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)

The use of a recently commissioned small-diameter, high-resolution positron emission tomography (PET) to obtain a measure of specific binding of 3 carbon-11 labelled ligands in rat striatum is described. Using cerebellum as a reference tissue, compartmental modelling was used to obtain individual estimates of striatal binding potential (defined as the ratio of rate constants to and from the specifically bound compartment) for [11C]raclopride (D2 receptors), [11C]SCH 23390 (D1 receptors) and [11C]RTI-121 (dopamine transporter). The coefficients of variation in control, anaesthetized rats were of the order of 10%. Using two models of human disease, namely striatal injection of ibotenic acid to produce postsynaptic cell loss as in Huntington's disease, and 6-hydroxydopamine injection into substantia nigra pars compacta to mimic dopaminergic terminal loss in Parkinson's disease, marked reductions in binding potential were observed for the corresponding pre- or postsynaptic markers. When the regions of interest are so small as to be of the order of the spatial resolution of the system, factor such as spill over and partial volume negate absolute quantification of tissue radioactivity. Nevertheless, the use of PET to monitor relative changes in dopaminergic integrity should be considered as a viable complement to established in vivo microdialysis and post mortem techniques.
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PMID:The potential of high-resolution positron emission tomography to monitor striatal dopaminergic function in rat models of disease. 887 75

In the development of novel Tc-99m-labeled tropane derivatives as dopamine transporter (reuptake site)-imaging agents, a series of neutral and lipophilic complexes containing bis-(aminoethanethiol) as a neutral complexing moiety for a [99mTc]TcO3+ center core was successfully prepared. Biological evaluation of the Tc-99m-labeled complexes 13-16 as central nervous system (CNS) dopamine transporter-imaging agents was reported. Synthesis of the tropane derivatives was achieved by stepwise reactions adding two aminoethanethiol units. The final free thiol ligands were obtained by deblocking the 4-methoxybenzyl protecting group with Hg(OAc)2 to obtain trifluoroacetate salts. All of the Tc-99m complexes, with the exception of 16, displayed good initial brain uptake and selective uptake in the striatal area, where dopamine transporters are concentrated. One of the compounds, [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethy] amino]ethanethiolato-(3-)-N2,N2',S2,S2'] oxo-[1R-(exo-exo)]- [99mTc]technetium,[99mTc]TRODAT-1 (13), displayed the highest initial uptake in rat brain (0.4% at 2 min post iv injection); the striatal/cerebellar (ST/ CB) ratio reached 2.8 at 60 min after an iv injection. The specific uptake in rat brain can be blocked by pretreating rats with a competing dopamine transporter binding agent, beta-CIT (RTI-55, 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane; iv, 1 mg/kg), which reduced the regional brain uptake ratio (ST/CB) to 1.2. In contrast, the specific striatal uptake was not affected by pretreating rats with a noncompeting ligand, haldol (iv, 1 mg/kg). After an iv injection of 9 mCi of [99mTc]TRODAT-1 (13), in vivo images of baboon brain using single-photon emission-computed tomography exhibited excellent localization in striatum (basal ganglia), where dopamine neurons are known to be concentrated. This series of compounds may provide a convenient source of short-lived imaging agents for routine diagnosis of CNS diseases (i.e., Parkinson's disease) in which changes in the dopamine transporter concentration are implicated.
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PMID:Synthesis and characterization of technetium-99m-labeled tropanes as dopamine transporter-imaging agents. 901 23

To estimate the threshold of nigrostriatal dysfunction required for symptomatic Parkinson's disease (PD), we employed [11C]RTI-32 and PET to study the dopamine transporter in striatal subdivisions of 11 L-dopa-naive patients with very early parkinsonism. As compared with the controls (N = 10), the PD group had on the side contralateral to the maximal clinical symptoms, significantly reduced binding in the posterior putamen (-56%) and anterior putamen (-28%), with the reduction in caudate (-12%) not significantly different. To the extent that dopamine transporter binding accurately reflects the number of nigrostriatal dopamine nerve terminals, these findings suggest that the clinical threshold for PD in the middle-age human is approximately 50% loss of dopaminergic innervation to the posterior putamen. Our data also suggest that damage to the putamen component of the striatum is sufficient for the clinical expression of PD.
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PMID:[11C]RTI-32 PET studies of the dopamine transporter in early dopa-naive Parkinson's disease: implications for the symptomatic threshold. 919 69

