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PubMed1989

Effect of exogenous L-dopa on behavior in the rat: an in vivo voltammetric study.

L-DOPA was administered intraperitoneally (i.p.) or intraventricularly (i.v.t.) to freely moving rats to investigate the effects of exogenous L-DOPA itself on behavior. Striatal dopamine (DA) in the extracellular fluid was examined with microcomputer-controlled in vivo voltammetry, and behavioral change was observed. When L-DOPA was administered (i.p.) after pretreatment with benserazide, a peripheral DOPA decarboxylase inhibitor, behavioral change was elicited before the elevation in DA and suppressed before its reduction. After pretreatment with NSD-1015, a central DOPA decarboxylase inhibitor, behavioral change was also elicited, although DA was still not increased. When L-DOPA was injected (i.v.t.), the behavioral effect was manifested at once; DA was still unchanged at this time, but it increased after behavioral activity reached the maximum level. L-DOPA was also injected (i.v.t.) into rats with striatal lesions induced by 6-hydroxydopamine (i.v.t.). Behavioral change was manifested promptly after the injection. When the dose-response curves to different dosages of L-DOPA were examined in normal rats without striatal lesions, it was found to exhibit a steeper rise than that of DA. Finally, when rats were injected (i.p. or i.v.t.) with 3-O-methyl-DOPA (3-methoxytyrosine), a major metabolite of L-DOPA, no behavioral change was elicited, and no increase in DA was recognized. These experimental results indicated that L-DOPA is related directly to the manifestation of behavioral change.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Assessment of dopamine and its metabolites in the intracellular and extracellular compartments of the rat striatum after peripheral administration of L-[11C]dopa.

Success in the synthesis of L-3,4-[beta-11C]dihydroxyphenylalanine (L-[11C]DOPA) and its application to positron emission tomography encouraged us to perform radioactive metabolite analyses in rats in an early phase after peripheral injection of L-[11C]DOPA. Following intravenous injection of [11C]DOPA, the radioactivity associated with DOPA and its metabolites was determined in the striatum after decapitation and in striatal extracellular fluid using in vivo brain microdialysis. Without pretreatment, 70-80% of 11C-radioactivity taken up into the striatum was associated with acidic metabolites of dopamine (DA) from 2 to 30 min after administration of L-[11C]DOPA with or without 300 micrograms/kg of unlabelled L-DOPA. In contrast, 80-90% of 11C-radioactivity in the striatum was associated with DOPA and DA after pretreatment with benserazide (25 mg/kg, i.p.) followed by administration of L-[11C]DOPA with or without unlabelled L-DOPA. The radioactivity in the DOPA fraction decreased with time (from 35% of 11C-radioactivity in the striatum at 5 min to 10% at 30 min), but that in the DA fraction increased (from 57% to 68%). The 11C-radioactivity in the extracellular fluid determined by brain microdialysis was less than 0.4% of that in the whole striatum and no radioactivity was present in the DA fraction. These results suggest that, in an early phase after administration of L-[11C]DOPA, [11C]DA is the main metabolite and is localized exclusively in the intracellular compartment within this time frame.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1976

Noradrenaline synthesis from L-DOPA in rodents and its relationship to motor activity.

