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PubMed2004

High- and low-affinity transport of L-leucine and L-DOPA by the hetero amino acid exchangers LAT1 and LAT2 in LLC-PK1 renal cells.

The present study examined the functional characteristics of the inward and outward L-[14C]DOPA and L-[14C]leucine transporters in LLC-PK1 cells. Uptake was initiated by the addition of Hanks' medium with a given concentration of L-[14C]DOPA or L-[14C]leucine. Saturation experiments were performed in cells incubated for 6 min with 0.25 microM concentration of the substrates in the absence and the presence of increasing concentrations of the nonlabeled substrates. Fractional outflow of intracellular L-[14C]DOPA or L-[14C]leucine was evaluated in cells loaded with 2.5 microM L-[14C]DOPA or 1 microM L-[14C]leucine for 6 min and then the corresponding efflux was monitored over 24 min. The high-affinity (Km = 5.1 microM) uptake of L-[14C]leucine and the low-affinity (Km = 120.0 microM) uptake of L-[14C]DOPA were largely promoted through a Na+-independent transporter. The uptake of the substrates was insensitive to N-(methylamino)-isobutyric acid but competitively inhibited by 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BCH). L- And D-neutral amino acids, but not acidic and basic amino acids, markedly inhibited L-[14C]DOPA and L-[14C]leucine accumulation. The uptake of L-[14C]leucine was a pH-insensitive process, whereas that of L-[14C]DOPA was sensitive to pH. The efflux of L-[14C]DOPA and L-[14C]leucine was markedly increased (P < 0.05) by L-cysteine, L-leucine, BCH, and L-DOPA but not by L-arginine. RT-PCR detected LAT1 and LAT2 transcripts in LLC-PK1 cells. It is concluded that LLC-PK1 cells express both LAT1 and LAT2 transcripts and transport L-[14C]leucine through the Na+-independent pH-insensitive and high-affinity LAT1 transporter, whereas L-[14C]DOPA is mainly transported through the Na+-independent pH-insensitive and low-affinity LAT2 transporter and a minor component through a Na+-dependent transporter.

Animals↗
PubMed1984

Estimation of in vitro activity of tuberoinfundibular dopaminergic neurons by measurement of DOPA synthesis in the median eminence of hypothalamic slices.

A new method for estimation of in vitro neurosecretory activity of tuberoinfundibular dopaminergic (TIDA) neurons was developed by measuring the rate of synthesis of dihydroxyphenylalanine (DOPA) in the median eminence of hypothalamic slices. Sagittal hypothalamic slices of ovariectomized rats were incubated in a medium containing 3-hydroxybenzylhydrazine (NSD 1015), an inhibitor of DOPA decarboxylase. DOPA accumulated in the median eminence following incubation with NSD 1015 was determined by high-performance liquid chromatography with electro-chemical detection. The amount of DOPA accumulated in vitro in the median eminence was maximal in a medium containing 10 mM NSD 1015 and linear up to 120 min at 37 degrees C. Increasing the concentration of tyrosine in medium stimulated the synthesis of DOPA in the median eminence. The synthesis of DOPA was blocked by 1 mM alpha-methyltyrosine, an inhibitor of tyrosine hydroxylase. The rate of in vitro synthesis of DOPA in the median eminence was 33% of that of in vivo synthesis. Incubation in a medium containing 50 mM K+ to depolarize neurons caused a 2.4-fold increase in DOPA synthesis in the median eminence. The high K+-induced increase in DOPA synthesis was blocked by omission of Ca2+ and addition of 1 mM EGTA into the medium, suggesting Ca2+ dependency of depolarization-activated DOPA synthesis. These results indicate that this in vitro assay is a useful means to study the regulatory mechanisms of TIDA neurons.

Animals↗
PubMed1991

Nanomolar L-dopa facilitates release of dopamine via presynaptic beta-adrenoceptors: comparative studies on the actions in striatal slices from control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 black mice, an animal model for Parkinson's disease.