Glial cell-line-derived neurotrophic factor (GDNF) has been shown to enhance the survival of dopaminergic neurones both in vitro and in vivo, and to protect the rodent dopaminergic system from neurotoxic damage. However, most previous studies have only examined the short-term protective effects of GDNF. We have investigated the long-term effects of GDNF on a 6-hydroxydopamine (6-OHDA)-induced lesion of the rat medial forebrain bundle (MFB), which results in complete and irreversible destruction of the nigrostriatal pathway, and is a robust model of Parkinson's disease. GDNF was administered ipsilaterally above the substantia nigra and into the lateral ventricle immediately before a unilateral 6-OHDA injection into the MFB. The effects of GDNF were examined in vivo by behavioural testing and positron emission tomography (PET) at weekly intervals, for 12 weeks. GDNF prevented the development of amphetamine-induced rotations at all time-points. PET studies, using [11C]-RTI-121 as a tracer for the dopamine transporter, indicated that GDNF prevented 6-OHDA-induced reduction of dopamine reuptake sites in the ipsilateral striatum. Post-mortem neurochemical analysis at 13 weeks after surgery found that GDNF significantly inhibited 6-OHDA-induced loss of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the ipsilateral striatum. Immunocytochemistry showed that GDNF reduced 6-OHDA-induced loss of tyrosine hydroxylase-positive neurones in both the substantia nigra pars compacta and ventral tegmental area. We have shown that a single treatment with GDNF can confer long-term protective effects against a 6-OHDA lesion, which suggests that this factor may be useful for the treatment of Parkinson's disease.
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PMID:Long-term protection of the rat nigrostriatal dopaminergic system by glial cell line-derived neurotrophic factor against 6-hydroxydopamine in vivo. 975 13

The mesolimbic dopamine (DA) system preferentially innervates the D3 receptor, whereas the D2 receptor is, in addition, a target of the nigrostriatal DA system. In human brain D3 receptors and D3 mRNA-expressing neurons are largely segregated to brain regions that are the targets of the mesolimbic DA system and the efferents of the "limbic striatum." Thus, D3 receptors may regulate effects of DA on the "limbic" cortico-striatal-pallidal-thalamic-cortical loop. The nigrostriatal DA system is considerably more damaged in Parkinson's disease (PD) than the mesolimbic DA system. We report here, using radioligands selective for the D2 and D3 receptor, that these receptors are independently changed in PD. Tissue collected at autopsy from nine subjects with a diagnosis of PD and eight age-matched subjects with no evidence of a neurologic disorder was processed for [125I]epidepride binding to D2 receptors, [125I] trans-7-OH-PIPAT binding to D3 receptors, [125I]RTI-55 for the DA transporter (DAT), and immunoautoradiography for tyrosine hydroxylase (TH) using autoradiographic methods. Dopaminergic innervation to the caudal putamen was profoundly reduced and to a lesser extent in the rostral putamen in PD. DAT sites but not TH protein levels were reduced in the nucleus accumbens (NAS) in PD compared with age-matched control subjects. This is consistent with a loss of dopaminergic innervation from the mesolimbic DA system but elevation in TH production. D3 receptors were significantly reduced in PD by 40-45% particularly in the NAS and putamen. D2 receptors were elevated in PD in the dorsal putamen by 15%. The reduction in D3 receptor number was not observed in PD cases with a diagnosis of less than 10 years. The changes in DA D3 receptor number is interesting in light of the development of antiparkinsonian agents that are D3-preferring agonists.
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PMID:Dopamine D3 receptor is decreased and D2 receptor is elevated in the striatum of Parkinson's disease. 975 47

