Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “DOPA”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 613 records · Page 34Linked to original sources
PubMed2003

Dual effects of intermittent or continuous L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-OHDA lesion.

Intermittent oral doses of levodopa (L-DOPA) are routinely used to treat Parkinson's disease, but with prolonged use can result in adverse motor complications, such as dyskinesia. Continuous administration of L-DOPA achieves therapeutic efficacy without producing this effect, yet the molecular mechanisms are unclear. This study examined, by in situ hybridization histochemistry, the effects of continuous or intermittent L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Results were compared to 6-OHDA-treated rats receiving vehicle. Our results provide original evidence that continuous L-DOPA normalizes the 6-OHDA-lesion-induced increase in mRNA levels encoding for the 67 kDa isoform of glutamate decarboxylase in neurons of the globus pallidus and cytochrome oxidase subunit I mRNA levels in the subthalamic nucleus. The extent of normalization did not differ between the continuous and intermittent groups. In addition, intermittent L-DOPA induced an increase in the mRNA levels encoding for the 65 kDa isoform of glutamate decarboxylase in globus pallidus neurons ipsilateral to the lesion and a bilateral increase in c-fos mRNA expression in the subthalamic nucleus. These results suggest that continuous L-DOPA tends to normalize the 6-OHDA-lesion-induced alterations in cell signaling in the pallido-subthalamic loop. On the other hand, we propose that chronic intermittent L-DOPA exerts a dual effect by normalizing cell signaling in a subpopulation of neurons in the globus pallidus and subthalamic nucleus while inducing abnormal signaling in another subpopulation.

Animals↗
PubMed2001

Inhibition of calcium-independent luminal uptake of L-dopa by calmodulin antagonists in immortalized rat capillary cerebral endothelial cells.

The present study examined the involvement of protein kinase A (PKA), protein kinase G (PKG), protein kinase C (PKC), protein tyrosine kinase (PTK) and Ca(2+)/calmodulin mediated pathways on the luminal uptake of L-DOPA through the L-type amino acid transporter in immortalized rat capillary cerebral endothelial (REB-4) cells. Non-linear analysis of the saturation curve for L-DOPA revealed a K(m)value (in microM) of 71+/-9 and a V(max)value of 17+/-1 (in nmol mg protein/6 min). L-DOPA uptake at the luminal cell border was a sodium-independent process and insensitive to N-(methylamino)-isobutyric acid (MeAIB, 1 m m), but sensitive to 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BHC, IC(50)=140 microM). The Ca(2+)/calmodulin inhibitors calmidazolium and trifluoperazine inhibited L-DOPA (2.5 microM) uptake with IC(50)s of 23 and 33 microM, respectively. The inhibitory effect of BHC on the accumulation of L-DOPA was of the competitive type, whereas that of calmidazolium and trifluoperazine was of the non-competitive type. Modulators of PKA (cyclic AMP, forskolin, isobutylmethylxanthine and cholera toxin), PKG (cyclic GMP, zaprinast, LY 83583 and sodium nitroprusside), PKC (phorbol 12,13-dibutyrate, staurosporine and chelerythrine) and PTK (genistein and tyrphostin 25) failed to affect the accumulation of a non-saturating (2.5 microM) concentration of L-DOPA. It is concluded that L-DOPA uptake in RBE-4 cells is promoted through the L-type amino acid transporter and appears to be under the control of calmodulin mediated pathways.

Amino Acids, Cyclic↗
PubMed1999

Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat.

