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)

18F-Dopa positron emission tomography (PET) provides a sensitive means of quantitating the loss of nigrostriatal dopaminergic fibres in Parkinson's disease and so can be used to diagnose its presence and to objectively follow the rate of disease progression. It can also be used, in principle, to determine the efficacy of putative neuroprotective agents and has already been extensively used to monitor the viability of striatal transplants of fetal mesencephalic tissue. Loss of dopaminergic projections produces significant changes in the patterns of both resting and activated cortical function. H2(15)O PET activation studies have suggested that the akinesia of Parkinson's disease is associated with failure to activate the supplementary motor and dorsal prefrontal areas, brain regions particularly involved in motor preparation and decision making. Activation of these cortical areas can be restored by administering dopaminergic medication, implanting the striatum with fetal mesencephalic tissue, and by pallidotomy. This article reviews the insight that PET studies have provided into the pathophysiology of Parkinson's disease.
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PMID:Motor disturbance and brain functional imaging in Parkinson's disease. 938

Ascorbic acid is well known to induce noradrenaline synthesis in sympathetic nervous cells. In a series of experiments we found that incubation of the neuroblastoma cell line SK-N-SH with ascorbic acid (100-500 microM) for 2 h results in a significantly enhanced synthesis of 3,4-dihydroxyphenylalanine (DOPA) and dopamine. Additionally, cDNA-polymerase chain reaction (cDNA-PCR) analysis of relative mRNA levels corresponding to the enzymes involved in catecholamine synthesis revealed a 3-fold increase of tyrosine hydroxylase gene expression after 5 days of incubation with ascorbic acid (200 microM), whereas expression of dopamine-beta-hydroxylase was found to be unaltered. In summary the data give evidence that ascorbic acid leads to enhanced DOPA production in SK-N-SH cells by two different mechanisms: at the metabolic level after short-term incubation and by increasing the tyrosine hydroxylase gene expression after long-term incubation. Based on these data we suppose that enhancement of DOPA synthesis by ascorbic acid may be useful in the treatment of early Parkinson's disease.
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PMID:Ascorbic acid stimulates DOPA synthesis and tyrosine hydroxylase gene expression in the human neuroblastoma cell line SK-N-SH. 957 38

The potential of a novel therapeutic approach for treating Parkinson's disease, which involves the transplantation of a transfected human astrocyte cell line SVG-TH, that stably expresses the rate-limiting enzyme for dopamine production, tyrosine hydroxylase, was examined. SVG-TH and untransfected parent cells were grafted into the diseased striatum of rats in which Parkinson's disease had been induced by the administration of 6-hydroxydopamine. The in situ production and spillover of 3,4-dihydroxyphenylalanine (the precursor of dopamine), dopamine and their metabolites in the striatal extracellular fluid of the grafted rats was determined in conscious animals using the microdialysis technique and a high pressure liquid chromatography apparatus. Alleviation of symptoms of Parkinson's disease (abnormal movements) was evaluated by rotation tests. Upon transplantation of the SVG-TH cells into the striatum of the parkinsonian rats, the levels of dopamine in extracellular fluid of the striatum reached those of the normal rats, and correlated well with the improvement (74%) in their rotating behaviour (behavioural deficit). The levels of the two main dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, were low in the lesioned rats, even after SVG-TH transplantation. An alternative route of metabolism of dopamine may occur in the transplanted striatum, since the dopamine metabolite, 3-O-methoxy-4-hydroxy-phenylethylamine, appeared, which indicates activity of catechol-O-methyl transferase. Upon blockade of L-aromatic-amino acid decarboxylase, 3,4-dihydroxyphenylalanine accumulated in extracellular fluid of the 6-hydroxydopamine-lesioned and SVG-TH-grafted rats, which indicated that these cells produced active tyrosine hydroxylase in vivo. These findings indicate the potential of treating Parkinson's disease by the intrabrain grafting of human astrocyte cells transfected with the rate limiting enzyme for dopamine production.
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PMID:Dopamine turnover and metabolism in the striatum of parkinsonian rats grafted with genetically-modified human astrocytes. 962 40

