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 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

We present development and human application of a method for determining the regional cerebral density of the type 2 vesicular monoamine transporter (VMAT2) using positron emission tomography (PET) and [11C]dihydrotetrabenazine (DTBZ). Previous animal studies indicate striatal VMAT2 density is linearly related to the integrity of substantia nigra dopamine neurons and is not subject to drug- or lesion-compensatory regulation. In the present studies, kinetic compartmental modeling was employed to estimate blood-brain [11C]DTBZ transport (K1) and VMAT2 binding site density (tissue-to-plasma DTBZ distribution volume, DV) from the cerebral and plasma DTBZ time courses after intravenous tracer injection. In controls, we found reductions of putamen DTBZ DVwith advancing age, corresponding to losses of 0.77% per year in specific VMAT2 binding. Parkinson's disease (PD) patients had reduction in specific DTBZ DV in the putamen (-61%) and in the caudate nucleus (-43%). There was no overlap of lowest specific putamen DTBZ DV between individual elderly controls and PD patients. The present results indicate the suitability of [11C]DTBZ PET for objective quantification of nigrostriatal integrity, including evaluation of PD progression and its possible therapeutic modification.
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PMID:Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging. 900 92

The cellular expression of DAT mRNA and VMAT2 mRNA was investigated in sections of the human post-mortem substantia nigra in control and Parkinson's disease tissue using in situ hybridisation techniques. Short synthetic oligodeoxynucleotides were used to detect these gene transcripts at the cellular level. In the control human nigra, high levels of expression were seen in all sub-divisions of the substantia nigra, especially within medial regions. By contrast, the level of expression of both DAT mRNA and VMAT2 mRNA was markedly reduced in Parkinson's disease; these reductions in hybridisation signal were associated with (i) a marked loss of dopamine-containing cells in the substantia nigra, and (ii) a reduction in both DAT and VMAT2 signal per cell in the remaining pigmented neurones. These disease-related decreases in the cellular abundance of both DAT and VMAT2 gene transcripts in the surviving cells of the parkinsonian nigra may reflect compensatory changes in catecholamine signalling or may be a consequence of neuronal dysfunction.
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PMID:Dopamine transporter (Dat) and synaptic vesicle amine transporter (VMAT2) gene expression in the substantia nigra of control and Parkinson's disease. 901 52

Orally administered levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD). The introduction of levodopa therapy is often delayed, however, because of the fear that it might be toxic for the remaining dopaminergic neurons and, thus, accelerate the deterioration of patients. However, in vivo evidence of levodopa toxicity is scarce. We have evaluated the effects of a 6-month oral levodopa treatment on several dopaminergic markers, in rats with moderate or severe 6-hydroxydopamine-induced lesions of mesencephalic dopamine neurons and sham-lesioned animals. Counts of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and ventral tegmental area showed no significant difference between levodopa-treated and vehicle-treated rats. In addition, for rats of the sham-lesioned and severely lesioned groups, immunoradiolabeling for TH, the dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) at the striatal level was not significantly different between rats treated with levodopa or vehicle. It was unexpected that quantification of immunoautoradiograms showed a partial recovery of all three dopaminergic markers (TH, DAT, and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa. Furthermore, the density of TH-positive fibers observed in moderately lesioned rats was higher in those treated chronically with levodopa than in those receiving vehicle. Last, that chronic levodopa administration reversed the up-regulation of D2 dopamine receptors seen in severely lesioned rats provided evidence that levodopa reached a biologically active concentration at the basal ganglia. Our results demonstrate that a pharmacologically effective 6-month oral levodopa treatment is not toxic for remaining dopamine neurons in a rat model of PD but instead promotes the recovery of striatal innervation in rats with partial lesions.
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PMID:Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. 958 50

Early diagnosis of Parkinson's disease (PD) is important for the potential application of neuroprotective therapies. The purpose of this study was to assess the detection of the early changes of PD by either imaging the dopamine transporter (DAT) or uptake of L-3,4-dihydroxyphenylalanine (L-DOPA). An early to advanced stage model of PD was induced in rats by stereotaxic injection of 1-10 microg 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta. Using adjacent sections of the same animals, the binding of [I-125]beta-CIT, which labels DAT and the uptake of [C-14]L-DOPA, were evaluated 4 weeks after induction of the lesion. Any decrease in dopaminergic neurons was evaluated by in situ hybridization histochemistry (ISH) by detection of DAT mRNA-positive neurons. In addition, the expression levels of DAT, dopa decarboxylase (DDC), and vesicular monoamine transporter (VMAT2) in each neuron were studied with ISH. Our results show a decrease in both [I-125]beta-CIT binding and [C-14]L-DOPA uptake in parallel with a decrease in DA neurons from early to advanced stage models of PD. The decrease in [C-14]L-DOPA uptake was smaller than that in [I-125]beta-CIT binding in the same animal (P < 0.0001). Expression levels of DAT, DDC, and VMAT2 mRNAs were also decreased with the progression of the disease. Although ISH failed to detect the origin of the discrepancy between [I-125]beta-CIT and [C-14]L-DOPA levels, it was concluded that [C-14]L-DOPA levels underestimated the decrease of dopaminergic neurons and that [I-125]beta-CIT levels more precisely reflected the decrease.
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PMID:Comparison between the decrease of dopamine transporter and that of L-DOPA uptake for detection of early to advanced stage of Parkinson's disease in animal models. 1002 35

