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  • 1
    Electronic Resource
    Electronic Resource
    Induction of Nitric Oxide Synthase Inhibits Gap Junction Permeability in Cultured Rat Astrocytes (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Nitric oxide (•NO) synthase (NOS) was induced in cultured rat astrocytes by incubation with lipopolysaccharide (LPS) for 18 h and gap junction permeability was assessed by the scrape-loading/Lucifer yellow transfer technique. Induction of NOS was confirmed by determining either the NG-methyl-l-arginine (NMMA)-inhibitable production of nitrites and nitrates or the conversion of l-[3H]arginine to l-[3H]citrulline. Incubation with LPS dose-dependently inhibited gap junction permeability to 63.3% at 0.05 µg/ml LPS and no further inhibition was observed on increasing the LPS concentration up to 0.5 µg/ml. LPS-mediated gap junction inhibition was irreversible but was prevented by incubation with the NOS inhibitor NMMA and with the superoxide anion (O2•−) scavenger superoxide dismutase. Incubation of the cells with both the •NO donor S-nitroso-N-acetylpenicillamine and the O2•−-generating system xanthine/xanthine oxidase inhibited gap junction permeability. These results suggest that the in situ reaction between •NO and O2•−, to form the peroxynitrite anion (ONOO−), may be responsible for the inhibition of gap junction permeability. Scavenging the ONOO− derivative hydroxyl radical (•OH) with either dimethyl sulfoxide or mannitol prevented the LPS-mediated inhibition of gap junction permeability. Finally, exposure of astrocytes to authentic ONOO− caused a dose-dependent inhibition of gap junction permeability (65.7% of inhibition at 0.5 mM ONOO−). The pathophysiological relevance of ONOO−-mediated inhibition of gap junctional communication in astrocytes after NOS induction by LPS is discussed, stressing the possible role played by this mechanism in some neurodegenerative diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66052091.x
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  • 2
    Electronic Resource
    Electronic Resource
    Effect of Peroxynitrite on the Mitochondrial Respiratory Chain: Differential Susceptibility of Neurones and Astrocytes in Primary Culture (1995)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 64 (1995), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The effect of the neurotoxic nitric oxide derivative, the peroxynitrite anion (ONOO−), on the activity of the mitochondrial respiratory chain complexes in cultured neurones and astrocytes was studied. A single exposure of the neurones to ONOO− (initial concentrations of 0.01–2.0 mM) caused, after a subsequent 24-h incubation, a dose-dependent decrease in succinate-cytochrome c reductase (60% at 0.5 mM) and in cytochrome c oxidase (52% at 0.5 mM) activities. NADH-ubiquinone-1 reductase was unaffected. In astrocytes, the activity of the mitochondrial complexes was not affected up to 2 mM ONOO−. Citrate synthase was unaffected in both cell types under all conditions studied. However, lactate dehydrogenase activity released to the culture medium was increased by ONOO− in a dose-dependent manner (40% at 0.5 mM ONOO−) from the neurones but not from the astrocytes. Neuronal glutathione concentration decreased by 39% at 0.1 mM ONOO−, but astrocytic glutathione was not affected up to 2 mM ONOO−. In isolated brain mitochondria, only succinate-cytochrome c reductase activity was affected (22% decrease at 1 mM ONOO−). We conclude that the acute exposure of ONOO− selectively damages neurones, whereas astrocytes remain unaffected. Intracellular glutathione appears to be an important factor for ameliorating ONOO−-mediated mitochondrial damage. This study supports the hypothesis that the neurotoxicity of nitric oxide is mediated through mitochondrial dysfunction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1995.64051965.x
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  • 3
    Electronic Resource
    Electronic Resource
    D-Glucose Prevents Glutathione Oxidation and Mitochondrial Damage After Glutamate Receptor Stimulation in Rat Cortical Primary Neurons (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 75 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The possible neuroprotective effect of D-glucose against glutamate-mediated neurotoxicity was studied in rat cortical neurons in primary culture. Brief (5-min) exposure of neurons to glutamate (100 μM) increased delayed (24-h) necrosis and apoptosis by 3- and 1.8-fold, respectively. Glutamate-mediated neurotoxicity was accompanied by a D-(-)-2-amino-5-phosphonopentanoate (100 μM) and Nω-nitro-L-arginine methyl ester (1 mM)-inhibitable, time-dependent ATP depletion (55% at 24 h), confirming the involvement