UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated synaptic levels of dopamine may induce striatal neurodegeneration in l-DOPA-unresponsive parkinsonism subtype of multiple system atrophy (MSA-P subtype), multiple system atrophy, and methamphetamine addiction. We examined the participation of dopamine and D1 dopamine receptors in the genesis of postsynaptic neurodegeneration. Chronic treatment of human SK-N-MC neuroblastoma cells with dopamine or H2O2 increased NO production and accelerated cytotoxicity, as indexed by enhanced nitrite levels and cell death. The antioxidant sodium metabisulfite or SCH 23390, a D1 dopamine receptor-selective antagonist, partially blocked dopamine effects but together ablated dopamine-mediated cytotoxicity, indicating the participation of both autoxidation and D1 receptor stimulation. Direct activation of D1 dopamine receptors with SKF R-38393 caused cytotoxicity, which was refractory to sodium metabisulfite. Dopamine and SKF R-38393 induced overexpression of the nitric-oxide synthase (NOS) isoforms neuronal NOS, inducible NOS (iNOS), and endothelial NOS in a protein kinase A-dependent manner. Functional studies showed that approximately 60% of total NOS activity was due to activation of iNOS. The NOS inhibitor N(G)-nitro-l-arginine methyl ester and genistein, wortmannin, or NF-kappaB SN50, inhibitors of protein tyrosine kinases phosphatidylinositol 3-kinase and NF-kappaB, respectively, reduced nitrite production by dopamine and SKF R-38393 but were less effective in attenuating H2O2-mediated effects. In rat striatal neurons, dopamine and SKF R-38393, but not H2O2, accelerated cell death through increased expression of neuronal NOS and iNOS but not endothelial NOS. These data demonstrate a novel pathway of dopamine-mediated postsynaptic oxidative stress and cell death through direct activation of NOS enzymes by D1 dopamine receptors and its associated signaling pathways.
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PMID:Chronic stimulation of D1 dopamine receptors in human SK-N-MC neuroblastoma cells induces nitric-oxide synthase activation and cytotoxicity. 1273 94

Transmissible spongiform encephalopathies (TSEs), also called prion diseases, are characterized by formation of the disease-associated isoform of prion protein (PrP(Sc)), which arises from a normal isoform termed PrP(c) by a post-translational conversion process occurring in an autocatalytic fashion. Oxidative stress has been proposed as a pathogenetic mechanism in TSEs and increased lipid peroxidation has recently been described in prion-infected cell cultures, suggesting an intrinsic link between the presence of prions and oxidative stress. We investigated if poly(ADP-ribose) formation can be detected in cultured cells upon prion infection, as this NAD+-consuming and DNA strand break-activated nuclear enzymatic reaction has the potential to cause rapid and lethal NAD+ depletion in cells under severe oxidative stress. Poly(ADP-ribose) production was analysed by immunofluorescence in freshly scrapie-infected Neuro2a-D11 mouse neuroblastoma cells, which had been confirmed by immunocytochemistry to produce PrP(Sc), and in uninfected controls. No spontaneous poly(ADP-ribose) specific signals were observed in infected or in uninfected cells, while both cell types readily reacted to H2O2 treatment with poly(ADP-ribose) synthesis in a dose-dependent manner, with no obvious difference in staining intensity at any dose tested. In summary, our data reveal that replication of scrapie agent in neuroblastoma cells can proceed without detectable stimulation of the cellular poly(ADP-ribosyl)ation system.
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PMID:In-situ analysis of cellular poly(ADP-ribose) production in scrapie-infected mouse neuroblastoma cells. 1276 68

The role of amyloid beta-peptide (Abeta) in the free-radical oxidative-stress model of neurotoxicity in Alzheimer's disease (AD) has received much attention recently. In this study, we have employed both in vitro and in vivo models displaying endogenous Abeta production to study the effects of Abeta on intracellular free radical levels. We employed a neuroblastoma cell line stably expressing an AD-associated double mutation, which exhibits both increased secretion and intracellular accumulation of Abeta when stimulated, as well as transgenic Caenorhabditis elegans constitutively expressing human Abeta. A rise in levels of hydrogen peroxide (H2O2) was observed in both in vitro and in vivo AD-associated transgenic models expressing the Abeta peptide compared with the wild type controls. Treatment of the cells or C. elegans with Ginkgo biloba extract EGb 761 significantly attenuated the basal as well as the induced levels of H2O2-related reactive oxygen species (ROS). Among individual EGb 761 components tested, kaempferol and quercetin provided maximum attenuation in both models. Furthermore, an age-dependent increase in H2O2-related ROS was observed in wild type C. elegans, which is accelerated in the AD-associated C. elegans mutant. These results support the hypothesis of the involvement of Abeta and ROS in association with AD.
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PMID:Elevation of oxidative free radicals in Alzheimer's disease models can be attenuated by Ginkgo biloba extract EGb 761. 1462 24

