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 (PQ, 1,1'-dimethyl-4,4'-bipyridinium), a widely-used herbicide, has been suggested as a potential etiologic factor for the development of Parkinson's disease. In recent years, many studies have focused on the mechanism(s) of PQ neurotoxicity. In this study, we examined the neuroprotective effect of manganese (III) meso-tetrakis (N,N'-diethylimidazolium) porphyrin (MnTDM), a superoxide dismutase/catalase mimetic, on PQ-induced oxidative stress and apoptosis in 1RB3AN27 (N27) cells, a dopaminergic neuronal cell line. The results indicated that MnTDM significantly attenuated PQ-induced loss of cell viability, glutathione depletion, and reactive oxygen species production. MnTDM also ameliorated PQ-induced morphological nuclear changes of apoptosis and increased rates of apoptosis. In addition, our data provide direct evidence that MnTDM suppressed PQ-induced caspase-3 cleavage, possibly a key event of PQ neurotoxicity. These observations suggested that oxidative stress and apoptosis are implicated in PQ-induced neurotoxicity and this toxicity could be prevented by MnTDM. These findings also proposed a novel therapeutic approach for Parkinson's disease and other disorders associated with oxidative stress.
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PMID:Protective effects of a new metalloporphyrin on paraquat-induced oxidative stress and apoptosis in N27 cells. 1823 74

The herbicide paraquat is a suspected etiologic factor in the development of Parkinson's disease (PD). Paraquat was therefore used to reproduce Parkinsonian syndromes in lab animals, in which it produces dopaminergic pathogenesis. However, the factors or mechanisms by which paraquat kills dopaminergic neurons are not fully understood. Based on reported evidence that paraquat increases p53 protein levels and inhibits mitochondrial function, it was hypothesized that paraquat induces cell death in dopaminergic neurons through a mechanism in which p53 and mitochondrial apoptotic pathway are linked. To explore this possibility, dopaminergic SY5Y cells were treated with paraquat for 48 h and p53 responses were investigated, as well as biomarkers of the mitochondrial intrinsic pathway of apoptosis. Paraquat significantly increased protein levels of p53 and one of its target genes, Bax. By 24 h, paraquat decreased mitochondrial complex I activity and mitochondrial transmembrane potential and induced the release of cytochrome c from mitochondria. In addition, paraquat increased the activities of caspases 9 and 3. Finally, nuclear condensation and DNA fragmentation occurred 48 h after treatment. The decrease of mitochondrial functions, the release of cytochrome c, the increase of caspase 9 and 3 activities, and DNA damage that were produced by paraquat were inhibited by a specific p53 inhibitor, pifithrin-alpha. These findings support the conclusion that paraquat produced apoptosis in SY5Y cells through the mitochondrial intrinsic pathway associated with p53.
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PMID:Paraquat-induced apoptosis in human neuroblastoma SH-SY5Y cells: involvement of p53 and mitochondria. 1825 95

An important feature of Parkinson's disease is the degeneration of dopaminergic neurons in the Substantia Nigra pars compacta. Paraquat (PQ) and MPTP cause the selective degeneration of these neurons in vivo, and combining PQ with maneb exacerbates that pathology. Elucidation of the cell death mechanisms involved is important to understand how multiple environmental toxins may contribute to sporadic Parkinson's disease. We recently reported that PQ induces neuronal apoptosis through Bak activation, in contrast to MPP(+), the toxic metabolite of MPTP, which relies on Bax and p53. Here we show that individually PQ and maneb activate Bak, but together they trigger Bax-dependent cell death. Focusing on mechanisms responsible for this synergy, we found that maneb+PQ increased the expression of three strong Bak inhibitors, Bfl-1, Bcl-xL and Mcl-1, and also induced Bax activators that included Bik and Bim. Those responses favor Bax-dependent MOMP and apoptosis. SiRNA knockdown of Bax and Bak confirmed that individually PQ and maneb induce Bak-dependent cell death, but together they block the Bak pathway and activate apoptosis through Bax.
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PMID:Maneb potentiates paraquat neurotoxicity by inducing key Bcl-2 family members. 1826 26

