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  • Blackwell Science Ltd  (13)
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  • 1
    Electronic Resource
    Electronic Resource
    Interleukin-1β stimulates macrophage inflammatory protein-1α and -1β expression in human neuronal cells (NT2-N) (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 84 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Chemokines are important mediators in immune responses and inflammatory processes of neuroimmunologic and infectious diseases. Although chemokines are expressed predominantly by cells of the immune system, neurons also express chemokines and chemokine receptors. We report herein that human neuronal cells (NT2-N) produce macrophage inflammatory protein-1α and -1β (MIP-1α and MIP-1β), which could be enhanced by interleukin (IL)-1β at both mRNA and protein levels. The addition of supernatants from human peripheral blood monocyte-derived macrophage (MDM) cultures induced MIP-1β mRNA expression in NT2-N cells. Anti-IL-1β antibody removed most, but not all, of the MDM culture supernatant-induced MIP-1β mRNA expression in NT2-N cells, suggesting that IL-1β in the MDM culture supernatants is a major factor in the induction of MIP-1β expression. Investigation of the mechanism(s) responsible for IL-1β-induced MIP-1α and -1β expression demonstrated that IL-1β activated nuclear factor kappa B (NF-κB) promoter-directed luciferase activity in NT2-N cells. Caffeic acid phenethyl ester, a potent and specific inhibitor of activation of NF-κB, not only blocked IL-1β-induced activation of the NF-κB promoter but also decreased IL-1β-induced MIP-1α and -1β expression in NT2-N cells. These data suggest that NF-κB is at least partially involved in the IL-1β-mediated action on MIP-1α and -1β in NT2-N cells. IL-1β-mediated up-regulation of β-chemokine expression may have important implications in the immunopathogenesis of inflammatory diseases in the CNS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.01609.x
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  • 2
    Electronic Resource
    Electronic Resource
    Astrocyte Leucine Metabolism: Significance of Branched-Chain Amino Acid Transamination (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: We studied astrocytic metabolism of leucine, which in brain is a major donor of nitrogen for the synthesis of glutamate and glutamine. The uptake of leucine into glia was rapid, with a Vmax of 53.6 ± 3.2 nmol/mg of protein/min and a Km of 449.2 ± 94.9 µM. Virtually all leucine transport was found to be Na+ independent. Astrocytic accumulation of leucine was much greater (3×) in the presence of α-aminooxyacetic acid (5 mM), an inhibitor of transamination reactions, suggesting that the glia rapidly transaminate leucine to α-ketoisocaproic acid (KIC), which they then release into the extracellular fluid. This inference was confirmed by the direct measurement of KIC release to the medium when astrocytes were incubated with leucine. Approximately 70% of the leucine that the glia cleared from the medium was released as the keto acid. The apparent Km for leucine conversion to extracellular KIC was a medium [leucine] of 58 µM with a Vmax of ∼2.0 nmol/mg of protein/min. The transamination of leucine is bidirectional (leucine + α-ketoglutarate ? KIC + glutamate) in astrocytes, but flux from leucine → glutamate is more active than that from glutamate → leucine. These data underscore the significance of leucine handling to overall brain nitrogen metabolism. The release of KIC from glia to the extracellular fluid may afford a mechanism for the “buffering” of glutamate in neurons, which would consume this neurotransmitter in the course of reaminating KIC to leucine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66010378.x
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  • 3
    Electronic Resource
    Electronic Resource