A 76-year old woman was affected by lethargic encephalitis in 1918, at the age of 3 months. Long-term clinical follow-up with late neuropsychological evaluation revealed post-encephalitic parkinsonism, which worsened very slowly and was improved by levodopa. Obsessive and compulsive disorders (OCD) were associated to nosophobia. Neuropsychological evaluation showed mild visuocontructional memory deficit, which was isolated. 18 Fluoro-Dopa PET demonstrated a severe bilateral and symmetrical reduction in fluoro-dopa uptake, which was more marked in the putamen than in the caudate. Thus, the pattern of dopaminergic denervation was similar to the one observed in idiopathic Parkinson's disease.
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PMID:PET study and neuropsychological assessment of a long-lasting post-encephalitic parkinsonism. 972 Sep 76

Current accepted clinical criteria for the diagnosis of Parkinson's disease (PD) provide high sensitivity for detecting parkinsonism but generally show poor specificity for identifying brainstem Lewy body disease. Biochemical markers that can be used to reliably diagnose clinical and preclinical PD have thus far been sought unsuccessfully. It is now known that some PD kindreds have a mutation of the alpha-synuclein gene, but this cannot be used as a genetic marker for most familial and sporadic cases. Functional imaging provides a means of discriminating typical from atypical PD, revealing characteristic patterns of loss of dopaminergic function. In addition, PET and SPECT show preserved levels of striatal metabolism and dopamine receptor binding in PD, whereas levels are reduced in the atypical variants. [18F]Dopa PET can also detect preclinical PD. In one series there was a reported 40% prevalence of preclinical dopaminergic dysfunction in asymptomatic adult relatives of familial PD patients. Finally, PET and SPECT can both be used to follow PD progression objectively. Such studies suggest an annual 4 to 12% loss of dopamine terminal function in early PD and a preclinical disease window of only a few years. In the future, functional imaging is likely to play an increasingly important role in assessing the efficacy of putative neuroprotective agents.
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PMID:The early diagnosis of Parkinson's disease. 974 69

Constipation is very common in Parkinson's disease. It is still not known whether constipation is due to a slow transit of the colon or an outlet obstruction. We examined 25 patients (11 women, 14 men, mean age 62 years) with newly diagnosed idiopathic Parkinson's disease. All patients had typical clinical symptoms (with an average score of 11.4 points on the Webster scale); the diagnosis was confirmed by 18F-Dopa-PET. In all patients the colon transit time was measured with radioopaque markers. Pudendal nerve lesions were excluded by neurography of the pudendal nerve. Electromyography of the external anal sphincter was performed with concentric needle electrodes in the right and left lateral position. Colon transit time in the patients averaged 3.7 days, with pathologically prolonged transit (> 4 days) in 6 patients (24%). Four patients (16%) showed mild neurogenic changes on sphincter EMG (16%). In three other cases (12%) long duration and large amplitude of motor unit action potentials (MUAPs), and a reduced interference pattern during maximal voluntary effort indicated a severe neurogenic lesion. One patient presented with involuntary contractions of the external anal sphincter at rest, which increased during strain (anism).
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PMID:Defecatory disorders in de novo Parkinsonians--colonic transit and electromyogram of the external anal sphincter. 978 72

We have explored the role of excitatory amino acids in the increased dopamine (DA) release that occurs in the neostriatum during stress-induced behavioral activation. Studies were performed in awake, freely moving rats, using in vivo microdialysis. Extracellular DA was used as a measure of DA release; extracellular 3,4-dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase provided a measure of apparent DA synthesis. Mild stress increased the synthesis and release of DA in striatum. DA synthesis and release also were enhanced by the intra-striatal infusion of N-methyl-D-aspartate (NMDA), an agonist at NMDA receptors, and kainic acid, an agonist at the DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA)/kainate site. Stress-induced increase in DA synthesis was attenuated by co-infusion of 2-amino-5-phosphonovalerate (APV) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and AMPA/kainate receptors, respectively. In contrast, intrastriatal APV, CNQX, or kynurenic acid (a non-selective ionotropic glutamate receptor antagonist) did not block the stress-induced increase in DA release. Stress-induced increase in DA release was, however, blocked by administration of tetrodotoxin along the nigrostriatal DA projection. It also was attenuated when APV was infused into substantia nigra. Thus, glutamate may act via ionotropic receptors within striatum to regulate DA synthesis, whereas glutamate may influence DA release via an action on receptors in substantia nigra. However, our method for monitoring DA synthesis lowers extracellular DA and this may permit the appearance of an intra-striatal glutamatergic influence by reducing a local inhibitory influence of DA. If so, under conditions of low extracellular DA glutamate may influence DA release, as well as DA synthesis, by an intrastriatal action. Such conditions might occur during prolonged severe stress and/or DA neuron degeneration. These results may have implications for the impact of glutamate antagonists on the ability of patients with Parkinson's disease to tolerate stress.
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PMID:Role of excitatory amino acids in the regulation of dopamine synthesis and release in the neostriatum. 987 42

Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.
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PMID:Pharmacokinetics and pharmacodynamics of L-Dopa after acute and 6-week tolcapone administration in patients with Parkinson's disease. 1004 30

Abnormal involuntary movements, or dyskinesias, plague current symptomatic approaches to the treatment of Parkinson's disease. The neural mechanisms underlying the generation of dyskinesia following repeated l-3,4-dihydroxyphenylalanine (L-DOPA) or dopamine agonist administration in Parkinson's disease remain unknown. However, de novo administration of bromocriptine or lisuride to either l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates or patients can alleviate parkinsonian symptoms without the development of dyskinesia. In this study, we have investigated behavioral responses and alterations in the expression of opioid neuropeptide precursors preproenkephalin-A (PPE-A, encoding methionine- and leucine-enkephalin) and preproenkephalin-B (PPE-B), the precursor encoding dynorphins (dynorphin A1-17 and B1-13, leucine-enkephalin, and alpha-neoendorphin) in striatal output pathways of the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. Expression was assessed following repeated L-DOPA, bromocriptine, or lisuride administration. Given the functional organization of basal ganglia circuitry into anatomically discrete parallel circuits, we investigated alterations in peptide expression with reference to the detailed topography of the striatum. Following repeated L-DOPA administration (6.5 mg/kg, b.d., 21 days) in the 6-OHDA-lesioned rat a rotational response was observed. This became markedly enhanced with repeated treatment. We have previously characterized the pharmacology of this enhanced response and have suggested that it is a useful model for the elucidation of the cellular and molecular mechanisms underlying L-DOPA- and dopamine agonist-induced dyskinesia. In contrast to l-DOPA, de novo administration of bromocriptine (1 or 5 mg/kg, b.d., 21 days) or lisuride (0.01 or 0.1 mg/kg, b.d., 21 days) did not lead to an enhanced behavioral response. In vehicle-treated, 6-OHDA-lesioned animals, PPE-A expression was elevated rostrally and dorsally, while PPE-B expression was reduced in the striatum at all rostrocaudal levels. Repeated l-DOPA administration was accompanied by elevations in striatal PPE-B mRNA levels and a further elevation, above lesion-induced levels, in PPE-A expression. This further elevation was restricted to the dorsolateral striatum. However, following repeated bromocriptine or lisuride administration no increase in PPE-B expression was observed and the lesion-induced increase in PPE-A expression was normalized to prelesion levels. Increased PPE-A and PPE-B levels may, through decreasing GABA and glutamate release, respectively, in output nuclei of the basal ganglia, play a role in the development of L-DOPA- and dopamine-agonist induced dyskinesia in Parkinson's disease. These studies suggest that anti-parkinsonian treatments which are not associated with an elevation in PPE-B and/or normalize elevated PPE-A precursor expression, such as NMDA-receptor antagonists or long-acting dopamine D2 receptor agonists, e.g., cabergoline or ropinirole, may reduce dyskinesia in Parkinson's disease.
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PMID:Effect of repeated L-DOPA, bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat. 1007 96

Dopa-responsive dystonia (DRD) is characterized by striatal dopamine depletion with preserved nigrostriatal terminals. Patients with DRD typically obtain a marked long-term benefit from low doses of levodopa, with no motor complications. By contrast, motor fluctuations and dyskinesias often occur in idiopathic parkinsonism (Parkinson's disease; PD). This suggests that nigrostriatal denervation may be necessary for the development of these levodopa-related motor complications. Six genetically confirmed DRD cases were studied. Three of the five patients who were on chronic levodopa therapy developed choreic dyskinesias, which disappeared on reduction of medication. Apomorphine also induced dyskinesias. In addition, two patients experienced acute dystonic reactions after exposure to dopamine receptor-blocking drugs. No patient showed dose-response motor flutuations during levodopa treatment. It is proposed that striatal dopamine deficiency might play a major role in the pathogenesis of drug-induced dyskinesias. Conversely, the loss of nigrostriatal dopamine terminals seems to be a prerequisite for the development of levodopa-related motor fluctuations.
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PMID:Drug-induced motor complications in dopa-responsive dystonia: implications for the pathogenesis of dyskinesias and motor fluctuations. 1044 51


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