Abnormal involuntary movements, or dyskinesias, plague current symptomatic approaches to the treatment of Parkinson's disease. The neural mechanisms underlying the generation of dyskinesia following repeated l-3,4-dihydroxyphenylalanine (L-DOPA) or dopamine agonist administration in Parkinson's disease remain unknown. However, de novo administration of bromocriptine or lisuride to either l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates or patients can alleviate parkinsonian symptoms without the development of dyskinesia. In this study, we have investigated behavioral responses and alterations in the expression of opioid neuropeptide precursors preproenkephalin-A (PPE-A, encoding methionine- and leucine-enkephalin) and preproenkephalin-B (PPE-B), the precursor encoding dynorphins (dynorphin A1-17 and B1-13, leucine-enkephalin, and alpha-neoendorphin) in striatal output pathways of the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. Expression was assessed following repeated L-DOPA, bromocriptine, or lisuride administration. Given the functional organization of basal ganglia circuitry into anatomically discrete parallel circuits, we investigated alterations in peptide expression with reference to the detailed topography of the striatum. Following repeated L-DOPA administration (6.5 mg/kg, b.d., 21 days) in the 6-OHDA-lesioned rat a rotational response was observed. This became markedly enhanced with repeated treatment. We have previously characterized the pharmacology of this enhanced response and have suggested that it is a useful model for the elucidation of the cellular and molecular mechanisms underlying L-DOPA- and dopamine agonist-induced dyskinesia. In contrast to l-DOPA, de novo administration of bromocriptine (1 or 5 mg/kg, b.d., 21 days) or lisuride (0.01 or 0.1 mg/kg, b.d., 21 days) did not lead to an enhanced behavioral response. In vehicle-treated, 6-OHDA-lesioned animals, PPE-A expression was elevated rostrally and dorsally, while PPE-B expression was reduced in the striatum at all rostrocaudal levels. Repeated l-DOPA administration was accompanied by elevations in striatal PPE-B mRNA levels and a further elevation, above lesion-induced levels, in PPE-A expression. This further elevation was restricted to the dorsolateral striatum. However, following repeated bromocriptine or lisuride administration no increase in PPE-B expression was observed and the lesion-induced increase in PPE-A expression was normalized to prelesion levels. Increased PPE-A and PPE-B levels may, through decreasing GABA and glutamate release, respectively, in output nuclei of the basal ganglia, play a role in the development of L-DOPA- and dopamine-agonist induced dyskinesia in Parkinson's disease. These studies suggest that anti-parkinsonian treatments which are not associated with an elevation in PPE-B and/or normalize elevated PPE-A precursor expression, such as NMDA-receptor antagonists or long-acting dopamine D2 receptor agonists, e.g., cabergoline or ropinirole, may reduce dyskinesia in Parkinson's disease.

Animals↗
PubMed1995

Lipid peroxidation in brain: interactions of L-DOPA/dopamine with ascorbate and iron.

Recent reports have stressed an accumulation of iron and enhanced levels of lipid peroxides in the substantia nigra as essential factors in the pathogenesis of Parkinson's disease. Many investigators believe that tissue antioxidants, such as ascorbate, play a protective role. On the other hand, L-DOPA, which is used extensively to treat Parkinson's disease, undergoes autoxidation (as does dopamine), thus generating reactive oxygen species. We studied lipid peroxidation (LPO) in mouse brain homogenates and evaluated the effects of iron (5 microM ferric-ADP), L-DOPA, dopamine and ascorbic acid, added either alone or in mixtures. Ascorbic acid was used at levels of 0.5 mM or 2.0 mM, approximating those present normally in brain. LPO in brain homogenates was stimulated by the addition of either ascorbic acid or iron, as well as by a combination of the two, in agreement with other reports. The effects of L-DOPA were complex: L-DOPA strongly suppressed LPO both with and without added iron-ADP. In sharp contrast, however, when ascorbic acid was also added, L-DOPA no longer suppressed LPO; indeed, L-DOPA stimulated LPO in the presence of added iron and ascorbic acid. Dopamine behaved similarly to L-DOPA. When ascorbic acid was studied over a concentration range, LPO was stimulated at 0.5, 1, 2 or 3 mM, with or without added iron and/or dopamine; 5 and 10 mM ascorbic acid were either not as effective or suppressed LPO below control levels. Deferoxamine, a powerful iron chelator, greatly suppressed LPO under all conditions, as did diethylenetriaminepentaacetate (DTPA). Added superoxide dismutase had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Biotransformation of L-dopa in striatum and substantia nigra of rats with a unilateral, nigrostriatal lesion: a microdialysis study.