Effects of L-DOPA (0.1-10,000 nM) on spontaneous release (Sp), evoked release (S) and tissue content (C) of dopamine (DA) were studied comparatively in superfused striatal slices from control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 black mice to obtain evidence for L-DOPA-induced facilitation of S via presynaptic beta-adrenoceptors. In control slices, isoproterenol-induced concentration-dependent increases in S were propranolol-sensitive. L-DOPA at 0.1-3 nM tended to increase the S of DA with a concomitant tendency of increases in Sp. L-DOPA at 10-1 x 10(4) nM concentration-dependently increased Sp. L-DOPA at 1-10 microM tended to increase S and 10 microM increased C. In slices from MPTP-treated mice, the absolute amounts of Sp, S and C decreased by half compared to those in control slices. L-DOPA at 3 nM facilitated S without increasing Sp. This facilitation was antagonized by propranolol at 3 nM. L-DOPA at 30 nM decreased S from the peak facilitation, which contrasted with no effect in the control slices. However, 10-100 nM L-DOPA increased Sp more markedly than that in the control slices. L-DOPA at 100 nM increased S and C, which contrasted with no effect in the control slices. In conclusion, nanomolar L-DOPA facilitates the S of DA via presynaptic beta-adrenoceptors at concentrations lower than those required to induce conversion to DA even in striatal slices from the MPTP-treated mice model for Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

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

[Tandospirone citrate, a selective 5-HT1A agonist, alleviates L-DOPA-induced dyskinesia in patients with Parkinson's disease].

A rapid and excessive increase in extracellular dopamine(DA) after L-DOPA administration is considered one of the major causes for L-DOPA-induced peak-dose dyskinesia. Therefore, inhibition of excessive rise in L-DOPA-derived DA is likely to be an ideal treatment for L-DOPA-induced dyskinesia. Based on our previous experimental studies that 8-OH-DPAT, a potent 5-HT1A agonist, attenuates an increase in L-DOPA-induced extracellular DA in the striatum of the rat model of Parkinson's disease, we hypothesized that L-DOPA-induced dyskinesia in patients with Parkinson's disease is alleviated by a 5-HT1A agonist. In the present study, we administered tandospirone citrate, a selective 5-HT1A agonist, to patients with Parkinson's disease suffering from L-DOPA-induced dyskinesia. Tandospirone(15-60 mg/day) was administered to 10 patients with L-DOPA-induced peak-dose dyskinesia. Twelve weeks after tandospirone treatment, duration of dyskinesia, subjective and objective severity of dyskinesia, and parkinsonian features were evaluated. Severity of dyskinesia was decreased in 5 patients; among these, 3 patients experienced slight worsening of parkinsonian features. Four patients showed no change in dyskinesia; among these, 2 patients showed worsening of parkinsonian features. One patient had slight worsening of dyskinesia without any change in parkinsonian features. The present study demonstrated that tandospirone is effective in alleviating L-DOPA-induced dyskinesia in 50% of the patients. However, at the same time 50% patients showed slight worsening of parkinsonian features. Both the anti-dyskinetic effect and the worsening of parkinsonian features are thought to be induced by tandospirone's potent 5-HT1A agonistic activity. Diverse effect of tandospirone may be caused by its partial agonist activity on 5-HT1A receptors, or may indicate that other causes for the expression of dyskinesia exist apart from excessive rise in brain DA levels. Administration of a 5-HT1A agonist is a choice for patients with dyskinesia if the care is taken so as not to induce worsening of parkinsonian features. Further studies such as double-blind trials are needed to confirm the usefulness of a 5-HT1A agonist for L-DOPA-induced dyskinesia.

Adult↗
PubMed1984

[Onset-and end-of-dose dyskinesias induced by L-dopa treatment in a patient with juvenile parkinsonism].