of NMDA receptor stimulation followed by nitric oxide synthesis in this process. Furthermore, the presence of D-glucose (20 mM), but not its inactive enantiomer, L-glucose, fully prevented glutamate-mediated delayed ATP depletion, necrosis, and apoptosis. Succinate- cytochrome c reductase activity, but not the activities of NADH-coenzyme Q1 reductase or cytochrome c oxidase, was inhibited by 32% by glutamate treatment, an effect that was abolished by incubation with D-glucose. Lactate accumulation in the culture medium was unmodified by any of these treatments, ruling out the possible involvement of the glycolysis pathway in either glutamate neurotoxicity or D-glucose neuroprotection. In contrast, D-glucose, but not L-glucose, abolished glutamate-mediated glutathione oxidation and NADPH depletion. Our results suggest that NADPH production from D-glucose accounts for glutathione regeneration and protection from mitochondrial dysfunction. This supports the notion that the activity of the pentose phosphate pathway may be an important factor in protecting neurons against glutamate neurotoxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0751618.x
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  • 4
    Electronic Resource
    Electronic Resource
    Oleic Acid Inhibits Gap Junction Permeability and Increases Glucose Uptake in Cultured Rat Astrocytes (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 69 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The role of oleic acid in the modulation of gap junction permeability was studied in cultured rat astrocytes by the scrape-loading/Lucifer yellow transfer technique. Incubation with oleic acid caused a dose-dependent inhibition of gap junction permeability by 79.5% at 50 µM, and no further inhibition was observed by increasing the oleic acid concentration to 100 µM. The oleic acid-mediated inhibition of gap junction permeability was reversible and was prevented by bovine serum albumin. The potency of oleic acid-related compounds in inhibiting gap junction permeability was arachidonic acid 〉 oleic acid 〉 oleyl alcohol 〉 palmitoleic acid 〉 stearic acid 〉 octanol 〉 caprylic acid 〉 palmitic acid 〉 methyloleyl ester. Oleic acid and arachidonic acid, but not methyloleyl ester, increased glucose uptake by astrocytes. Neither oleic acid nor arachidonic acid increased glucose uptake in the poorly coupled glioma C6 cells. These results support that the inhibition of gap junction permeability is associated with the increase in glucose uptake. We suggest that oleic acid may be a physiological mediator of the transduction pathway leading to the inhibition of intercellular communication.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.69020721.x
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  • 5
    Electronic Resource
    Electronic Resource
    Nitric Oxide-Mediated Mitochondrial Damage in the Brain: Mechanisms and Implications for Neurodegenerative Diseases (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 68 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Within the CNS and under normal conditions, nitric oxide (•NO) appears to be an important physiological signalling molecule. Its ability to increase cyclic GMP concentration suggests that •NO is implicated in the regulation of important metabolic pathways in the brain. Under certain circumstances •NO synthesis may be excessive and •NO may become neurotoxic. Excessive glutamate-receptor stimulation may lead to neuronal death through a mechanism implicating synthesis of both •NO and superoxide (O2•−) and hence peroxynitrite (ONOO−) formation. In response to lipopolysaccharide and cytokines, glial cells may also be induced to synthesize large amounts of •NO, which may be deleterious to the neighbouring neurones and oligodendrocytes. The precise mechanism of •NO neurotoxicity is not fully understood. One possibility is that it may involve neuronal energy deficiency. This may occur by ONOO− interfering with key enzymes of the tricarboxylic acid cycle, the mitochondrial respiratory chain, mitochondrial calcium metabolism, or DNA damage with subsequent activation of the energy-consuming pathway involving poly(ADP-ribose) synthetase. Possible mechanisms whereby ONOO− impairs the mitochondrial respiratory chain and the relevance for neurotoxicity are discussed. The intracellular content of reduced glutathione also appears important in determining the sensitivity of cells to ONOO− production. It is concluded that neurotoxicity elicited by excessive •NO production may be mediated by mitochondrial dysfunction leading to an energy deficiency state.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.68062227.x
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  • 6
    Electronic Resource