Microdialysis was used to study the biotransformation of L-DOPA in the striatum and substantia nigra of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra. The animals were pretreated with carbidopa (50 mg/kg p.o.) for 5 days. They were anaesthetized, and microdialysis probes were implanted into the intact and denervated striatum and into the intact and lesioned substantia nigra. The biotransformation of L-DOPA (5 mg/kg i.p.) in these regions was investigated. These results were compared with those obtained after administration of a much higher dose of L-DOPA (100 mg/kg i.p.). Changes in extracellular L-DOPA, 3-O-methyldopa (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by HPLC with electrochemical detection. Although rats with a unilateral nigrostriatal lesion did not show rotational behaviour after 5 mg/kg L-DOPA, DA levels were increased significantly both in the intact and the denervated striatum and in the intact and the lesioned substantia nigra. This increase was most pronounced in the denervated striatum. At 100 mg/kg L-DOPA, the increases in extracellular dopamine in intact and denervated striatum were about twice as high as the increases observed at the lower dose. A similar increase was observed in the intact substantia nigra. However, in the lesioned substantia nigra there was a fourfold increase. L-DOPA, at both doses, was evenly distributed between the brain areas studied and the lesion had no effect on the uptake of the drug at the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1975

The effect of L-dopa on young patients with simple schizophrenia, treated with neuroleptic drugs: a double-blind cross-over trial with Madopar and placebo.

Thirteen out of 18 young out-patients with simple schizophrenia under neuroleptic treatment completed a double-blind cross-over trial with Madopar [L-Dopa + benserazid (a peripheral decarboxylase inhibitor)] and placebo. Nine patients were given 900 mg L-Dopa + 225 mg benserazid daily, 1 patient received 600 mg L-Dopa + 150 mg benserazid, and 3 patients, 300 mg L-Dopa + 75 mg benserazid. In these doses, L-Dopa was effective against emotional withdrawal, blunted affect, tendency to isolation and apathy, without inducing or aggravating productive, accessory symptoms. The activity score, according to the specific activity-withdrawal scale, was significantly increased (P less than 0.05), whereas the total BPRS score (Brief Psychiatric Rating Scale) was slightly, but significantly reduced (P less than 0.05). In cases where L-Dopa had to be limited to 600 and 300 mg daily, a tendency to anxiety, distortion of thinking, and a sense of unreality were observed, depending on the dose of L-Dopa. In no case were gastrointestinal, cardiovascular or neurological side-effects observed.

Adult↗
PubMed1977

Locomotor stimulation by L-dopa: relative importance of noradrenaline receptor activation.

The importance of brain noradrenaline synthesis and receptor activation for the hyperkinesia induced by carbidopa plus L-Dopa in reserpine-treated or normal mice was analyzed in four different models. After pretreatment with reserpine and the monoamine oxidase inhibitor nialamide, the hyperkinesia induced by L-Dopa (25 mg/kg i.p.) was partly mediated via stimulation of noradrenaline receptors since it was significantly antagonized by the noradrenaline receptor-blocking agent phenoxybenzamine. Treatment with reserpine plus L-Dopa (125 mg/kg i.p.) produced an increase in motor activity probably due to stimulation of dopamine receptors since it was not accompanied by an accumulation of noradrenaline and it was not inhibited by phenoxybenzamine. The hyperkinesia following treatment with reserpine and a higher dose of L-Dopa (250 mg/kg i.p.) was probably due to stimulation of both dopamine and noradrenaline receptors since the dopamine-beta-hydroxylase inhibitor FLA-63 partly reduced the effect of L-Dopa. Phenoxybenzamine potentiated the motor stimulation by L-Dopa (125 mg/kg i.p.) in mice not pretreated with reserpine, perhaps depending on a slight enhancement of the net accumulation of brain dopamine. Thus, noradrenaline receptor activation is of importance for the L-Dopa-induced hyperkinesia, at least after high doses or after monoamine oxidase inhibition.

