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)

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese (Mn) compound added to unleaded gasoline. It has been suggested that the combustion products of MMT containing Mn, such as manganese phosphate, could cause neurological symptoms similar to Parkinson's disease in humans. The aim of this work was to investigate the exposure-response relationship of bioaccumulation, neuropathology, and neurobehavior following a subchronic inhalation exposure to manganese phosphate in Sprague-Dawley male rats. Rats were exposed 6 h/day, 5 days/week for 13 consecutive weeks at 30, 300, or 3000 microg/m(3) Mn phosphate and compared to controls. Some rats were implanted with chronic EMG electrodes in the gastrocnemius muscle of the hind limb to assess tremor at the end of Mn exposure. Spontaneous motor activity was measured for 36 h using a computerized autotrack system. Rats were then sacrificed by exsanguination and Mn level in different brain tissues and other organs was determined by instrumental neutron activation analysis. Neuronal cell counts were obtained by assessing the sum of five grid areas for the caudate/putamen and the sum of two adjacent areas for the globus pallidus. Increased manganese concentrations were observed in all tissues of the brain and was dose-dependent in olfactory bulb and caudate/putamen. In fact, beginning with the highest level of exposure (3000 microg/m(3)) and ending with the control group, Mn concentrations in the olfactory bulb were 2.47 vs 1.28 vs 0.77 vs 0.64 ppm (P < 0.05) while for the caudate/putamen, Mn concentrations were 1.06 vs 0.73 vs 0.62 vs 0.47 ppm (P < 0.05). The Mn concentrations in lung were also dose-dependent (10.30 vs 1.40 vs 0.42 vs 0.17 ppm; P < 0.05). No statistical difference was observed for loss of neurons in caudate/putamen and globus pallidus. Locomotor activity assessment and tremor assessment did not reveal in neurobehavioral changes between the groups. Our results reinforce the hypothesis that the olfactory bulb and caudate/putamen are the main brain tissues for Mn accumulation after subchronic inhalation exposure.
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PMID:Assessment of bioaccumulation, neuropathology, and neurobehavior following subchronic (90 days) inhalation in Sprague-Dawley rats exposed to manganese phosphate. 1238 53

High levels of neuropeptide Y (NPY) are found in basal ganglia where it is co-localised with somatostatin (SOM) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH/d) in a population of striatal GABA containing interneurones. Although alterations occur in the levels of various neuropeptides in basal ganglia in Parkinson's disease (PD), it is not known whether NPY is affected. Using in situ hybridisation immunohistochemistry, we have examined the distribution of NPY mRNA in the caudate nucleus, putamen and nucleus accumbens of normal individuals and patients with PD. NPY mRNA was weakly expressed in the caudate nucleus, putamen and nucleus accumbens in normal individuals with a scattered labelling of neurones. However, there was no regional localisation within any brain area and no obvious differences between brain regions. In PD, the number of NPY mRNA-expressing cells was increased as was the density of the silver grains overlying each positive cell. The increase was more pronounced in the nucleus accumbens and in the ventral part of the caudate nucleus. The increase in NPY mRNA expression observed in patients with PD may reflect the loss of dopaminergic tone on striatal NPY containing interneurones, although a role for chronic L-DOPA therapy cannot be ruled out.
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PMID:Increased neuropeptide Y mRNA expression in striatum in Parkinson's disease. 1259 Nov 54

Parkinson's disease is the second most common neurodegenerative disorder, and the cause is unknown; however, substantial evidence implicates the aggregation of alpha-synuclein as a critical factor in the etiology of the disease. alpha-Synuclein is a relatively abundant brain protein of unknown function, and the purified protein is intrinsically unfolded. The amino acid sequence has seven repeats with an apolipoprotein lipid-binding motif, which are predicted to form amphiphilic helices. We have investigated the interaction of alpha-synuclein with lipid vesicles of different sizes and properties by monitoring the effects on the conformation of the protein and the kinetics of fibrillation. The nature of the interaction of alpha-synuclein with vesicles was highly dependent on the phospholipid composition, the ratio of alpha-synuclein to phospholipid, and the size of the vesicles. The strongest interactions were between alpha-synuclein and vesicles composed of 1,2-dipalmitoyl-sn-glycero-3-phosphate/1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phospho-RAC-(1-glycerol)/1,2-dipalmitoyl-sn-glycero-3-phosphocholine and involved formation of helical structure in alpha-synuclein. A strong correlation was observed between the induction of alpha-helix in alpha-synuclein and the inhibition of fibril formation. Thus, helical, membrane-bound alpha-synuclein is unlikely to contribute to aggregation and fibrillation. Given that a significant fraction of alpha-synuclein is membrane-bound in dopaminergic neurons, this observation has significant physiological significance.
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PMID:Lipid binding inhibits alpha-synuclein fibril formation. 1262 Oct 30