A 33-year-old male with diphasic dyskinesia was presented. He began to have difficulty with walking at the age of 27, and was diagnosed to have juvenile parkinsonism. For the past two years, L-dopa has been prescribed with good initial response. One year ago peripheral dopa decarboxylase inhibitor in combination with L-dopa was started, and he began to have involuntary movements. One hour after taking 2 tablets of EC dopa (L-dopa 100 mg + benserazide 25 mg), violent involuntary ballistic movements appeared in all four extremities which lasted for 15 minutes. For the following 50 minutes, his symptoms of parkinsonism markedly improved. The score of parkinsonism reduced by 58%, and he was able to walk. The plasma dopa level was increasing during this period. However, during decreasing period of plasma dopa concentration, he did not have end-of-dose dyskinesia. On the other hand, one hour after taking 500 mg of L-dopa involuntary choreic movements appeared in his right upper extremity for several minutes without any improvement of parkinsonism. Three hours and 20 minutes after taking L-dopa, he developed mild choreic movements for several minutes followed by marked improvement of parkinsonism for 30 minutes. The score of parkinsonism reduced by 79%. Thirty minutes later, he developed violent ballistic movements in all four extremities, lasting for 30 minutes followed by reappearance of parkinsonism. The concentration of plasma dopa was decreasing during this period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1982

Effect of L-dopa on renal handling of uric acid.

Several reports have indicated that L-dopa may cause hyperuricemia and gout. The reports of hyperuricemia have generally been explained on the basis that L-dopa is known to produce a false hyperuricemia by interfering in the colorimetric analysis of uric acid. Our studies of the interference of L-dopa in the analysis of uric acid revealed that the false elevation of uric acid produced by therapeutic plasma concentrations of L-dopa is minor. The present studies used the Sperber in vivo chicken technique to determine whether L-dopa interferes with the renal excretion of uric acid. We found that a 440 mg/kg dose of L-dopa given by stomach tube results in a 30% decrease in the renal tubular excretory transport of [14C]uric acid. L-Dopa infused along with [14C]uric acid into the renal portal circulation also decreases the excretory transport of [14C]uric acid. In addition, i.v. L-dopa at 8.5 or 11.6 mumol/min/leg causes an increase in plasma urate of 26 or 45%, respectively. During infusion of L-[14C]dopa into the peritubular circulation, the 14C-label was excreted into the urine at a rate equivalent to 35% that of simultaneously infused p-aminohippuric acid or [3H] tetraethylammonium. The excretory transport of 14C-label was inhibited by probenecid. Because the renal tubular excretory transport of uric acid in chickens has many similarities to that of man, the results suggest that inhibition of uric acid excretory transport may be one of the effects of L-dopa, or its metabolites, in man.

Animals↗
PubMed1993

[Reevaluation of the I-dopa test in acromegaly: anatomo-clinical and prognostic correlations].

