Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to explore involvement of nitric oxide (NO) in the experimental models of Parkinson's disease. Neurodegeneration was induced by unilateral injections of 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS) in the right striatum. Lesions were functionally evaluated by amphetamine-induced asymmetrical behaviour and by decrease in the tyrosine hydroxylase (TH) immunostaining. An induction in the expression of iNOS and augmentation in nitrite content was observed in both the models. The extent of increase in iNOS expression was, however, different but the elevation in the nitrite content was comparable in both the models. The increase in iNOS expression inversely correlated with the tyrosine hydroxylase (TH) immunolabeling. Animals pretreated with a NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), exhibited complete protection against amphetamine induced rotations in both the models. Thus, augmented NO availability subsequent to iNOS induction seems to play an important role in the initial phase of neurodegeneration.
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PMID:Involvement of nitric oxide in neurodegeneration: a study on the experimental models of Parkinson's disease. 1594 31

Poly(ADP-ribosyl) ation is a reversible post-translational protein modification implicated in the regulation of a number of biological functions. Whereas an 18 member superfamily of poly(ADP-ribose) polymerase (PARP) enzymes synthesize poly(ADP-ribose) (PAR), a single protein, PAR glycohydrolase (PARG) is responsible for the catabolism of the polymer. PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 activated by DNA breaks cleaves NAD(+) into nicotinamide and ADP-ribose and uses the latter to synthesize long branching PAR polymers covalently attached to acceptor proteins including histones, DNA repair enzymes, transcription factors and PARP-1. Whereas activation of PARP-1 by mild genotoxic stimuli may facilitate DNA repair and cell survival, irreparable DNA damage triggers apoptotic or necrotic cell death. In apoptosis, early PARP activation may assist the apoptotic cascade [e.g. by stabilizing p53, by mediating the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus or by inhibiting early activation of DNases]. In most severe oxidative stress situations, excessive DNA damage causes over activation of PARP-1, which incapacitates the apoptotic machinery and switches the mode of cell death from apoptosis to necrosis. Besides serving as a cytotoxic mediator, PARP-1 is also involved in transcriptional regulation, most notably in the NF kappaB and AP-1 driven expression of inflammatory mediators. Pharmacological inhibition or genetic ablation of PARP-1 provided remarkable protection from tissue injury in various oxidative stress-related disease models ranging from stroke, diabetes, diabetic endothelial dysfunction, myocardial ischemia-reperfusion, shock, Parkinson's disease, arthritis, colitis to dermatitis and uveitis. These beneficial effects are attributed to inhibition of the PARP-1 mediated suicidal pathway and to reduced expression of inflammatory cytokines and other mediators (e.g. inducible nitric oxide synthase).
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PMID:Structure and function of poly(ADP-ribose) polymerase-1: role in oxidative stress-related pathologies. 1602 17

A glial reaction associated with up-regulation of inflammatory molecules has been suggested to play an important role in dopaminergic neuron loss in Parkinson's disease (PD). Among inflammatory molecules, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have been focused upon as key factors in the pathogenesis. However, the mechanism of how these molecules are induced in PD brains is not clearly understood. We focused on CD 40, which is expressed on neural cells and could be implicated in the neuroinflammation by inducing inflammatory molecules. We showed that both iNOS and COX-2 were up-regulated in microglia and astrocytes by CD 40 stimulation in association with a low dose of interferon-gamma (IFN-gamma) in vitro. Selective loss of dopaminergic neurons was induced by costimulation with CD 40 and IFN-gamma in mesencephalic cultures, which was protected by selective inhibitors of iNOS and/or COX-2. We also found in CD 40-stimulated astrocytes an increase of a low-affinity IgE receptor CD 23, which is known to induce iNOS expression. Together these data suggest that up-regulated iNOS and COX-2 via the CD 40 pathway may lead to dopaminergic neuron loss and may participate in the neuroinflammaory pathway of PD.
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PMID:Loss of dopaminergic neurons by the induction of inducible nitric oxide synthase and cyclooxygenase-2 via CD 40: relevance to Parkinson's disease. 1604 99