Evidence has been obtained for an increase in noradrenaline (NA) turnover after administration of L0DOPA to rodents. Normal mice, and those pre-treated with either reserpine or alpha-methyl-p-tyrosine (AMPT) were given L-DOPA (200 mg/kg) plus MK 486 (alpha-methyldopahydrazine; 25 mg/kg). In all cases L-DOPA produced a rise in cerebral dopamine (DA) levels. Cerebral NA levels were increased by L-DOPA in reserpinised and AMPT-treated mice. The same dose of L-DOPA produced no change in NA in normal mice, although pre-treatment with the monoamine oxidase inhibitor pargyline (200 mg/kg) resulted in a greater rise in NA 1 hr after L-DOPA compared to animals receiving pargyline alone. This evidence suggests that NA is synthesized from- L-DOPA in all these situations. But whole brain 3-methoxy-4-hydroxyphenylglocol sulphate (MOPEG-SO4), a major metabolite of NA, measured after administration of the same dose of L-DOPA plus MK 486, was unaltered in normal and AMPT-treated rats, and was significantly decreased in reserpinised rats. However, an elevation of whole brain MOPEG-SO4 was found in reserpinised and AMPT-treated rats after a lower dose of L-DOPA (50 mg/kg). This discrepancy may be explained by high doses of L-DOPA causing inhibiton of catechol-O-methyl transferase (COMT), which is suggested by the observation that the forebrain homovanillic acid (HVA): 3,4-dihydroxyphenylacetic acid (DOPAC) ratio was significantly lower after the high dose of L-DOPA than in untreated mice. Such an inhibition would prevent formation of MOPEG-SO4. Pretreatment with dopamine-beta-hydroxylase inhibitor FLA (63(bis-(1-methyl-4-monopiperazinyl-thiocarbonyl)disulphide) prevented the increase in NA And MOPEG-SO4 formation observed following L-DOPA induced motor activity in these groups of animals suggesting the involvement of NA in the production of such behaviour.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

Effects of L-DOPA on aggressive behavior and central monoaminergic activity in the lizard Anolis carolinensis, using a new method for drug delivery.

The dopamine (DA) precursor, L-DOPA (500 microg), was injected into living crickets, which were ingested (one each) by adult male Anolis carolinensis. This method of delivery elevated plasma L-DOPA and DA concentrations by approximately 1000-fold. In contrast, plasma epinephrine (Epi) and norepinephrine (NE) were not influenced by L-DOPA treatment, although they were elevated following the consumption of the cricket. Lizards that ingested L-DOPA treated crickets had elevated L-DOPA in all brain regions measured, with DA and/or DOPAC also increased significantly in most brain regions studied. Despite increased DA levels in the striatum and nucleus accumbens as a response to L-DOPA, the treatment had no influence on general motor activity. Central serotonin, NE, and Epi systems were not affected in any brain region by oral L-DOPA treatment. In addition, aggression was inhibited by this dose of L-DOPA, even though there was no effect on serotonergic systems. This is surprising because controlling aggressive behavior is usually considered the province of serotonergic activity. Aggression was measured before and after treatment, and while saline-treated lizards retained the full vigor of aggressive activity, those fed a cricket injected with L-DOPA were only one-third as aggressive after treatment. As L-DOPA treatment did not affect general motor activity, the effect appears to be directly associated with aggression. This is supported by the observation that L-DOPA treatment delayed latency to eyespot darkening, which predicts the latency to aggression.

Administration, Oral↗
PubMed2005

Cross-sensitization between caffeine- and L-dopa-induced behaviors in hemiparkinsonian mice.

Adenosine A(2A) receptor (A(2A)R) antagonists, including the non-specific adenosine antagonist caffeine, have been proposed as a novel, non-dopaminergic treatment strategy for Parkinson's disease (PD). However, the long-term interaction between caffeine and L-dopa treatment in PD models has not been characterized. We examined the interaction between caffeine and L-dopa following a repeated treatment paradigm in hemiparkinsonian mice. In contrast to the progressively sensitized rotational behavior induced by daily L-dopa (2.0 mg/kg) treatment, tolerance for the rotational response to daily caffeine (2.5 or 10 mg/kg) treatment tended to develop over several weeks. However, after a subsequent two-week washout, challenge with same drug demonstrated an extinction of the sensitized L-dopa-induced rotation, but a sensitization of the caffeine-induced rotation. In a cross-challenge paradigm, daily treatment of mice with L-dopa (compared to daily saline) produced a three-fold enhancement in the rotational response to a subsequent re-challenge with caffeine. Similarly, daily treatment of mice with caffeine produced a six-fold enhancement in the rotational response to a subsequent re-challenge with L-dopa. Furthermore, daily co-administration of caffeine plus L-dopa produced enhanced rotational behavior, compared to caffeine or L-dopa alone, indicating an additive or synergistic interaction between caffeine and L-dopa during repeated treatment. Cross-sensitization between caffeine and L-dopa following repeated treatment and their positive interaction during chronic co-adminstration in hemiparkinsonian mice suggest that repeated exposure to caffeine may alter L-dopa responses in PD.