In order to establish causal or protective treatments for Parkinson's disease (PD), it is necessary to identify the cascade of deleterious events that lead to the dysfunction and death of dopaminergic neurons. Paraquat (PQ) is a pesticide used as xenobiotic compound to model PD. However, the mechanism(s) of PQ-induced cell death and the mechanism(s) of cytoprotection in a single cell model are still unknown. In this study, lymphocytes were treated with (0.1-1 mM) PQ. Apoptotic morphology was assessed with acridine orange/ethidium bromide staining. Further evaluation included (i) superoxide radicals, reflected by nitroblue tetrazolium reduction to formazan, (ii) the production of hydrogen peroxide, reflected by rhodamine-positive fluorescent cells, (iii) the generation of hydroxyl radicals, reflected by dimethylsulfoxide and melatonin ( radical)OH scavengers, (iv) activation and/or translocation of NF-kappaB, p53 and c-Jun transcription factors showed by immunocytochemical staining, and by ammonium pyrrolidinedithiocarbamate, pifithrin-alpha and SP600125 inhibition and (V) caspase-3 activation, reflected by caspase Ac-DEVD-cho inhibition. To elucidate the mechanism of cytoprotection, lymphocytes were treated with PQ in the presence of cannabinoids, insulin-like growth factor-1 and glucose. We provide evidence that PQ induces apoptosis in lymphocytes in a concentration- and time-dependent fashion by an oxidative stress mechanism involving O(2)( radical - ), H(2)O(2)/(( radical)OH) generation, simultaneous activation of NF-kappaB/p53/c-Jun transcription factors, mitochondrial depolarization and caspase-3 activation leading to morphological apoptosis. Moreover, dying lymphocytes are protected and rescued from PQ noxious stimuli by direct antioxidant effect by cannabinoids, receptor mediated signaling by IGF-1, and/or energetic protection by glucose. It is concluded that PQ-induced apoptosis in lymphocytes by a mechanism involving reactive oxygen species generation, mitochondrial dysfunction, transcriptional factors and caspase-3 activation. However, this cell death routine can be reversed by the action of cannabinoids, IGF-1 and glucose. These data may provide innovating therapeutic strategies to intervene environmentally or genetically susceptible PD population to oxidative stress.
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PMID:Paraquat induces apoptosis in human lymphocytes: protective and rescue effects of glucose, cannabinoids and insulin-like growth factor-1. 1836 79

Paraquat, an herbicide widely used in the agricultural industry, has been associated with lung, liver, and kidney toxicity in humans. In addition, it is linked to an increased risk of Parkinson's disease. For this reason, we had previously investigated the effects of paraquat in mice and showed that it influenced striatal nicotinic receptor (nAChR) expression but not nAChR-mediated dopaminergic function. Because nonhuman primates are evolutionarily closer to humans and may better model the effects of pesticide exposure in man, we examined the effects of paraquat on striatal nAChR function and expression in monkeys. Monkeys were administered saline or paraquat once weekly for 6 weeks, after which nAChR levels and receptor-evoked [(3)H]dopamine ([(3)H]DA) release were measured in the striatum. The functional studies showed that paraquat exposure attenuated dopamine (DA) release evoked by alpha3/alpha6beta2(*) (nAChR that is composed of the alpha3 or alpha6 subunits, and beta2; the asterisk indicates the possible presence of additional subunits) nAChRs, a subtype present only on striatal dopaminergic terminals, with no decline in release mediated by alpha4beta2(*) (nAChR containing alpha4 and beta2 subunits, but not alpha3 or alpha6) nAChRs, present on both DA terminals and striatal neurons. Paraquat treatment decreased alpha4beta2(*) but not alpha3/alpha6beta2(*) nAChR expression. The differential effects of paraquat on nAChR expression and receptor-evoked [(3)H]DA release emphasize the importance of evaluating changes in functional measures. The finding that paraquat treatment has a negative impact on striatal nAChR-mediated dopaminergic activity in monkeys but not mice indicates the need for determining the effects of pesticides in higher species.
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PMID:Paraquat exposure reduces nicotinic receptor-evoked dopamine release in monkey striatum. 1860 71

