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)

Transplantation of fetal dopamine neurons to the adult striatum potentially offers a means to reverse the striatal dopamine deficiency that characterizes Parkinson's disease. Many investigations in rodents have supported the hope that neural grafting may be a useful treatment for parkinsonism. However, clinical studies have generally produced more modest improvements in motor abnormalities than observed in lower species. It is possible that the number of fetal dopamine neurons that survive transplantation is insufficient to restore dopaminergic innervation of the large human striatum to a level where striking recovery is obtained. In fact, there has been no quantitative study of graft outgrowth to indicate what portion of the dopamine-depleted striatum might be reinnervated with present techniques. Furthermore, it has been speculated that regeneration of the host dopamine system in response to the implantation surgery may play an important role in the beneficial effects of neural grafting in primates. The present study used nine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys to investigate these issues. Sham implantation procedures produced no increase in either dopamine transporter density (measured by quantitative autoradiography) or tissue dopamine concentration (measured by HPLC) in the striatum of MPTP-treated monkeys. In sham-grafted and nonimplanted MPTP-treated monkeys, the striatal dopamine concentration was reduced by 99%, based on analysis of 16 sampled sites in the caudate nucleus and putamen of each monkey. No behavioral recovery was seen in the sham-grafted and nonimplanted MPTP-treated groups. In contrast, transplantation of fetal dopamine neurons to the caudate nucleus or putamen of MPTP-treated monkeys resulted in a significant elevation of dopamine transporter density and dopamine levels in the grafted striatal nucleus. Each grafted MPTP-treated monkey received ventral mesencephalon dopamine neurons from one donor harvested during putative neurogenesis. Donor ventral mesencephalon was divided equally and implanted into six sites either in the caudate nucleus or putamen. One graft site in each monkey was examined by dopamine transporter autoradiography. In sections in which graft fibers were present, a mean of one-third of the volume of the grafted nucleus was occupied by an elevated density of dopamine transporters. This increase in dopamine transporter density was defined to be at least 5-10% of the control density. However, full behavioral recovery was not observed in the grafted MPTP-treated group. These data provide no support for the hypothesis that regeneration of the host dopamine system occurs in response to a sham implantation procedure in severely parkinsonian monkeys. The current study illustrates the power of the applied techniques for delineating the relationship between the level of host dopamine depletion, the extent of graft-induced dopaminergic restoration, and behavioral recovery.
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PMID:Restoration of dopamine transporter density in the striatum of fetal ventral mesencephalon-grafted, but not sham-grafted, MPTP-treated parkinsonian monkeys. 868 42

Neurological disorders in rat model of hemi-Parkinson's disease can be compensated by the transplantation of fetal nigral cells. However, the role of the dopamine transporter (DAT) in this recovery has not been clarified. To clarify this mechanism, we examined the expression of DAT in the caudate putamen (CPu) by in situ hybridization histochemistry (mRNA) and autoradiography (using the ligand [125I] beta-CIT, which labels DAT) and compared them with the recovery of motor disturbance revealed with methamphetamine-induced rotation. Models were made with the stereotaxic injection of 6-hydroxydopamine into the left side of the substantia nigra pars compacta. Cell suspensions from rat fetus (embryonic day 14-15) were transplanted into the lesioned side of CPu. Methamphetamine-induced rotation, expression of DAT mRNA, and [125I] beta-CIT binding were evaluated 2, 4 and 12 weeks after the transplantation. Methamphetamine-induced rotation recovered partly in the 2nd week and significantly in the 4th week. [125I] beta-CIT binding increased with time and the dense binding was detected 4 and 12 weeks after the transplantation. In all transplanted rats, cells expressing DAT mRNA were found in CPu. These results indicated that transplanted fetal dopaminergic cells maturated in CPu of host animals and extended nerve terminals where high density of DAT binding sites were found.
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PMID:Expression of dopamine transporter mRNA and its binding site in fetal nigral cells transplanted into the striatum of 6-OHDA lesioned rat. 880 21

A patient with Parkinson's disease received bilateral fetal human nigral implants from six donors aged 6.5 to 9 weeks post-conception. Eighteen months following a post-operative clinical course characterized by marked improvement in clinical function, this patient died from events unrelated to the grafting procedure. Post-mortem histological analyses revealed the presence of viable grafts in all 12 implant sites, each containing a heterogeneous population of neurons and glia. Approximately 210,146 implanted tyrosine hydroxylase-immunoreactive (TH-ir) neurons were found. A greater number of TH-ir grafted neurons were observed in the right (128,162) than the left (81,905) putamen. Grafted TH-ir neurons were organized in an organotypic fashion. These cells provided extensive TH-ir and dopamine transporter-ir innervation to the host striatum which occurred in a patch-matrix fashion. Quantitative evaluations revealed that fetal nigral grafts reinnervated 53% and 28% of the post-commissural putamen on the right and left side, respectively. Grafts on the left side innervated a lesser area of the striatum, but optical density measurements were similar on both sides. There was no evidence that the implants induced sprouting of host TH-ir systems. Electron microscopic analyses revealed axo-dendritic and occasional axo-axonic synapses between graft and host. In contrast, axo-somatic synapses were not observed. In situ hybridization for TH mRNA revealed intensely hybridized grafted neurons which far exceeded TH mRNA expression within residual host nigral cells. In addition, gamma-amino butyric acid (GABA)-ergic neurons were observed within the graft that formed a dense local neuropil which was confined to the implant site. Serotonergic neurons were not observed within the graft. Cytochrome oxidase activity was increased bilaterally within the grafted post-commissural putamen, suggesting increased metabolic activity. In this regard, a doubling of cytochrome oxidase activity was observed within the grafted post-commissural putamen bilaterally relative to the non-grafted anterior putamen. The grafts were hypovascular relative to the surrounding striatum and host substantia nigra. Blood vessels within the graft stained intensely for GLUT-1, suggesting that this marker of blood--brain barrier function is present within human nigral allografts. Taken together, these data indicate that fetal nigral neurons can survive transplantation, functionally reinnervate the host putamen, establish synaptic contacts with host neurons, and sustain many of the morphological and functional characteristics of normal nigral neurons following grafting into a patient with PD.
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PMID:Functional fetal nigral grafts in a patient with Parkinson's disease: chemoanatomic, ultrastructural, and metabolic studies. 880 31

