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)

Recently, there has been a surge in the research regarding the pharmacologic and surgical treatment of Parkinson's disease. This article reviews the latest modes of medical and surgical therapy for Parkinson's disease. The latest drug therapy has consisted of levodopa, a combination of levodopa and carbidopa (Sinemet/Sinemet CR), and monoamine oxidase type B (MAO-B) inhibitors (selegiline hydrochloride). The surgical treatment modalities have been stereotaxic implantations of dopamine-producing tissues (such as adrenal medulla and fetal mesencephalon) into the caudate nucleus and ventral pallidotomy of patients with Parkinson's disease. The most recent work has been in the field of gene therapy. The implantation of cells genetically modified to express trophic factors and tyrosine hydroxylase for the synthesis of L-dopa from tyrosine has been proposed as a possible route for the treatment of Parkinson's disease. Although the etiology of the disease is still unknown, two recent theories are discussed.
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PMID:Current trends in the pharmacologic and surgical treatment of Parkinson's disease. 893 28

SIB-1765F, a novel nicotinic acetylcholine receptor agonist, was tested for its efficacy in attenuating reserpine-induced hypolocomotion in rats. SIB-1765F was administered alone or in combination with L-DOPA and its effects were compared to those of nicotine, d-amphetamine and amantadine in the same conditions. Consistent with previous reports, reserpine-induced hypolocomotion was reversed by L-DOPA (plus benserazide), d-amphetamine and amantadine in a dose-dependent manner and the effect of L-DOPA in reserpine-treated rats was potentiated by amantadine. SIB-1765F also increased the locomotor activity of reserpine-treated rats and potentiated the effect of L-DOPA on reserpine-induced hypolocomotion. The onset of potentiation of L-DOPA by SIB-1765F was rapid (< 5 min) compared to the onset of potentiation by amantadine (> 105 min). Interestingly, nicotine did not attenuate reserpine-induced hypolocomotion nor did it affect the action of L-DOPA on reserpine-treated rats. Biochemical analysis of levels of dopamine and its metabolites, dihydroxyphenylacetic and homovanillic acid, indicated that, in contrast to amphetamine, SIB-1765F did not inhibit dopamine reuptake. The effect of SIB-1765F in reserpine-treated rats was attenuated by alpha-methyl-p-tyrosine, implying that SIB-1765F acts by releasing dopamine from both reserpine-insensitive and reserpine-sensitive pools. Our findings demonstrate that nicotinic acetylcholine receptor agonists may offer a new therapeutic approach to the symptomatic treatment of the motor deficits in patients with Parkinson's disease.
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PMID:Interactions between a novel cholinergic ion channel agonist, SIB-1765F and L-DOPA in the reserpine model of Parkinson's disease in rats. 899 20

Somatodendritic dopamine (DA) released in substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) may mediate extrasynaptic neuronal signaling. The concentration of extracellular DA ([DA]o) attained during somatodendritic activation will be governed by the density of release sites and properties of DA uptake. We evaluated these factors in SNc, VTA, and dorsal striatum with carbon-fiber microelectrodes and fast-scan cyclic voltammetry to monitor [DA]o during local electrical stimulation (10 Hz, 5 s) in guinea pig brain slices. Stimulated DA efflux was site specific, with significantly higher [DA]o in caudal (0.48 +/- 0.03 microM, mean +/- SE) than rostral SNc (0.16 +/- 0.01 microM), averaged over their mediolateral extents, and higher [DA]o in VTA (0.74 +/- 0.07 microM) than in medial (0.43 +/- 0.04 microM) or lateral SNc (0.29 +/- 0.05 microM), averaged rostrocaudally. Throughout SNc, evoked [DA]o correlated positively (r = 0.91) with the density of tyrosine-hydroxylase-immunoreactive cells. Modulation of evoked [DA]o by uptake was also site specific. The selective DA uptake inhibitor GBR 12909 significantly increased evoked [DA]o in caudal SNc (to 185 +/- 27%) and striatum (408 +/- 24%), but had no effect in rostral SNc or VTA. Conversely, the norepinephrine (NE) uptake inhibitor desipramine did not alter stimulated [DA]o in caudal SNc or striatum, but caused significant enhancement in rostral SNc (196 +/- 17%) and VTA (126 +/- 12%). Paroxetine, a selective 5-hydroxytryptamine uptake inhibitor had little effect in any region tested. Site-specific sensitivity to desipramine mandated evaluation of dopamine-beta-hydroxylase immunoreactivity (D beta H-ir) in midbrain. The density of filaments positive for D beta H-ir was greater in rostral SNc and VTA than in caudal SNc, suggesting DA clearance via the NE transporter in these regions. Importantly, D beta H-ir was most dense in sections rostral to SNc where no catecholamine signal was detected and no enhancement was observed with desipramine, indicating a lack of NE contribution to evoked release in any region examined. Taken together, these data confirmed that evoked somatodendritic [DA]o depends on DA cell density and on local uptake properties. Uptake was less efficient in SNc and VTA than in striatum. Moreover, enhancement of stimulated [DA]o by GBR 12909 demonstrated that evoked release from dendrites is not via reversal of the DA transporter. Lastly, the heterogeneous patterns of DA uptake within SNc and VTA were consistent with the pattern of degeneration in Parkinson's disease; less vulnerable DA cells, e.g., those in VTA, have less DA uptake than the more vulnerable cells of caudal SNc.
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PMID:Heterogeneity of electrically evoked dopamine release and reuptake in substantia nigra, ventral tegmental area, and striatum. 906 55

