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)

Putative modulatory effects of L-3,4-dihydroxyphenylalanine (L-DOPA) on D2 dopamine receptor function in the striatum of anaesthetised rats were investigated using both in vivo microdialysis and positron emission tomography (PET) with carbon-11 labelled raclopride as a selective D2 receptor ligand. A single dose of L-DOPA (20 or 100mg/kg i.p.) resulted in an increase in [11C]raclopride binding potential which was also observed in the presence of the central aromatic decarboxylase inhibitor NSD 1015, confirming that the effect was independent of dopamine. This L-DOPA evoked D2 receptor sensitisation was abolished by a prior, long-term administration of L-DOPA in drinking water (5 weeks, 170mg/kg/day). In the course of acute L-DOPA treatment (20mg/kg), extracellular GABA levels were reduced by approximately 20% in the globus pallidus. It is likely that L-DOPA sensitising effect on striatal D2 receptors, as confirmed by PET, may implicate striato-pallidal neurones, hence a reduced GABA-ergic output in the projection area. Since the L-DOPA evoked striatal D2 receptor supersensitivity habituates during long-term treatment, the effects reported here may contribute to the fluctuations observed during chronic L-DOPA therapy in Parkinson's disease.
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PMID:Modulatory effects of L-DOPA on D2 dopamine receptors in rat striatum, measured using in vivo microdialysis and PET. 972 Sep 67

Idiopathic Parkinson's disease involves the loss of midbrain dopaminergic neurons, resulting in the presynaptic breakdown of dopaminergic transmission in the striatum. Huntington's disease and some neurodegenerative diseases with Parkinsonian features have postsynaptic defects caused by striatal cell death. Mice were generated in which an attenuated form of the diphtheria toxin gene (tox-176) was expressed exclusively in D1 dopamine receptor (D1R)-positive cells with the aim of determining the effect of this mutation on development of the basal ganglia and on the locomotor phenotype. Transgenic mice expressing Cre, a site-specific DNA recombinase, were crossed with a second line in which a transcriptionally silenced tox-176 gene was inserted into the D1R gene locus by homologous recombination. Young doubly transgenic mutant mice expressing the tox-176 gene displayed bradykinesia, dystonia, and had falls caused by myoclonic jerks. The mutant brain had evidence of apoptosis and reactive gliosis and, consistent with the D1R expression pattern, the striatum was reduced in volume, and the Islands of Calleja were absent. In contrast, the cortex was of normal thickness. D1Rs were not detectable in mutants by in situ hybridization or ligand autoradiography, whereas D2 dopamine receptor (D2R) mRNA and protein was present in the striatum. In addition, substance P and dynorphin, neuropeptides known to be expressed in D1R-positive striatonigral projection neurons were not detectable. Enkephalin, a marker found in D2-positive striatopallidal projection neurons was expressed in the mutant brain. The mutant represents a novel neurodegenerative disease model with a dramatic extrapyramidal phenotype.
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PMID:Targeted expression of a toxin gene to D1 dopamine receptor neurons by cre-mediated site-specific recombination. 982 43

Signaling through D2 class dopamine receptors is crucial to correct brain development and function, and dysfunction of this system is implicated in major neurological disorders such as Parkinson's disease and schizophrenia. To investigate potential novel mechanisms of D2 receptor regulation, the third cytoplasmic loop of the D2 dopamine receptor was used to screen a rat hippocampal yeast two-hybrid library. Spinophilin, a recently characterized F-actin and protein phosphatase-1-binding protein with a single PDZ domain was identified as a protein that specifically associates with this region of D2 receptors. A direct interaction between spinophilin and the D2 receptor was confirmed in vitro using recombinant fusion proteins. The portion of spinophilin responsible for interacting with the D2 third cytoplasmic loop was narrowed to a region that does not include the actin-binding domain, the PDZ domain, or the coiled-coil. This region is distinct from the site of interaction with protein phosphatase-1, and both D2 receptors and protein phosphatase-1 may bind spinophilin at the same time. The interaction is not mediated via the unique 29-amino acid insert in D2long; both D2long and D2short third cytoplasmic loops interact with spinophilin in vitro and in yeast two-hybrid assays. Expression of D2 receptors containing an extracellular hemagglutinin epitope in Madin-Darby canine kidney cells results in co-localization of receptor and endogenous spinophilin as determined by immunocytochemistry using antibodies directed against spinophilin and the HA tag. We hypothesize that spinophilin is important for establishing a signaling complex for dopaminergic neurotransmission through D2 receptors by linking receptors to downstream signaling molecules and the actin cytoskeleton.
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PMID:Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein. 1039 35