Animals↗
PubMed1983

Chronic L-dopa treatment of rats and mice does not change the sensitivity of post-synaptic dopamine receptors.

The effects of L-Dopa + benserazide (L-Dopa + B) treatment on pre- and postsynaptic dopamine (DA) receptors were studied. Mice treated once daily P.O. with L-Dopa (200 mg/kg) + B (50 mg/kg) or vehicle for 10 days were used on the 11th day. After premedication with reserpine and alpha-methyltyrosine (alpha-MT), apomorphine (0.5-2.0 mg/kg) produced locomotor stimulation which was of equal intensity in the 3 treatment groups, even when the treatment dose of L-Dopa was increased to 400 mg/kg per day. In contrast, low doses of apomorphine (0.1-0.5 mg/kg) produced locomotor depression in B- and vehicle-treated mice but not in L-Dopa + B-treated mice. In rats treated I.P. twice daily with L-Dopa (200 mg/kg) + B (50 mg/kg), B (50 mg/kg) or vehicle for 12 days, apomorphine produced an equivalent degree of stereotypy on the 13th day in each of the 3 treatment groups. There were no treatment group differences in the binding of [3H]-spiperone or [3H]-leu-enkephalin to rat striatal membranes. The data suggest that long-term L-Dopa + B treatment of mice and rats does not change the sensitivity of postsynaptic DA receptors but may affect the sensitivity of DA autoreceptors.

Animals↗
PubMed1982

Alpha-Monofluoromethyldopa (MFMD) in combination with L-DOPA Effects on tissue catecholamines and blood pressure in rats.

We have investigated the interaction of alpha-monofluoromethyldopa (MFMD) with the effects of i.p. injected L-DOPA (200 mg.kg-1) on blood pressure and tissue catecholamines in normal and spontaneously hypertensive rats (SHR). MFMD 10 mg.kg-1 (i.p.) effectively antagonizes the L-DOPA induced increase in heart dopamine (DA). This action is also seen after 15 or 50 mg.kg-1. The accumulation of DA in the brain is very much reduced by MFMD 50 mg.kg-1 while after 15 or, especially, 10 mg.kg-1 more DA is formed in the brain than after L-DOPA alone, probably due to the peripheral decarboxylase inhibition which presents more L-DOPA to the brain. We conclude that MFMD 10 mg.kg-1 gives a relatively selective peripheral inhibition of the decarboxylation of L-DOPA and this dose combination was accordingly found to result in a reduction of blood pressure in conscious animals. This hypotensive response to L-DOPA was attenuated after MFMD 15 mg.kg-1 and was absent after MFMD 50 mg.kg-1. Interestingly, the hypotensive effect of L-DOPA after MFMD 10 or 15 mg.kg-1 was more pronounced in SHR.

Animals↗
PubMed1981

Effect of L-dopa treatment on cerebral amino acid levels in rats after portocaval anastomosis.

L-Dopa therapy has been suggested as effective in the reversal of hepatic coma both in humans and in animals. Beneficial effects have been reported also in chronic hepatic encephalopathy. There are many possible mechanisms through which L-dopa could ameliorate this pathological state. The present study was carried out to clarify whether the L-dopa effect could be mediated through an improvement of the brain neutral amino acid patterns, since it competes for the same transport carrier at the blood-brain barrier. A first group of rats was orally administered L-dopa (10 mg/100 g body weight daily) for 1 month following portocaval anastomosis. A second group was intraperitoneally injected (1.5 mg/100 g body weight daily) for 1 week, a month after portocaval shunt. Amino acid levels were determined in plasma and in four cerebral regions. No beneficial effects were observed clinically (in general condition, body weight, or hypertonic posture) in rats receiving L-dopa compared to controls. The large increase of tyrosine, phenylalanine, tryptophan, histidine, and glutamine that occurs in the cerebral tissue after portocaval shunt was also not affected by L-dopa administration. In conclusion, in this experimental condition we had no clinical improvement in shunted animals receiving L-dopa. Moreover, this compound did not seem to influence the pathological increase of aromatic amino acids in the brain, which is considered to play an important role in hepatic encephalopathy.

