Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Bone marrow stromal cells can be used as an alternative source of cells for neural transplantation and repair. Here, the efficacy of genetically modified marrow stromal cells was examined in a rat model of Parkinson disease. Rat marrow stromal cells (rMSCs) and human marrow stromal cells (hMSCs) were genetically engineered by transduction with retroviruses encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase I, the enzyme necessary for production of the tetrahydrobiopterin cofactor for TH (BH4). Transduced cells synthesized 3,4-dihydroxyphenylalanine (L-DOPA) in vitro and maintained their multipotentiality after retroviral transduction. To examine the cells in vivo, transduced rMSCs were injected into the striatum of 6-hydroxydopamine-lesioned rats. L-DOPA and metabolites were detected by microdialysis in the denervated striatum of rats that received doubly transduced rMSCs. Also, there was a significant reduction in apomorphine-induced rotation when compared with controls. The cells engrafted and survived for at least 87 days. However, expression of the transgenes ceased at about 9 days, an observation consistent with reports from other laboratories in which similar retroviruses were used to express transgenes in the brain.
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PMID:Multipotential marrow stromal cells transduced to produce L-DOPA: engraftment in a rat model of Parkinson disease. 1054 18

Astrocytes secreting a large amount of 3,4-dihydroxyphenylalanine (dopa) were generated by adenoviral transduction of the human tyrosine hydroxylase (TH) gene. After characterizing in vitro, the effect of transplantation of these astrocytes to the striatum of hemiparkinsonian model rats was investigated. Subconfluent cortical astrocytes were infected by replication-defect adenovirus type 5 carrying the human TH-1 gene or the LacZ reporter gene under the promoter of the glial fibrillary acidic protein (AdexGFAP-HTH-1, AdexGFAP-NL-LacZ). Dopa secretion was not evident at 3 days after the transduction of the HTH-1 gene but it increased from 7 days up to at least 4 months. The secretion was substrate (tyrosine)-dependent, and was enhanced by loading tetrahydrobioputerin (BH4) concentration-dependently. One-third of the hemiparkinsonian model rats, that were transplanted the HTH-1 gene-transduced astrocytes or introduced the direct injection of the viral vector to the striatum, showed a reduction of methamphetamine-induced rotations for at least 6 weeks. Apomorphine-induced rotation was decreased to the 50% level of the control's, but the reduction was obtained equally by the transplantation of HTH-1 gene-transduced or LacZ reporter gene-transduced astrocytes, or by the introduction of HTH-1 or LacZ gene carrying adenovirus. Treatment with FK506 for 3 weeks improved the late-phase apomorphine-induced rotations following the introduction of the HTH-1 gene carrying adenovirus. Histological examination revealed that, in animals that showed a reduction of methamphetamine-rotation, the TH positive astrocytes-like cells were distributed widely in the host striatum for at least 4 weeks. The number of TH positive astrocytes-like cells and their immunoreactivity decreased after 6 weeks when OX-41 positive microglias/macrophages were infiltrated. Data indicate that the adenoviral transduction of the human TH gene to astrocytes and its introduction to the striatum is a promising approach for the treatment of Parkinson's disease. However, the further technical improvements are required to optimize the adenoviral gene delivery, such as the control of viral toxicity and the regulation of the immune response.
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PMID:Dopa-producing astrocytes generated by adenoviral transduction of human tyrosine hydroxylase gene: in vitro study and transplantation to hemiparkinsonian model rats. 1061 14

Studies with cerebrospinal fluid from subjects with Parkinson's disease suggest that purine abnormalities may be present in this disorder. The effects of purines on dopamine metabolism have not been characterized, though adenosine is known to inhibit dopaminergic neurotransmission. In this study, dopamine, its precursor 3,4-dihydroxyphenylalanine (DOPA), and its degradation products 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured in rat pheochromocytoma PC12 cells following 24-h incubation with 5, 50, and 500 microM adenosine, adenine, guanosine, guanine, hypoxanthine, xanthine, and uric acid. Incubation with adenosine increased DOPA, DOPAC, and HVA, while adenine treatment decreased DOPA. Guanosine (500 microM) decreased DOPA, dopamine, and DOPAC, while lower concentrations increased DOPAC and HVA. Incubation with guanine decreased dopamine, and xanthine decreased dopamine and DOPAC. Hypoxanthine and uric acid exerted minimal effects. These results indicate that purines exert a variety of effects on dopamine metabolism. The influence of purine metabolism on the dopaminergic deficit in the Parkinsonian brain merits further investigation.
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PMID:Purine-induced alterations of dopamine metabolism in rat pheochromocytoma PC12 cells. 1097 96