    Electronic Resource
    Induction of Glucose-6-Phosphate Dehydrogenase by Lipopolysaccharide Contributes to Preventing Nitric Oxide-Mediated Glutathione Depletion in Cultured Rat Astrocytes (1999)
    Oxford UK : Blackwell Science Ltd
    Journal of neurochemistry 72 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Treatment of cultured rat astrocytes with lipopolysaccharide (LPS; 1 μg/ml) increased mRNA expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting step in the pentose phosphate pathway (PPP), in a time-dependent fashion (0-24 h). This effect was accompanied by an increase in G6PD activity (1.74-fold) and in the rate of glucose oxidation through the PPP (6.32-fold). Inhibition of inducible nitric oxide synthase (iNOS) activity by 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT; 50 μM) did not alter the LPS-mediated enhancement of G6PD mRNA expression or PPP activity. Blockade of nuclear factor κB (NF-κB) activation by N-benzyloxycarbonyl-Ile-Glu-(O-tert-butyl)-Ala-leucinal (1 μM) prevented the expression of both iNOS mRNA and G6PD mRNA, suggesting that iNOS and G6PD are co-induced by LPS through a common transcriptional pathway involving NF-κB activation. Incubation of cells with LPS for 24 h increased intracellular NADPH concentrations (1.63-fold) as compared with untreated cells, but GSH concentrations were not modified by LPS treatment up to 60 h of incubation. However, inhibition of G6PD activity by dehydroepiandrosterone (DHEA; 100 μM), which prevented LPS-mediated enhancements in PPP activity and NADPH concentrations, caused a 50% decrease in the GSH/GSSG ratio after 24-36 h and in GSH concentrations after 60 h of incubation. Furthermore, the changes in glutathione concentrations caused by DHEA were abolished by AMT, suggesting that nitric oxide and/or its reactive derivatives would be involved in this process. From these results, we conclude that LPS-mediated G6PD expression prevents GSH depletion due to nitric oxide and suggest that this phenomenon may be a contributing factor in the defense mechanisms that protect astrocytes against nitric oxide-mediated cell injury.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.721750.x
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  • 7
    Electronic Resource
    Electronic Resource
    Depletion of glutathione up-regulates mitochondrial complex I expression in glial cells (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 76 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Glutathione deficiency is commonly associated with mitochondrial complex I dysfunction and loss of viability in neurones, but not in glia. In order to address the possible mechanism responsible for this cellular difference, the regulation of mitochondrial complex I expression by glutathione depletion was investigated in glial cells. Incubation of rat-cultured astrocytes and C6 glioma cells with the specific γ-glutamylcysteine synthetase inhibitor l-buthionine-(S,R)-sulfoximine (l-BSO; 0.1–1 mm) decreased the total specific content of glutathione in a dose- and time-dependent fashion. Northern blot analyses revealed that glutathione deficiency caused by l-BSO (0.1 mm) was associated with a twofold enhancement in complex I regulatory subunit ND6 (mitochondrially encoded) mRNA expression after 24–72 h. This effect was accompanied by a twofold increase in complex-I activity at 72 h in l-BSO-treated cells, as compared with control cells, but complex II–III, complex IV and citrate synthase activities were unaltered. It is suggested that the oxidative stress caused by glutathione depletion in glial cells would up-regulate complex-I activity by enhancing the expression of the mitochondrially encoded regulatory subunit. These results could offer further insight into the different degree of cellular susceptibility observed in glial vs. neuronal cells against oxidative stress.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00223.x
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  • 8
    Electronic Resource
    Electronic Resource
    Increased mitochondrial respiration maintains the mitochondrial membrane potential and promotes survival of cerebellar neurons in an endogenous model of glutamate receptor activation (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 92 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: It is thought that the combination of extracellular glutamate accumulation and mitochondrial damage is involved in neuronal death associated with brain ischemia and hypoglycemia, and some neurodegenerative diseases such as Huntington's disease. However, the mechanism whereby those two factors interact together to trigger neurodegeneration in this and other neurodegenerative disorders is still elusive. Here, we have addressed