The pre-synaptic protein, alpha-synuclein, has been associated with the pathogenesis of Parkinson's disease. The present study indicates that alpha-synuclein, but not its mutants (A53T, A30P), can protect CNS dopaminergic cells from the parkinsonism-inducing drug 1-methyl-4-phenylpyridinium (MPP+), whereas it cannot protect from the dopaminergic toxin, 6-hydroxydopamine, hydrogen-peroxide, or the beta-amyloid peptide, A-beta. Protection from MPP+ was directly correlated with the preservation of mitochondrial function. Specifically, alpha-synuclein rescued cells from MPP+ mediated decreases in mitochondrial dehydrogenase activity and loss of ATP levels by utilizing ketosis. It also prevented toxin-induced activation of the creatine kinase/creatine phosphate system. Similarly, alpha-synuclein protected cells from the complex I inhibitor rotenone and 3-nitroproprionic acid, a complex II inhibitor. Wild-type alpha-synuclein-mediated neuroprotection and subsequent alterations in energy were not found in dbcAMP-differentiated cells. These results suggest that the normal physiological role for alpha-synuclein may change during development.
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PMID:Alpha-synuclein protects naive but not dbcAMP-treated dopaminergic cell types from 1-methyl-4-phenylpyridinium toxicity. 1280 39

Rotenone, a widely used pesticide, causes a syndrome in rats that mimics, both behaviorally and pathologically, the symptoms of Parkinson's disease. The present study evaluated the role of nitric oxide in rotenone-induced nigro-striatal injury. After administration of rotenone in rats for 40 days, there was a moderate but significant injury of the nigro-striatal pathway indicated by a 47% decrease in striatal dopamine levels and a 28% loss of substantia nigra tyrosine hydroxylase-immunopositive neurons. Furthermore, a significant (37%) increase in the number of cells positive for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) in the striatum was observed, accompanied by a 83% increase in nitric oxide synthase (NOS) activity and a significant increase in the production of 3-nitrotyrosine (3-NT). There was a significant increase (45%) in the optical density of NADPH-d staining and an increase (72%) in NOS activity in the substantia nigra. Moreover, administration of the neuronal NOS inhibitor 7-nitroindazole significantly attenuated the increased NOS activity and 3-NT production, and provided significant protection against rotenone-induced nigro-striatal injury. Our data suggest that chronic rotenone administration can lead to significant injury to the nigro-striatal system, mediated by increased generation of nitric oxide.
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PMID:Role of nitric oxide in rotenone-induced nigro-striatal injury. 1295 Apr 43

The aim of the present study was to assess degenerative changes in the nitric oxide (NO) system of basal ganglia in animals with experimentally induced Parkinson's disease. In one procedure, rats were stereotaxically injected with 6-hydroxydopamine (6-OHDA) in the right medial forebrain bundle; in a second procedure, electrodes were implanted in the right substantia nigra pars compacta (SNc). After 15 and 30 days animals were tested for rotational asymmetry induced by apomorphine. Apomorphine induced rotation in lesioned animals, towards the ipsilateral side after electrolytic lesion and towards contralateral side in 6-OHDA animals. Structural deficits in basal ganglia were quantified by nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and by nitric oxide synthase (NOS) immunoreactivity. 6-OHDA and electrolytic lesions induced a significant decrease in the number of NADPH-d/NOS positive cells in the lesion ipsilateral to SNc, in contrast with cell number increase in the ipsilateral dorsal striatum. By contrast, 6-OHDA-treated animals showed a decrease in the number of NOS immunoreactive cells in the contralateral nucleus accumbens. We conclude that populations of NO-synthesizing neurons are differentially regulated in Parkinson's disease induced by different experimental procedures.
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PMID:Effects of electrolytic and 6-hydroxydopamine lesions of rat nigrostriatal pathway on nitric oxide synthase and nicotinamide adenine dinucleotide phosphate diaphorase. 1463 84

The central nervous system is an important target for manganese (Mn) intoxication in humans; it may cause neurological symptoms similar to Parkinson's disease. Manganese compounds emitted from the tailpipe of vehicles using methylcyclopentadienyl manganese tricarbonyl (MMT) are primarily Mn phosphate, Mn sulfate, and Mn phosphate/sulfate mixture. The purpose of this study is to compare the patterns of Mn distribution in various brain regions (olfactory bulb, frontal parietal cortex, globus pallidus, striatum and cerebellum) and other tissues (lung, liver, kidney, testis) and the neurobehavioral damage following inhalation exposure of rats to three Mn species. Rats (n=15 rats per Mn species) were exposed 6 h per day, 5 days per week for 13 consecutive weeks to metallic Mn, Mn phosphate or Mn phosphate/sulfate mixture at about 3000 microgm(-3) and compared to controls. At the end of the exposure period, spontaneous motor activity was measured for 36 h using a computerized autotrack system. Mn in tissues was determined by instrumental neutron activation analysis (INAA). The Mn concentrations in the brain were significantly higher in rats exposed to Mn phosphate and Mn phosphate/sulfate mixture than in control rats or rats exposed to metallic Mn. Exposure to Mn phosphate/sulfate mixture caused a decrease in the total ambulatory count related to locomotor activity. Our results confirm that Mn species and solubility have an influence on the brain distribution of Mn in rats.
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PMID:Manganese distribution in the brain and neurobehavioral changes following inhalation exposure of rats to three chemical forms of manganese. 1501 6

