Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The structure of catechol O-methyltransferase (COMT) has been recently characterized and a series of new and selective COMT inhibitors developed. 2. Entacapone, nitecapone and tolcapone are nitrocatechol-type potent COMT inhibitors in vitro (Ki in nanomolar range). They are also very selective for COMT and active in vivo even after oral administration. CGP 28014 is a pyridine derivative that is active only in vivo. 3. In animal studies, these compounds inhibit effectively the O-methylation of L-dopa, thus improving its bioavailability and brain penetration and potentiating its behavioural effects. 4. Entacapone and nitecapone have mainly a peripheral effect whereas tolcapone and CGP 28014 also inhibit O-methylation in the brain. 5. In man, entacapone, nitecapone and tolcapone all inhibit dose dependently the COMT activity in erythrocytes. These COMT inhibitors also decrease the amount of COMT dependent metabolites of adrenaline and noradrenaline in plasma. 6. In human volunteers, entacapone, tolcapone and CGP 28014 improve the bioavailability of L-dopa and inhibit the formation of 3-O-methyldopa. 7. In the first clinical studies in patients with Parkinson's disease, both entacapone and tolcapone potentiate and prolong the therapeutic effect of L-dopa.
Gen Pharmacol 1994 Sep
PMID:General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase. 783 24

Catalepsy--a state of postural immobility (akinesia) with muscular rigidity (rigor)--and reduced locomotion in animals are behavioral deficits showing similarities with symptoms of Parkinson's disease (PD). The effects of the glycine site antagonists 7-chlorokynurenate and (R)-HA-966 on haloperidol-(D 2 antagonist) and SCH 23390- (D 1 antagonist) induced catalepsy and reduced locomotion are investigated in rats. Both antagonists dose-dependently counteract dopamine D 2 receptor mediated catalepsy but they have no influence on locomotion. Neither 7-chlorokynurenate nor (R)-HA-966 has any effect on dopamine D 1 receptor mediated catalepsy. This finding is surprising, since NMDA receptor antagonists counteract both, dopamine D 1 and D 2 receptor mediated catalepsy. D 1 and D 2 receptors are located on different populations of neurons. Thus, the present findings suggest that these different neuronal populations have different sensitivity for ligands binding at the glycine binding site of the NMDA receptor.
J Neural Transm Gen Sect 1994
PMID:Glycine site antagonists abolish dopamine D2 but not D1 receptor mediated catalepsy in rats. 786 67

It was shown in the present study that several structurally diverse antagonists of the glycine site of the NMDA receptor, including (R)-HA-966, L689,560, 5,7-dichlorokynurenic acid, 7-chlorokynurenic acid, and two of ZENECA's novel pyridazinoindole glycine antagonists, caused marked reversal of akinesia when administered intrastriatally to monoamine depleted mice. Coinjection of the glycine agonist D-serine antagonized this locomotor stimulation. In addition, all glycine antagonists tested did not cause significant locomotor stimulation when intrastriatally administered to normal mice. These data suggest that glycine antagonists may offer therapeutic utility in the treatment of idiopathic Parkinson's disease.
J Neural Transm Gen Sect 1994
PMID:Centrally-administered glycine antagonists increase locomotion in monoamine-depleted mice. 787 28