The occurrence of side effects with long-term levodopa therapy, such as fluctuations in motor performance or abnormal movements, led to a search for new antiparkinsonian drugs. Dopamine agonists include ergot derivatives such as bromocriptine, lisuride, pergolide, and cabergoline and other agents which do not possess the ergot structure such as pramipexole and ropinirole. They all are powerful stimulators of the D2 dopamine receptor which probably underlies their therapeutic effects. The clinical consequences of their binding to other dopamine receptor subtypes (D1 or D3) remains unknown. They are usually prescribed in combination with levodopa when late side effects begin to occur. This review summarizes the available pharmacologic and clinical data to support the early use of dopamine agonists in Parkinson's disease. Several strategies can be used, such as monotherapy or "early" or "late" combination with levodopa. Results of recent well-performed, modern clinical trials show that early use of the new dopamine agonists is able to effectively control the clinical symptoms for more than 3 years thereby offering the possibility of delaying the occurrence of levodopa-induced late motor side effects.
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PMID:Treatment of Parkinson's disease should begin with a dopamine agonist. 1075

Selective D(1) dopamine receptor agonists exert antiparkinsonian effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's disease and in human Parkinson's disease. Motor impairment in idiopathic Parkinson's disease progresses from mild to severe, but the therapeutic potential of D(1) dopamine receptor agonists in early and advanced stages of parkinsonism is not known. To compare the effectiveness of D(1) agonists at different levels of impairment, we developed a model of mild and advanced parkinsonism in nonhuman primates and a rating scale that differentiated the two models. D(1) dopamine receptor agonists (SKF 81297, dihydrexidine) and D(2) dopamine receptor agonists [quinelorane, (+)-PHNO were administered to monkeys (Macaca fascicularis) displaying either mild parkinsonism (two doses of 0.6 mg/kg i.v. MPTP 1 month apart) or advanced parkinsonism (three doses of 0.6 mg/kg i.v. MPTP within 10 days). In normal monkeys (n = 3), SKF 81297 and dihydrexidine did not promote increased motor activity. In advanced parkinsonism (n = 4), D(1) and D(2) dopamine agonists effectively reversed the motor deficits. In contrast, the therapeutic benefits of D(1) agonists SKF 81297 and dihydrexidine were relatively limited in mild parkinsonism (n = 4). The D(2) agonists quinelorane and (+)-PHNO alleviated some symptoms in mild parkinsonism but also reduced balance and induced more dyskinesias than did D(1) agonists. Mild and advanced parkinsonism in nonhuman primates can be produced with fixed dosing regimens of MPTP. Based on the therapeutic efficacy and side effect profiles derived from these models, D(1) agonists are more promising for the treatment of advanced than of mild Parkinson's disease.
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PMID:D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated monkeys. 1064 Mar 10

The novel selective adenosine A(2A) receptor antagonist KW-6002 improves motor disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia. In this study we have investigated whether KW-6002 in combination with l-DOPA or selective D1 or D2 dopamine receptor agonists enhances antiparkinsonian activity in MPTP-treated common marmosets. Combination of KW-6002 with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produced an additive improvement in motor disability. Coadministration of KW-6002 with a low dose of L-DOPA also produced an additive improvement in motor disability, and increased locomotor activity. The ability of KW-6002 to enhance antiparkinsonian activity was more marked with L-DOPA and quinpirole than with the D1 agonist. However, despite producing an enhanced antiparkinsonian response KW-6002 did not exacerbate L-DOPA-induced dyskinesia in MPTP-treated common marmosets previously primed to exhibit dyskinesia by prior exposure to L-DOPA. Selective adenosine A(2A) receptor antagonists, such as KW-6002, may be one means of reducing the dosage of L-DOPA used in treating Parkinson's disease and are potentially a novel approach to treating the illness both as monotherapy and in combination with dopaminergic drugs.
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PMID:Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. 1073 38

