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)

Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
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PMID:Free radicals and antioxidants in normal physiological functions and human disease. 1697 5

We investigated whether the cytokines produced in activated microglia in the substantia nigra (SN) and putamen in sporadic Parkinson's disease (PD) are neuroprotective or neurotoxic. In autopsy brains of PD, the number of MHC class II (CR3/43)-positive activated microglia, which were also ICAM-1 (CD 54)-, LFA-1 (CD 11a)-, TNF-alpha-, and IL-6-positive, increased in the SN and putamen during progress of PD. At the early stage activated microglia were mainly associated with tyrosine hydroxylase (TH)-positive neurites in the putamen, and at the advanced stage with damaged TH-positive neurons in the SN. The activated microglia in PD were observed not only in the nigro-striatal region, but also in various brain regions such as the hippocampus and cerebral cortex. We examined the distribution of activated microglia and the expression of cytokines and neurotrophins in the hippocampus of PD and Lewy body disease (LBD). The levels of IL-6 and TNF-alpha mRNAs increased both in PD and LBD, but those of BDNF mRNA and protein drastically decreased specifically in LBD, in which neuronal loss was observed not only in the nigro-striatum but also in the hippocampus. The results suggest activated microglia in the hippocampus to be probably neuroprotective in PD, but those to be neurotoxic in LBD. As an evidence supporting this hypothesis, two subsets of microglia were isolated from mouse brain by cell sorting: one subset with high production of reactive oxygen species (ROS) and the other with no production of ROS. When co-cultured with neuronal cells, one microglia clone with high ROS production was neurotoxic, but another clone with no ROS production neuroprotective. On the other hand, Sawada with coworkers found that a neuroprotective microglial clone in a culture experiment converted to a toxic microglial clone by transduction of the HIV-1 Nef protein with increasing NADPH oxidase activity. Taken together, all these results suggest that activated microglia may change in vivo from neuroprotective to neurotoxic subtsets as degeneration of dopamine neurons in the SN progresses in PD. We conclude that the cytokines from activated microglia in the SN and putamen may be initially neuroprotective, but may later become neurotoxic during the progress of PD. Toxic change of activated microglia may also occur in Alzheimer's disease and other neurodegenerative diseases in which inflammatory process is found.
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PMID:Role of cytokines in inflammatory process in Parkinson's disease. 1701 56

Increasing evidence suggests that reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, act as necessary signaling molecules in processes underlying cognition. Moreover, ROS have been shown to be necessary in molecular process underlying signal transduction, synaptic plasticity, and memory formation. Research from several laboratories suggests that NADPH oxidase is an important source of superoxide in the brain. Evidence is presented here to show that ROS are in fact important signaling molecules involved in synaptic plasticity and memory formation. Moreover, evidence that the NADPH oxidase complex is a key regulator of ROS generation in synaptic plasticity and memory formation is discussed. Understanding redox signaling in the brain, including the sources and molecular targets of ROS, are important for a full understanding of the signaling pathways that underlie synaptic plasticity and memory. Knowledge of ROS function in the brain also is critical for understanding aging and neurodegenerative diseases of the brain given that several of these disorders, including Alzheimer's disease and Parkinson disease, may be exacerbated by the unregulated generation of ROS.
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PMID:Sources and targets of reactive oxygen species in synaptic plasticity and memory. 1711 36

Pyrethroids are a class of insecticides involved in different neurological disorders. They cross the blood-brain barrier and exert their effect on dopaminergic system, contributing to the burden of oxidative stress in Parkinson's disease through several pathways. The aim of the present study was to evaluate the effect of neonatal exposition to permethrin and cypermethrin (1/10 of DL(50)) in rats from the eighth to the fifteenth day of life. Open-field studies showed increased spontaneous locomotor activity in the groups treated with permethrin and the one treated with cypermethrin, while a higher number of center entries and time spent in the center was observed for the cypermethrin-treated group. Lower dopamine and higher homovanillic acid levels were measured in the striatum from both treated groups. A reduction of blood glutathione peroxidase content was measured, while no change in blood superoxide dismutase was observed. Carbonyl group formation increased in striatum, but not in erythrocytes. Lipid peroxidation occurred in erythrocytes, but not in striatum. No changes in fluidity at different depths of plasma membrane were measured in striatum or erythrocytes. The activation of monocyte NADPH oxidase by phorbol esters (PMA) shows that superoxide anion production was reduced in the pyrethroid-treated groups compared to the control group. Our studies suggest that neonatal exposition to permethrin or cypermethrin induces long-lasting effects after developmental exposure giving changes in open-field behaviors, striatal monoamine level, and increased oxidative stress. Although the action of pyrethroids on various target cells is different, a preferential interaction with the extracellular side of plasma membrane proteins can be observed.
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PMID:Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids. 1714 Jul 20