It is known that in acromegalic patients the GH secretion exhibits a pattern of response to various stimuli that differs from that observed in normal subjects. We have evaluated the paradoxical GH response to 1-Dopa in acromegaly, in order to clarify the relationships between this datum and the tumour size, the basal GH secretion, the GH response to TRH and the long-term prognosis. MATERIALS AND METHODS. 34 acromegalic patients, 12 men and 22 women, aged 35-70 yr, participated in this study. They were divided in 4 classes, according to Hardy's classification of pituitary neoplasias: (1) intrasellar microadenomas, < 10 mm (n = 8); (2) intrasellar macroadenomas, > 10 mm (n = 14); 3) adenomas with local expansion (n = 9); (4) adenomas with extrasellar expansion (n = 3). All patients underwent a 1-Dopa-test; 18 of them underwent a TRH-test. Basal postoperative GH and basal pre- and postoperative PRL levels were also determined. RESULTS. The basal preoperative GH values in all patients ranged between 16 and 278 ng/ml. 22 patients showed a paradoxical response to 1-Dopa, 12 were non-responders. The following results were observed in the different classes: [table: see text] Moreover, 10 subjects (56%) were TRH-responders (9 of them were also 1-Dopa-responders, 1 was non-responder) and 8 were TRH non responders (6 were 1-Dopa non-responders, 2 were 1-Dopa responders). Basal postoperative GH values were > 5 in 17 1-Dopa responders and in 9 non responders. Basal preoperative PRL levels were > 25 ng/ml in 7 1-Dopa responders and in 2 non responders. After surgery, basal PRL became normal in 5 responder patients. DISCUSSION. In a previous work we have correlated the paradoxical GH response to TRH with tumour size and GH levels, observing a higher percentage of paradoxical response in patients in class I and II and, postoperatively, lower GH levels in preoperative TRH responders. So, we have underlined the good prognostic feature of a preoperative paradoxical response. In this paper we have evaluated the paradoxical GH response to 1-Dopa in the different Hardy's classes and compared it with the GH levels and the GH response to TRH. The results show that a paradoxical response can be observed more frequently in small (class I) adenomas than in greater size ones, and in presence of lower GH basal levels. Moreover, a concordance between 1-Dopa and TRH tests can be observed. CONCLUSIONS. The results clearly indicate that the responses to dynamic GH tests should be evaluated considering the anatomic characteristics of the neoplasias. It could be suggested that the paradoxical response can be expressed only when hypothalamus-pituitary interactions are intact.

Acromegaly↗
PubMed1976

[Facilitation of the effects of L-DOPA by alpha-methyldopa].

Alpha-methyl-DOPA increased the duration of excitation induced by L-DOPA in mice, alpha-methyl-DOPA potentiated the anticataleptogenic activity of L-DOPA in mice pretreated with reserpine or haloperidol. Alpha-methyl-DOPA given to cats 30 min prior to L-DOPA diminished the influence of L-DOPA on the blood pressure and the contraction of the nictitating membrane. When given 4 to 6 hours prior to L-DOPA alpha-methyl DOPA enhanced the reaction of the blood pressure and contraction of the nictitating membrane induced by L-DOPA or dopamine.

Animals↗
PubMed2005

Comparison of FP-CIT SPECT with F-DOPA PET in patients with de novo and advanced Parkinson's disease.

PURPOSE: Diagnosis of Parkinson's disease (PD) can be difficult. F-DOPA PET is able to quantify striatal dopa decarboxylase activity and storage capacity of F-dopamine, but is expensive and not generally available. FP-CIT binds to the dopamine transporter, and FP-CIT SPECT is cheaper and more widely available, but has a lower resolution. The aim of this study was to compare these two methods in the same patients with different stages of PD to assess their power in demonstrating deficits of the striatal dopaminergic system. METHODS: Thirteen patients with de novo PD and 17 patients with advanced PD underwent FP-CIT SPECT and static F-DOPA PET. After data transfer to standard stereotactic space, a template with regions of interest was used to sample values of the caudate, putamen and an occipital reference region. The outcome value was striato-occipital ratios. Patients were clinically examined in the "off state" (UPDRS-III and H&Y stage). RESULTS: Good correlations were found between striatal F-DOPA uptake and striatal FP-CIT uptake (r = 0.78) and between putaminal F-DOPA uptake and putaminal FP-CIT uptake (r = 0.84, both p < 0.0001). Both striatal uptake of FP-CIT and that of F-DOPA correlated moderately with H&Y stage (rho = -0.52 for both techniques), UPDRS-III (rho = -0.38 for F-DOPA; rho = -0.45 for FP-CIT) and disease duration (rho = -0.59 for F-DOPA; rho = -0.49 for FP-CIT, all p < 0.05). CONCLUSION: FP-CIT values correlate well with F-DOPA values. Both methods correlate moderately with motor scores and are equally able to distinguish patients with advanced PD from patients with de novo PD.

Adult↗
PubMed2000

Bacterial-injection-induced syntheses of N-beta-alanyldopamine and Dopa decarboxylase in the hemolymph of coleopteran insect, Tenebrio molitor larvae.

