↗

PubMed1976

[Attempt at potentiation of the action of L-dopa on the secretion of growth hormone by benserazide, disulfiram and propranolol].

Two tests of stimulation of growth hormone secretion were performed in 3 groups of normal children. In the first test L-Dopa was used on its own; in the second, L-Dopa was combined with Benserazide (group A), with Disulfirame (group B), or with Propranolol (group C). In group A the mean peak value after L-Dopa was 9.1 +/- 1.6 ng/ml; with the combination of L-Dopa and Benserazide it was 12.4 +/- 2.4 ng/ml. The difference between the means is not significant. In group B the mean peak value after L-Dopa was 8.9 +/- 3.6 ng/ml; with the combination of L-Dopa and Disulfirame it was 14.5 +/- 4.4 ng/ml. The difference is not significant. In group C the mean peak value after L-Dopa was 9.8 +/- 2.6 ng/ml; with the combination of L-Dopa and Propranolol, it was 10.1 +/- 1.9 ng/ml. Again the difference is not significant. These findings do not provide evidence in favour of the effect of L-Dopa on the secretion of growth hormone being facilitated by an inhibitor of L-Dopa decarboxylase (Benserazide) or of Dopamine beta hydroxylase (Disulfirame), or by a beta blocking agent (Propranolol). The mechanisms of action of L-Dopa and of the various combinations studied are discussed.

Adolescent↗

PubMed1982

Endogenous dopamine synthesis and dopa-decarboxylase activity in rat renal cortex.

The dopamine content of either cortical slices or isolated glomeruli prepared from rat kidneys and of their incubation medium was measured at different times both under basal conditions and in the presence of L-DOPA. Production of dopamine from L-DOPA by purified cytosolic proteins of the whole cortex was also measured. Dopamine synthesized by these 3 renal preparations accumulated linearly with time over 60 min. Dopamine produced by the glomeruli was more rapidly released into the incubation medium than that produced by the cortical slices. The dopamine synthetic rate was very low in the absence of L-DOPA but increased rapidly when L-DOPA was added to the incubation medium. No plateau was reached in the range of concentrations studied (0-100 microM) when cortical slices or cytosolic proteins were studied whereas dopamine production by isolated glomeruli reached an equilibrium above 10 microM L-DOPA. Dopamine synthesis in the presence of 100 microM L-DOPA was linearly related to the amount of renal protein. The synthetic rates were 43, 2.2 and 0.2 nmoles . h-1 . mg -1 for the cytosolic proteins, the cortical slices and the isolated glomeruli respectively. Dopamine synthesis by the cortical slices in the presence of 100 microM L-DOPA was progressively inhibited by increasing concentrations of alpha-methyl-DOPA. Cortical slices prepared from rats treated by benserazide, an inhibitor of L-DOPA decarboxylase, synthesized much less dopamine than those from control rats. These results show that rat renal cortex deprived of neuronal supply can synthesize dopamine in vitro from extracellular L-DOPA.

Animals↗

PubMed1997

A kinematic comparison of L-DOPA-induced air-stepping and swimming in developing rats.

In Experiment 1, rats of 5, 10, 15, and 20 days of age were injected with L-DOPA to elicit stepping and videotaped while suspended in air and in warm water. Inter- and intralimb coordination were similar for L-DOPA-induced air-stepping and swimming at all ages. Other parameters of locomotion, such as step length and step rate, varied by substrate. In Experiment 2, pups of 5 to 20 days of age received an injection of L-DOPA or the vehicle and were videotaped while freely swimming. L-DOPA-induced free swimming was more stereotyped and "automatonlike" than that of vehicle-injected animals. Through 15 days of age, all pups swam using all four limbs, but L-DOPA induced stricter synchrony of movement in diagonal limbs than was used by pups injected with the vehicle. At postnatal Day 20, vehicle-injected pups adopted the adult swimming pattern in which only the hindlimbs were used, whereas L-DOPA-injected pups continued to use the immature pattern, diagonal progression with all four limbs. These results suggest that L-DOPA-induced air-stepping and swimming are manifestations of the same central mechanisms and that parameters of L-DOPA-induced stepping are modified by the sensory and/or biomechanical effects of the substrate. Although the free swimming of L-DOPA-injected pups was kinematically similar to vehicle-treated pups, L-DOPA retarded transition to the adult swimming pattern.

Aging↗

PubMed1997

Increased neostriatal dopamine activity after intraperitoneal or intranasal administration of L-DOPA: on the role of benserazide pretreatment.