Numerous research has pointed out that serotonin2c (5-HT2C) receptor, a subtype of 5-HT receptors belonging to the G-protein-coupled receptor superfamily, modulates the activity of mesencephalic dopamine (DA) neurons, the dysfunction of which is involved in devastating diseases such as schizophrenia, Parkinson's disease, and drug addiction. In the present study, using in vivo intracerebral microdialysis and Chinese hamster ovary (CHO) cells expressing 5-HT2C receptors to identify appropriate 5-HT2C receptor ligands, we sought to determine whether the property of 5-HT2C receptors to spontaneously activate intracellular signaling pathways in vitro (constitutive activity) participates in the tonic inhibitory control that they exert on DA release in the rat striatum and nucleus accumbens in vivo. In CHO cells, the purported antagonist 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole hydrochloride (SB 206553), but not 6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridin-3-yl carbamoyl] indoline (SB 242084), decreased basal inositol phosphate accumulation, thus behaving as a 5-HT2C inverse agonist. Its effect was prevented by SB 242084. In vivo, SB 206553 (1-10 mg/kg) elicited a dose-dependent and clear-cut increase in accumbal and striatal DA release compared with SB 242084 (1-10 mg/kg), and the 5-HT2C agonist S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine hydrochloride (Ro-60-0175) (0.3-3 mg/kg) inhibited DA release. Pretreatment by SB 242084 reversed the change in DA release elicited by Ro-60-0175 and SB 206553. Furthermore, SB 206553-stimulated DA release was insensitive to reduction of 5-HT neuronal function induced by the 5-HT1A agonist (+/-)-8-hydroxy-2-dipropylaminotetralin or intra-raphe injections of 5,7-dihydroxytryptamine neurotoxin. The obtained results provide the first in vivo evidence that constitutive activity of the 5-HT2C receptor tonically inhibits mesencephalic DA neurons and underscore the need for a better understanding of the pathophysiological role of constitutive receptor activity.
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PMID:Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. 1505 2

In 0.1 M phosphate buffer, pH 7.4, dopamine reacts with glyoxal, a cytotoxic and genotoxic alpha-oxoaldehyde produced by oxidative degradation of carbohydrates, to give three main products, two of which could be isolated and identified as the isomeric tetrahydrobiisoquinolines 1 and 2 by extensive two-dimensional NMR and mass spectrometric analysis. Time course studies indicated that 1 is the first intermediate in the process and changes slowly to 2 via an unstable species that escaped all efforts at isolation and structural identification. Products 1 and 2 were detected also among the species formed by the interaction of dopamine with oxidized carbohydrates, such as glucose, ribose, and fructose. Mechanistic evidence suggests that the formation of 1 proceeds by an unusual reaction pathway involving intramolecular cyclization of a double Schiff base intermediate followed by glyoxal-induced oxidation of the resulting octahydrobiisoquinoline intermediate (4). Subsequent conversion of 1 to 2 would involve a complex redox mechanism depending on an initial oxidation step. Product 2 was only poorly toxic to PC12 cells, whereas its methylated derivative 3 was as toxic as salsolinol, an established neurotoxin. Overall, these results throw light on a novel pathway of dopamine modification of potential relevance to the mechanisms underlying neurodegenerative changes in Parkinson's disease and other disorders characterized by a prooxidant state.
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PMID:Tetrahydrobiisoquinoline derivatives by reaction of dopamine with glyoxal: a novel potential degenerative pathway of catecholamines under oxidative stress conditions. 1537 52

Reactive oxygen species derived from dopamine metabolism can induce oxidative stress and thus may contribute to Parkinson's disease (PD) pathogenesis. The quinone oxidoreductases, nicotinamide adenine dinucleotide (phosphate) (NAD[P]H): quinone oxidoreductase 1 (NQO1) and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) detoxify quinones and quinonoid compounds. We investigated associations of genetic polymorphisms of NQO1 (C609T) and NQO2 (I/D, 29 base pairs) with PD in a population-based case-control study of 190 idiopathic PD cases and 305 unrelated controls matched on age and sex. No associations were detected for either gene variant or for any allele combinations.
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PMID:No associations between Parkinson's disease and polymorphisms of the quinone oxidoreductase (NQO1, NQO2) genes. 1569 56


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