Dopaminergic cells in the substantia nigra are highly vulnerable to the neurodegenerative process of Parkinson's disease. Therefore, mechanisms that enhance their susceptibility to injury bear important implications for disease pathogenesis. Repeated injections with the herbicide paraquat cause oxidative stress and a selective loss of dopaminergic neurons in mice. In this model, the first paraquat exposure, though not sufficient to induce any neurodegeneration, predisposes neurons to damage by subsequent insults. The purpose of this study was to elucidate the mechanisms underlying this "priming" event. We found that a single paraquat exposure was followed by an increase in the number of cells with immunohistochemical, morphological and biochemical characteristics of activated microglia, including induction of NADPH oxidase. If this microglial response was inhibited by the anti-inflammatory drug minocycline, subsequent exposures to the herbicide failed to cause oxidative stress and neurodegeneration. On the other hand, if microglial activation was induced by pre-treatment with lipopolysaccharide, a single paraquat exposure became capable of triggering a loss of dopaminergic neurons. Finally, mutant mice lacking functional NADPH oxidase were spared from neurodegeneration caused by repeated paraquat exposures. Data indicate that microglial activation and consequent induction of NADPH oxidase may act as risk factors for Parkinson's disease by increasing the vulnerability of dopaminergic cells to toxic injury.
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PMID:Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degeneration. 1716 27

alpha-Synuclein, a gene whose mutations, duplication, and triplication has been linked to autosomal dominant familial Parkinson's disease (fPD), appears to play a central role in the pathogenesis of sporadic PD (sPD) as well. Enhancement of neurodegeneration induced by mutant alpha-synuclein has been attributed to date largely to faster formation of alpha-synuclein aggregates in neurons. Recently, we reported that microglial activation enhances wild type (WT) alpha-synuclein-elicited dopaminergic neurodegeneration. In the present study, using a primary mesencephalic culture system, we tested whether mutated alpha-synuclein could activate microglia more powerfully than WT alpha-synuclein, thereby contributing to the accelerated neurodegeneration observed in fPD. The results showed that alpha-synuclein with the A30P or A53T mutations caused greater microglial activation than WT alpha-synuclein. Furthermore, the extent of microglial activation paralleled the degree of dopaminergic neurotoxicity induced by WT and mutant alpha-synuclein. Mutant alpha-synuclein also induced greater production of reactive oxygen species than WT alpha-synuclein by NADPH oxidase (PHOX), and PHOX activation was linked to direct activation of macrophage antigen-1 (Mac-1) receptor, rather than alpha-synuclein internalization via scavenger receptors. These results have, for the first time, demonstrated that microglia are also critical in enhanced neurotoxicity induced by mutant alpha-synuclein.
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PMID:Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein. 1760 Mar 40

Excess production of reactive oxygen species (ROS) is an important mechanism underlying the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease (PD) which is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Exposure to paraquat, an herbicide with structure similar to the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium (MPP+), has been shown to produce PD-like symptoms. Despite previous focus on the dopaminergic neurons and signaling pathways involved in their cell death, recent studies have implicated microglial cells as a major producer of ROS for damaging neighboring neurons. In this study, we examined the source of ROS and the underlying signaling pathway for paraquat-induced cytotoxicity to BV-2 microglial cells. Paraquat-induced ROS production (including superoxide anions) in BV-2 cells was accompanied by translocation of the p67phox cytosolic subunit of NADPH oxidase to the membrane. Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol. Apocynin and DPI also rescued cells from paraquat-induced toxicity. The inhibitors for protein kinase C delta (PKCdelta) or extracellular signal-regulated kinases (ERK1/2) could partially attenuate paraquat-induced ROS production and cell death. Rottlerin, a selective PKCdelta inhibitor, also inhibited paraquat-induced translocation of p67phox. Taken together, this study demonstrates the involvement of ROS from NADPH oxidase in mediating paraquat cytotoxicity in BV-2 microglial cells and this process is mediated through PKCdelta- and ERK-dependent pathways.
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PMID:Cytotoxicity of paraquat in microglial cells: Involvement of PKCdelta- and ERK1/2-dependent NADPH oxidase. 1766 68