Adenosine A2 Receptor Antagonists↗
PubMed2006

Delayed L-DOPA-induced hyperalgesia.

Previously we reported on L-DOPA's antinociceptive effect on substance P-induced nociceptive behaviors in mice [Shimizu T, Iwata S, Morioka H, Masuyama T, Fukuda T, Nomoto M. Antinociceptive mechanism of L-DOPA. Pain 2004;110;246-9.]. Since significant hyperalgesia was noted following antinociception, our study was designed to investigate the mechanism of this hyperalgesia. Nociceptive behaviors were enhanced 2 h after L-DOPA administration. L-DOPA induced hyperalgesia occurred after conversion to dopamine because co-administration of benserazide, a DOPA decarboxylase inhibitor, completely abolished the L-DOPA-induced hyperalgesia. The D2 receptor agonist, quinpirole, depressed these behaviors entirely, while the D1 antagonist, SCH23390, inhibited the enhancement of these behaviors by L-DOPA. The D2 receptor antagonist, sulpiride, which induced hyperalgesia of the substance P-induced behaviors in naive mice, did not have any effects on L-DOPA-induced hyperalgesia. Spinal cord dopamine content increased rapidly after L-DOPA administration, exhibiting levels 100 times greater than baseline, and then returned to control after 1 h. These results suggested that the dopaminergic inhibitory system for pain sensation was temporarily impaired by excess amounts of exogenous dopamine that were derived from L-DOPA and both D1 and D2 receptors were involved in L-DOPA-induced hyperalgesia.

Animals↗
PubMed2000

Time-course and dose-response study on the effects of chronic L-DOPA administration on striatal dopamine levels and dopamine transporter following MPTP toxicity.

Despite a long-lasting therapeutic use of L-DOPA in Parkinson's disease, doubts still remain concerning the possibility that chronic L-DOPA might accelerate the progression of this movement disorder. To address this point, in the present study we examined the effects of chronic L-DOPA administration either in intact or MPTP-treated parkinsonian mice. We produced an intermediate striatal dopamine loss by administering a low dose of MPTP (30 mg/kg); then, we treated mice chronically, for different time intervals, with a daily dose of L-DOPA (50 mg/kg). In particular, to study the time-course of the effects of L-DOPA on the recovery of nigrostriatal dopamine axons, mice were sacrificed at 5, 30, 60, and 90 days after a daily L-DOPA administration. To evaluate presynaptic integrity of the nigrostriatal pathway we measured dopamine, metabolite levels, and dopamine uptake sites. In the same animals, we measured striatal serotonin levels and we analysed monoamine content in the olfactory bulb. Administration of MPTP produced a neurotoxic effect, which fully recovered in 2-3 months. Daily L-DOPA administration did not modify this recovery process. Additionally, there was no significant effect of L-DOPA in intact mice, despite a slight decrease in striatal dopamine levels at 5 and 30 days. However, this effect was neither worsened nor reproduced by administering higher doses of L-DOPA (up to 400 mg/kg) for the same amount of time. These data rule out neurotoxic effects induced by prolonged L-DOPA administration, both in intact and MPTP-treated mice. Moreover, administration of L-DOPA does not change the recovery process which takes place after a nigrostriatal lesion.

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

L-DOPA transport properties in an immortalised cell line of rat capillary cerebral endothelial cells, RBE 4.