this issue using a model of mild and sustained accumulation of extracellular glutamate in cerebellar cultured neurons, which are mostly glutamatergic and commonly used to study glutamate neurotoxicity. The resulting stimulation of glutamate receptors triggered a ∼ 50% persistent increase in mitochondrial respiration that was associated with free radicals formation, and which was found to be necessary to prevent the collapse of the mitochondial membrane potential (Δψm) and apoptotic cell death. In fact, hampering the glutamate-mediated increase in mitochondrial respiration with an inhibitor of the mitochondrial respiratory chain stopped neurons from producing free radicals, but led them to undergo rapid and profound Δψm collapse and apoptotic cell death. Thus, we suggest that the formation of reactive oxygen species by glutamate receptor activation is the unavoidable consequence of an increase in the mitochondrial respiration aimed to prevent Δψm collapse and neurodegeneration. These results may be relevant to understand the pathophysiology of those neurodegenerative diseases associated with both mitochondrial respiratory chain and glutamate transporter defects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02851.x
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  • 9
    Electronic Resource
    Electronic Resource
    Oxygen and glucose deprivation induces mitochondrial dysfunction and oxidative stress in neurones but not in astrocytes in primary culture (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 81 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In order to investigate the potential neuroprotective role played by glucose metabolism during brain oxygen deprivation, the susceptibility of cultured neurones and astrocytes to 1 h of oxygen deprivation (hypoxia) or oxygen and glucose deprivation (OGD) was examined. OGD, but not hypoxia, promotes dihydrorhodamine 123 and glutathione oxidation in neurones but not in astrocytes reflecting free radical generation in the former cells. A specific loss of mitochondrial complex-I activity, mitochondrial membrane potential collapse, ATP depletion and necrosis occurred in the OGD neurones, but not in the OGD astrocytes. Furthermore, superoxide anion but not nitric oxide formation was responsible for these effects. OGD decreased neuronal but not astrocytic NADPH concentrations; this was not observed in hypoxia and was independent of superoxide or nitric oxide formation. These results suggest that glucose metabolism would supply NADPH, through the pentose–phosphate pathway, aimed at preventing oxidative stress, mitochondrial damage and neurotoxicity during oxygen deprivation to neural cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.00827.x
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  • 10
    Electronic Resource
    Electronic Resource
    Expression of glucose transporter GLUT3 by endotoxin in cultured rat astrocytes: the role of nitric oxide (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 79 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The induction of nitric oxide (NO) synthase in astrocytes by endotoxin and/or cytokine treatment is associated with increased glucose consumption and glycolysis, but the mechanism whereby this phenomenon occurs remains obscure. In this work, we have addressed this issue and found that incubation of cultured rat astrocytes with lipopolysaccharide (LPS; 1 µg/mL) for 24 h increased the level of constitutively expressed GLUT1 glucose transporter mRNA, and triggered GLUT3 mRNA expression, which was absent in normal astrocytes. The occurrence of GLUT3 protein after LPS treatment was corroborated by western blotting and immunocytochemistry. A 4-h incubation of astrocytes in the absence of glucose, or under an oxygen-poor (3%) atmosphere also resulted in GLUT3 mRNA overexpression. Experiments performed with 2-deoxy-d-[U-14C]glucose (at 0.1 mm of d-glucose) confirmed that LPS (0.1–10 µg/mL) dose-dependently increased the rate of glucose uptake (by a factor of 1.6 at 1 µg/mL of LPS), which was paralleled with the increase in NO synthesis. Furthermore, blockade of NO synthase with 2-amino-5,6-dihydro-6-methyl-(4H)-1,3-thiazine (AMT; 50 µm) partially (by 45%) prevented the LPS-mediated increase in glucose uptake. Finally, incubation of astrocytes with the NO donor 1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA; 100 µm) increased by a factor of 1.4 the rate of glucose uptake. We conclude that the increase in GLUT3-driven glucose uptake in astrocytes would have a neuroprotective role under conditions in which NO formation is combined with hypoglycaemia, such as in brain ischemia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00523.x
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