Growth/differentiation factor 5 is a member of the transforming growth factor beta superfamily, which has neurotrophic and neuroprotective effects on dopaminergic neurons both in vitro and in vivo. Here we investigate the effects of growth/differentiation factor 5 on foetal mesencephalic grafts transplanted into a rat model of Parkinson's disease, and compare them with those of glial cell line-derived neurotrophic factor. Mesencephalic tissue was suspended in solutions containing either growth/differentiation factor 5 or glial cell line-derived neurotrophic factor prior to transplantation into the left striatum of rats with 6-hydroxydopamine lesions of the left medial forebrain bundle. Both proteins enhanced graft-induced compensation of amphetamine-stimulated rotations. Positron emission tomography studies showed that both neurotrophins increased graft-induced recovery of striatal binding of [11C]RTI-121, a marker for dopaminergic nerve terminals. Post mortem analysis at 8 weeks after transplantation showed that both neurotrophins significantly increased the survival of grafted dopaminergic neurons. This study shows that growth/differentiation factor 5 is at least as effective as glial cell line-derived neurotrophic factor in enhancing the survival and functional activity of mesencephalic grafts, and thus is an important candidate for use in the treatment of Parkinson's disease.
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PMID:Growth/differentiation factor 5 and glial cell line-derived neurotrophic factor enhance survival and function of dopaminergic grafts in a rat model of Parkinson's disease. 987 47

We investigated the effect of MPTP-induced lesion of the substantia nigra pars compacta (SNpc) dopaminergic neurons on GABA(B) receptors in the basal ganglia of mice and monkeys using receptor autoradiography and in situ hybridization. The extent of the lesion was measured with striatal catecholamine content, striatal binding of (125)I-RTI-121 to dopamine transporter (DAT), and DAT expression in the SNpc. GABA(B) receptors in mice brain were evaluated using (3)H-CGP54626 and its expression was measured with oligonucleotides probes targeting the mRNAs of GABA(B(1a+b)), GABA(B(1a)), GABA(B(1b)), GABA(B(2)) subunits. In monkeys, (125)I-CGP64213 and selective probes for GABA(B(1a+b)) and GABA(B(2)) mRNAs were used. In mice, dopamine content, (125)I-RTI-121 binding, and DAT expression were reduced by 44%, 40%, and 39% after a dose of 40 mg/kg of MPTP and 74%, 70%, and 34% after 120 mg/kg of MPTP, respectively. In monkeys, dopamine content and DAT expression were decreased by more than 90% and 80%, respectively. In the striatum and the subthalamic nucleus, GABA(B) receptors were unchanged following MPTP in both species. In the SNpc of mice, MPTP (120 mg/kg) induced a significant decrease of (3)H-CGP54626 binding (-10%) and of the expression of GABA(B(1a+b)) mRNA (-13%). The decrease of the expression of GABA(B(1a+b)) mRNA was correlated with dopamine content, (125)I-RTI-121 binding and DAT expression. In MPTP-treated monkeys, (125)I-CGP64213 binding (-40%), GABA(B(1a+b)) mRNA (-69%) and GABA(B(2)) mRNA (-66%) were also significantly decreased in the SNpc. Our results suggest that MPTP-induced denervation is associated with a decrease of GABA(B) receptors restricted to the SNpc. These observations may be relevant to the pathophysiology of motor disorders involving dysfunction of the basal ganglia such as Parkinson disease.
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PMID:Effect of MPTP-induced denervation on basal ganglia GABA(B) receptors: correlation with dopamine concentrations and dopamine transporter. 1130 60