Alzheimer's disease (AD) is characterized by the age-related deposition of beta-amyloid (A beta) 40/42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for A beta in the pathophysiology of AD. A beta is generated by the regulated cleavage of a = 700 amino acid A beta precursor protein (betaAPP). Full-length betaAPP can undergo proteolytic cleavage either within the A beta domain to generate secreted sbetaAPP alpha or at the N-terminal and C-terminal domain(s) of A beta to generate amyloidogenic A beta peptides. Several epidemiological studies have reported that estrogen replacement therapy protects against the development of AD in postmenopausal women. The aim of this study was to elucidate the antioxidant neuroprotective mechanism of Bombusae concretio Salicea (BC). BC was effective protectants against oxidative glutamate toxicity in the murine neuroblastoma cells (N2a) and human neuroblastoma cells (SK-N-MC). BC exhibited similar protective properties against oxidative glutamate toxicity and H2O2 toxicity. BC exhibited an antioxidant activity at approximately 20 microg/ml. BC of 5 microg/ml was ineffective in preventing the oxidative modification of LDL. The half-maximal effective concentration for BC was 16 microg/ml. These results suggested that BC supplementation in elderly men may be protective in the treatment of Alzheimer's disease (AD). We report here that treatment with BC increases the secretion of the nonamyloidogenic APP fragment, sbetaAPP alpha and decreases the secretion of A beta peptides from N2a cells and rat primary cerebrocortical neurons. These results raise the possibility that BC supplementation in elderly men may be protective in the treatment of AD.
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PMID:Inhibitory effects of Bombusae concretio Salicea on neuronal secretion of Alzheimer's beta-amyloid peptides, a neurodegenerative peptide. 1464 18

AMP-activated protein kinase (AMPK) was recently suggested to have a pro-apoptotic effect although its primary function is believed to mediate cellular adaptation to metabolic stresses. Here, we investigated the effect of the AMPK activator 5-aminoimidazole-4-carboxamide-ribonucleoside (AICAR) on oxidative stress-induced apoptosis using mouse Neuro 2a neuroblastoma cells. H2O2-induced apoptosis was increased by AMPK activation, either with AICAR pretreatment or with overexpression of active AMPK. AICAR also induced nuclear factor-kappaB (NF-kappaB) activation along with activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. Correlation between NF-kappaB activation and the AICAR-enhanced apoptotic cell death was observed. In addition, NF-kappaB inhibitor SN50 prevented the augmented cell death by AICAR. Thus, our data suggest that NF-kappaB mediates the pro-apoptotic effect of AICAR.
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PMID:5-Aminoimidazole-4-carboxamide-ribonucleoside enhances oxidative stress-induced apoptosis through activation of nuclear factor-kappaB in mouse Neuro 2a neuroblastoma cells. 1470 Jul 30

