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)

We studied the time course of dopamine (DA) terminal loss in three macaca fascicularis injected with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) intravenously every 10-14 days for up to 389 days. Striatal DA terminal loss was monitored in vivo by positron emission tomography using 11C-CFT (WIN 35,428), a cocaine derivative that labels the DA transporter. The 11C-CFT uptake rate constant in the striatum of MPTP-treated monkeys decreased exponentially over time, with the putamen significantly more affected than the caudate. Spontaneous locomotor activity decreased in parallel with the decline of the 11C-CFT uptake rate; however, overt parkinsonian signs appeared only after the 11C-CFT uptake rate had declined to about 30% of the pretreatment values. We conclude that a long-term intermittent mode of administration of MPTP can lead to a pattern of terminal loss that closely resembles idiopathic Parkinson disease.
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PMID:Dopamine terminal loss and onset of motor symptoms in MPTP-treated monkeys: a positron emission tomography study with 11C-CFT. 792 29

Parkinson's Disease (PD) is characterized by a selective loss of nigrostriatal dopaminergic neurons that results in a marked reduction of dopaminergic nerve terminals in the striatum. Recently, 11C-WIN 35,428, a cocaine analogue that specifically labels the dopamine transporter, was developed and can be used to label dopaminergic nerve terminals in vivo by positron emission tomography. In healthy control subjects, binding of 11C-WIN 35,428 is highest in the striatum. In addition, 2 symmetrical focal areas of low binding were observed in the midbrain. The cerebellum functioned as an appropriate region for nonspecific binding. The binding of 11C-WIN 35,428 in patients with PD (Hoehn-Yahr II) was compared with that in healthy control subjects by using the (region-cerebellum)/cerebellum ratio for data acquired 34 to 82 minutes after injection. In control subjects, this ratio varied, at approximately 2, in the striatum. In patients with PD, binding in the posterior putamen was reduced by 78%, whereas the anterior putamen and the caudate nucleus showed a reduction of 59 and 39%, respectively. The reduction in 11C-WIN 35,428 binding was highest in the midbrain (84%). The high specific/nonspecific binding ratio and the pronounced reduction in binding in mild PD may permit detection of even earlier stages of PD or presymptomatic individuals with dopaminergic cell loss.
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PMID:Positron emission tomographic imaging of the dopamine transporter with 11C-WIN 35,428 reveals marked declines in mild Parkinson's disease. 812 97

The number of neuronal synaptic vesicular monoamine transporters (vesicular monoamine transporter type 2; VMAT2) has been recently proposed as an index of monoamine presynaptic terminal density. The present study investigated the possible regulation of the vesicular monoamine transporter. Rats were treated for 2 weeks with drugs known to influence dopaminergic neurotransmission, including those commonly used in the treatment of Parkinson's disease. Autoradiographic assays were performed using [3H]methoxytetrabenazine, [3H]raclopride, and [3H]WIN 35,428 ([3H]2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane) to measure vesicular monoamine transporter, dopamine D2 receptor and synaptic plasma membrane dopamine re-uptake site bindings, respectively. None of the drug treatments significantly modified levels of vesicular monoamine transporter binding. In contrast, both dopamine D2 receptors and dopamine re-uptake sites were altered by some of the treatment regimens. These data extend preliminary results that suggest the vesicular monoamine transporter is not easily regulated and confirm the plasticity of dopamine D2 receptors and the dopamine re-uptake site. Measures of striatal vesicular monoamine transporter density may, thus, provide objective estimates of monoaminergic innervation in neurodegenerative diseases, unaffected by the use of symptomatic therapies.
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PMID:The vesicular monoamine transporter is not regulated by dopaminergic drug treatments. 875 Jul 21

To determine the extent that different dopamine (DA) neuronal markers provide similar estimates of striatal (caudate and putamen) DA nerve terminal loss in idiopathic Parkinson's disease (PD), we compared, in postmortem striatum of 12 patients with PD and 10 matched controls, levels of five different DA neuronal markers. These markers included DA itself, three different estimates of the density of the DA transporter (DAT) ([3H])GBR 12,935 and [3H]WIN 35,428 binding; DAT protein immunoreactivity), and one estimate of the vesicular monoamine transporter (VMAT2; [3H]DTBZ binding). Striatal levels of all examined DA markers in PD were significantly intercorrelated. However, the magnitude of loss relative to controls was unequal (DAT protein = DA > [3H]WIN 35,428 > [3H]DTBZ > [3H]GBR 12, 935), with the differences more marked in the severely affected putamen. The less severe reduction of binding of the DAT/VMAT2 radioligands relative to DA and DAT protein could be explained by differential regulation/degeneration of different DA nerve terminal components or lack of specificity of the radioligands for the DA neuron. These postmortem data may help in interpretation of in vivo neuroimaging studies in PD in which only one radioligand is routinely employed.
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PMID:Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson's disease. 879 70

