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

[3H]Spiperone binding was investigated in the caudate nucleus, substantia nigra (s. nigra) and frontal cortex of control subjects and of patients with Parkinson's disease and the Shy-Drager syndrome. Binding sites for [3H]spiperone were interpreted as dopamine receptors in caudate and s. nigra, and as 5-hydroxytryptamine (5-HT) receptors in frontal cortex. Scatchard analysis showed that the Bmax (maximal number of binding sites) in caudate was similar in the 3 groups, whereas in s. nigra the Bmax was reduced by approximately 60% in both Parkinsons disease and Shy-Drager syndrome. The dissociation constant (Kd) for [3H]spiperone binding in s. nigra was similar in the 3 groups. In caudate nucleus, the Kd was similar in control and Parkinson groups; however, there was a significant increase in the dissociation constant in the caudate nucleus from cases of Shy-Drager syndrome. No differences in binding characteristics were observed in the frontal cortex. These results are taken to reflect a loss of dopamine receptor sites in the s. nigra in both Parkinson's disease and Shy-Drager syndrome, and a reduced affinity of dopamine receptor sites in the caudate nucleus in Shy-Drager syndrome.
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PMID:Alterations in [3H]spiperone binding in human caudate nucleus, substantia nigra and frontal cortex in the Shy-Drager syndrome and Parkinson's disease. 52 36

We studied the effect of intracerebroventricular infusion of dopamine and dopamine agonists in rat and primate models of Parkinson's disease as an experimental approach to the treatment of levodopa-induced fluctuations. The infusion of dopamine, lisuride, and pergolide into the ventricle ipsilateral to the lesion, by 6-hydroxydopamine, of the nigrostriatal pathway induced a contralateral rotation which was maximal 24-48 h after infusion and whose intensity progressively decreased over the period of 1 week. [3H]Spiperone binding was decreased by the infusion of dopamine but the responses to subcutaneous apomomorphine were unchanged. The infusion of dopamine also restored the levels of monoamines in the rat brain. In chronic reserpized rats, the infusion of dopamine restored brain levels of dopamine but did not reverse akinesia unless monoamine oxidase inhibitors were simultaneously administered, either systemically or intracerebroventricularly. Lisuride and pergolide proved much weaker than dopamine in reversing the effects of reserpine. Intracerebroventricular infusion of dopamine plus deprenyl reversed MPTP induced akinesia in monkeys but the pump used for the delivery was not well tolerated, because of its size, by the animals.
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PMID:Continuous intracerebroventricular infusion of dopamine and dopamine agonists through a totally implanted drug delivery system in animal models of Parkinson's disease. 290 48

[3H]Spiperone binding to lymphocytes in Parkinson's disease (PD), Wilson's disease (WD), and age-matched control groups was studied. In the untreated PD group, [3H]spiperone binding was lower than in young controls, but did not differ from elderly healthy persons. After treatment with levodopa, the number of [3H]spiperone binding sites increased. In WD, lower binding of [3H]spiperone compared with age-matched controls was found. However, the magnitude of the differences in [3H]spiperone binding to lymphocytes in PD was too small to permit its use as a routine indicator of the disease state or the adequacy of pharmacological treatment in individual patients. [3H]Spiperone binding to lymphocytes decreases with age. Changes in [3H]spiperone binding to lymphocytes may be a general phenomenon for all states where dopamine is depleted, including normal aging. The nature of [3H]spiperone binding to lymphocytes remains unclear. The possible influence of dopamine on immune reactivity is discussed.
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PMID:[3H]spiperone binding to lymphocyte in extrapyramidal disease and in aging. 297 11