We tested the effects of clozapine, and "atypical" neuroleptic with high affinity for the D4 (dopaminergic), and the 5-HT1c and 5-HT2 (serotonergic) receptor subtypes on locomotor activity in an animal model of Parkinson's disease showing a bimodal response curve to increasing doses of a D2 agonist. Sulpiride (D2 antagonist) and ritanserin (5-HT1c and 5-HT2 antagonist) were used for comparison. The D1 agonist SKF 38393 at a dose of 8 mg/kg significantly reversed the akinesia induced by chronic reserpine treatment (1 mg/kg for 5 days) and alpha-methyl-p-tyrosine pretreatment (300 mg/kg). In this model, the addition of a low dose of a D2 agonist, LY 171555 (quinpirole, 1 microgram/kg), inhibited the effects of SKF 38393, whereas the same drug at higher doses (5-50 microgram/kg) restored and potentiated the stimulatory response to D1 stimulation. Clozapine inhibited the inhibitory phase and potentiated the stimulatory phase of the curve. Sulpiride inhibited both phases of the dose-response curve (inhibitory/stimulatory), whereas ritanserin had no effect. We believe these results may reflect a disinhibition phenomenon possible mediated by the blockade by clozapine of a subpopulation of inhibitory, dopamine (DA) receptors belonging to the D2 "family."
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PMID:Mechanism of action of clozapine-induced modification of motor behavior in an animal model of the "super-off" phenomenon. 908 73

PDZ domains are multifunctional protein-interaction motifs that often bind to the C-terminus of protein targets. Nitric oxide (NO), an endogenous signaling molecule, plays critical roles in nervous, immune, and cardiovascular function. Although there are numerous physiological functions for neuron-derived NO, produced primarily by the neuronal NO synthase (nNOS), excess nNOS activity mediates brain injury in cerebral ischemia and in animal models of Parkinson's disease. Subcellular localization of nNOS activity must therefore be tightly regulated. To determine ligands for the PDZ domain of nNOS, we screened 13 billion distinct peptides and found that the nNOS-PDZ domain binds tightly to peptides ending Asp-X-Val. This differs from the only known (Thr/Ser)-X-Val consensus that interacts with PDZ domains from PSD-95. Preference for Asp at the -2 peptide position is mediated by Tyr-77 of nNOS. A Y77D78 to H77E78 substitution changes the binding specificity from Asp-X-Val to Thr-X-Val. Guided by the Asp-X-Val consensus, candidate nNOS interacting proteins have been identified including glutamate and melatonin receptors. Our results demonstrate that PDZ domains have distinct peptide binding specificity.
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PMID:PDZ domain of neuronal nitric oxide synthase recognizes novel C-terminal peptide sequences. 909 34