The vesicular monoamine transporter (VMAT2) has been suggested to be an excellent marker of presynaptic dopaminergic nerve terminals in the striatum of Parkinson's disease patients based on its high level of expression and insensitivity to drugs used to treat the disease. Previous in vivo imaging and postmortem binding studies have detected a loss in striatal VMAT2 binding in Parkinson's diseased (PD) brain; however, these techniques have poor spatial resolution and may suffer from nonspecific binding of some ligands. In this study, we use novel polyclonal antibodies to distinct regions of human VMAT2 to quantify and localize the protein. Western blot analysis demonstrated marked reductions in VMAT2 immunoreactivity in putamen, caudate, and nucleus accumbens of PD brain compared to control cases. Immunohistochemistry revealed VMAT2 immunoreactive fibers and puncta that were dense throughout the striatum of control brains, but which were drastically reduced in putamen of PD brains. In PD brains the caudate showed a significant degree of sparing along the border of the lateral ventricle and the nucleus accumbens was relatively preserved. The distribution of VMAT2 in striatum and its loss in PD paralleled that of the dopamine transporter (DAT), a phenotypic marker of dopamine neurons. Thus, immunochemical analysis of VMAT2 protein provides novel and sensitive means for localizing and quantifying VMAT2 protein and nigrostriatal dopamine terminals in PD. Furthermore, the relative expression of VMAT2 compared to that of DAT may predict the differential vulnerability of dopamine neurons in PD.
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PMID:Immunochemical analysis of vesicular monoamine transporter (VMAT2) protein in Parkinson's disease. 1019 85

The plasma membrane dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2) are essential for normal dopamine neurotransmission. DAT terminates the actions of dopamine by rapidly removing dopamine from the synapse, whereas VMAT2 loads cytoplasmic dopamine into vesicles for storage and subsequent release. Recent data suggest that perturbation of the tightly regulated balance between these two transporters predisposes the neurone to damage by a variety of insults. Most notable is the selective degeneration of DAT- and VMAT2-expressing dopamine nerve terminals in the striatum thought to underlie Parkinson's disease. DAT and VMAT2 expression can predict the selective vulnerability of neuronal populations, which suggests that therapeutic strategies aimed at altering DAT and VMAT2 function could have significant benefits in a variety of disorders.
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PMID:Dopamine transporters and neuronal injury. 1049 56

Epidemiological data support a relationship between pesticide exposure and Parkinson's disease; however, no experimental evidence has been provided to support this association. Here we report that subchronic administration of the organochlorine insecticide heptachlor (0, 3, 6, 9, or 12 mg/kg given 3 times over a 2 week period) leads to a pronounced increase in both the plasma membrane transport of dopamine and the expression of the plasma membrane dopamine transporter (DAT), as well as the vesicular monoamine transporter (VMAT2) in the striatum of C57BL mice. To address possible mechanisms of increased DAT and VMAT2 expression, we performed transport studies in cell lines expressing the human forms of either DAT or VMAT2. In a DAT expressing cell line, acute treatment with the putative toxic species of heptachlor, heptachlor epoxide, did not alter plasma membrane dopamine uptake. In a VMAT2 expressing cell line, heptachlor epoxide significantly inhibited vesicular uptake of dopamine (45% reduction at 10 microM). Since DAT has been proposed to be the molecular gateway for dopaminergic toxins, such as the parkinsonism-inducing neurotoxin MPP, and VMAT2 has been proposed to protect cells from MPP and other toxins by sequestering the toxin into vesicles, the combined effects of heptachlor could increase the susceptibility of the nigrostriatal dopamine system to neurodegeneration. We further propose that altered dopamine transport by exposure to pesticides may provide a molecular basis for the increased incidence of Parkinson's disease.
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PMID:Heptachlor alters expression and function of dopamine transporters. 1049 61

Methamphetamine (METH)-induced neurotoxicity within the striatum and substantia nigra of the vervet monkey was characterized by heterogeneous decreases in immunoreactivity (IR) for dopamine system phenotypic markers. Decreases in IR for tyrosine hydroxylase (TH), dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) were observed 1 week after METH HCI (2x2 mg/kg; 24 h apart). Regional changes throughout the rostrocaudal extent of the striatum were characterized by a gradient of neurotoxic effect (lateral greater than medial) and the preservation of patches of IR. The decreases in IR in the caudate and putamen were greater than those in the nucleus accumbens. The reduced IR in the METH-exposed striatum allowed for the visualization of dopamine phenotype cell bodies. Within the ventral midbrain, the METH-exposed substantia nigra pars compacta (SNc) also showed a heterogeneous loss of IR (lateral greater than medial). In contrast, the ventral tegmental area (VTA) showed only minor decreases in IR. The magnitude of the decreases in the SNc and VTA subregions corresponded to those observed in their respective striatal projection areas, suggesting that nigrostriatal neuron subpopulations were differentially reactive to METH. The profile of these drug-induced nigrostriatal dopamine system deficits resembles aspects of Parkinson's disease pathology and, as such, may provide a useful model with which to evaluate neuroprotective and neurorestorative strategies.
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PMID:Regional heterogeneity of dopaminergic deficits in vervet monkey striatum and substantia nigra after methamphetamine exposure. 1095 25


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