Amino Acids↗
PubMed1992

The mechanism of perturbation in monoamine metabolism by L-dopa therapy: in vivo and in vitro studies.

In the cerebrospinal fluid of the patients with Parkinson's disease treated with L-DOPA, L-3-O-methyldopa was the major metabolite of administered L-DOPA. Using a dopaminergic cell model, clonal rat phenochromocytoma PC 12h cells, and by microdialysis of the rat striatum it was proved that L-3-O-methyldopa was taken up into monoamine neurons by transport system specific for aromatic L-amino acids and inhibited transport of L-DOPA and other amino acids competitively. L-3-O-Methyldopa depleted allosteric regulation of the biopterin cofactor on activity of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis. Depletion of the allostery may perturb the buffer action of endogenous L-DOPA synthesis that stabilizes dopamine level in the brain. By these mechanisms L-3-O-methyldopa may reduce clinical effectiveness of administered L-DOPA and be involved in wearing-off phenomenon. L-DOPA inhibited the activity of tryptophan hydroxylase and thus serotonin synthesis, which may be related to psychiatric side-effects in the patients under L-DOPA therapy.

Aged↗
PubMed1981

Lack of an effect of melatonin on the basal and L-dopa stimulated growth hormone secretion in men.

The oral administration of melatonin to men has been reported to cause a rapid and significant elevation of serum GH, and to inhibit GH release after stimulation by L-Dopa. We studied the effect of melatonin i.v. on the basal and L-Dopa stimulated GH secretion in four young men. Each subject's control response to L-Dopa was first studied by an oral administration to 500 mg of L-Dopa under a placebo infusion and was followed 2 weeks later by a similar study under melatonin infusion, 2.1 mg/min (total dose of 500 mg). The infusion of melatonin was given for a 4-hour period, 2 hours before and 2 hours after the L-Dopa stimulation. Blood samples for GH were obtained at 30-min intervals. Basal values of serum GH did not rise under the melatonin infusion and peak GH values following L-Dopa stimulation during the control infusion and the melatonin infusion also did not differ (2 +/- 0.5 to 22 +/- 6 and 2 +/- 0.8 to 25 +/- 4 ng/ml respectively). Our data suggest that under an acute constant infusion melatonin does not stimulate GH secretion, nor does it interfere with the L-Dopa stimulated GH response in men.

Adult↗
PubMed1996

L-DOPA modulation of corpus striatal dopamine and dihydroxyphenylacetic acid output from intact and 6-OHDA lesioned rats.

In the present report we examined the differences in in vitro dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) efflux from the corpus striatum (CS) of intact versus 6-hydroxydopamine (6-OHDA) lesioned (in substantia nigra) male rats in response to different doses of two pulse infusions of L-dihydroxyphenylalanine (L-DOPA). In the first experiment, we tested the effects of two 20-min infusions of 5 uM L-DOPA. In the second experiment we repeated this protocol using 50 uM L-DOPA. There was an overall significantly greater output of DA for intact versus 6-OHDA lesioned rats for both doses. Moreover, in Experiment 1, the 5 uM L-DOPA produced a peak DA response to the second infusion which was significantly higher than that of the first infusion in the intact, but not lesioned rats. In Experiment 2, the 50 uM L-DOPA group showed no significant differences in DA output between the two infusions for both intact and lesioned rats. In contrast to DA responses, there were no overall significant differences in DOPAC output between intact and 6-OHDA lesioned rats for both doses. However, for both doses tested, the peak DOPAC output from the second infusion was significantly increased in lesioned, but not intact rats. These data demonstrate that L-DOPA evoked DA and DOPAC output are differentially modulated in intact and 6-OHDA lesioned striatum. The lesions of the striatal dopaminergic system may alter these responses through changes in intraneuronal storage and metabolism of DA following L-DOPA infusion.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1979

L-Dopa inhibits metoclopramide stimulation of the lower esophageal sphincter in man.