L-DOPA provides the most potent medication to treat Parkinson's disease, and such systemic treatment is usually combined with a peripheral amino acid decarboxylase inhibitor to amplify its central effectiveness. Since L-DOPA can lose its efficacy or can lead to adverse effects with prolonged application, current pharmacokinetic and dynamic research is aimed at improving the drug's applicability. In a previous study, performed with in vivo microdialysis in the anesthetized rat, we have shown that intranasal L-DOPA administration (without prior decarboxylase inhibition) can increase extracellular dopamine levels in the neostriatum. Using similar experimental conditions in the present experiment, we tested the neurochemical effects of L-DOPA treatment in combination with the peripheral amino acid decarboxylase inhibitor benserazide. In accordance with other data, it was found that the combination of i.p. benserazide and i.p. L-DOPA led to pronounced increases of extracellular levels of dopamine, dihydroxyplenylacetic acid and homovanillic acid in the neostriatum, whereas i.p. L-DOPA alone only moderately increased dopamine, but strongly increased the metabolite levels. Furthermore, increased dopamine levels, and weaker increases of dihydroxyplenylacetic acid and homovanillic acid were observed after i.p. benserazide followed by intranasal L-DOPA. Finally, we found that i.p. benserazide alone can lead to pronounced increases in neostriatal dopamine and moderate increases of dihydroxyplenylacetic acid levels, whereas it did not affect homovanillic acid. Thus, not only the combination of L-DOPA (i.p. or intranasal) with the presumed peripheral L-DOPA decarboxylase inhibitor benserazide, but also each component alone can affect dopamine activity in the brain. Especially the findings with benserazide treatment might be of relevance for understanding the mechanisms of current L-DOPA therapy, since they indicate that part of the treatment's actions may possibly be determined by central dopaminergic effects of the accompanying amino acid decarboxylase inhibitor.

Administration, Intranasal↗

PubMed2001

Chronic L-DOPA administration is not toxic to the remaining dopaminergic nigrostriatal neurons, but instead may promote their functional recovery, in rats with partial 6-OHDA or FeCl(3) nigrostriatal lesions.

In this study, we have examined the effects of chronic L-3,4-dihydroxyphenylalanine (L-DOPA) administration on the remaining dopaminergic neurons in rats with 6-hydroxydopamine (6-OHDA) or buffered FeCl(3) partial lesions to the nigrostriatal tract. L-DOPA administration increased the turnover of dopamine in the striatum. L-DOPA administration for 1 week produced an increase in the level of striatal RTI-121 binding, a specific marker for dopamine uptake sites on the dopaminergic nerve terminals in the striatum. However, longer periods of L-DOPA treatment decreased the level of RTI-121 binding in the striatum. In the partial 6-OHDA lesion model, L-DOPA treatment had a time-dependent effect on the number of neurons demonstrating a dopaminergic phenotype i.e., neurons that are tyrosine hyrdoxylase (TH)-immunopositive, on the lesioned side of the brain. In the first few weeks of treatment, L-DOPA decreased the number of TH-positive neurons but with long-term treatment, i.e., 24 weeks, L-DOPA increased the number of neurons demonstrating a dopaminergic phenotype. Even in the buffered FeCl(3) infusion model, where the levels of iron were increased, L-DOPA treatment did not have any detrimental effects on the number of TH-positive neurons on the lesioned side of the brain. Consequently, chronic L-DOPA treatment does not have any detrimental effects to the remaining dopaminergic neurons in rats with partial lesions to the nigrostriatal tract; indeed in the 6-OHDA lesion model, long-term L-DOPA may increase the number of neurons, demonstrating a dopaminergic phenotype.

Adrenergic Agents↗

PubMed1998

De novo administration of ropinirole and bromocriptine induces less dyskinesia than L-dopa in the MPTP-treated marmoset.

In contrast to levodopa (L-dopa), de novo administration of the D2-like receptor agonist bromocriptine to patients with Parkinson's disease (PD) or to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated subhuman primates is not associated with the onset of significant dyskinesia. We now compare the ability of the novel D2-like selective dopamine agonist ropinirole with that of bromocriptine and L-dopa to induce dyskinesia in MPTP-treated common marmosets. MPTP-treated common marmosets were treated with placebo, L-dopa plus carbidopa, ropinirole, or bromocriptine daily for 30 days (n = 4 per group) in doses that were titrated to similarly increase locomotion and improve motor disability. L-dopa rapidly induced dyskinesia of moderate to severe intensity, whereas ropinirole and bromocriptine produced mild dyskinesia over the course of the study that was significantly less severe than in the L-dopa-treated group (p < 0.05). However, in a separate group of marmosets previously primed with L-dopa to exhibit dyskinesia, ropinirole administration elicited severe dyskinesias comparable with that of L-dopa in a dose-dependent fashion. Ropinirole, in common with bromocriptine, has a lesser tendency than L-dopa to produce dyskinesia while similarly improving motor performance in drug-naive MPTP-treated marmosets. However, in common with other dopamine agonists, ropinirole will elicit comparable dyskinesia once L-dopa priming has occurred. These results predict a similar response to ropinirole and other long-acting dopamine agonists in L-dopa-naive patients with PD and emphasize the importance of avoiding initial dyskinesia induction through early use of dopamine agonist drugs.

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