Intravenous administration of 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) leads to the progressive development of a model of Parkinson's disease in the primate. The development of damage occurring in the striatal area during MPTP-treatment was followed "in vivo" in a baboon by positron emission tomography (PET). Spiperone labelled with a positron emitter 76Br (76Br-BSP) was used for the quantitative "in vivo" imaging of D2 dopamine receptors. The decrease in the striatal binding of 76Br-BSP measured "in vivo", after three series of MPTP injections, paralleled the increase in the severity of behavioral symptoms seen immediately after administration of the neurotoxin. At the end of the MPTP-treatment when neurological symptoms were the most important, a 36% decrease in the 76Br-BSP specific binding was measured. Between the series of MPTP injections a partial recovery in the quantitative measurement of the 76Br-BSP specific binding occurring in the striatum was well correlated with the disappearance of the neurological syndrome. Post-mortem histological and biochemical studies in nigro-striatal anatomical structures of MPTP-intoxicated primates compared with control animals showed a 80% loss of neuronal cell bodies in the substantia nigra compacta and a 42% decrease in the density (Bmax) of D2 receptors (in vitro 3H-spiperone binding). All these results showed that the use of PET and 76Br-BSP allow to follow in a noninvasive way both the degenerative processes and the subsequent partial recovery which occur in dopaminergic striatal receptor function during MPTP-treatment.
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PMID:"In vivo" visualization by positron emission tomography of the progressive striatal dopamine receptor damage occurring in MPTP-intoxicated non-human primates. 348 75

Ergot derivatives have been proposed to have ameliorative effects in various pathological conditions where dopaminergic transmission is believed to be impaired, namely Parkinson's disease, amenorrhea-galactorrhea syndrome, and in the treatment of behavioural disturbances of the elderly. To get more insight into a possible involvement of a direct action of ergot derivatives on dopamine receptors we studied the effect of acute and chronic dihydroergotoxine (DHT) treatment on 3H-Spiroperidol and 3H-N-Propylnorapomorphine (3H-NPA) binding to rat striatal membrane preparations. The results are in favor of an interaction of ergot derivatives with dopamine recognition sites both after acute and chronic treatment.
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PMID:Chronic dihydroergotoxine treatment affects the number of dopamine recognition sites in rat striatum. 646 97

Eleven patients with previously untreated Parkinson's disease were treated with L-Methionine for periods from 2 weeks to 6 months. The treatment was well supported and good improvement in clinical signs, particularly akinesia and rigidity, appeared within approximately three weeks, the effect on tremor being less marked. Therapeutic effects were similar to those observed with L-dopa treatment. Correlation of clinical effects with a marked increase in the number of 3H-Spiroperidol binding sites (Bmax) to lymphocytes was noted. This therapeutic effect suggests the role played by modifications of membrane fluidity on dopaminergic receptors, both lymphocytic and striatal, in the etiology of Parkinson's disease, and opens up new therapeutic possibilities in this disease.
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PMID:[L-Methionine treatment of Parkinson's disease: preliminary results]. 713 22

To explore the possible therapeutic use of electric convulsive treatment in Parkinson's disease (PD), the authors examined the biochemical effects of electroconvulsive shock (ECS) on dopaminergic systems in a rodent model of PD, induced with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP increased dopamine turnover, as indicated by an increase in the ratio of the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to dopamine. [3H]Spiperone binding to the D2 site increased after lesioning of striatal dopamine terminals. With ECS alone, no changes were found in monoamine levels, brain monoamine oxidase activity, or the D2-labeled sites measured 24 hours after the last treatment. [3H]SCH-23390 binding to the D1 site increased after ECS. In MPTP-treated mice, ECS also increased [3H]SCH-23390 binding to the D1 site, whereas [3H]spiperone binding to the D2 site was unchanged compared to control or to only ECS-treated animals, and decreased compared to the MPTP-treated group that did not receive ECS. ECS appears to selectively modify both the D1 and D2 sites when given after MPTP, increasing the binding of a D1 radioligand and decreasing the binding of a D2 radioligand.
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PMID:The effects of electroconvulsive shock on dopamine-1 and dopamine-2 receptor ligand binding activity in MPTP-treated mice. 758 Jan 73