Current theories regarding the mechanisms of degeneration of dopaminergic nigrostriatal neurons in Parkinson's disease suggest a pivotal role for excitotoxicity. In this study, the effects of chronic exposure of rat ventral mesencephalic slice cultures to the excititoxin N-methyl-D-aspartate, were investigated. Chronic (18 day) exposure to N-methyl-D-aspartate produced widely varying, dose-dependent effects. High doses (100 mu M) caused a pronounced toxicity upon tyrosine hydroxylase-positive neurons, with the surviving neurons possessing shrunken somata and stunted neurites: co-administration of the N-methyl-D-aspartate receptor antagonist MK-801, inhibited N-methyl-D-aspartate-induced toxicity. In contrast, exposure to a low concentration of N-methyl-D-aspartate (0.1 mu M), stimulated the outgrowth of tyrosine hydroxydase-positive neurites from the culture; this effect was abolished by MK-801. Chronic application of glutamate had similar, though not as pronounced, growth-promoting actions. However, the concentration of glutamate required was 1000 times that of N-methyl-D-aspartate, due to the presence ot high-affinity glutamate transport mechanisms. Cultures exposed to a submicromolar concentration of N-methyl-D-aspartate exhibited a significant resistance to subsequent exposure to a lethal (300 mu M) concentration of the toxin. It would thus appear that N-methyl-D-aspartate may have both trophic and toxic actions upon dopaminergic neurons in culture. Moreover, the ability of low doses of N-methyl-D-aspartate to protect neurons in this critical brain region may be of relevance to future attempts to arrest the degeneration associated with Parkinson's disease. The putative mechanisms of these phenomena are discussed.
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PMID:Neurotoxic and neurotrophic effects of chronic N-methyl-D-aspartate exposure upon mesencephalic dopaminergic neurons in organotypic culture. 915 19

We measured the CSF levels of 21, and the plasma levels of 26, amino acids in 31 patients with Parkinson's disease (PD) and in 45 matched controls. We used an ion-exchange chromatography method. When compared to controls, PD patients had lower CSF levels of taurine, alanine, valine, leucine, isoleucine, ethanolamine, citrulline, ornithine, lysine, histidine, arginine, and alpha-aminobutyric acid. PD patients not treated with levodopa or with dopamine agonists had higher CSF tyrosine and phenylalanine levels than those not treated with these drugs and also than controls. PD patients had higher plasma levels of phosphoserine, threonine, methionine, tyrosine, sarcosine and alpha-aminoadipic acid, and lower plasma levels of valine, leucine, and tryptophan, than controls. The CSF/plasma ratio of many of these amino acids was significantly lower in PD patients than those of controls, suggesting that PD patients might have a dysfunction in the transport of neutral and basic amino acids across the blood-brain barrier.
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PMID:Decreased cerebrospinal fluid levels of neutral and basic amino acids in patients with Parkinson's disease. 926 38

The concentration of catecholamines and indoleamines in the cerebrospinal fluid of patients with vascular parkinsonism (VP) was compared to that in patients with Parkinson's disease (PD) and controls. Compared to the controls, the concentration of tyrosine was significantly higher, and the concentration of L-dopa and 3-O-methyldopa (3-OMD) was significantly lower in both VP and PD patients. The balance between the 3-OMD/L-dopa and dopamine (DA)/L-dopa ratios was changed in favor of 3-OMD/L-dopa in both VP patients and PD patients suggesting the preservation of a compensatory mechanism. All these changes were less marked in VP patients than in PD patients. A remarkable finding was that in contrast to PD patients the concentration of DA and norepinephrine (NE) was significantly higher in VP patients than in the controls. The decrease in the concentration of 5-hydroxytryptamine (5-HT) was significantly greater in VP patients than in PD patients. In PD patients, the concentration of DA, NE, and 5-HT showed significant correlation with the severity of motor symptoms. In VP patients, the concentration of 5-HT alone showed significant correlation with the severity of motor symptoms and cognitive dysfunction. These findings suggest that VP patients may have similar disturbances in the DA synthesis pathway as PD patients, but differ from PD patients in that the concentrations of DA and NE are elevated and the decrease in the 5-HT concentration is greater in VP patients.
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PMID:Concentration of catecholamines and indoleamines in the cerebrospinal fluid of patients with vascular parkinsonism compared to Parkinson's disease patients. 929 76