Recent pathophysiological models of basal ganglia function in Parkinson's disease predict that specific neurochemical changes in the indirect pathway would follow the lack of stimulation of D(2) dopamine receptors. Post mortem studies of the basal ganglia in genetically modified mice lacking functional copies of the D(2) dopamine receptor gene allowed us to test these predictions. When compared with their congenic N(5) wild-type siblings, mice lacking D(2) receptors show an increased expression of enkephalin messenger RNA in the striatum, and an increased activity and expression of cytochrome oxidase I in the subthalamic nucleus, as expected. In addition, D(2) receptor-deficient mice display a reduced expression of glutamate decarboxylase-67 messenger RNA in the globus pallidus, as the basal ganglia model predicts. This reduction contrasts with the lack of change or increase in glutamate decarboxylase-67 messenger RNA expression found in animals depleted of dopamine after lesions of the mesostriatal dopaminergic system. Furthermore, D(2) receptor-deficient mice show a significant decrease in substance P messenger RNA expression in the striatonigral neurons which form the direct pathway. Finally, glutamate decarboxylase-67 messenger RNA expression in the basal ganglia output nuclei was not affected by mutations in the D(2) receptor gene, a fact that could probably be related to the absence of a parkinsonian locomotor phenotype in D(2) receptor-deficient mice. In summary, these findings provide compelling evidence demonstrating that the lack of endogenous stimulation of D(2) receptors is sufficient to produce subthalamic nucleus hyperactivity, as assessed by cytochrome oxidase I histochemistry and messenger RNA expression, and strongly suggest the existence of interactions between the basal ganglia direct and indirect pathways.
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PMID:The indirect basal ganglia pathway in dopamine D(2) receptor-deficient mice. 1097 27

Studies of dopamine (DA) receptor binding in early parkinsonian patients, or in models of Parkinson's disease, have revealed a supersensitivity of the D2-like receptor subtype as compared to age-matched controls. The lack of upregulation in advanced patients is often attributed to the effects of prolonged antiparkinsonian therapy, but the impact of therapy vs. intrinsic mechanisms in untreated patients or animals with long-term lesions of the DA nigrostriatal pathway has been difficult to address. We studied, in vivo, by PET using the DA D2 receptor ligand raclopride, the status of the DA receptors in normal rhesus monkeys and those with acute (3 months) or long-term (10 years) MPTP-induced nigrostriatal lesions. Compared to age-matched controls, there was no change in raclopride binding in MPTP-treated animals without parkinsonian symptoms. There was a significant increase in raclopride binding in the putamen (but not caudate nucleus) of all the animals displaying rigidity, hypo- and bradykinesia. This increase was greater in the animals with acute lesions (32%) than with established, long-term lesions (18%). There was no correlation between the postmortem striatal DA concentrations and in vivo raclopride binding but there was a correlation between PET raclopride binding and [(3)H]raclopride binding in vitro. Complex changes in D2 receptor binding occur in various stages of parkinsonism. Antiparkinsonian therapy is unlikely to be solely responsible for the lack of upregulation found in advanced parkinsonian patients but may be a contributing factor.
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PMID:In vivo PET studies of the dopamine D2 receptors in rhesus monkeys with long-term MPTP-induced parkinsonism. 1101 84