It is well known that tolerance develops to the actions of caffeine, which acts as an antagonist on adenosine A(1) and A(2A) receptors. Since selective adenosine A(2A) antagonists have been proposed as adjuncts to 3,4-dihydroxyphenylalanine (L-DOPA) therapy in Parkinson's disease we wanted to examine if tolerance also develops to the selective A(2A) receptor antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo [1,5-c]pyrimidine (SCH 58261). SCH 58261 (0.1 and 7.5 mg/kg) increased basal locomotion and the motor stimulation afforded by apomorphine. Neither effect was subject to tolerance following long-term treatment with the same doses given intraperitoneally twice daily. There were no adaptive changes in A(1) and A(2A) adenosine receptors or their corresponding messenger RNA or in dopamine D(1) or D(2) receptors. These results demonstrate that the tolerance that develops to caffeine is not secondary to its inhibition of adenosine A(2A) receptors. The results also offer hope that long-term treatment with an adenosine A(2A) receptor antagonist may be possible in man.
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PMID:Lack of tolerance to motor stimulant effects of a selective adenosine A(2A) receptor antagonist. 1104 Mar 41

We developed sample preparation methods for the detection of various biogenic phenylethylamine derivatives such as 3,4-dihydroxyphenylalanine, and their cyclisation products with aldehydes, i.e., 1,2,3,4-tetrahydroisoquinoline derivatives in blood samples. 1,2,3,4-Tetrahydroisoquinolines are considered to play an essential role as neurotoxic compounds in the pathomechanism of Parkinson's disease. We used reversed-phase high-performance liquid chromatography with ultraviolet and fluorescence detection for separation and identification. Ultrafiltration, protein precipitation and solid-phase extraction were investigated for purification of blood samples and enrichment of various compounds with a wide range of hydrophilicity and hydrophobicity. Protein precipitation by methanol and perchloric acid is a fast method to separate the analytes from the plasma matrix. A higher yield of the analytes is attained with prior addition of an alkylsulfonic acid giving a fine-grained precipitate. With the addition of ion pairing compounds into the sample it is possible to enrich not only lipophilic compounds such as norharman, tryptamine and melatonin, but also hydrophilic ones such as 3,4-dihydroxyphenylalanine by reversed-phase solid-phase extraction. Ultrafiltration is not useful as a screening method.
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PMID:Development of a method for sample preparation for subsequent identification and measurement of 1,2,3,4-tetrahydroisoquinolines and other potentially neurotoxic compounds by high-performance liquid chromatography with ultraviolet and fluorescence detection in blood plasma of Parkinson's disease patients. 1107 81

L-3,4-Dihydroxyphenylalanine (L-DOPA) is a common and effective treatment for Parkinson's disease, but dyskinesia continues to be a serious adverse effect with chronic use. Evidence suggests that L-DOPA induces increases in dopamine, which then binds to supersensitive dopamine receptors, resulting in dyskinesia. We have shown previously that L-DOPA directly causes stereotypy in rats, suggesting that chronic L-DOPA-induced dyskinesia is also caused by L-DOPA itself. This raises the possibility that other L-DOPA metabolites have a role in dyskinesia. We examined the behavioral effects of five L-DOPA metabolites (3-methoxytyramine, 3-MT; 3,4-dihydroxyphenylalanine, DOPAC; dopamine; homovanillic acid, and 3-o-methyl-DOPA) in rats. A unilateral, intracerebroventricular injection of 3-MT (10-200 microg, 40 microl) over 30 min, dose-dependently increased behavioral activity and stereotypy. This effect was suppressed by the dopamine D1/5-receptor antagonist SCH 23390, but not by the dopamine D2/3/4-receptor antagonist sulpiride. Dopamine denervation resulted in behavioral supersensitivity to 3-MT. Neither dopamine nor DOPAC levels increased in the striatum after 3-MT administration, as measured using in vivo voltammetry. The behavioral changes paralleled a rise in 3-MT in the contralateral striatum. DOPAC also caused behavioral changes and stereotypy, but to a smaller degree than 3-MT. Dopamine-denervated rats did not exhibit a supersensitive response to DOPAC, however. Other L-DOPA metabolites did not cause behavioral effects. These data suggest that 3-MT directly induced dopamine-D1/5-receptor-mediated behavioral changes in rats, and that 3-MT may have a role in dyskinesia due to chronic L-DOPA treatment in Parkinson's disease patients.
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PMID:Behavioral activity and stereotypy in rats induced by L-DOPA metabolites: a possible role in the adverse effects of chronic L-DOPA treatment of Parkinson's disease. 1187 3