Parkinson's disease (PD) is a neurodegenerative disease that mainly affects dopaminergic (DA-ergic) neurons in the substantia nigra pars compacta (SNc). Glutamate modulates neuronal excitability, and a high concentration of glutamatergic receptors is found on DA-ergic neurons in the SNc. Paraquat (PQ) is a putative causative agent for PD. Its effects on synaptic glutamate transmission in SNc DA-ergic neurons were evaluated using whole-cell voltage-clamp recording in brain slices from 7- to 14-day-old Wistar rats. In the presence of bicuculline (BIC), strychnine, and dl-aminophosphonovaleric acid, PQ reversibly suppressed AMPA receptor-mediated evoked excitatory postsynaptic currents (eEPSCs) in a concentration-dependent manner (P<0.05). In the presence of tetrodotoxin (1 microM), PQ (50 microM) significantly reduced the amplitudes, but not the frequencies, of miniature EPSCs in the SNc, suggesting PQ inhibited eEPSCs through a postsynaptic mechanism. Exogenous application of AMPA to induce AMPA-mediated inward currents excluded involvement of a presynaptic response. The AMPA-induced currents in the SNc were significantly reduced by PQ (50 microM) to 74% of control levels (P<0.05), supporting that PQ acts on postsynaptic AMPA receptors. No effect of PQ on eEPSCs was seen in the LD thalamic nucleus and hippocampus, showing PQ specifically inhibited DA-ergic neurons in the SNc. Our results demonstrate a novel mechanism of action of PQ on glutamate-gated postsynaptic AMPA receptors in SNc DA-ergic neurons. This effect may attenuate the excitability and function of DA-ergic neurons in the SNc, which may contribute to the pathogenesis of PD.
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PMID:Paraquat inhibits postsynaptic AMPA receptors on dopaminergic neurons in the substantia nigra pars compacta. 1876 27

Parkinson's disease (PD) features oxidative stress and accumulation of misfolded (unfolded, alternatively folded, or mutant) proteins with associated loss of dopaminergic neurons. Oxidative stress and the accumulated misfolded proteins elicit cellular responses that include an endoplasmic reticulum (ER) stress response that may protect cells against the toxic buildup of misfolded proteins. Chronic ER stress and accumulation of misfolded proteins in excessive amounts, however, overwhelm the cellular 'quality control' system and impair the protective mechanisms designed to promote correct folding and degrade faulty proteins, ultimately leading to organelle dysfunction and neuronal cell death. Paraquat belongs to a class of bipyridyl herbicides and triggers oxidative stress and dopaminergic cell death. Epidemiological studies suggest an increased risk for developing PD following chronic exposure to paraquat. The present study was carried out to determine the role of paraquat in triggering cellular stress particularly ER stress and to elucidate the pathways that couple ER stress to dopaminergic cell death. We demonstrate that paraquat triggers ER stress, cell dysfunction, and dopaminergic cell death. p23, a small co-chaperone protein, is cleaved during ER stress-induced cell death triggered by paraquat and blockage of the caspase cleavage site of p23 was associated with decreased cell death. Paraquat also inhibits proteasomal activity that may further trigger accumulation of misfolded proteins resulting in ER stress. Our results indicate a protective role for p23 in PD-related programmed cell death. The data also underscore the involvement of ER, caspases, and the proteasomal system in ER stress-induced cell death process.
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PMID:Coupling endoplasmic reticulum stress to the cell death program in dopaminergic cells: effect of paraquat. 1877 10