The present study aimed to determine the kinetics of L-3, 4-dihydroxyphenylalanine (L-DOPA) uptake in an immortalised cell line of rat capillary cerebral endothelial cells (clones RBE 4 and RBE 4B), to define the type of inhibition produced by L-5-hydroxytryptophan (L-5-HTP), 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BHC) and N-(methylamino)-isobutyric acid (MeAlB) and its sodium dependence. Non-linear analysis of the saturation curves for L-DOPA and L-5-HTP revealed in RBE 4 cells Km values (in microM) of 72 and 102 and in RBE 4B cells Km values (in microM) of 60 and 118, respectively. IC50 values for L-5-HTP (RBE 4, 1026 microM; RBE 4B, 831 microM) obtained in the presence of a nearly saturating (250 microM) concentration of L-DOPA were almost 5-fold those obtained when non-saturating (25 microM) concentrations of L-DOPA were used. IC50 values for BHC obtained in the presence of a nearly saturating (250 microM) concentration of L-DOPA were also 6- to 5-fold those obtained when non-saturating (25 microM) concentrations of L-DOPA were used. MeAlB (up to 2.5 mM) was found not to interfere with the uptake of L-DOPA. In RBE 4 cells, Vmax values for L-DOPA uptake were identical in the absence and the presence of 150 microM L-5-HTP or 150 microM BHC, but Km values (microM) were significantly greater (P<0.05) when L-DOPA uptake was studied in the presence of L-5-HTP or BHC. Similar findings were observed when RBE 4B cells were used. Uptake of (250 microM) L-DOPA in the absence of sodium in the incubation medium was similar to that observed in the presence of increasing concentrations of sodium (20 to 140 mM). It is concluded that RBE 4 and RBE 4B cells are endowed with the L-type amino acid transporter through which L-DOPA and L-5-HTP can be taken up, and suggested that this immortalised cell line of rat capillary cerebral endothelium might constitute an interesting in vitro model for the study of BBB mechanisms, namely those concerning solute and nutrient transfer across the brain capillary endothelium.

Animals↗
PubMed2001

Effects of acute and repeated treatment with a novel dopamine D2 receptor ligand on L-DOPA-induced dyskinesias in MPTP monkeys.

(S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine ((-)-OSU6162) is a phenylpiperidine derivative which exhibits low affinity to the dopamine D2 receptor in vitro. However, in vivo, positron emission tomography scanning studies show that the compound displaces the selective dopamine D2 receptor antagonist, raclopride. We have evaluated, in this study, the effect of (-)-OSU6162, on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a primate model of Parkinson's disease. Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-DOPA were used in this study. The monkeys were housed in observation cages equipped with an electronic motility monitoring system. They were injected subcutaneously (s.c.) with L-DOPA methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-DOPA/benserazide) alone or in combination with (-)-OSU6162 (1.0, 3.0, 6.0 or 10 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-DOPA/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of (-)-OSU6162 with L-DOPA/benserazide produced a significant reduction in L-DOPA-induced dyskinesias. This improvement in L-DOPA-induced dyskinesias occurred mainly at the onset of the L-DOPA/benserazide effect as reflected by an increase in the duration of the "ON" state without dyskinesias up to 3.4 fold after (-)-OSU6162 co-administration as compared to L-DOPA/benserazide alone. The anti-dyskinetic effect of (-)-OSU6162 was maintained during 14 days and no tolerance to this effect was observed. Our data suggests that (-)-OSU6162 could be of significant clinical value to reduce L-DOPA-induced dyskinesias in fluctuating advanced Parkinson's disease patients.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

DOPA causes glutamate release and delayed neuron death by brain ischemia in rats.

DOPA seems to be a neuromodulator in striata and hippocampal CA1 and a neurotransmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii (NTS) and baroreflex pathways in the caudal ventrolateral medulla and rostral ventrolateral medulla in the brainstem of rats. DOPA recognition sites differ from dopamine (DA) D(1) and D(2) and ionotropic glutamate receptors. Via DOPA sites, DOPA stereoselectively releases by itself neuronal glutamate from in vitro and in vivo striata. In the cultured neurons, DOPA and DA cause neuron death via autoxidation. In addition, DOPA causes autoxidation-irrelevant neuron death via glutamate release. Furthermore, DOPA released by four-vessel occlusion seems to be an upstream causal factor for glutamate release and resultant delayed neuron death by brain ischemia in striata and hippocampal CA1. Glutamate has been regarded as a neurotransmitter of baroreflex pathways. Herein, we propose a new pathway that DOPA is a neurotransmitter of the primary aortic depressor nerve and glutamate is that of secondary neurons in neuronal microcircuits of depressor sites in the NTS. DOPA seems to release unmeasurable, but functioning, endogenous glutamate from the secondary neurons via DOPA sites. A common following pathway may be ionotropic glutamate receptors-nNOS activation-NO production-baroreflex neurotransmission and delayed neuron death. However, we are concerned that DOPA therapy may accelerate neuronal degeneration process especially at progressive stages of Parkinson's disease.