In order to investigate the diagnostic value of 3H-spiperone binding capacity to lymphocytes in the differential diagnosis of de novo Parkinson's disease (idiopathic Parkinson syndrome, PD), we performed a double blind prospective study of spiperone binding capacity of 123 patients and 23 healthy control persons, belonging to different diagnostic groups (PD, Parkinsonian syndrome due to vascular lesions, multiple system atrophy [MSA], essential tremor). Diagnoses were based on medical history, clinical examination, CT or MRI scan, acute response to dopamimetic drugs, one year follow up, and long term response to L-DOPA treatment. Spiperone binding was assayed using ten different concentrations (0.03-3 nmol) in absence or presence of 1 mumol (+)-butaclamol to determine nonspecific binding. There was no significant difference in spiperone binding between patients with PD not treated with L-DOPA, and patients with other basal ganglia disorders including parkinsonian syndrome due to vascular lesions, multiple system atrophy, or progressive supranuclear palsy, and age matched controls. Binding was significantly higher in parkinsonian patients with PD treated with L-DOPA and patients with essential tremor. It is concluded that at present 3H-spiperone binding gives no further information in the differential diagnosis of de novo Parkinson's disease.
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PMID:3H-spiperone binding to lymphocytes fails in the differential diagnosis of de novo Parkinson syndromes. 768 43

Activated microglia appear to selectively attack dopamine (DA) neurons in the Parkinson's disease (PD) substantia nigra. We investigated potential mechanisms using culture models. As targets, human SH-SY5Y cells were left undifferentiated (UNDIFF) or were differentiated with retinoic acid (RA) or RA plus brain-derived neurotrophic factor (RA/BDNF). RA/BDNF-treated cells were immunoreactive for tyrosine hydroxylase and the DA transporter, took up exogenous DA, and released DA after K(+) stimulation. Undifferentiated and RA-treated cells lacked these characteristics of a DA phenotype. Co-culture of target cells with human elderly microglia resulted in elevated toxicity in DA phenotype (RA/BDNF) cells. Lipopolysaccharide (LPS) plus K(+)-stimulated DA release enhanced toxicity by 500-fold. DA induced microglial chemotaxis in Boyden chambers. Spiperone inhibited this effect. Cultured human elderly microglia expressed mRNAs for D1-D4 but not D5 DA receptors. The microglia, as well as PD microglia in situ, were also immunoreactive for D1-D4 but not D5 DA receptors. These findings demonstrate that activated microglia express DA receptors, and suggest that this mechanism may play a role in the selective vulnerability of DA neurons in PD.
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PMID:Microglial responses to dopamine in a cell culture model of Parkinson's disease. 1832 35

Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated glia cells can secrete various proinflammatory cytokines and neurotoxic mediators, which may influence neuronal cell survival. Recent studies have demonstrated that glia cell-mediated neuroinflammation is also related to the pathophysiology of schizophrenia. In the present study, anti-inflammatory and neuroprotective effects of antipsychotics were investigated using cultured brain cells as a model. The results showed that spiperone significantly decreased the production of nitric oxide in lipopolysaccharide-stimulated BV-2 microglia cells, primary microglia and primary astrocyte cultures. Spiperone also significantly inhibited nitric oxide production in adenosine 5'-triphosphate (ATP)-stimulated primary microglia cultures. Spiperone markedly decreased the production of tumor necrosis factor-alpha in BV-2 microglia cells. Spiperone attenuated the expression of inducible nitric oxide synthase and proinflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha at mRNA levels in BV-2 microglia cells. Spiperone inhibited nuclear translocation and DNA binding of the p65 subunit of nuclear factor kappa B (NF-kappaB), inhibitor of kappa B (IkappaB) degradation, and phosphorylation of p38 mitogen-activated protein kinase in the lipopolysaccharide-stimulated BV-2 microglia cells. Moreover, spiperone was neuroprotective, as the drug reduced microglia-mediated neuroblastoma cell death in the microglia/neuron co-culture. These results imply that the antipsychotic spiperone has anti-inflammatory and neuroprotective effects in the central nervous system by modulating glial activation.
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PMID:The antipsychotic spiperone attenuates inflammatory response in cultured microglia via the reduction of proinflammatory cytokine expression and nitric oxide production. 1878 64


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