    α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionate (AMPA) Receptors Mediate Excitotoxicity in the Oligodendroglial Lineage (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: We demonstrate by reverse transcriptase-polymerase chain reaction and Southern blotting that an immortalized rat oligodendroglial cell line (CG-4) expresses the non-N-methyl-d-aspartate (non-NMDA) glutamate receptor (GluR) genes GluR2–7, KA-1, and KA-2 and that nonimmortalized cells of the rat oligodendroglial lineage express the GluR1–3, GluR5–7, KA-1, and KA-2 genes. Lactic dehydrogenase release assays show that both immortalized and nonimmortalized cells of the oligodendroglial lineage are damaged by a 24-h exposure to 500 µM kainate or 5 mMl-glutamate, but not by a 24-h exposure to up to 10 mMα-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). Damage is prevented by the non-NMDA GluR channel inhibitor 6-cyano-7-nitroquinoxaline-2,3-dione and is also averted if Ca2+ is removed from the culture medium. Cyclothiazide, which blocks desensitization of AMPA-preferring GluRs, increases cytotoxicity of kainate as well as inducing toxicity of AMPA. We conclude that cells of the oligodendroglial lineage express a population of AMPA-preferring and possibly also kainate-preferring GluR channels that are capable of mediating Ca2+-dependent excitotoxicity and that AMPA-induced cytotoxicity is blocked by desensitization of AMPA-preferring GluRs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1995.64062442.x
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  • 4
    Electronic Resource
    Electronic Resource
    Expression of Non-NMDA Glutamate Receptor Channel Genes by Clonal Human Neurons (1994)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 63 (1994), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Treatment of the human teratocarcinoma line NTera2/c1.D1 (NT2) with retinoic acid induces terminal neuronal differentiation. In a previous study, we found that the neurons obtained in this way express functional N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptor channels. We now show by reverse transcriptase-polymerase chain reaction and Southern blotting that these neurons transcribe each of the nine known non-NMDA glutamate receptor genes (GluR1-7, Ka-1, and Ka-2) and that four of these genes (GluR2, GluR6, GluR7, and Ka-1) are also transcribed by undifferentiated NT2 cells. Patch clamp studies demonstrate that individual non-NMDA glutamate receptor channels are readily isolated from NT2-derived neurons and that these channels are potently modulated by the desensitization blocker cyclothiazide. NT2-derived neurons are susceptible to kainate excitotoxicity but are not injured by prolonged exposure to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. We expect that the NT2-derived human neuronal culture system will facilitate studies of human neuronal non-NMDA glutamate receptor channels and of the pathophysiology of neuronal excitotoxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1994.63020482.x
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  • 5
    Electronic Resource
    Electronic Resource
    Inhibition of Astrocyte Glutamine Production by α-Ketoisocaproic Acid (1994)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 63 (1994), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We have evaluated the effect of α-ketoisocaproic acid (KIC), the ketoacid of leucine, on the production of glutamine by cultured astrocytes. We used 15NH4Cl as a metabolic tracer to measure the production of both [5-15N]glutamine, reflecting amidation of glutamate via glutamine synthetase, and [2-15N]glutamine, representing the reductive amination of 2-oxoglutarate via glutamate dehydrogenase and subsequent conversion of [15N]-glutamate to [2-15N]glutamine. Addition of KIC (1 mM) to the medium diminished the production of [5-15N]glutamine and stimulated the formation of [2-15N]glutamine with the overall result being a significant inhibition of net glutamine synthesis. An external KIC concentration as low as 0.06 mM inhibited synthesis of [5-15N]glutamine and a level as low as 0.13 mM enhanced labeling (atom% excess) of [2-15N]glutamine. Higher concentrations of KIC in the medium had correspondingly larger effects. The presence of KIC in the medium did not affect flux through glutaminase, which was measured using [2-15N]glutamine as a tracer. Nor did KIC inhibit the activity of glutamine synthetase that was purified from sheep brain. Addition of KIC to the medium caused no increased release of lactate dehydrogenase from the astrocytes, suggesting that the ketoacid was not toxic to the cells. KIC treatment was associated with an approximately twofold increase in the formation of 14CO2 from [U-14C]glutamate, indicating that transamination of glutamate with KIC increases intraastrocytic α-ketoglutarate, which is oxidized in the tricarboxylic acid cycle. KIC inhibited glutamine synthesis more than any other ketoacid tested, with the exception of hydroxypyruvate. The data indicate that KIC diminishes flux through glutamine synthetase by lowering the intraastrocytic glutamate concentration below the Km of glutamine synthetase for glutamate, which we determined to be ∼7 mM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1994.63041508.x
