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)

Manganese is an essential trace element for human metabolism, but at higher concentrations it is a potent neurotoxin that presents clinical symptoms similar to those of Parkinson's disease. Since the toxicity of manganese may be related to its ability to accelerate the oxidation of catecholamines, we have examined the effect of aqueous Mn2+ on the formation and decay of the dopamine semiquinone radical ion. ESR spectroscopy was used to measure the kinetics of the disappearance of the semiquinone radical spectrum and the simultaneous appearance of the six-line spectrum of aqueous Mn2+ in Tris buffer. From the proposed mechanism for the autoxidation of dopamine to the quinone, the rate expression for semiquinone radical disappearance has the functional form -rate = k'[D(OH)2][Mn2+] at constant pH and molecular oxygen concentration, while the pH dependence is given by -log(rate) = log(constant) + (2 x pH), in agreement with the experimental results. The autoxidation of dopamine is catalyzed by manganese through the formation of a highly reactive complex. The effect of manganese is due to the fact that it can participate in a redox cycle which involves intramolecular electron transfer between manganese and the dopamine ligand.
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PMID:Mechanism of the manganese-catalyzed autoxidation of dopamine. 770 54

To assess the frequency of subjective and objective dysphagia and its possible pulmonary sequelae, we prospectively studied 22 out-patients with Parkinson's disease; 15 spouses served as controls. All subjects answered a standard questionnaire concerning swallowing and respiratory functions and underwent barium swallow videofluoroscopy. Possible pulmonary infection was investigated by recordings of body temperature, ESR, leucocyte count, and chest X-ray. Patients had significantly more symptoms than controls, especially choking, piece-meal deglutition and regurgitation. Videofluoroscopy revealed tracheal aspiration in one patient, vestibular aspiration in one patient and in one control. Non-fluent swallowing movements were common in patients: abnormal bolus formation, delayed swallowing reflex, vallecular stasis, and piriform sinus residue. None of the subjects had signs of pulmonary infection. Both subjective and objective oro-pharyngeal dysfunction is frequent in ambulant Parkinson patients, but apparently does not produce demonstrable pulmonary infection.
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PMID:Dysphagia in ambulant patients with Parkinson's disease: common, not dangerous. 818 Sep 6

The interaction between sodium ascorbate and dopamine was investigated by three different parameters: radical intensity, prooxidant action, and cytotoxicity induction. Sodium ascorbate and dopamine produced the doublet and quartet ESR signals under alkaline conditions (pH 8.0-9.5), respectively. Addition of increasing concentrations of sodium ascorbate completely scavenged the dopamine radical and replaced the latter with its own radical. Similarly, dopamine slightly, but significantly reduced the radical intensity of sodium ascorbate. These two compounds stimulated the methionine oxidation and hydrogen peroxide generation in culture medium, but in combination, their stimulation activities were weakened. Both of these two compounds dose-dependently reduced the viable cell number of human oral squamous carcinoma HSC-4 cells, and their cytotoxic activity was significantly reduced by catalase. When these two compounds were mixed together before adding to HSC-4 cells, both of their cytotoxic activities were diminished. The present study demonstrates the interaction between sodium ascorbate and dopamine, which might modify their biological activities and generation of nerve disorders such as Parkinson's disease.
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PMID:Interaction between sodium ascorbate and dopamine. 987 May 54

Within the central nervous system uncontrolled production of large amounts of nitric oxide (NO) by activated glial cells might be the common pathogenesis of several neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. In the present investigation, we measured the effect of a novel antioxidant gamma-L-glutamyl-S-[2-[[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl]oxy]carbonyl]-3-[[2-(1H-indol-3-yl)ethyl]amino]-3-oxopropyl]-L-cysteinyl-glycine sodium salt (ESeroS-GS) on NO production in cultured rat astrocytes. Upon stimulation with 1 microg/mL lipopolysaccharide plus 100 U/mL interferon-gamma which induced the expression of inducible nitric oxide synthase, cultured astrocytes generated large amounts of NO as measured by nitrite assay and ESR technique. The endogenous NO caused oxidative damage in astrocytes, which was confirmed by the accumulation of both cytosolic and extracellular peroxides, the decrease in the cellular glutathione level, and the formation of thiobarbituric acid reactive substrates. Production of endogenous NO resulted in cell death finally. Pretreatment with the novel antioxidant ESeroS-GS effectively decreased the expression of iNOS gene, inhibited the formation of endogenous NO, and prevented NO-induced oxidative damage and cell death in astrocytes. The results suggest that ESeroS-GS might be used as a potential agent for the prevention and therapy of diseases associated with the overproduction of NO by activated astrocytes.
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PMID:The antioxidant ESeroS-GS inhibits NO production and prevents oxidative stress in astrocytes. 1281 68