Animals↗
PubMed2001

L-DOPA produced nitric oxide in the vitreous and caused greater vasodilation in the choroid and the ciliary body of melanotic rats than in those of amelanotic rats.

The nitrogen cycle initiates direct reduction of N2 to NH3 by enzymatic reactions. We hypothesize that L-dihydroxyphenylalanine (L-DOPA), a catecholamine, could be a source of nitric oxide (NO). In order to determine whether L-DOPA generates NO and induces any biological change in the eye, we measured the generation of NO in vitro and in vivo, and investigated the histopathological changes caused by injection of L-DOPA into the vitreous of rats. We also hypothesized that melanin granules may affect the generation of NO during the metabolism of L-DOPA, since L-DOPA is a precursor of melanin in the brain and the eye. Therefore, we compared the effects of L-DOPA on the generation of NO between amelanotic and melanotic rats. NO was measured as diffusion currents by NO electrodes. In vitro, various concentrations of L-DOPA (5, 29.9, 79.4, 152.7, and 249 microM) were added to the medium. The inhibition of NO generation by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide (carboxy-PTIO) was tested. In vivo, NO generation in the vitreous of rats was measured and the eyes were enucleated under anesthesia after L-DOPA injection. The ocular tissues were subjected to histological examination. NO was produced from L-DOPA in a dose-dependent manner and was scavenged by carboxy-PTIO in vitro. NO in the vitreous of melanotic rats was generated from L-DOPA. Histological examination with hematoxylin-eosin staining revealed vasodilation in the ciliary vessels and the choroid after L-DOPA injection. Both effects were greater in melanotic rats than in amelanotic rats. The vasodilation may be attributable to NO as well as to superoxides, which can be regulated by the existence of melanin.

Animals↗
PubMed1997

Neurotrophic effects of L-DOPA in postnatal midbrain dopamine neuron/cortical astrocyte cocultures.

L-DOPA is toxic to catecholamine neurons in culture, but the toxicity is reduced by exposure to astrocytes. We tested the effect of L-DOPA on dopamine neurons using postnatal ventral midbrain neuron/cortical astrocyte cocultures in serum-free, glia-conditioned medium. L-DOPA (50 microM) protected against dopamine neuronal cell death and increased the number and branching of dopamine processes. In contrast to embryonically derived glia-free cultures, where L-DOPA is toxic, postnatal midbrain cultures did not show toxicity at 200 microM L-DOPA. The stereoisomer D-DOPA (50-400 microM) was not neurotrophic. The aromatic amino acid decarboxylase inhibitor carbidopa (25 microM) did not block the neurotrophic effect. These data suggest that the neurotrophic effect of L-DOPA is stereospecific but independent of the production of dopamine. However, L-DOPA increased the level of glutathione. Inhibition of glutathione peroxidase by L-buthionine sulfoximine (3 microM for 24 h) blocked the neurotrophic action of L-DOPA. N-Acetyl-L-cysteine (250 microM for 48 h), which promotes glutathione synthesis, had a neurotrophic effect similar to that of L-DOPA. These data suggest that the neurotrophic effect of L-DOPA may be mediated, at least in part, by elevation of glutathione content.

Animals↗
PubMed2000

L-DOPA does not enhance hydroxyl radical formation in the nigrostriatal dopamine system of rats with a unilateral 6-hydroxydopamine lesion.