Parkinson's disease, known also as striatal dopamine deficiency syndrome, is a degenerative disorder of the central nervous system characterized by akinesia, muscular rigidity, tremor at rest, and postural abnormalities. In early stages of parkinsonism, there appears to be a compensatory increase in the number of dopamine receptors to accommodate the initial loss of dopamine neurons. As the disease progresses, the number of dopamine receptors decreases, apparently due to the concomitant degeneration of dopamine target sites on striatal neurons. The loss of dopaminergic neurons in Parkinson's disease results in enhanced metabolism of dopamine, augmenting the formation of H2O2, thus leading to generation of highly neurotoxic hydroxyl radicals (OH.). The generation of free radicals can also be produced by 6-hydroxydopamine or MPTP which destroys striatal dopaminergic neurons causing parkinsonism in experimental animals as well as human beings. Studies of the substantia nigra after death in Parkinson's disease have suggested the presence of oxidative stress and depletion of reduced glutathione; a high level of total iron with reduced level of ferritin; and deficiency of mitochondrial complex I. New approaches designed to attenuate the effects of oxidative stress and to provide neuroprotection of striatal dopaminergic neurons in Parkinson's disease include blocking dopamine transporter by mazindol, blocking NMDA receptors by dizocilpine maleate, enhancing the survival of neurons by giving brain-derived neurotrophic factors, providing antioxidants such as vitamin E, or inhibiting monoamine oxidase B (MAO-B) by selegiline. Among all of these experimental therapeutic refinements, the use of selegiline has been most successful in that it has been shown that selegiline may have a neurotrophic factor-like action rescuing striatal neurons and prolonging the survival of patients with Parkinson's disease.
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PMID:Oxidative stress and antioxidant therapy in Parkinson's disease. 883 Mar 46

The present study was undertaken to investigate whether the relatively selective neuronal nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), protects against methamphetamine (METH)-induced neurotoxicity. Male Swiss Webster mice received the following treatments (i.p.; q 3 h x 3): (a) vehicle/saline, (b) 7-NI (25 mg/kg)/saline, (c) vehicle/METH (5 mg/kg), and (d) 7-NI (25 mg/kg)/METH (5 mg/kg). On the second day, groups (a) and (b) received two vehicle injections, and groups (c) and (d) received two 7-NI injections (25 mg/kg, each). Administration of vehicle/METH resulted in 68, 44, and 55% decreases in the concentration of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid, respectively, and a 48% decrease in the number of [3H]mazindol binding sites in the striatum compared with control values. Treatment with 7-NI (group d) provided full protection against the depletion of dopamine and its metabolites and the loss of dopamine transporter binding sites. Administration of 7-NI/saline (group b) affected neither the tissue concentration of dopamine and its metabolites nor the binding parameters of [3H] mazindol compared with control values. 7-NI had no significant effect on animals' body temperature, and it did not affect METH-induced hyperthermia. These findings indicate a role for nitric oxide in methamphetamine-induced neurotoxicity and also suggest that blockade of NOS may be beneficial for the management of Parkinson's disease.
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PMID:The neuronal nitric oxide synthase inhibitor, 7-nitroindazole, protects against methamphetamine-induced neurotoxicity in vivo. 885 65

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

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 main neuropathological feature in Parkinson's disease (PD) is a severe degeneration of the dopaminergic neurons in the substantia nigra resulting in a loss of dopamine in the striatum. Recently, a new radioligand (beta-CIT) for single photon emission computed tomography (SPECT) became available for in vivo imaging of the dopamine transporter on nerve endings of dopaminergic neurons in the striatum. The present results demonstrate that [123I]-beta-CIT SPECT allows a discrimination between early and late PD patients. In our opinion, these preliminary data suggest that [123I]-beta-CIT SPECT should be used from now on in longitudinal studies (such as the DATATOP study) in which the effects of (putative) neuroprotective interventions in PD are monitored.
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PMID:Evaluation of [123I] beta-CIT binding with SPECT in controls, early and late Parkinson's disease. 899 76

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

Parkinsonism is most of the time caused by idiopathic Parkinson's disease (IPD). Considering the differences in therapeutic response and prognosis, in vivo discrimination between IPD and "parkinsonism-plus" syndromes is important. Recently, ligands have become available for imaging the pre- and postsynaptic dopaminergic system by Single Photon Emission Computed Tomography (SPECT). Visualization of postsynaptic D2 dopamine receptors using 123I-iodobenzamide (123I-IBZM) may contribute to the differential diagnosis between IPD and "parkinsonism-plus" syndromes as IPD is a pure presynaptic disease. Imaging of the presynaptic dopamine transporters using [123I] beta-CIT (2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) may be used as a diagnostic technique. Early disease detection in subjects suspected to be at risk for developing IPD has become possible using [123I] beta-CIT or other ligands for the dopamine transporter. Furthermore, with SPECT one is probably able to monitor in an objective way the efficacy of new pharmacological therapies.
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PMID:IBZM- and CIT-SPECT of the dopaminergic system in parkinsonism. 912 Apr 22


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