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)

Paraquat structurally resembles N-methyl-4-phenyltetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenylpyridine (MPP+). MPTP and MPP+ are neurotoxic chemicals, which induce in exposed humans and in animal-models a Parkinson's disease. A high correlation between the incidence of Parkinson's disease and herbicide use in Canada led to the assumption that paraquat could give rise to parkinsonism. We have therefore carried out a follow-up study with patients having had dermal contact with paraquat or having swallowed paraquat accidentally or in a suicidal attempt. 7 patients took part in the study. Three of them had dermal contact. One had ingested paraquat by accident and three were survivors from suicidal paraquat intake. It was possible to exclude parkinsonism in all patients. One patient exhibited tardive dykinesia most likely due to a long term therapy with neuroleptic drugs.
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PMID:[No Parkinsonian syndrome following acute paraquat poisoning]. 290 65

In 1984 we made the first observation of a correlation between early age exposure to rural environment (and drinking well water) and development of idiopathic Parkinson's disease (IPD). These findings were subsequently confirmed elsewhere (Barbeau, 1985;25 Tanner, 1985). Analysis of all early age onset IPD (EPD) cases born and raised in Saskatchewan revealed that 20 of 22 had exclusively rural exposure during the first 15 years of life. This distribution was significantly different from the general population (p = 0.0141). Further study of the EPD group included sampling and metal analysis of childhood sources of drinking water in 18 cases and 36 age and sex-matched controls. Water collected from the two groups was analyzed for 23 metals (including 7 elements implicated in the etiology of IPD). There was no difference in the metal composition of the water between the two groups. Finally, a review of herbicide and pesticide use in Saskatchewan agriculture was undertaken to determine if there was an increased incidence of EPD following utilization of any particular chemical. No increase was found in the incidence of EPD with the introduction of any pesticide or herbicide, including Paraquat, for agricultural use. We conclude that there is a strong correlation between early age rural environmental exposure and development of IPD. We believe well water is a likely vehicle for the causal agent, but neither water metal concentration nor any of the herbicides and pesticides used in Saskatchewan agriculture are related to the cause.
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PMID:Geography, drinking water chemistry, pesticides and herbicides and the etiology of Parkinson's disease. 367 17

Paraquat was reduced to the paraquat radical via complex I in bovine cerebral mitochondria and accelerated lipid peroxidation. Thirty-kilodalton subunit of complex I was considered to be the radical formation site, because of its marked destruction by the paraquat radical. The lipid peroxidation by the paraquat radical was suppressed not only by superoxide dismutase (SOD) but also by mannitol. The destruction of complex I subunits via lipid peroxidation must have been caused by the hydroxyl radical which was formed from the superoxide radical. The same phenomenon was observed by using 1-methylnicotinamide (MNA), which contains the same partial structure as paraquat in itself and is metabolized from nicotinamide in a living body. We observed NADH oxidation by MNA via cerebral complex I (Km = 26.3 mM), and MNA destroyed some complex I subunits, especially 30-kilodalton protein. Paraquat might be useful for studying the pathogenesis of Parkinson's disease (PD) in vitro, and MNA is expected to be one of the causal substances of PD from the viewpoint of the oxidative stress theory.
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PMID:Radical formation site of cerebral complex I and Parkinson's disease. 858 7

Paraquat has been implicated as an environmental toxin which may induce the syndrome of Parkinson's disease after exposure to this agent. However, the biochemical mechanism by which paraquat causes cell death and neurodegeneration has not been extensively studied. Paraquat was rapidly taken up by nerve terminals isolated from mouse cerebral cortices. It induced lipid peroxidation in a concentration dependent manner in the presence of NADPH and ferrous ion. The maximal stimulation effect was obtained at a paraquat concentration around 100 microM and the Km value for paraquat was 46.7 microM. The lipid peroxidation required microsomal enzymes. Antioxidants, such as superoxide dismutase, catalase and promethazine significantly inhibited paraquat-induced lipid peroxidation. Due to its structural similarity to the pyridinium compound MPP+ (N-methyl-4-phenyl pyridium ion), it may be taken up by dopamine neurons and cause lipid peroxidation and cell death resulting in the manifestation of Parkinsonian syndrome.
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PMID:Paraquat-induced free radical reaction in mouse brain microsomes. 948 66

Paraquat was taken up by PC12 cells in a carrier-mediated, saturable manner. When PC12 cells were permeabilized with digitonin (50 microg/ml) lipid peroxidation was observed after paraquat treatment in the presence of NADPH and chelated iron. The fact that lipid peroxidation preceded the appearance of LDH release provides positive evidence that lipid peroxidation may be one of the important factors leading to cytotoxicity of cells. Furthermore, the fact that addition of superoxide dismutase, catalase and promethazine efficiently blocked the malondialdehyde formation and attenuated the cell death indicated the involvement of reactive oxygen radicals in mediating the cytotoxicity induced by paraquat. Taken together the results present in vitro evidence that neurotoxicity of paraquat may be a consequence of cellular lipid peroxidation, which leads to cell death and may have great implications in assessing the risk of exposure to paraquat in Parkinson's disease.
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PMID:Paraquat-induced cell death in PC12 cells. 981 49

alpha-Synuclein-containing aggregates represent a feature of a variety of neurodegenerative disorders, including Parkinson's disease (PD). However, mechanisms that promote intraneuronal alpha-synuclein assembly remain poorly understood. Because pesticides, particularly the herbicide paraquat, have been suggested to play a role as PD risk factors, the hypothesis that interactions between alpha-synuclein and these environmental agents may contribute to aggregate formation was tested in this study. Paraquat markedly accelerated the in vitro rate of alpha-synuclein fibril formation in a dose-dependent fashion. When mice were exposed to the herbicide, brain levels of alpha-synuclein were significantly increased. This up-regulation followed a consistent pattern, with higher alpha-synuclein at 2 days after each of three weekly paraquat injections and with protein levels returning to control values by day 7 post-treatment. Paraquat exposure was also accompanied by aggregate formation. Thioflavine S-positive structures accumulated within neurons of the substantia nigra pars compacta, and dual labeling and confocal imaging confirmed that these aggregates contained alpha-synuclein. The results suggest that up-regulation of alpha-synuclein as a consequence of toxicant insult and direct interactions between the protein and environmental agents are potential mechanisms leading to alpha-synuclein pathology in neurodegenerative disorders.
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PMID:The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. 1170 29