Opossum lower esophageal sphincter smooth muscle contains inhibitory dopaminergic receptors. Since metoclopramide is a dopaminergic antagonist in many experimental situations, the present study was designed to investigate whether this mechanism could explain the lower esophageal sphincter (LES) stimulating action of metoclopramide in man. The interactions of (1) oral L-dopa, a dopamine precursor, and metoclopramide; and (2) L-dopa and the cholinergic agent, bethanechol, on lower esophageal sphincter pressure (LESP) in normal subjects were examined. Oral L-dopa significantly inhibited LESP response to either oral metoclopramide 20 mg (P less than 0.05), or intravenous metoclopramide 20 mg (P less than 0.05). In contrast, L-dopa did not inhibit the LESP response to subcutaneous bethanechol (0.07 mg/kg). Mean basal LESP measured 50 min after ingestion of 1000 mg L-dopa, 19.3 +/- 3.1 mm Hg, was significantly less than basal LESP after L-dopa placebo, 29.3 +/- 4 mm Hg (P less than 0.01). It is concluded that (1) L-dopa inhibited the metoclopramide-induced rise in LESP but not peak stimulation of LESP by bethanechol; (2) there is evidence for the possibility of LES dopaminergic inhibitory receptors in man; and (3) these data are consistent with the hypothesis that metoclopramide acts on the LES by blocking a dopaminergic pressure-lowering mechanism.

Adult↗
PubMed1998

Pharmacological approaches to counter the toxicity of Dopa.

Dopa and related catecholamines and their degradation products have been demonstrated to have neurotoxic potential in a number of cellular and in vivo experiments. Several mechanisms have been hypothesized to be involved including generation of prooxidant products that subsequently oxidize membrane lipids and exposed macromolecules. We have utilized a neuronal culture of cerebellar granule cells to study the toxicity of Dopa and the ability of various neuroprotective and antiparkinsonian compounds to offer protection therefrom. This model is apparently based on the ability of Dopa to non-enzymatically induce an oxidative injury to the neuronal cultures. Evidence for this arises from the equal neurotoxic potency of L- and D-Dopa in these cells and the ability of catalase, superoxide dismutase and glutathione to protect the neurons from this toxicity. Further, we found that the neuroprotective antioxidant, PNU-101033 is more effective and potent than vitamin E and deprenyl in this regard. Similarly the D2/D3 agonist, pramipexole is also capable of blocking Dopa toxicity in this model and this effect is independent of dopamine receptor affinity as both enantiomers are equally potent in this assay but disparate in receptor affinity. Also the protection by pramipexole is accompanied by the preservation of reduced glutathione. Thus, this activity seems to be a function of the oxidation potential of pramipexole and it's consequent antioxidant property. Potent antioxidants are effective blockers of Dopa toxicity. If the mechanisms involved in this toxicity have relevance to the progression of Parkinson's pathology in Dopa treated (or untreated) patients, these compounds have the potential to alter the course of the illness.

Animals↗
PubMed2003

Dopamine- or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease.

Dopamine (DA)- or L-dihydroxyphenylalanine-(L-DOPA-) induced neurotoxicity is thought to be involved not only in adverse reactions induced by long-term L-DOPA therapy but also in the pathogenesis of Parkinson's disease. Numerous in vitro and in vivo studies concerning DA- or L-DOPA-induced neurotoxicity have been reported in recent decades. The reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of DA induce neuronal damage and/or apoptotic or non-apoptotic cell death; the DA-induced damage is prevented by various intrinsic and extrinsic antioxidants. DA and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells mainly due to the generation of highly reactive DA and DOPA quinones which are dopaminergic neuron-specific cytotoxic molecules. DA and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. For example, the formation of DA quinone-alpha-synuclein consequently increases cytotoxic protofibrils and the covalent modification of tyrosine hydroxylase by DA quinones. The melanin-synthetic enzyme tyrosinase in the brain may rapidly oxidize excess amounts of cytosolic DA and L-DOPA, thereby preventing slowly progressive cell damage by auto-oxidation of DA, thus maintainng DA levels. Since tyrosinase also possesses catecholamine-synthesizing activity in the absence of tyrosine hydroxylase (TH), the double-edged synthesizing and oxidizing functions of tyrosinase in the dopaminergic system suggest its potential for application in the synthesis of DA, instead of TH in the degeneration of dopaminergic neurons, and in the normalization of abnormal DA turnover in the long-term L-DOPA-treated Parkinson's disease patients.