Injection of Escherichia coli into larvae of the coleopteran Tenebrio molitor resulted in the appearance of a dopamine-like substance on the electrochemical detector. To characterize this dopamine-like substance, we purified it to homogeneity from the immunized hemolymph and determined its molecular structure to be N-beta-alanyldopamine using the liquid chromatographic/tandem mass spectrometric method. Chemically synthesized N-beta-alanyldopamine showed the same retention time on HPLC as the purified N-beta-alanyldopamine from immunized larvae. To elucidate the molecular mechanism of N-beta-alanyldopamine synthesis in vivo, we examined the enzyme activity of Dopa decarboxylase against E. coli-injected hemolymph of T. molitor larvae. The enzyme activity of Dopa decarboxylase increased dramatically approximately 8 h after injection; Dopa decarboxylase activity of injected larvae being 10-times higher than naive larvae after 24 h. To evaluate the extent of quantitative changes of Dopa decarboxylase in response to bacterial challenge, Tenebrio Dopa decarboxylase was purified to homogeneity from the whole larvae and a cDNA clone for Tenebrio Dopa decarboxylase was isolated. RNA blot hybridization revealed that expression of the Dopa decarboxylase gene was activated transiently 3-8 h after E. coli challenge. Immunoprecipitation experiments showed that Tenebrio Dopa decarboxylase was detected from 8 to 24 h in E. coli-injected larval extract. Thus, bacterial injection into T. molitor larvae might induce transcriptional activation of a Dopa decarboxylase gene, and then synthesis of N-beta-alanyldopamine. The synthesized N-beta-alanyldopamine might be used as a substrate by phenoloxidase during melanin synthesis in the humoral defense response or the melanotic encapsulation reaction of the cellular defense response.

Amino Acid Sequence↗
PubMed1978

Radioenzymatic assay of DOPA (3,4-dihydroxyphenylalanine).

We modified the single-isotope radioenzymatic assay for catecholamines [Life Sci. 21, 625 (1977)] to assay 3, 4-dihydroxyphenylalanine (DOPA). DOPA decarboxylase is used to convert DOPA to dopamine, which concurrently is converted to [3H]-3-O-methyldopamine in the presence of catechol-O-methyltransferase and [methyl-3H]-S-adenosylmethionine and assayed radioenzymatically. For assay of plasma DOPA, 50 microliter of untreated plasma is added directly into the incubation mixture. A duplicate mixture containing an internal standard requires a second 50-microliter aliquot of plasma. Because the assay measures both DOPA and endogenous dopamine, two additonal aliquots of plasma must be assayed for dopamine in the absence of the decarboxylase by the differential assay; DOPA is estimated by difference. The assay is sensitive to 25 pg (500 ng/liter of plasma). Analysis of DOPA (DOPA plus dopamine) and the concurrent differential assay of catecholamines in at least 10 samples can be done in a single working day. Plasma DOPA concentrations for 42 normotensive adults were 1430 +/- 19 ng/liter (mean +/- SEM). In contrast, do-pamine concentrations for these same subjects averaged 23 +/- 20 ng/liter. Values for the 24 women subjects (15 10 +/- 62 ng/liter) significantly (P = 0.04) exceeded those for the men (1320 +/- 75 ng/liter).

Adult↗
PubMed2000

Effects of dopamine and L-DOPA on survival of PC12 cells.