The neurotoxin, 6-hydroxydopamine (6-OHDA) has been implicated in the neurodegenerative process of Parkinson's disease. The current study was designed to elucidate the toxicological effects of 6-OHDA on energy metabolism in neuroblastoma (N-2A) cells. The toxicity of 6-OHDA corresponds to the total collapse of anaerobic/aerobic cell function, unlike other mitochondrial toxins such as MPP+ that target specific loss of aerobic metabolism. The toxicity of 6-OHDA paralleled the loss of mitochondrial oxygen (O2) consumption (MOC), glycolytic activity, ATP, H+ ion gradients, membrane potential and accumulation of the autoxidative product, hydrogen peroxide (H2O2). Removing H2O2 with nonenzymatic stoichiometric scavengers, such as carboxylic acids, glutathione and catalase yielded partial protection. The rapid removal of H2O2 with pyruvate or catalase restored only anaerobic glycolysis, but did not reverse the loss of MOC, indicating mitochondrial impairment is independent of H2O2. The H2O2 generated by 6-OHDA contributed toward the loss of anaerobic glycolysis through lipid peroxidation and lactic acid dehydrogenase inhibition. The ability of 6-OHDA to maintain oxidized cytochrome c (CYT-C-OX) in its reduced form (CYT-C-RED), appears to play a role in mitohondrial impairment. The reduction of CYT-C by 6-OHDA, was extensive, occurred within minutes, preceded formation of H2O2 and was unaffected by catalase or superoxide dismutase. At similar concentrations, 6-OHDA readily altered the valence state of iron [Fe(III)] to Fe(II), which would also theoretically sustain CYT-C in its reduced form. In isolated mitochondria, 6-OHDA had negligible effects on complex I, inhibited complex II and interfered with complex III by maintaining the substrate, CYT-C in a reduced state. 6-OHDA caused a transient and potent surge in isolated cytochrome oxidase (complex IV) activity, with rapid recovery as a result of 6-OHDA recycling CYT-C-OX to CYT-C-RED. Typical mitochondrial toxins such as MPP+, azide and antimycin appeared to inhibit the catalytic activity of ETC enzymes. In contrast, 6-OHDA alters the redox of the cytochromes, resulting in loss of substrate availability and obstruction of oxidation-reduction events. Complete cytoprotection against 6-OHDA toxicity and restored MOC was achieved by combining catalase with CYT-C (horse heart). In summary, CYT-C reducing properties are unique to catecholamine neurotransmitters, and may play a significant role in selective vulnerability of dopaminergic neurons to mitochondrial insults.
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PMID:The role of oxidative stress, impaired glycolysis and mitochondrial respiratory redox failure in the cytotoxic effects of 6-hydroxydopamine in vitro. 1503 17

Ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8] naphthyridine-3-carboxylate (ITH4012) is a novel tacrine derivative that can reduce cell death induced by various compounds with different mechanisms of action, such as thapsigargin (reticular stress), H2O2 (free radicals), and veratridine (calcium overload), in bovine chromaffin cell. Cell viability, quantified as lactic dehydrogenase release, was significantly reduced by ITH4012 at concentrations ranging from 0.01 to 3 microM. In the human neuroblastoma cell line SH-SY5Y, ITH4012 also reduced amyloid beta25-35-induced apoptosis, determined by flow cytometry. ITH4012 caused a slight elevation in the cytosolic concentration of Ca2+ in fura 2-loaded bovine chromaffin cells, which could be related to the induction of protein synthesis relevant for cell survival. Blockade of protein synthesis by cycloheximide or blockade of Bcl-2's active site with HA14-1 (ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) reversed the cytoprotective action of ITH4012. Furthermore, exposure of bovine chromaffin cells for 24 or 48 h to neuroprotective concentrations of this compound enhanced, nearly 3-fold, the expression of the antiapoptotic protein Bcl-2. In conclusion, ITH4012 is a tacrine derivative that maintains acetylcholinesterase-inhibiting activity (IC50=0.8 microM) but has the additional property of acting as a calcium promotor, a property leading to neuroprotection through the induction of antiapoptotic proteins.
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PMID:ITH4012 (ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8]naphthyridine-3-carboxylate), a novel acetylcholinesterase inhibitor with "calcium promotor" and neuroprotective properties. 1511 41

Oxidative stress has been demonstrated to produce modifications in several intracellular proteins that lead to alterations in their activities. Alzheimer's disease is related to an increase of oxidative stress markers, which may be an early event in the progression of the disease and neurofibrillary tangles formation. Abnormal phosphorylation of tau has been implicated in the etiopathogenesis of Alzheimer's disease. By using phospho-specific antibodies, we analyzed the changes in tau phosphorylation patterns after treatment of rat hippocampal and SHSY5Y human neuroblastoma cells with H2O2. We found that tau isoforms were hypophosphorylated at the Tau1 epitope after 2 h in the presence of H2O2. The decrease in the phosphorylation levels of tau protein were prevented by pretreatment with N-acetyl-L-cysteine. These changes were shown to depend on the activity of the cdk5/p35 complex, since a 3-fold increase in substrate phosphorylation and a 2-fold increase for the complex association were observed. Also, a decrease in the amount of inhibitor-2 bound to phosphatase PP1 was found in SHSY5Y cells under oxidative stress conditions. This decrease of inhibitor-2 bound to PP1 is due to an increased phosphorylation of the inhibitor-2 protein, thus leading to increased PP1 activity. Therefore, we propose that oxidative stress-induced activation of cdk5 leads to inhibitor-2 phosphorylation, relieving its inhibitory effect on PP1.
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PMID:Oxidative stress promotes tau dephosphorylation in neuronal cells: the roles of cdk5 and PP1. 1513 75