Idiopathic Parkinson's disease (PD) is characterized by loss of dopaminergic terminals in the basal ganglia. The cocaine analog, CFT (WIN 35,428), has been shown to bind selectively to the pre-synaptic dopamine transporters and thus represents an important probe for monitoring disease progression. In this study, we evaluated [11C] labeled CFT as a PET ligand for the quantitative in vivo assay of dopamine transporter density in three normal rhesus monkeys (Macaca mulatta). One of the animals was studied after treatment with the neurotoxin, MPTP. Simulation studies demonstrated that a three injection protocol is necessary for quantitation of dopamine transporter density. The protocol consists of an initial high specific activity injection, a low specific activity "displacement dose" at 30 min, and a final high specific activity injection at approximately 90 min. Dynamic PET imaging and arterial blood sampling were started immediately before the first injection and continued for 2 h. Blood data were corrected for [11C] labeled CFT metabolites. Compartmental models describing the dynamics of labeled and the unlabeled ligand explicitly were fitted to the PET and metabolite corrected blood data. Prior to MPTP treatment, modeling of the striatal data required a saturable receptor term and yielded mean estimates of: B'max = 113 pmol/g and KD = 33 nm (n = 3). These values for B'max are in reasonable agreement with published values for [3H] CFT binding in vitro. After multiple treatments with MPTP (0.6 mg/kg x 3), B'max in one of the animals was reduced from 122 to 10.2 pmol/g. KD was relatively unaffected by MPTP treatment. These data provide additional basis for the use of [11C] CFT in monitoring the progression of Parkinson's disease and other conditions that are associated with the loss of dopaminergic nerve terminals.
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PMID:Quantification of dopamine transporter density in monkeys by dynamic PET imaging of multiple injections of 11C-CFT. 892 67

The purpose of this study was to investigate the influence of drugs competing for the dopamine transporter (DAT) or changing intra- and/or extracellular dopamine levels on the binding of a novel technetium-99m labeled tropane derivative, technetium, [2-[[2-[[[3-(4-chloro- phenyl)-8-methyl-8-azabicyclo[3, 2, 1]oct-2-yl]methyl] (2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3)]-oxo-[1R-(exo -exo)]-, [99mTc]TRODAT-1, to DAT. This paper describes the further characterization of [99mTc]TRODAT-1 binding sites in rats under conditions which may exist in patients receiving various drug treatments. All experiments were carried out using an i.v. injection of [99mTc]TRODAT-1 into male Sprague-Dawley rats. Measurements of % dose/gram ratio of (striatum-cerebellum)/cerebellum at 1 h post injection were used as an indicator for specific DAT binding. The biodistribution studies were performed in the presence of drugs which compete for the binding site, such as CFT (WIN 35,428) and methylphenidate, drugs which influence dopamine levels, such as L-DOPA, gamma-hydroxybutyrolactone, and alpha-methyl-p-tyrosine, and d-amphetamine, which both acts as a competitor for DAT binding and increases dopamine levels. Additionally, the influence of dopamine receptor agonists, such as apomorphine and (+)bromocriptine, on biodistribution was tested. Binding of [99mTc]TRODAT-1 to DAT was found to be inhibited by CFT, methylphenidate, and d-amphetamine in a dose-dependent manner. The specific binding of [99mTc]TRODAT-1 was not altered by dopamine receptor agonists or by drugs which cause minor changes in dopamine levels. When administered in high doses (634 micromol/kg), L-DOPA also decreased the binding of [99mTc]TRODAT-1. It is likely that a low dose of L-DOPA (normally needed in the treatment of Parkinson's disease) will not affect the results on [99mTc]TRODAT-1 single-photon emission tomographic (SPET) imaging studies. In conclusion, the results clearly demonstrate the specificity of [99mTc]TRODAT-1 binding to DAT in vivo. Competition for [99mTc]TRODAT-1 binding was observed only with drug treatment that significantly increases dopamine levels or actively competes for binding at DAT. The results suggest that prior knowledge of whether patients are receiving various drug treatments may assist in the interpretation of DAT status as assessed by SPET imaging studies using [99mTc]TRODAT-1.
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PMID:Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc]TRODAT-1 to the central dopamine transporters in rats. 939 72