Free radicals damage both lipids and proteins and evidence has accumulated for the presence of both oxidised lipids and proteins in aged tissue samples as well as those from a variety of pathologies including atherosclerosis, diabetes, and Parkinson's disease. Oxidation of the protein and lipid moieties of low-density lipoprotein is of particular interest due to its potential role in the unregulated uptake of lipids and cholesterol by macrophages; this may contribute to the initial stage of foam cell formation in atherosclerosis. In the study reported here, we examined the comparative time-courses of lipid and protein oxidation during copper-ion-mediated oxidation of low-density lipoprotein. We show that there is an early, lipid-mediated loss of 40-50% of the Trp residues of the apoB100 protein. There is no comparable loss over an identical period during the copper-ion-mediated oxidation of lipid-free BSA. Concomitant with Trp loss, the antioxidant alpha-tocopherol is consumed with subsequent extensive lipid peroxidation. Further changes to the protein, including the copper-ion-dependent 3.5-fold increase in 3,4-dihydroxyphenylalanine and the copper-ion-independent 3-5-fold increase in o-tyrosine, oxidation products of Tyr and Phe, respectively, only occur after maximal lipid peroxidation. Long incubation periods result in depletion of 3,4-dihydroxyphenylalanine, presumably reflecting further oxidative changes. Overall, copper-ion-mediated oxidation of LDL appears to proceed initially by lipid radical-dependent processes, even though some of the earliest detectable changes occur on the apoB100 protein. This is followed by extensive lipid peroxidation and subsequent additional oxidation of aromatic residues on apoB100, though it is not yet clear whether this late protein oxidation is lipid-dependent or occurs as a result of direct radical attack.
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PMID:Comparative time-courses of copper-ion-mediated protein and lipid oxidation in low-density lipoprotein. 1205 33

Historically, 3,4-dihydroxyphenylalanine (DOPA) has been considered to be an inert amino acid that alleviates the symptoms of Parkinson's disease by its conversion to dopamine via the enzyme aromatic L-amino acid decarboxylase. In contrast to this generally accepted idea, we propose that DOPA itself is a neurotransmitter and/or neuromodulator in addition to being a precursor of dopamine. Several criteria such as synthesis, metabolism, active transport, existence, physiological release, competitive antagonism and physiological or pharmacological responses must be satisfied before a compound is accepted as a neurotransmitter. Recent evidence suggests that DOPA fulfills these criteria in its involvement in baroreflex neurotransmission.
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PMID:Is DOPA a neurotransmitter? 1208 31

Catechol-O-methyltransferase (COMT) inhibitors such as entacapone and tolcapone are used as adjuncts to L-DOPA ( l-3,4-dihydroxyphenylalanine, levodopa) in the treatment of Parkinson's disease. Tolcapone has been reported to associate with diarrhoea, a common reason for study withdrawal. The mechanism of this adverse effect is not yet understood. Cholera toxin causes diarrhoea by permanent activation of G(s) proteins, resulting in increased adenylyl cyclase (AC) activity. The aim of this study was to examine the effects of the COMT inhibitors entacapone and tolcapone on AC activity in membranes isolated from rat striatum, a brain structure enriched with dopaminergic G-protein-coupled receptors and AC activity. This study demonstrates differential effects of tolcapone and entacapone on Gpp(NH)p/dopamine-stimulated AC activity. Entacapone enhanced the stimulatory effect of Gpp(NH)p/dopamine, whereas tolcapone attentuated this effect, suggesting that diarrhoea associated with tolcapone treatment is not caused by permanent activation of G(s) proteins.
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PMID:Different modes of action of catecholamine-O-methyltransferase inhibitors entacapone and tolcapone on adenylyl cyclase activity in vitro. 1211 68


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