Recent studies indicate that NF-E2 related factor 2 (Nrf2) is a substrate for the ubiquitin-proteasome pathway. The present study is aimed to determine whether increased protein stability is a mechanism by which quinone compounds, like tert-butylhydroquinone (tBHQ), may enhance Nrf2-mediated transcriptional activation and subsequent antioxidant protection. H2O2-induced necrotic cell death, evidenced by transmission electronic microscope (TEM) imaging with no caspase 3 activation and PARP cleavage, was significantly attenuated by pretreatment with tBHQ or overexpression of Nrf2 through advenovirus-mediated infection in human neural stem cells (hNSCs). Microarray analysis showed that those identified antioxidant genes, responsible for antiapoptotic action in IMR-32 cells (J. Li et al., 2002, J. Biol. Chem. 277, 388-394), were also coordinately upregulated through Nrf2-dependent antioxidant responsive element (ARE) activation in hNSC. The stabilization of Nrf2 by tBHQ in IMR-32 cells was evidenced by a pulse-chase assay showing no significant increase in Nrf2 protein synthesis after tBHQ treatment, and by ubiquitin immunoprecipitation showing that tBHQ stabilized ubiquitinated Nrf2. An in vitro proteasomal activity assay showed that tBHQ did not act as a 20S/26S proteasome inhibitor. Nrf2 stabilization by tBHQ also was observed in hNSCs. Taken together, this study suggests that identified antioxidant genes, which were upregulated through tBHQ induced Nrf2 stabilization, confer protection on target cells against H2O2-induced apoptotic cell death in neuroblastoma cells as well as the necrotic cell death in the hNSC. Nrf2 stabilization by pharmacological modulation or adenovirus-mediated Nrf2 overexpression, therefore, might be viable strategies to prevent a wide-spectrum of oxidative stress-related neuronal cell injuries.
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PMID:Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. 1552 90

Epidemiological studies consistently report an inverse correlation between cigarette smoking and associated risk for Parkinson's disease (PD). The degeneration of dopaminergic neurons may involve the toxic metabolic products of glial cell monoamine oxidase (MAO) and inducible nitric oxide synthase (iNOS). This study evaluates the direct protective effects of cigarette smoke (CS) against potential neurotoxic products of MAO, such as 1-methyl-4-phenylpyridinium (MPP+), 6-hydroxydopamine (6-OHDA) and hydrogen peroxide (H2O2) in brain neuroblastoma. Moreover, the effects of CS were also evaluated on endotoxin/cytokine activated glioma iNOS protein expression and MAO enzyme activity. Cigarette smoke condensates (CSCs) were acquired from Marlboro 20 Class A and Kentucky 2R4F reference research (2R4F) cigarettes. The CSCs did not protect against 6-OHDA or H2O2 toxicity in neuroblastoma, and exhibited a very mild protective effect [approximately 10%] against MPP+. Neither CSC demonstrated antioxidant capability, but conversely contained high concentration of NO2-. Paradoxically, in glioma cells, iNOS protein expression and endogenous enzymatic NO2- production were significantly blocked by both CSCs. Both CSCs also inhibited glioma MAO-A and MAO-B [1.4.3.4]. Kinetic analysis indicated that 2R4F-CSC displayed competitive inhibition and the Marlboro-CSC exerted potent competitive and non-competitive inhibition. In conclusion, these data suggest that cigarette smoke does not appear to directly protect against the toxicity of the selected neurotoxins. In contrast, CS exerts pronounced effects on glia, whereby its presence can simultaneously attenuate cytokine induction of iNOS and MAO.
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PMID:Inhibitory effects of cigarette smoke on glial inducible nitric oxide synthase and lack of protective properties against oxidative neurotoxins in vitro. 1552 73

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