Sustained reactive microgliosis may contribute to the progressive degeneration of nigral dopaminergic neurons in Parkinson's disease (PD), in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposed human and in non-human primates. However, the temporal relationship between glial cell activation and nigral cell death is relatively unexplored. Consequently, the effects of acute (24 h) and chronic (30 days) glial cell activation induced by unilateral supranigral lipopolysaccharide (LPS) administration were studied in rats. At 24 h, LPS administration caused a marked reduction in the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra (SN) but striatal TH-ir was unaffected. By 30 days, the loss of TH-positive neurons in the LPS-treated nigra was no greater than at 24 h although a heterogeneous loss of striatal TH-ir was present. The loss of nigrostriatal neurons was of functional significance, as at 30 days, LPS-treated rats exhibited ipsiversive circling in response to (+)-amphetamine administration. At 24 h, there was a moderate increase in glial fibrillary acidic protein (GFAP)-ir astrocytes in the SN but a marked elevation of p47phox positive OX-42-ir microglia, and intense inducible nitric oxide synthase (iNOS)-ir and 3-nitrotyrosine (3-NT)-ir was present. However, by 30 days the morphology of OX-42-ir microglia returned to a resting state, the numbers were greatly reduced and no 3-NT-ir was present. At 30 days, GFAP-ir astrocytes were markedly increased in number and iNOS-ir was present in fibrillar astrocyte-like cells. This study shows that acute glial activation leading to dopaminergic neuron degeneration is an acute short-lasting response that does not itself perpetuate cell death or lead to prolonged microglial activation.
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PMID:The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation. 1604 85

Oxidative stress and inflammation are implicated in neurodegenerative diseases including Parkinson's disease (PD) and Huntington's disease (HD). Celastrol is a potent anti-inflammatory and antioxidant compound extracted from a perennial creeping plant belonging to the Celastraceae family. Celastrol is known to prevent the production of proinflammatory cytokines, inducible nitric oxide synthase and lipid peroxidation. Mice were treated with celastrol before and after injections of MPTP, a dopaminergic neurotoxin, which produces a model of PD. A 48% loss of dopaminergic neurons induced by MPTP in the substantia nigra pars compacta was significantly attenuated by celastrol treatment. Moreover, celastrol treatment significantly reduced the depletion in dopamine concentration induced by MPTP. Similarly, celastrol significantly decreased the striatal lesion volume induced by 3-nitropropionic acid, a neurotoxin used to model HD in rats. Celastrol induced heat shock protein 70 within dopaminergic neurons and decreased tumor necrosis factor-alpha and nuclear factor kappa B immunostainings as well as astrogliosis. Celastrol is therefore a promising neuroprotective agent for the treatment of PD and HD.
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PMID:Celastrol protects against MPTP- and 3-nitropropionic acid-induced neurotoxicity. 1609 42

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes the damage of dopaminergic neurons as seen in Parkinson's disease. Oxidative stress has been as one of several pathogenic hypotheses for Parkinson's disease. Here we investigated whether arundic acid, an astrocyte-modulating agent, can protect against alterations of nitric oxide synthase (NOS) and superoxide dismutase (SOD) expression on MPTP neurotoxicity in mice, utilizing an immunohistochemistry. For this purpose, anti-tyrosine hydroxylase (TH) antibody, anti-dopamine transporter (DAT) antibody, anti-Cu/Zn-SOD antibody, anti-Mn-SOD antibody, anti-nNOS antibody, anti-eNOS antibody and anti-iNOS antibody were used. The present study showed that the arundic acid had a protective effect against MPTP-induced neuronal damage in the striatum and substantia nigra of mice. The protective effect may be, at least in part, caused by the reductions of the levels of reactive nitrogen (RNS) and oxygen species (ROS) against MPTP neurotoxicity. These results suggest that the pharmacological modulation of astrocyte may offer a novel therapeutic strategy for the treatment of Parkinson's disease. Furthermore, our results provide further evidence that a combination of nNOS inhibitors, iNOS inhibitors and free radical scavengers may be effective in the treatment of neurodegenerative diseases. Thus our present results provide valuable information for the pathogenesis of degeneration of the nigrostriatal dopaminergic neuronal pathway.
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PMID:Neuroprotective effect of arundic acid, an astrocyte-modulating agent, in mouse brain against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity. 1630 47

It is well documented that manganese neurotoxicity induces clinical symptoms similar to those of idiopathic Parkinson's disease. Although microglial cytotoxic mediator-induced neurotoxicity is suggested, the mechanism by which manganese up-regulates cytotoxic mediator, such as nitric oxide (NO), remains poorly understood. Therefore, in this study, we investigated the mechanism of manganese on induction of iNOS in microglial cells. iNOS promoter/luciferase assay revealed that manganese (500 (M) regulated the iNOS expression at the transcriptional level. Immunoblot analysis also revealed that phosphorylation levels of ERK, JNK MAPKs and Akt (PKB, PI 3-kinase downstream effector), were increased. Both protein and mRNA levels of iNOS expression were abrogated by specific inhibitors, SP600125 (JNK inhibitor, 20 microM), PD98059 (ERKs inhibitor, 50 microM), or LY294002 (PI 3-kinase inhibitor, 20 microM), but not by SB203580 (20 microM), a p38 specific inhibitor. These data lead to the conclusion that manganese regulates the iNOS expression at the transcriptional level in BV2 microglial cells and the increased iNOS protein expression is mediated via both JNK-ERK MAPK and PI3K/Akt signaling pathways, but not via p38 MAPK pathway. Increased iNOS protein level was also found in RAW264.7 murine macrophage cells.
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PMID:Manganese induces inducible nitric oxide synthase (iNOS) expression via activation of both MAP kinase and PI3K/Akt pathways in BV2 microglial cells. 1641 67