Alpha-synuclein is likely to play a role in neurodegenerative processes, including the degeneration of nigrostriatal dopaminergic neurons that underlies Parkinson's disease. However, the toxicological properties of alpha-synuclein remain relatively unknown. Here, the relationship between alpha-synuclein expression and neuronal injury was studied in mice exposed to the herbicide paraquat. Paraquat neurotoxicity was compared in control animals versus mice with transgenic expression of human alpha-synuclein driven by the tyrosine hydroxylase (TH) promoter. In control mice, paraquat caused both the formation of alpha-synuclein-containing intraneuronal deposits and the degeneration of nigrostriatal neurons, as demonstrated by silver staining and a reduction of the counts of TH-positive and Nissl-stained cells. Mice overexpressing alpha-synuclein, either the human wild-type or the Ala53Thr mutant form of the protein, displayed paraquat-induced protein aggregates but were completely protected against neurodegeneration. These resistant animals were also characterized by increased levels of HSP70, a chaperone protein that has been shown to counteract paraquat toxicity in other experimental models and could therefore contribute to neuroprotection in alpha-synuclein transgenic mice. The results indicate a dissociation between toxicant-induced alpha-synuclein deposition and neurodegeneration. They support a role of alpha-synuclein against toxic insults and suggest that its involvement in human neurodegenerative processes may arise not only from a gain of toxic function, as previously proposed, but also from a loss of defensive properties.
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PMID:Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. 1271 14

Paraquat (1,1'-dimethyl-4,4'-bipyridinium, PQ) is a herbicide to possibly induce Parkinson's disease (PD), since a strong correlation has been found between the incidence of the disease and the amount of PQ used. In this study, we examined PQ toxicity in rat organotypic midbrain slice cultures. PQ dose dependently reduced the number of dopaminergic neurons in cultured slices. Since this damage was prevented by GBR-12909, the dopamine transporter could be an initial step of the PQ induced dopaminergic neurotoxicity. The sequential treatments with lower PQ and 1-methyl-4-phenyl pyridinium (MPP+) doses, where each dose alone was not lethal, markedly killed dopamine neurons, suggesting that the exposure of a lower dose of PQ could lead to the vulnerability of dopaminergic neurons. This cell death was prevented by the inhibitors of NMDA, nitric oxide synthase (NOS), cycloheximide and caspase cascade. Neurons expressing NOS were identified inside and around the regions where dopamine neurons were packed. The cell death induced by the sequential treatments with PQ and MPP+ was also rescued by L-deprenyl and dopamine D2/3 agonists. These results strongly support that the constant exposure to low levels of PQ would lead to the vulnerability of dopaminergic neurons in the nigrostriatal system by the excitotoxic pathway, and might potentiate neurodegeneration caused by the exposure of other substances and aging.
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PMID:Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture. 1287 74

While advancing age is the only unequivocally accepted risk factor for idiopathic Parkinson's disease, it has been postulated that exposure to environmental neurotoxicants combined with ageing could increase the risk for developing Parkinson's disease. The current study tested this hypothesis by exposing C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb-induced reductions in locomotor activity and motor coordination were age dependent, with 18-month-old mice most affected and exhibiting failure to recover 24 h post-treatment. Three months post-treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5-month-old and further reduced in 18-month-old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18-month-old paraquat + maneb and paraquat groups 3 months post-treatment. Increased tyrosine hydroxylase enzyme activity compensated for striatal tyrosine hydroxylase protein and/or dopamine loss following treatment in 6-week-old and 5-month-old, but not 18-month-old paraquat and paraquat + maneb mice. Numbers of nigrostriatal dopaminergic neurons were reduced in all age groups following paraquat alone and paraquat + maneb exposure, but these losses, along with decreases in striatal tyrosine hydroxylase protein levels, were progressive in 18-month-old paraquat and paraquat + maneb groups between 2 weeks and 3 months post-exposure. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity.
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PMID:Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype. 1291 55

We examined the toxicity of paraquat, a possible environmental risk factor for neurodegenerative disorders like Parkinson's disease (PD). Paraquat is structurally similar to the neurotoxin MPP+ that can induce Parkinsonian-like features in rodents, non-human primates and human. Exposure of cerebellar granule cells to relatively low concentrations of paraquat (5 microM) produces apoptotic cell death with a reduction in mitochondrial cytochrome c content, proteolytic activation and caspase-3 activity increase and DNA fragmentation. Paraquat-induced apoptosis was significantly attenuated by co-treatment of cerebellar granule cells with the radical scavenger vitamin E, suggesting that paraquat-induced free radicals serve as important signal in initiation of cell death. As a decrease in mitochondrial cytochrome c content is also prevented by allopurinol, we suggest that xanthine oxidase plays an important role in the free radical production that precedes the apoptotic cascade and cell death after paraquat exposition.
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PMID:Paraquat-induced apoptotic cell death in cerebellar granule cells. 1515 3


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