The effects of dopamine and L-DOPA on survival were examined in differentiated PC12 cells. Addition of dopamine to the culture medium at 3-30 microM prevented cell death induced by depletion of serum and nerve growth factor (NGF). At 100 microM, dopamine induced cell death. The cell-protective effect of dopamine was not affected by nomifensine, an inhibitor of dopamine uptake, or pargyline, an inhibitor of monoamine oxidase, suggesting that dopamine is working outside the cell. The cell-protective effect of dopamine was blunted by SCH-23390, a D(1) antagonist, but not sulpiride, a D(2) antagonist, indicating that the cell protective effect of dopamine is mediated by D(1) receptors in PC12 cells. L-DOPA also protected PC12 cells from cell death induced by depletion of serum and NGF at low concentrations and showed toxicity at high concentration. The effect of L-DOPA was unchanged after inhibition of conversion of L-DOPA to dopamine by m-hydroxybenzylhydrazine (NSD-1015), an inhibitor of DOPA decarboxylase, suggesting that L-DOPA itself is working for cell protection. Intracellular Ca(2+) concentration and mitogen-activated protein (MAP) kinase activity were increased by both dopamine and L-DOPA. The effects of dopamine and L-DOPA on cell survival were blunted by nicardipine, a Ca(2+) channel blocker, and PD-98059, an inhibitor of MAP kinase kinase (MEK). These results taken together raised the possibility that dopamine and L-DOPA protect PC12 cells from cell death at low concentrations by activating MAP kinase activity via elevation of intracellular Ca(2+) concentration.

Animals↗
PubMed2002

Repeated administration of piribedil induces less dyskinesia than L-dopa in MPTP-treated common marmosets: a behavioural and biochemical investigation.

Piribedil ([1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine]; S 4200) is a dopamine agonist with equal affinity for D(2)/D(3) dopamine receptors effective in treating Parkinson's disease as monotherapy or as an adjunct to levodopa (L-dopa). However, its ability to prime basal ganglia for the appearance of dyskinesia is unknown. We now report on the ability of repeated administration of piribedil to induce dyskinesia in drug naïve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -lesioned common marmosets compared with L-dopa and its actions on the direct and indirect striatal outflow pathways. Administration of piribedil (4.0-5.0 mg/kg orally) or L-dopa (12.5 mg/kg orally plus carbidopa 12.5 mg/kg orally twice daily) produced equivalent increases in locomotor activity and reversal of motor deficits over a 28-day study period. Administration of L-dopa resulted in the progressive development of marked dyskinesia over the period of study. In contrast, administration of piribedil produced a significantly lower degree and intensity of dyskinesia. Surprisingly, piribedil caused an increase in vigilance and alertness compared to L-dopa, which may relate to the recently discovered alpha(2)-noradrenergic antagonist properties of piribedil. The behavioural differences between piribedil and L-dopa are reflected in the biochemical changes associated with the direct striatal output pathway. Administration of L-dopa or piribedil did not reverse the MPTP-induced up-regulation of preproenkephalin A mRNA in rostral or caudal areas of the putamen or caudate nucleus. In contrast, administration of either piribedil or L-dopa reversed the downregulation of preprotachykinin mRNA induced by MPTP in rostral and caudal striatum. L-dopa, but not Piribedil, reversed the decrease in preproenkephalin B mRNA produced by MPTP treatment.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Opossum kidney cells take up L-DOPA through an organic cation potential-dependent and proton-independent transporter.

The present work was aimed at studying the kinetics and nature of the L-DOPA transporter in opossum kidney (OK) cells. Saturation experiments were performed in OK cells incubated for 6 min with increasing concentrations of L-DOPA (10 to 2500 microM); non-linear analysis of the saturation curve revealed for L-DOPA a K(m) of 129 microM (114, 145) and Vmax of 30.0 +/- 0.4 nmol mg protein-1 6 min-1. The uptake of L-DOPA (250 microM) was inhibited in a concentration-dependent manner by cyanine 863, an organic cation inhibitor, with a Ki value of 638 (430, 947) microM; the organic anion inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS), was devoid of effect upon the uptake of L-DOPA. The uptake of L-DOPA (250 microM) was significantly (P < 0.02) decreased (25% reduction) when cells were incubated in the presence of 137 mM K+ plus 5 mM Na+, when compared with the control condition (137 mM Na+ plus 5 mM K+); substitution of NaCl by choline chloride (137 mM) did not affect L-DOPA uptake. Similarly, inwardly or outwardly directed proton gradients of 0.5 pH units (7.9, 7.4, 6.9, 6.4 and 5.9) were found not to change L-DOPA uptake. In conclusion, the L-DOPA uptake system in OK cells has the characteristics of an organic cation potential-dependent and proton-independent transporter.