We present for discussion a possible molecular mechanism explaining the formation of reactive oxygen species involved in the neurodegenerative process of dopaminergic system in Parkinson's disease. This new hypothesis involves one-electron reduction of aminochrome to o-semiquinone radical, which seems to be the reaction responsible for neurodegenerative process of dopaminergic system. Leukoaminochrome o-semiquinone is extremely reactive with oxygen, which reoxidizes by reducing oxygen to superoxide radicals. Superoxide radicals enzymatically or spontaneously dismutate to dioxygen and hydrogen peroxide which is a precursor of hydroxyl radicals. ESR-experiments have showed that aminochrome o-semiquinone is extremely reactive in the presence of oxygen compared to dopamine o-semiquinone. In addition, the antioxidant enzymes superoxide dismutase and catalase play a prooxidant role by increasing the autoxidation rate and formation of superoxide radicals. One electron reduction of aminochrome to o-semiquinone can be performed by flavoenzymes which use NADPH and NADH as electron donator. The ability of aminochrome o-semiquinone to autoxidize in the presence of oxygen gives rise to a redox cycling process which will continue until oxygen, NADH and/or NADPH are depleted. Depletion of NADPH will prevent glutathione reductase from reducing glutathione, which is one of the main antioxidants in the cell. In addition depletion of NADH will prevent the formation of ATP in the electron transport chain in the mitochondria. Two antioxidants, probably, neuroprotective reactions are also discussed.
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PMID:The possible role of one-electron reduction of aminochrome in the neurodegenerative process of the dopaminergic system. 1471 70

Leukoaminochrome o-semiquinone radical is generated during one-electron reduction of dopamine oxidation product aminochrome when DT-diaphorase is inhibited. Incubation of 100 microM aminochrome with 100 microM dicoumarol, an inhibitor of DT-diaphorase during 2 h, induces 56% cell death (P < 0.001) with concomitant formation of (i) intracellular hydroperoxides (4.2-fold increase compared to control; P < 0.001); (ii) hydroxyl radicals, detected with ESR and spin trapping agents (2.4-fold increase when cells were incubated with aminochrome in the presence of dicoumarol compared to aminochrome alone); (iii) intracellular edema, and cell membrane deterioration determined by transmission electron microscopy; (iv) absence of apoptosis, supported by using anexin-V with flow cytometry; (v) a strong decrease of mitochondrial membrane potential determined by the fluorescent dye 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanineiodide (P < 0.01); (vi) swelling and disruption of outer and inner mitochondrial membranes determined by transmission electron microscopy. These results support the proposed role of leukoaminochrome o-semiquinone radical as neurotoxin in Parkinson's disease neurodegeneration and DT-diaphorase as neuroprotective enzyme.
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PMID:On the neurotoxicity mechanism of leukoaminochrome o-semiquinone radical derived from dopamine oxidation: mitochondria damage, necrosis, and hydroxyl radical formation. 1519 3

Ergot derivative dopamine agonists, e.g. pergolide, bromocriptine, dihydroergocriptine used in treatment of Parkinson's disease can cause pleural, pericardial, retroperitoneal and valvular fibrotic changes. Case No 1: A 56-year-old woman with PD was treated with pergolide 3mg/24h since July 2002. In June 2003, edema of lower extremities was first noticed and echocardiography found a minor mitral regurgitation without any morphological changes of the valve. In January 2004, left- sided cardiac failure rapidly developed and echocardiography revealed multivalvular insufficiency with predominating severe mitral regurgitation. Mitral valve replacement was performed and pergolide was changed to ropinirole. Until now, neither cardiac functions nor motor status are sufficiently compensated. Case No 2: A 66-year-old-man with PD since 1996 was treated with pergolide 3 mg/day since 1999. In the beginning of 2004, leg edema appeared. On examination, bilateral hydronephrosis with ureteric strictures and incipient renal insufficiency was found. Bilateral ureteroplasty was performed and the histology showed periureteric fibrosis. Treatment with steroids was initiated and pergolide was changed to pramipexole. Despite the treatment, the fibrosis progressed, requiring ureteral stenting. Based on the literature review and on our own experience, we propose following guidelines to minimize the risk of complications: A. Not to use EAD as the first-line dopamine agonists. B. Regularly follow all patients treated with EAD, especially monitor the majorsymptoms: dyspnea, cough, fatigue, leg edema (also asymmetric), symptoms of urinary outflow obstruction, cardiac insufficiency, chest pain, heart murmur. An elevated ESR, C-reactive protein or anemia support the diagnosis. C. All symptomatic patients should undergo workup for serosal fibrosis (according to type of complication): chest X-ray or CT scan, spirometry, renal functions, renal ultrasound, CT of retroperitoneum. D. Before the introduction of EAD therapy, examine the renal functions, perform chest X-ray and echocardiography. Screening echocardiography should be performed in 3-6 months and subsequently in every 6-12 months.
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PMID:[Organ changes induced by ergot derivative dopamine agonist drugs: time to change treatment guidelines in Parkinson's disease?]. 1580