Common marmosets (Callithrix jacchus) with near-complete unilateral 6-hydroxydopamine denervation of the dopaminergic input received a single injection of saline or L-DOPA (15mg/kg plus 6.25mg/kg benserazide). Using in situ hybridization, the effects of these treatments on c-fos messenger RNA expression in the cerebral cortex, the striatal complex and the external layer of the pallidum were studied. Moreover, receptor autoradiography was used to determine the levels of dopamine D(1) and D(2) receptors in these areas. In the cerebral cortex, animals treated with L-DOPA displayed a high expression of c-fos messenger RNA restricted to the dopamine-denervated hemisphere. No changes in the levels of cortical D(1) and D(2) receptors were found in the dopamine-denervated hemisphere. L-DOPA treatment also induced a strong expression of c-fos messenger RNA in the striatal complex in the dopamine-denervated hemisphere. The levels of striatal D(2), but not D(1), receptors were increased in the dopamine-denervated hemisphere. In the external pallidum, the major terminal region for D(2) dopamine receptor-containing striatal projection neurons, L-DOPA treatment induced c-fos messenger RNA expression in both the intact and the dopamine-denervated hemispheres.Thus, using c-fos messenger RNA as a biochemical marker of postsynaptic neuronal activation, these results provide evidence that near-complete dopamine depletion causes a profound supersensitization to L-DOPA treatment in the cerebral cortex and in the striatal complex, but not in the external layer of the pallidum, of the primate brain. The cortical response may be unique to the primate brain, but c-fos messenger RNA activation within the striatum has also been reported in the rodent. The effects of L-DOPA probably depend both on a direct activation of supersensitized dopamine receptors by dopamine produced in the few remaining, but hyperactive, dopaminergic nerve terminals and in serotonergic nerve terminals, as well as on indirect actions of L-DOPA related to activation of circuitries connecting cerebral cortex and basal ganglia structures. These results provide novel information on the mechanisms underlying L-DOPA's action in the cerebral cortex, striatum and external pallidum in a primate model of Parkinson's disease.
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PMID:L-DOPA produces strong induction of c-fos messenger RNA in dopamine-denervated cortical and striatal areas of the common marmoset. 1102 38

This paper reviews the preclinical study of the novel dopamine agonist pramipexole and its use in early Parkinson's disease (PD). Emphasis will be given to those properties distinguishing this drug from other dopamine agonists, the relevance of the preclinical data to clinical trial results in early PD, and the putative neuroprotective properties of the compound. The conventional dopamine agonists are ergot-derived compounds that are most widely used as adjunctive therapies in advancing Parkinson's disease (PD). Examples of conventional agonists are bromocriptine and pergolide. Pramipexole is an aminobenzothiazole compound, recently introduced for the treatment of both early and advanced PD. Its nonergot structure may reduce the risk of side-effects, considered unique to ergot drugs, such as membranous fibrosis. Pramipexole is a full dopamine agonist with high selectivity for the D2 dopamine receptor family. This family includes the D2, D3 and D4 receptor subtypes. Pramipexole has a 5- to 7-fold greater affinity for the D3 receptor subtype with lower affinities for the D2 and D4 receptor subtypes. The drug has only minimal alpha2-adrenoceptor activity and virtually no other receptor agonism or antagonism. The optimal dopamine receptor activation for the safe and effective treatment of PD is not known. Findings in animal models and clinical studies indicate that activation of the postsynaptic D2 receptor subtype provides the most robust symptomatic improvement in PD. Given its pharmacological profile, it is not surprising that pramipexole was found to be effective in ameliorating parkinsonian signs in animal models. This therapeutic effect has been confirmed in clinical trials in both early and advanced PD. In early disease, it provides a clear reduction in the chief motor manifestations of PD and improved activities of daily living. Perhaps most striking is the large number of clinical trial patients who have remained on pramipexole monotherapy for many months. The majority of these subjects have been maintained on pramipexole for an excess of 24 months without requiring additional symptomatic treatment with levodopa. This is in contrast to the general clinical experience with older conventional agonists. Pramipexole also has a favourable pharmacokinetic profile. It is rapidly absorbed with peak levels appearing in the bloodstream within 2 h of oral dosing. It has a high absolute bioavailability of > 90% and can be administered without regard to meals. It has no significant effects on other antiparkinson drugs such as levodopa or selegiline. Its excretion is primarily renal and, thus, has little or no impact on hepatic cytochrome P450 enzymes or other related metabolic pathways. Pramipexole has also been theorized to have 'neuroprotectant' properties. Oxyradical generation is posited as a cause or accelerant of brain nigral cell death in PD. Pramipexole stimulates brain dopamine autoreceptors and reduces dopamine synthesis and turnover which may minimize oxidative stress due to dopamine metabolism. Furthermore, the compound has a low oxidation potential that may serve as an oxyradical scavenger in the PD brain. In summary, pramipexole is a new antiparkinson medication found to have unique dopamine agonist characteristics and putative neuroprotective properties.
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PMID:Pre-clinical studies of pramipexole: clinical relevance. 1105 54


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