Paraquat (PQ) (1,1-dimethyl-4,4'-bipyridinium dichloride), a widely used herbicide, has been suggested as a potential etiologic factor for the development of Parkinson's disease (PD). In this sense, understanding of the molecular mechanism underlying PQ-induced toxicity to neural cells is important for optimal use as well as for the development of new drugs. To gain insights into PQ-induced neurotoxicity, polymerase chain reaction (PCR) array analysis focused on a panel of apoptosis-related genes was performed using neuroblastoma SH-SY5Y cells. Up to 65 apoptosis-related genes were monitored. Our analysis of apoptotic process through microarray technology showed that in PQ-induced neuroblastoma SH-SY5Y cells, there is a different expression of BIK, CASP3, CASP7, CRADD, DAPK, FAS, and other related genes, in comparison to unstimulated cells. Evaluation of genes regulated differentially is essential for the development of therapeutic approaches in multifactorial diseases as PD. Our data provide a useful basis for screening candidate targets for early diagnosis and further intervention in PQ-mediated toxicity of neural cells.
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PMID:Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. 1883 21

Paraquat (1,1'-dimethyl-4,4'-bipyridinium dichloride) is widely used as a redox cycler to stimulate superoxide production in organisms, cells, and mitochondria. Paraquat is also used to induce symptoms of Parkinson's disease in experimental models of this neurodegenerative disorder. Paraquat causes extensive mitochondrial oxidative damage, and in mammalian systems, complex I of the respiratory chain has been identified as the major site of superoxide production by paraquat. Although much progress has been made at explaining how paraquat interacts with mitochondria, several aspects remain to be clarified-most notably the pathway of paraquat uptake into mitochondria. This chapter describes methods for further investigating the interaction of paraquat with mitochondria and also provides practical information for the general use of paraquat as a superoxide generator and agent of oxidative stress. The techniques covered include the detection and quantitation of the paraquat dication and the paraquat monocation radical (by electron paramagnetic resonance, spectrophotometry, and with an ion-selective electrode); assays for measuring paraquat-induced superoxide production by intact mitochondria or mitochondrial membranes (including aconitase inactivation, and coelenterazine chemiluminescence); methods for assessing paraquat uptake by mitochondria; and screens for identifying paraquat sensitivity or resistance in yeast mutants.
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PMID:Chapter 22 The uptake and interactions of the redox cycler paraquat with mitochondria. 1934 1

Oxidative stress is the common downstream effect of a variety of environmental neurotoxins that are strongly implicated in the pathogenesis of Parkinson's disease. We demonstrate here that the activation of NADPH oxidase 1 (Nox1), a specialized superoxide-generating enzyme complex, plays a key role in the oxidative stress and subsequent dopaminergic cell death elicited by paraquat. Paraquat increased the expression of Nox1 in a concentration-dependent manner in rat dopaminergic N27 cells. Rac1, a key component necessary for Nox1-mediated superoxide generation, also was activated by paraquat. Paraquat-induced reactive oxygen species generation and dopaminergic cell death were significantly reduced after pretreatment with apocynin, a putative NADPH oxidase inhibitor, and Nox1 knockdown with siRNA. Male C57BL/6 mice received intraperitoneal (IP) injections of paraquat (10 mg/kg) once every 3 days and showed increased Nox1 levels in the substantia nigra as well as a 35% reduction in tyrosine hydroxylase-positive dopaminergic neurons 5 days after the last injection. Preadministration of apocynin (200 mg/kg, IP) led to a significant decrease in dopaminergic neuronal loss. Our results suggest that Nox1-generated superoxide is implicated in the oxidative stress elicited by paraquat in DA cells, and it can serve as a novel target for pharmacologic intervention.
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PMID:The role of NADPH oxidase 1-derived reactive oxygen species in paraquat-mediated dopaminergic cell death. 1945 58


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