Animals↗
PubMed2000

Noradrenoceptor antagonism with idazoxan improves L-dopa-induced dyskinesias in MPTP monkeys.

Treatment of Parkinson's disease with L-dopa is plagued in a majority of patients by dyskinesias. Noradrenaline/dopamine interactions are proposed on behavioral, biochemical, physiological and anatomical grounds. The aim of the study was to test the potential antidyskinetic effect of the alpha2-adrenoceptor antagonist, idazoxan, in a primate model of Parkinson's disease. Six female cynomolgus monkeys previously rendered parkinsonian by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and presenting an unchanged syndrome for several months were used. All responded readily to L-dopa but had developed dyskinesias which were manifested with each dose. In the first part of the study, seven doses of idazoxan (ranging from 0.25 mg/kg to 10 mg/kg, p.o.) were administered together with the vehicle or in combination with a fixed dose of L-dopa/benserazide (100/25 mg, p.o.). In the second part of the study, a fixed dose of idazoxan (7.5 mg/kg) was administered daily for 10 days and L-dopa was added to idazoxan on days 1, 4, 7 and 10. Vehicle (empty capsule) was used as control. Idazoxan, by itself (ranging from 5 mg/kg to 10 mg/kg), increased locomotor activity and improved the disability score with virtually no dyskinesias in three animals. In combination with L-dopa, idazoxan did not impair the antiparkinsonian response but significantly reduced dyskinesias in all six animals up to 65% at doses of 7.5 mg/kg and 10 mg/kg and delayed their onset, so that the "ON" state without dyskinesias was prolonged. The antidyskinetic effect of idazoxan was maintained when repeatedly administered for 10 days. On day 10, the locomotor response to L-dopa was significantly potentiated by chronic administration of idazoxan. Our results indicate that idazoxan has some antiparkinsonian effect of its own and may constitute a useful adjunct to L-dopa as it can reduce dyskinesias without impairing the relief of symptoms, this effect being maintained over time in this model.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2000

The novel type B MAO inhibitor PF9601N enhances the duration of L-DOPA-induced contralateral turning in 6-hydroxydopamine lesioned rats.

The present study examined the effect of the highly potent and selective MAO B inhibitor PF9601N on L-DOPA-induced rotational behavior in unilateral nigrostriatal 6-hydroxydopamine lesioned rats. Three doses of PF9601N (20, 40 and 60mg/kg) were administered 30 min before an injection of L-DOPA (25mg/kg), and both contralateral and ipsilateral rotational behavior was measured. In addition, we also studied the effect produced by another MAO B inhibitor, deprenyl (20mg/kg), the MAO A inhibitor, clorgyline (20mg/kg), and the dopamine reuptake inhibitor, GBR2909 (7.5 mg/kg) on L-DOPA-induced rotational behavior. The results showed that PF9601N plus L-DOPA significantly enhanced the duration of contralateral rotational behavior with respect to L-DOPA plus vehicle in a dose-related manner. At the dose of 40 and 60mg/kg, PF9601N produced significantly more overall contralateral turning than L-DOPA plus vehicle, and at the dose of 60mg/kg, PF9601N produced significantly more turning behavior than L-DOPA plus deprenyl. These results suggest that PF9601N may be used as a novel tool in the treatment of Parkinson's disease.

Adrenergic Agents↗