Animals↗
PubMed2001

Coadministration of (-)-OSU6162 with l-DOPA normalizes preproenkephalin mRNA expression in the sensorimotor striatum of primates with unilateral 6-OHDA lesions.

The substituted phenylpiperidine (-)-OSU6162 is a novel modulator of the dopaminergic systems with low affinity for dopamine D(2) receptors and potent normalizing effects on l-DOPA-induced dyskinesias. We studied the effects of coadministration of (-)-OSU6162 with l-DOPA on the regulation of striatal preproenkephalin (PPE) and prodynorphin (PDyn) mRNA expression in the primate brain by in situ hybridization histochemistry. Common marmoset monkeys sustaining unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway received l-DOPA/carbidopa, l-DOPA/carbidopa plus (-)-OSU6162, or vehicle over 14 days. In vehicle-treated animals, PPE mRNA levels were markedly increased in the sensorimotor territory of the lesioned striatum. By contrast, a rather uniform lesion-induced reduction of PDyn mRNA levels was found in the vehicle group. Subchronic l-DOPA treatment induced a further increase in PPE mRNA expression in a number of sensorimotor and associative subregions of the denervated striatum. Coadministration of (-)-OSU6162 with l-DOPA partially reversed the lesion- and l-DOPA-induced elevation of PPE expression and, by affecting PPE mRNA expression differentially on the intact and lesioned striatum, markedly reduced the side-to-side difference in PPE mRNA expression. The effects on PPE mRNA expression were apparent throughout the rostrocaudal extent of the putamen and the dorsal portions of the caudate nucleus. l-DOPA treatment resulted in an enhancement in PDyn mRNA expression in all functional compartments of the striatum. Coadministration of (-)-OSU6162 had no apparent influence on these l-DOPA-induced changes in PDyn mRNA expression. The present results suggest that (-)-OSU6162 acts primarily by modifying striatal output via the indirect pathway.

Animals↗
PubMed1982

The effect of cysteine on oxidation of tyrosine, dopa, and cysteinyldopas.

The influence of cysteine on the oxidation of tyrosine, dopa, and monocysteinyldopas by mushroom tyrosinase was reexamined. During oxidation of tyrosine in the presence of cysteine the concentration of dopa increased slowly, whereas the concentration of cysteinyldopas increased more rapidly. When the concentration of cysteine decreased the cysteinyldopas were rapidly consumed and dopa concentrations increased sharply. Experiments on the oxidation of dopa by tyrosinase in the presence of cysteine showed that this thiol does not inhibit the oxidation. Dopa concentrations decreased more rapidly in the presence of cysteine because cysteine addition to dopaquinone prevented reformation of dopa from dopaquinone. Both 2-S-cysteinyldopa and 5-S-cysteinyldopa are substrates for tyrosinase. The oxidation of cysteinyldopas was inhibited at high cysteine concentrations. The greater part of 2,5-S,S-dicysteinyldopa formed during the oxidation of monocysteinyldopas in the presence of cysteine is derived from 5-S-cysteinyldopa, which is a better substrate for tyrosinase than 2-S-cysteinyldopa. The fact that cysteine binds more rapidly to 5-S-cysteinyldopaquinone than to 2-S-cysteinyldopaquinone further stresses the importance of 5-S-cysteinyldopa in the formation of 2,5-S,S-dicysteinyldopa. Oxidation of dopa in the presence of cysteine and glutathione or methionine showed that glutathione is added to dopaquinone but less rapidly than cysteine. Methionine showed insignificant addition to dopaquinone. When dopa or 5-OH-dopa is added to an incubate of cysteinyldopa and tyrosinase the oxidation of cysteinyldopa is accelerated owing to oxidation of cysteinyldopa by dopaquinone or 5-OH-dopaquinone.