The expression of preproenkephalin messenger RNA was studied in the brain of Parkinson disease (PD) patients using in situ hybridization. All these patients were treated with levodopa (LD) and the development of motor complications was recorded. Eleven normal controls and 14 PD patients were used, of which 4 developed dyskinesias, 3 developed wearing-off, 3 developed both dyskinesias and wearing-off, and 4 developed no adverse effect following dopaminomimetic therapy. Nigrostriatal denervation was similar between the subgroups of PD patients as assessed using 125I-RTI-specific binding to the dopamine transporter and measures of catecholamine concentrations by HPLC. A significant increase of preproenkephalin messenger RNA levels was observed in the lateral putamen of dyskinetic patients in comparison to controls (+210%; p < 0.01) and in comparison to nondyskinetic patients (+112%; p < 0.05). No change was observed in medial parts of the putamen or in the caudate nucleus. No relationship between preproenkephalin messenger RNA levels and other clinical variables such as development of wearing-off, age of death, duration of disease, or duration of LD therapy was found. These findings suggest that increase synthesis of preproenkephalin in the medium spiny output neurons of the striatopallidal pathway play a role in the development of dyskinesias following long-term LD therapy in Parkinson disease.
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PMID:Increase of preproenkephalin mRNA levels in the putamen of Parkinson disease patients with levodopa-induced dyskinesias. 1185 20

The effect of MK-801, a noncompetitive NMDA receptor antagonist, on both in vivo and in vitro binding of [(125)I]beta-CIT (RTI-55) was investigated in a rat model of Parkinson's disease. The binding experiments were performed 2 weeks after unilateral intranigral microinjection of 6-hydroxydopamine (6-OHDA). In the in vitro binding study, no alterations in [(125)I]beta-CIT binding in rat brain sections were observed after addition of MK-801, 0.03 microM or 3 microM, to the incubation medium. However, in vivo [(125)I]beta-CIT binding to the dopamine transporter in both nonlesioned and 6-OHDA-lesioned striatum was significantly increased by pretreatment with MK-801. In vivo [(125)I]beta-CIT binding to the serotonin (5HT) transporter in nonlesioned cerebral cortex, hypothalamus, and thalamus was also significantly increased by MK-801. However, the degree of change in the specific binding of [(125)I]beta-CIT induced by MK-801 was smaller in the lesioned cerebral cortex. Kinetic analysis, by a simplified three-compartment model with the cerebellum as the reference region, revealed that these alterations in the in vivo [(125)I]beta-CIT binding induced by MK-801 were mainly due to changes in the rate constants of in vivo binding, the input rate constant, k(3), and the output rate constant, k(4). These results indicate that the glutamatergic system significantly affects the function of dopamine transporters in the degenerated dopaminergic neurons in Parkinson's disease.
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PMID:Effect of glutamatergic systems on in vivo binding of [(125)I]beta-CIT in the brain of a rat model of Parkinson's disease. 1221 Oct 97

Brain samples from 14 Parkinson's disease patients, 10 of whom developed motor complications (dyskinesias and/or wearing-off) on dopaminomimetic therapy, and 11 controls were analyzed. Striatal 3beta-(4-(125)I-iodophenyl)tropane-2beta-carboxylic acid isopropyl ester ([(125)I]RTI-121) -specific binding to dopamine transporter and concentration of dopamine were markedly decreased, but no association between level of denervation and development of motor complications was observed. The homovanillic acid/dopamine ratio of concentrations was higher in putamen of patients with wearing-off compared to those without. Striatal (35)S-labeled t-butylbicyclophosphorothionate ([(35)S]TBPS) and [(3)H]flunitrazepam binding to GABA(A) receptors were unchanged in patients with Parkinson's disease, whereas [(125)I]CGP 64213 -specific binding to GABA(B) receptors was decreased in the putamen and external segment of the globus pallidus of parkinsonian patients compared with controls. [(3)H]Flunitrazepam binding was increased in the putamen of patients with wearing-off compared to those without. [(35)S]TBPS-specific binding was increased in the ventral internal globus pallidus of dyskinetic subjects. These data suggest altered dopamine metabolism and increased GABA(A) receptors in the putamen related to the pathophysiology of wearing-off. The present results also suggest that an up-regulation of GABA(A) receptors in the internal globus pallidus is linked to the pathogenesis of levodopa-induced dyskinesias.
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PMID:Changes of GABA receptors and dopamine turnover in the postmortem brains of parkinsonians with levodopa-induced motor complications. 1262 27


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