Rats were treated intraperitoneally with a mixture of 250 mg/kg L-DOPA and 40 mg/kg carbidopa or with vehicle and sacrificed 30 min later. Plasma, heart and cortex, midbrain, brainstem and cerebellum were removed from each animal and assayed by HPLC for L-DOPA and a large number of amino acids and related amino compounds. L-DOPA levels increased from undetectable (<0.2 nmol/ml or g) to 1,146, 1,007, 399, 376, 368 and 850 nmol/ml or g in the above tissues. In addition, several amino compounds were significantly affected by L-DOPA/carbidopa (p < or = 0.01). Plasma concentrations of phosphoserine, oxidized glutathione, citrulline, phenylalanine, tyrosine and 1-methylhistidine increased and arginine, glutamic acid and lysine decreased. In the heart, concentrations of phosphoserine, taurine, reduced glutathione, threonine, serine, glutamine, glycine, alanine, valine, GABA, ethanolamine, ammonia and arginine decreased. In the cortex, camosine and homocarnosine increased. In the midbrain, valine increased and leucine, ornithine and oxidized glutathione decreased. In the cerebellum, citrulline increased. In the brainstem, threonine, serine, asparagine, glutamine, oxidized glutathione, alanine, and leucine decreased. In the brainstem, arginine was slightly decreased with a concomitant increase in citrulline (p < 0.05), indicative of nitrous oxide formation. These results show that administration of L-DOPA/ carbidopa not only raises dopamine levels but can also affect other biochemicals and that the observed changes in amino acids and related compounds can perhaps contribute to the beneficial and/or adverse effects of L-DOPA/carbidopa therapy of Parkinson's disease.
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PMID:Effects of L-DOPA/carbidopa administration on the levels of L-DOPA, other amino acids and related compounds in the plasma, brain and heart of the rat. 934 99

The purpose of this study was to investigate the influence of drugs competing for the dopamine transporter (DAT) or changing intra- and/or extracellular dopamine levels on the binding of a novel technetium-99m labeled tropane derivative, technetium, [2-[[2-[[[3-(4-chloro- phenyl)-8-methyl-8-azabicyclo[3, 2, 1]oct-2-yl]methyl] (2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3)]-oxo-[1R-(exo -exo)]-, [99mTc]TRODAT-1, to DAT. This paper describes the further characterization of [99mTc]TRODAT-1 binding sites in rats under conditions which may exist in patients receiving various drug treatments. All experiments were carried out using an i.v. injection of [99mTc]TRODAT-1 into male Sprague-Dawley rats. Measurements of % dose/gram ratio of (striatum-cerebellum)/cerebellum at 1 h post injection were used as an indicator for specific DAT binding. The biodistribution studies were performed in the presence of drugs which compete for the binding site, such as CFT (WIN 35,428) and methylphenidate, drugs which influence dopamine levels, such as L-DOPA, gamma-hydroxybutyrolactone, and alpha-methyl-p-tyrosine, and d-amphetamine, which both acts as a competitor for DAT binding and increases dopamine levels. Additionally, the influence of dopamine receptor agonists, such as apomorphine and (+)bromocriptine, on biodistribution was tested. Binding of [99mTc]TRODAT-1 to DAT was found to be inhibited by CFT, methylphenidate, and d-amphetamine in a dose-dependent manner. The specific binding of [99mTc]TRODAT-1 was not altered by dopamine receptor agonists or by drugs which cause minor changes in dopamine levels. When administered in high doses (634 micromol/kg), L-DOPA also decreased the binding of [99mTc]TRODAT-1. It is likely that a low dose of L-DOPA (normally needed in the treatment of Parkinson's disease) will not affect the results on [99mTc]TRODAT-1 single-photon emission tomographic (SPET) imaging studies. In conclusion, the results clearly demonstrate the specificity of [99mTc]TRODAT-1 binding to DAT in vivo. Competition for [99mTc]TRODAT-1 binding was observed only with drug treatment that significantly increases dopamine levels or actively competes for binding at DAT. The results suggest that prior knowledge of whether patients are receiving various drug treatments may assist in the interpretation of DAT status as assessed by SPET imaging studies using [99mTc]TRODAT-1.
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PMID:Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc]TRODAT-1 to the central dopamine transporters in rats. 939 72


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