The debate about the toxicity of L-DOPA to dopaminergic neurons has not been resolved. Even though enzymatic and nonenzymatic metabolism of L-DOPA can produce hydrogen peroxide and oxygen free radicals, there has been controversy as to whether L-DOPA generates an oxidant stress in vivo. This study determined whether acute or repeated administration of L-DOPA caused in vivo production of hydroxyl radicals in striatum and other brain regions in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal projections. Salicylate trapping combined with in vivo microdialysis provided measurements of extracellular 2,3-dihydroxybenzoic acid (2,3-DHBA) in striatum following L-DOPA administration systemically (100 mg/kg, i.p.) or by intrastriatal perfusion (1 mM, via the microdialysis probe). Tissue concentrations of 2,3-DHBA and salicylate were also measured in striatum, ventral midbrain, and cerebellum following repeated administration of L-DOPA (50 mg/kg, i.p., once daily for 16 days). In each instance, treatment with L-DOPA did not increase 2,3-DHBA concentrations, regardless of the nigrostriatal dopamine system's integrity. When added to the microdialysis perfusion medium, L-DOPA resulted in a significant decrease in the striatal extracellular concentration of 2,3-DHBA. These results suggest that administration of L-DOPA, even at high doses, does not induce hydroxyl radical formation in vivo and under some conditions may actually diminish hydroxyl radical activity. Furthermore, prior damage to the nigrostriatal dopamine system does not appear to predispose surviving dopaminergic neurons to increased hydroxyl radical formation following L-DOPA administration. Unlike L-DOPA, systemic administration of methamphetamine (10 mg/kg, s.c.) produced a significant increase in the concentration of 2,3-DHBA in striatal dialysate, suggesting that increased formation of hydroxyl radicals may contribute to methamphetamine neurotoxicity.

Animals↗
PubMed2001

Endogenously released DOPA is a causal factor for glutamate release and resultant delayed neuronal cell death by transient ischemia in rat striata.

Glutamate is implicated in neuronal cell death. Exogenously applied DOPA by itself releases neuronal glutamate and causes neuronal cell death in in vitro striatal systems. Herein, we attempt to clarify whether endogenous DOPA is released by 10 min transient ischemia due to four-vessel occlusion during rat striatal microdialysis and, further, whether DOPA, when released, functions to cause glutamate release and resultant delayed neuronal cell death. Ischemia increased extracellular DOPA, dopamine, and glutamate, and elicited neuronal cell death 96 h after ischemic insult. Inhibition of striatal L-aromatic amino acid decarboxylase 10 min before ischemia increased markedly basal DOPA, tripled glutamate release with a tendency of decrease in dopamine release by ischemia, and exaggerated neuronal cell death. Intrastriatal perfusion of 10-30 nM DOPA cyclohexyl ester, a competitive DOPA antagonist, 10 min before ischemia, concentration-dependently decreased glutamate release without modification of dopamine release by ischemia. At 100 nM, the antagonist elicited a slight ceiling effect on decreases in glutamate release by ischemia and protected neurons from cell death. Glutamate was released concentration-dependently by intrastriatal perfusion of 0.3-1 mM DOPA and stereoselectively by 0.6 mM DOPA. The antagonist elicited no hypothermia during and after ischemia. Endogenously released DOPA is an upstream causal factor for glutamate release and resultant delayed neuronal cell death by brain ischemia in rat striata. DOPA antagonist has a neuroprotective action.

Animals↗
PubMed2001

L-DOPA and glia-conditioned medium have additive effects on tyrosine hydroxylase expression in human catecholamine-rich neuroblastoma NB69 cells.