The intracellular deposition of fibrillar aggregates of alpha-synuclein is a characteristic feature of Parkinson disease. Alternatively, as a result of its unusual conformational plasticity, alpha-synuclein may fold into an amphipathic helix upon contact with a lipid-water interface. Using spin label ESR and fluorescence spectroscopy, we show here that alpha-synuclein affects the lipid packing in small unilamellar vesicles. The ESR hyperfine splittings of spin-labeled phospholipid probes revealed that alpha-synuclein induces chain ordering at carbon 14 of the acyl chains below the chain melting phase transition temperature but not in the liquid crystalline state of electroneutral vesicle membranes. Binding of alpha-synuclein leads to an increase in the temperature and cooperativity of the phase transition according to the fluorescence anisotropy of the hydrophobic polyene 1,6-diphenylhexatriene and of the fluorescence emission maxima of the amphiphilic probe 6-dodecanoyl-2-dimethylaminonaphthalene. Binding parameters were obtained from the fluorescence anisotropy measurements in combination with our previous determinations by titration calorimetry (Nuscher, B., Kamp, F., Mehnert, T., Odoy, S., Haass, C., Kahle, P. J., and Beyer, K. (2004) J. Biol. Chem. 279, 21966-21975). We also show that alpha-synuclein interacts with vesicle membranes containing sphingomyelin and cholesterol. We propose that the protein is capable of annealing defects in curved vesicle membranes, which may prevent synaptic vesicles from premature fusion.
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PMID:Binding of alpha-synuclein affects the lipid packing in bilayers of small vesicles. 1645 67

We demonstrate the use of pulsed ESR spectroscopy to measure intramolecular distances in the Parkinson's disease-associated protein alpha-synuclein bound to detergent and lysophospholipid micelles. We show that the inter-helical separation between the two helices formed upon binding to micelles is dependent on micelle composition, with micelles formed from longer acyl chains leading to an increased splaying of the two helices. Our data suggest that the topology of alpha-synuclein is not strongly constrained by the linker region between the two helices and instead depends on the geometry of the surface to which the protein is bound.
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PMID:Inter-helix distances in lysophospholipid micelle-bound alpha-synuclein from pulsed ESR measurements. 1688 16

We apply pulsed dipolar ESR spectroscopy (Ku-band DEER) to elucidate the global conformation of the Parkinson's disease-associated protein, alpha-synuclein (alphaS) bound to small unilamellar phospholipid vesicles, rodlike SDS micelles, or lipid bicelles. By measuring distances as long as approximately 7 nm between introduced pairs of nitroxide spin labels, we show that distances are close to the expectations for a single continuous helix in all cases studied. In particular, we find distances of 7.5 nm between sites 24 and 72; 5.5 nm between sites 24 and 61; and 2 nm between sites 35 and 50. We conclude that alphaS does not retain a "hairpin" structure with two antiparallel helices, as is known to occur with spheroidal micelles, in agreement with our earlier finding that the protein's geometry is determined by the surface topology rather than being constrained by the interhelix linker. While the possibility of local helix discontinuities in the structure of membrane-bound alphaS remains, our data are more consistent with one intact helix. Importantly, we demonstrate that bicelles produce very similar results to liposomes, while offering a major improvement in experimentally accessible distance range and resolution, and thus are an excellent lipid membrane mimetic for the purpose of pulse dipolar ESR spectroscopy.
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PMID:Membrane-bound alpha-synuclein forms an extended helix: long-distance pulsed ESR measurements using vesicles, bicelles, and rodlike micelles. 1877 5


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