Four experiments were performed to investigate whether or not coadministration of NMDA-antagonists potentiate the effect of an ineffective dose of L-Dopa on motor activity in hypoactive MPTP-treated mice. Motor activity was measured in an automated system recording both locomotion (horizontal) and rearing (vertical) activity. L-Dopa alone, at doses of 10 and 20 mg/kg, but not 5 mg/kg, expressed an anti-akinesia effect in MPTP-treated mice. The non-competitive NMDA-antagonist MK-801 (0.03, 0.1, and 0.3 mg/kg) increased by itself both locomotion (0.1 and 0.3 mg/kg) and rearing (0.03 mg/kg) in control (saline-treated) mice whereas no effect was seen in the MPTP-treated mice. Combined with 5 mg/kg L-Dopa, MK-801 (0.1 mg/kg) increased locomotion in MPTP-treated mice. There was no interaction seen between L-Dopa and MK 801 in the control mice. CGP40116 and CGP40117, the active D- and the inactive L-stereoisomer of the competitive NMDA-inhibitor CGP37849, respectively, were also administered together with 5 mg/kg L-Dopa. Both doses (0.003 and 0.03 mg/kg) of CGP40116 in contrast to CGP40117, produced anti-akinesia effect in MPTP-treated mice. CGP40116 (0.0001 to 0.1 mg/kg) together with 5 mg/kg L-Dopa did not affect behaviour in control mice but produced (0.01 mg/kg CGP40116 and 5 mg/kg L-Dopa) in the MPTP-treated mice an anti-akinesia effect. Our findings indicate that the non-competitive NMDA-antagonist MK-801, at doses with reported side-effects, only increase locomotion while rearing remained unaltered in MPTP-treated mice when combined with 5 mg/kg L-Dopa. Only the active stereoisomer CGP40116 in contrast to CG40117, at doses far below reported side-effects, dose-dependently modulated the anti-akinesia effect of a subthreshold dose of L-Dopa. Such data thus support the notion that this behavioural modulation was regulated via NMDA-receptors. The synergism between L-Dopa and the competitive NMDA-antagonist CGP40116 has a potential in treatment of Parkinson's disease to reduce the side-effects of doses of L-Dopa that are used today.
J Neural Transm Gen Sect 1994
PMID:Synergistic interactions between NMDA-antagonists and L-dopa on activity in MPTP-treated mice. 787 29

1-Methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-Methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) is taken up into dopaminergic terminals and selectively destroys dopaminergic neurons, serving as a valuable tool in animal model of Parkinson's disease. Cocultures from ventral mesencephalon and neostriatum of embryonic C57/BL6 mouse brains were used to study the sensitivity of dopaminergic neurons to the toxic agent MPP+. Cultures were grown for 9 days in vitro and exposed to different concentrations of MPP+ for various times. Treatment with (0.1-1.0 microM) MPP+ for 24 hours decreased 3H-dopamine (3H-DA) uptake with an IC50 at 0.2 microM. Exposure of cells to 1 microM MPP+ over time decreased the 3H-DA uptake to 38% of controls within the first two hours of incubation and to 8% after 48 hours. Loss of tyrosine hydroxylase (TH) positive cells became evident at 0.1 microM MPP+ (80% of control) leading to maximal toxicity at 10 microM (20% of control). MPP+ reduced the dopamine content in the cultures in a dose dependent manner (IC50 at 0.1 microM) and failed to show reversibility in recovery studies. These findings provide evidence that exposure of MPP+ even at low concentrations and for short time in our coculture model results in irreversible toxicity for dopaminergic neurons.
J Neural Transm Gen Sect 1993
PMID:Functional changes in cocultures of mesencephalon and striatal neurons from embryonic C57/BL6 mice due to low concentrations of 1-methyl-4-phenylpyridinium (MPP+). 790 17

The dopaminergic innervation of the prefrontal cortex is able to transsynaptically regulate the activity of subcortical dopamine innervations. Disruption of the prefrontal cortical DA innervation results in the enhanced biochemical responsiveness of the dopamine innervation of the nucleus accumbens. We present recent data indicating that distinct prefrontal cortical dopamine innervations can be functionally dissociated on the basis of responsiveness to stress. The ventral striatal projection target (nucleus accumbens shell) of the prefrontal cortical region that is stress sensitive is also responsive to stress. In this manner interconnected cortico-striato-pallido-mesencephalic loops can be defined on the basis of the biochemical responsive of local dopamine systems to stress and on the basis of responsiveness to antipsychotic drugs. These data suggest the functional derangement of a distinct corticofugal loops in schizophrenia and in certain aspects of Parkinson's disease.
J Neural Transm Gen Sect 1993
PMID:Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease. 809 97