Positron emission tomography (PET) and carbon-11-labeled 2B-carbomethoxy-3B-(4-fluorophenyl)tropane (11C-CFT or 11-WIN 35,428) were used as molecular markers for striatal presynaptic dopamine (DA) transporters in a unilateral Parkinson's disease rat neurotransplantation model. In the lesioned striatum, the binding ratio measured by the DA presynaptic marker was reduced to 15% to 35% of the intact side (or unoperated control). After grafting with non-DA cells (from dorsal mesencephalon), the DA binding ratio remained reduced to levels observed before transplantation and rats showed no behavioral recovery. In contrast, after DA neuronal transplantation, behavioral recovery occurred only after the 11C-CFT binding ratio had increased to 75% to 85% of the intact side. This study provides direct in vivo evidence for the dopaminergic molecular basis of functional recovery in the lesioned nigrostriatal system after neural transplantation.
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PMID:In vivo PET imaging in rat of dopamine terminals reveals functional neural transplants. 950 57

Methamphetamine and methcathinone are psychostimulant drugs with high potential for abuse. In animals, methamphetamine and related drugs are known to damage brain dopamine (DA) neurons, and this damage has recently been shown to be detectable in living nonhuman primates by means of positron emission tomography (PET) with [11C]WIN-35,428, a DA transporter (DAT) ligand. The present studies determined whether living humans with a history of methamphetamine or methcathinone abuse showed evidence of lasting decrements in brain DAT density. PET studies were performed in 10 control subjects, six abstinent methamphetamine users, four abstinent methcathinone users, and three patients with Parkinson's disease (PD). On average, subjects had abstained from amphetamine use for approximately 3 years. Before PET studies, all subjects underwent urine and blood toxicology screens to rule out recent drug use. Compared with controls, abstinent methamphetamine and methcathinone users had significant decreases in DAT density in the caudate nucleus (-23 and -24%, respectively) and putamen (-25 and -16%, respectively). Larger decreases in DAT density were evident in patients with PD (47 and 68% in caudate and putamen, respectively). Neither methamphetamine nor methcathinone users showed clinical signs of parkinsonism. Persistent reductions of DAT density in methamphetamine and methcathinone users are suggestive of loss of DAT or loss of DA terminals and raise the possibility that as these individuals age, they may be at increased risk for the development of parkinsonism or neuropsychiatric conditions in which brain DA neurons have been implicated.
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PMID:Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428. 976 84

We analysed the expression of dopamine receptor subtypes in the subthalamic nucleus by means of reverse transcriptase-polymerase chain reaction. We also studied, using autoradiography, all pharmacologically characterized dopamine receptors in four subregions of the subthalamic nucleus. For comparison, dopamine receptor subtypes were also evaluated in brain regions where they are more abundant and well characterized. The radioligands used were: [3H]SCH-23390, [3H]emonapride and [3H]2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene for dopamine D1, D2 and D3 receptors, respectively; and [3H]YM-09151-2 in the presence of raclopride for dopamine D4 receptors. Finally, we also evaluated the effect of unilateral 6-hydroxydopamine injection into the medial forebrain bundle on dopamine receptor levels expressed in the ipsilateral subthalamic nucleus. The lesion was estimated by decrease in the binding of [3H]WIN-35428, a specific dopamine transporter label. D1, D2 and D3 receptor messenger RNAs and binding sites were present in the subthalamic nucleus, but no messenger RNA for D4 receptors was found, although specific binding sites for these receptors were observed. As compared to the intact side, the 6-hydroxydopamine lesion did not change D1 receptors, increased D2 receptors, and decreased D3 receptors and the dopamine transporter. The results suggest that postsynaptic D1, D2 or D3 receptors can mediate the effect of dopamine on subthalamic nucleus neuronal activity. D4 receptors would mediate exclusively presynaptic effects. These results reinforce the idea that dopamine receptors in the subthalamic nucleus may play an important role in the physiology of the basal ganglia and in the pathophysiology of Parkinson's disease.
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PMID:Expression of dopamine receptors in the subthalamic nucleus of the rat: characterization using reverse transcriptase-polymerase chain reaction and autoradiography. 1036 12

To explore the mechanisms underlying L-dopa response, we studied, by postmortem autoradiography, selective makers of dopamine presynaptic terminals, [3H]WIN 35428, and dopamine D2 receptors, [3H]nemonapride, in the putamen of four Parkinson's disease (PD) and one striatonigral degeneration (SND) neuropathologically confirmed brains as compared with six matched control brains. Dopamine uptake transporter was dramatically decreased (> 90%) both in PD and SND striatum. Dopamine D2 receptors were preserved in PD, but clearly reduced (> 76%) in the SND putamen. These data confirm that L-dopa response is closely associated with the preservation of striatal dopamine D2 receptors.
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PMID:Loss of dopamine uptake sites and dopamine D2 receptors in striatonigral degeneration. 1066 19


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