There is increasing evidence to suggest that neuroinflammatory processes contribute to the cascade of events that lead to the progressive neuronal damage observed in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Therefore, treatment regimes aimed at modulating neuroinflammatory processes may act to slow the progression of these debilitating brain disorders. Recently, a group of dietary polyphenols known as flavonoids have been shown to exert neuroprotective effects in vivo and in neuronal cell models. In this review we discuss the evidence relating to the modulation of neuroinflammation by flavonoids. We highlight the evidence which suggests their mechanism of action involves: 1) attenuation of the release of cytokines, such as interleukin-1beta (IL-1beta and tumor necrosis factor-alpha (TNF-alpha); 2) an inhibitory action against inducible nitric oxide synthase (iNOS) induction and subsequent nitric oxide (NO(*)) production; 3) inhibition of the activation of NADPH oxidase and subsequent reactive oxygen species generation; 4) a capacity to down-regulate the activity of pro-inflammatory transcription factors such as nuclear factor-kappaB (NF-kappaB); and 5) the potential to modulate signalling pathways such as mitogen-activated protein kinase (MAPK) cascade. We also consider the potential of these dietary compounds to represent novel therapeutic agents by considering their metabolism in the body and their ability to access the brain via the blood brain barrier. Finally, we discuss future areas of study which are necessary before dietary flavonoids can be established as therapeutic agents against neuroinflammation.
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PMID:Neuroinflammation and its modulation by flavonoids. 1789 48

Oxidative stress is widely recognized as a key mediator of degenerative processes in Parkinson's disease (PD). Recently, we demonstrated that the dopaminergic toxin MPP+ initiates oxidative stress to cause caspase-3-dependent apoptotic cell death in mesencephalic dopaminergic neuronal (N27) cells. In this study, we determined the source of reactive oxygen species (ROS) produced during MPP+-induced apoptotic cell death. In addition to mitochondria, plasma membrane NADPH oxidase is considered a major producer of ROS inside the cell. Here, we show that N27 neuronal cells express key NADPH oxidase subunits gp91phox and p67phox. We used structurally diverse NADPH oxidase inhibitors, aminoethyl-benzenesulfonylfluoride (AEBSF, 100-1000microM), apocynin (100-1000microM), and diphenylene iodonium (DPI, 3-30microM), to inhibit intrinsic NADPH oxidase activity in N27 cells. Flow cytometric analysis using the ROS-sensitive dye hydroethidine revealed that AEBSF blocked 300microM MPP+-induced ROS production for over 45min in N27 cells, in a dose-dependent manner. Further treatment with DPI, apocynin, and SOD also blocked MPP+-induced ROS production. In Sytox cell death assays, co-treatment with AEBSF, apocynin, or DPI for 24h significantly suppressed MPP+-induced cytotoxic cell death. Similarly, co-treatment with these inhibitors also significantly attenuated MPP+-induced increases in caspase-3 enzymatic activity. Furthermore, quantitative DNA fragmentation ELISA assays revealed that AEBSF, DPI, and apocynin rescue N27 cells from MPP+-induced apoptotic cell death. Together, these results indicate for the first time that intracellular ROS generated by NAPDH oxidase are present within the mesencephalic neuronal cells, and are a key determinant of MPP+-mediated dopaminergic degeneration in in vitro models of dopaminergic degeneration. This study supports a critical role of NADPH oxidase in the oxidative damage in PD; targeting this enzyme may lead to novel therapies for PD.
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PMID:Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells. 1790 25

Exposure to pesticides has been speculated to contribute to the development of sporadic Parkinson's disease (PD) characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway. Activation of brain microglia that produce various neurotoxic factors including cytokines and reactive oxygen species (ROS) has been increasingly associated with dopaminergic neurodegeneration induced by various toxicants. Dieldrin, a highly persistent organochlorinated pesticide found enriched in the substantia nigra of some postmortem PD brains, has been shown to be toxic to dopamine neurons. In this study, we set out to determine the effect of dieldrin on the production of ROS and the underlying mechanism of action in murine microglia. Treatment of microglial cells with 0.1 nM to 1 microM dieldrin for 24 h resulted in a concentration-dependent generation of ROS. The dieldrin-induced microglial ROS generation was time-dependent in that significant ROS production was observed in cells 12-24 h, but not 6 h after dieldrin treatment. Furthermore, the dieldrin-induced microglial ROS generation was significantly reduced by inhibitors of NADPH oxidase, gene transcription and protein synthesis. In addition to immortalized microglial cells, dieldrin induced a concentration-dependent ROS generation in primary microglia, but not in primary astroglia. These results demonstrate that nanomolar concentrations of dieldrin can stimulate microglia to produce ROS that may contribute to the degeneration of dopamine neurons known to be vulnerable to oxidative damage. These findings provide important information on the potential role of microglia in dieldrin-induced neurodegeneration in relevance to the development of idiopathic PD.
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PMID:Induction of microglial reactive oxygen species production by the organochlorinated pesticide dieldrin. 1799 24


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