The aim of this study was to investigate the effect of L-DOPA and glia-conditioned medium (GCM) on cell viability, tyrosine hydroxylase (TH) expression, dopamine (DA) metabolism and glutathione (GSH) levels of NB69 cells. L-DOPA (200 microM) induced differentiation of NB69 cells of more than 4 weeks in vitro, as shown by phase-contrast microscopy and TH immunocytochemistry, and decreased replication, as shown by 5-bromodeoxyuridine immunostaining. L-DOPA did not increase the number of necrotic or apoptotic cells, as shown by morphological features, Trypan Blue, lactate dehydrogenase activity, bis-benzimide staining and TUNEL assay. Furthermore, L-DOPA (200 microM) increased Bcl-xL protein expression. Incubation of cells with L-DOPA (50, 100, 200 microM) for 24 h resulted in an increase in TH protein levels (174, 196 and 212% versus control). Neither carbidopa, an inhibitor of L-aromatic amino acid decarboxylase enzyme, nor L-buthionine sulfoximine, which inhibits GSH synthesis, or ascorbic acid, an antioxidant, blocked the L-DOPA-induced effect on TH protein expression. L-DOPA (0, 50, 100 and 200 microM) plus GCM further increased the amount of TH protein (346, 446, 472 and 424%). L-DOPA (200 microM) increased TH protein levels to 132, 191 and 245% of controls after incubation for 24, 48 and 72 h. DA metabolism in NB69 cells was increased in cultures treated with either L-DOPA (200-300 microM) or GCM and these two agents had a synergistic effect on DA metabolism. In addition, L-DOPA (200 microM) or/and GCM-treated cells increased their GSH extracellular levels (223, 257, 300% of controls) after 48 h of treatment. The L-DOPA-induced increase of TH protein expression in NB69 cells was independent of DA production, free radicals and GSH up-regulation.

Antioxidants↗
PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of L-Dopa after acute and 6-week tolcapone administration in patients with Parkinson's disease.

Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.

Antiparkinson Agents↗
PubMed2006

Role of striatal L-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats.

We explored possible differences in the peripheral and central pharmacokinetics of L-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically with L-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs). Comparisons between dyskinetic and non-dyskinetic cases were then carried out with regard to plasma and striatal L-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection of L-DOPA, plasma L-DOPA concentrations did not differ between dyskinetic and non-dyskinetic animals, whereas peak levels of L-DOPA in the striatal extracellular fluid were about fivefold larger in the former compared with the latter group. Interestingly, the time course of the AIMs paralleled the surge in striatal L-DOPA levels. Intrastriatal infusion of L-DOPA by reverse dialysis concentration dependently induced AIMs in all 6-OHDA lesioned rats, regardless of a previous priming for dyskinesia. Steady-state levels of DA and its metabolites in striatal and cortical tissue did not differ between dyskinetic and non-dyskinetic animals, indicating that the observed difference in motor response to L-DOPA did not depend on the extent of lesion-induced DA depletion. These results show that an elevation of L-DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability of L-DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease.

Animals↗
PubMed1995

Effects of 3-O-methyl on L-dopa-facilitated synthesis and efflux of dopamine from rat striatal slices.

1. The effect of L-dopa on the spontaneous and KCl-evoked efflux of dopamine from rat striatal slices, measured by high performance liquid chromatography (h.p.l.c.) with electrochemical detection (e.c.d.) was investigated in the absence and presence of 3-O-methyl dopa (OMD), an O-methylated metabolite of L-dopa. 2. The addition of exogenous L-dopa (10 microM) significantly increased both the spontaneous efflux of dopamine and that evoked by KCl. 3. In the presence of 50 microM OMD, the effects of L-dopa on the spontaneous and KCl-evoked efflux of dopamine were smaller but only the former was significantly different from that in the absence of OMD. However, the total efflux of dopamine during the overall superfusion time (70 min) including KCl depolarization was significantly lower than in the absence of OMD. 4. Analysis of tissue content after superfusion revealed that the levels of dopa and dopamine in slices superfused with L-dopa in the presence of OMD were significantly higher than those superfused with L-dopa alone. 5. The finding that OMD significantly reduced the efflux of dopamine whilst increasing its concentration in striatal slices after L-dopa superfusion could explain the reduced efficacy seen after long-term therapy with L-dopa and a peripheral dopa decarboxylase inhibitor in Parkinsonian patients when plasma and brain OMD are very high.

3,4-Dihydroxyphenylacetic Acid↗