Although the pathogenesis of Parkinson's disease (PD) remains unknown, it appears that microglial activation is associated with enhanced neurodegeneration in animal models of PD as well as in PD patients. Experimentally, C57BL/6 and SWR/J mice demonstrate striking differences in the extent of dopaminergic (DAergic) neurodegeneration induced by a parkinsonian toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The purpose of this study was to determine whether differences in microglial activation between these two strains of mice could provide insight into the variability seen in toxicant induced neuronal death, and subsequently to use a high-throughput proteomic method, combining stable isotope labeling with amino acids in cell culture (SILAC) with liquid chromatography and tandem mass spectrometry, to compare the microglial proteomes of C57BL/6 and SWR/J mice after stimulation with a classical microglial activator, lipopolysaccharide (LPS). We found that DAergic neurotoxicity induced by LPS in a primary neuron-microglia coculture was twofold greater with microglia isolated from the brains of C57BL/6 mice compared with that of SWR/J mice. Upon proteomic analysis we found that, out of over 1,000 proteins identified and quantified, 400 displayed a significant difference in their relative abundance between these two murine strains. Several proteins, which had relatively higher levels in C57BL/6 mice, have previously been implicated in LPS-mediated microglial activation, including those involved in the COX-2 pathway and in prostaglandin E-2 (PGE(2)) production. To validate our proteomic results we confirmed the increased expression level of iNOS in C57BL/6 vs. SWR/J microglia with semiquantitative Western blot. Further analysis of our proteomic discovery data will likely reveal numerous novel proteins involved in inflammation-mediated neurotoxicity in PD.
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PMID:Proteomic analysis of microglial contribution to mouse strain-dependent dopaminergic neurotoxicity. 1641 87

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons and a substantial decrease in the neurotransmitter dopamine in the nigro-striatal region of the brain. Increased markers of oxidative stress, activated microglias and elevated levels of pro-inflammatory cytokines have been identified in the brains of patients with PD. Although the precise mechanism of loss of neurons in PD remains unclear, these findings suggest that microglial activation may contribute directly to loss of dopaminergic neurons in PD patients. In the present study, we tested the hypothesis that activated microglia induces nitric oxide-dependent oxidative stress which subsequently causes death of dopaminergic neuronal cells in culture. We employed lipopolysaccharide (LPS) stimulated mouse macrophage cells (RAW 264.7) as a reactive microglial model and SH-SY5Y cells as a model for human dopaminergic neurons. LPS stimulation of macrophages led to increased production of nitric oxide in a time and dose dependent manner as well as subsequent generation of other reactive nitrogen species such as peroxynitrite anions. In co-culture conditions, reactive macrophages stimulated SH-SY5Y cell death characterized by increased peroxynitrite concentrations and nitration of alpha-synuclein within SH-SY5Y cells. Importantly 1,400 W, an inhibitor of the inducible nitric oxide synthase provided protection from cell death via decreasing the levels of nitrated alpha-synuclein. These results suggest that reactive microglias could induce oxidative stress in dopaminergic neurons and such oxidative stress may finally lead to nitration of alpha-synuclein and death of dopaminergic neurons in PD.
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PMID:Reactive macrophages increase oxidative stress and alpha-synuclein nitration during death of dopaminergic neuronal cells in co-culture: relevance to Parkinson's disease. 1647 1

The aim of present study is to explore the cytoprotection of curcumin against 1-methyl-4-phenylpridinium ions (MPP(+))-induced apoptosis and the molecular mechanisms underlying in PC12 cells. Our findings indicated that MPP(+) significantly reduced the cell viability and induced apoptosis of PC12 cells. Curcumin protected PC12 cells against MPP(+)-induced cytotoxicity and apoptosis not only by inducing overexpression of Bcl-2, but also reducing the loss of mitochondrial membrane potential (MMP), an increase in intracellular reactive oxygen species (ROS) and overexpression of inducible nitric oxide synthase (iNOS). The selective iNOS inhibitor AG partly blocked MPP(+)-induced apoptosis of PC12 cells. The results of present study suggested that the cytoprotective effects of curcumin might be mediated, at least in part, by the Bcl-2-mitochondria-ROS-iNOS pathway. Because of its non-toxic property, curcumin could be further developed to treat the neurodegenerative diseases which are associated with oxidative stress, such as Parkinson's disease (PD).
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PMID:Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by bcl-2-mitochondria-ROS-iNOS pathway. 1654 87


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