Ascorbic Acid↗
PubMed1995

Synergistic interactions between COMT-/MAO-inhibitors and L-Dopa in MPTP-treated mice.

Four experiments were performed to investigate the anti-akinesia effects of combining a sub-threshold dose (5 mg/kg, s.c.) of L-Dopa with different doses and combinations of COMT and MAO inhibitors upon the hypokinesia observed in MPTP-treated mice. Ro 40-7592 (1 and 3 mg/kg, s.c.), a novel COMT inhibitor, 60 min before L-Dopa reinstated both locomotion and rearing during a 2-hr interval after L-Dopa in MPTP mice; control mice were unaffected. The combination of Ro 40-7592 (3 mg/kg, s.c.) and pargyline (5 mg/kg, s.c.), a MAO inhibitor, with L-Dopa produced increases in both the peak effect and duration of action indicating a distinct potentiation of the effects of Ro 40-7592 by pargyline. L-Deprenyl, a MAOB inhibitor, together with L-Dopa, restored locomotion and rearing behaviour at all three doses applied (1, 3 and 10 mg/kg, s.c.); in control mice, motor activity was stimulated at the higher doses (3 and 10 mg/kg, s.c.), independent of L-Dopa administration. Combining L-Deprenyl (3 mg/kg, s.c.) with Ro 40-7592 (3 mg/kg, s.c.) one hr before L-Dopa to MPTP mice potentiated the restorative effects of each compound by itself, although no increase in peak effect was obtained. In the control mice, L-Deprenyl plus Ro 40-7592 or L-Deprenyl, by itself, stimulated motor activity following injection of L-Dopa. Marked dopamine (DA) depletions in the striatum of MPTP-treated mice were evident. The present results demonstrate that the effects of the COMT/MAO inhibitors in combination, and in conjunction with L-Dopa (at a dose that was without effect by itself), were well in excess of a summation of their individual effects. It was concluded therefore that a synergism of the restorative, anti-akinesic action of these compounds in MPTP-treated mice could offer a broader therapeutic spectrum in the treatment of Parkinson's disorder.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Tolerance to a suprathreshold dose of L-Dopa in MPTP mice: effects of glutamate antagonists.

Three experiments were performed to study the development and manipulation of tolerance to a suprathreshold dose of L-Dopa (20 mg/kg, s.c.) in MPTP-treated and control (saline-injected) C57 Bl/6 mice. The motor activity reinstatement effect of this dose of L-Dopa upon MPTP-treated mouse behaviour deteriorated from the 13th injection (Test Day 8) of L-Dopa onwards and reached basal level (i.e. no stimulatory effects of the drug) by the 16th administration (Test Day 10). Administration of L-Dopa to control mice reduced locomotor and rearing activity throughout the tolerance development period (Test Days 1-12) during the first hour after injection, and then increased locomotor activity during the second hour. The effects of combining either a noncompetitive, MK-801, or a competitive, CGP 40116, glutamate antagonist with L-Dopa, following tolerance development, were assessed in MPTP mice on the 23rd day of L-Dopa administration (Test Day 13). MK-801 (0.1 mg/kg, s.c.) reinstated the locomotory and rearing behaviour induced by L-Dopa; CGP 40116 did so also to a greater extent in the dose range 0.01 to 0.03 mg/kg. These results indicate that MPTP-treated mice continue to offer a useful parkinsonian model also for the examination of different aspects of the "wearing-off" phenomenon of L-Dopa tolerance and in particular the putative glutamatergic involvement. The clinical consequences may be far-reaching for the utility of L-Dopa in Parkinson's disease, whether the effects demonstrated be of a reinstatement or synergistic nature, once therapeutically adequate glutamate antagonists are more readily available.

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