Current antiparkinsonian therapies focus on either replacing dopamine via precursor (L-DOPA) administration, or directly stimulating post-synaptic dopamine receptors with dopamine agonists. Unfortunately, this approach is associated with numerous side effects and these drugs lose efficacy with disease progression. This article reviews recent evidence which suggests that negative modulation of glutamatergic neurotransmission has antiparkinsonian effects in a variety of rodent and primate models of parkinsonism. The pronounced synergism between dopaminergic agents and glutamate receptor antagonists may provide a means of using very low doses of the two drug classes in concert to treat Parkinson's disease effectively and minimize dose-related drug side effects.
J Neural Transm Gen Sect 1993
PMID:Glutamate-dopamine interactions in the basal ganglia: relationship to Parkinson's disease. 809

The dopamine hypothesis of schizophrenia and the emphasis on other neurotransmitters, most notably norepinephrine, serotonin, and acetylcholine, in the pathogenesis of depression, have focused attention away from substantial evidence implicating dopamine in affective disorders. The clinical evidence includes alterations in depressive symptoms with aging (concomitant with possible changes in dopamine metabolism), potential dopaminergic involvement in several subtypes of depression, similarities between some of the symptoms of Parkinson's disease and those of depression (including psychomotor retardation and diminished motivation), and potential dopaminergic abnormalities in seasonal mood disorder. The biochemical evidence in patients with depression derives from studies of homovanillic acid, a dopamine metabolite, indicating diminished dopamine turnover. In addition, there is a considerable amount of pharmacologic evidence regarding the efficacy of antidepressants with dopaminergic effects in the treatment of depression. We conclude that dopamine likely contributes significantly to the pathophysiology of depression. However, the role of dopamine in this syndrome must be understood in the context of existing theories involving other neurotransmitters which may act independently, and interact with dopamine and other neurochemicals, to contribute to depression.
J Neural Transm Gen Sect 1993
PMID:Dopamine and depression. 809 1

Amantadine was introduced for the pharmacological management of neuroleptic malignant syndrome (NMS) because of its beneficial effects in Parkinson's disease which were attributed to dopaminomimetic properties. While the dopaminomimetic effects of amantadine are weak under experimental conditions, recent studies have confirmed that amantadine is an antagonist at the N-methyl-D-aspartate (NMDA) type of the glutamate receptor. Amantadine has psychotomimetic properties in patients with Parkinson's disease and normal controls. Two of four patients who received amantadine for NMS suffered an exacerbation of their psychiatric illness. Our observations support the glutamate hypothesis of schizophrenia which suggests that reduced glutamatergic transmission causes a relative dopaminergic excess in the basal ganglia and the limbic system.
J Neural Transm Gen Sect 1993
PMID:Amantadine and the glutamate hypothesis of schizophrenia. Experiences in the treatment of neuroleptic malignant syndrome. 810 Oct 93

Single photon emission computerized tomography (SPECT) studies in non-human primates have previously shown that the cocaine derivative [123I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane ([123I]beta-CIT) labels dopamine transporters in the striatum and serotonin transporters in the hypothalamus-midbrain area. Here, we report on the regional kinetic uptake of [123I]beta-CIT in the brain of 4 normal volunteers and 2 patients with Parkinson's disease. In healthy subjects striatal activity increased slowly to reach peak values at about 20 hours post injection. In the hypothalamus-midbrain area peak activities were observed at about 4 hours with a slow decrease thereafter. Low activity was observed in cortical and cerebellar areas. The striatal to cerebellar ratio was about 4 after 5 hours and 9 after 20 hours. In 2 patients with idiopathic Parkinson's disease striatal activity was markedly decreased while the activity in hypothalamus-midbrain areas was only mildly diminished. Uptake into cortical and cerebellar areas appeared to be unchanged in Parkinson's disease. Consequently, in Parkinson's disease the striatal to cerebellar ratio was decreased to values around 2.5 after 20 hours. These preliminary methodological studies suggest that [123I]beta-CIT is a useful SPECT ligand for studying dopamine and possibly also serotonin transporters in the living human brain.
J Neural Transm Gen Sect 1993
PMID:SPECT imaging of dopamine and serotonin transporters with [123I]beta-CIT. Binding kinetics in the human brain. 811 Apr 40


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