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  • 6
    Electronic Resource
    Electronic Resource
    Cyclic GMP/Cyclic GMP-Dependent Protein Kinase System Prevents Excitotoxicity in an Immortalized Oligodendroglial Cell Line (2000)
    Oxford UK : Blackwell Science Ltd
    Journal of neurochemistry 74 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Previously, we have demonstrated that excitotoxicity of oligodendrocyte-like cells (OLC), differentiated from immortalized rat O-2A progenitor cells (CG-4 cells), is prevented by cyclic AMP-elevating agents. We now report that some agents that elevate cyclic GMP prevent OLC excitotoxicity. Kainate-induced injury was prevented by cyclic GMP analogues (8-bromo-cyclic GMP and dibutyryl cyclic GMP), a guanylate cyclase activator [atrial natriuretic peptide (ANP)], and phosphodiesterase inhibitors [3-isobutyl-1-methylxanthine (IBMX), ibudilast, propentofylline, and rolipram]. When both forskolin and 8-bromo-cyclic GMP were added, kainate-induced injury was additively prevented. There was a strong positive correlation between suppression of kainate-induced Ca2+ influx and prevention of injury by these chemicals. The measurement of intracellular cyclic AMP and cyclic GMP by radioimmunoassay demonstrated the following: an increase of cyclic GMP with treatment with 8-bromo-cyclic GMP, dibutyryl cyclic GMP, and ANP; an increase of cyclic AMP with treatment with ibudilast and rolipram; and an increase of both cyclic AMP and cyclic GMP with treatment with IBMX and propentofylline. Kainate-induced Ca2+ influx was decreased by 8-(4-chlorophenylthiol)-guanosine-3′,5′-monophosphate, an activator of cyclic GMP-dependent protein kinase (PKG), or okadaic acid, an inhibitor of protein phosphatases 1 and 2A. RT-PCR and western blotting of OLC demonstrated transcription of PKG II gene and translation of PKG Iβ mRNA, but no translation of PKG Iα mRNA. Therefore, we concluded that the cyclic GMP/PKG system prevents OLC excitotoxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.740633.x
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  • 7
    Electronic Resource
    Electronic Resource
    Opposing Contributions of NR1 and NR2 to Protein Kinase C Modulation of NMDA Receptors (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: N-Methyl-d-aspartate (NMDA) receptors mediate increases in intracellular calcium that can be modulated by protein kinase C (PKC). As PKC modulation of NMDA receptors in neurons is complex, we studied the effects of PKC activation on recombinant NMDA receptor-mediated calcium rises in a nonneuronal mammalian cell line, human embryonic kidney 293 (HEK-293). Phorbol 12-myristate 13-acetate (PMA) pretreatment of HEK-293 cells enhanced or suppressed NMDA receptor-mediated calcium rises based on the NMDA receptor subunit composition. NR2A or NR2B, in combination with NR1011, conveyed enhancement whereas NR2C and NR2D conveyed suppression. The PKC inhibitor bisindolylmaleimide blocked each of these effects. The region on NR2A that conveyed enhancement localized to a discrete segment of the C terminus distal to the portion of NR2C that is homologous to NR2A. Calcium-45 accumulation, but not intracellular calcium store depletion, matched PMA effects on NMDA receptor-mediated calcium changes, suggesting that these effects were not due to effects on intracellular calcium stores. The suppression of intracellular calcium transients seen with NR2C was eliminated when combined with NR1 splice variants lacking C-terminal cassette 1. Thus, the intracellular calcium effects of PMA were distinguishable based on both the NR1 splice variant and the NR2 subunit type that were expressed. Such differential effects resemble the diversity of PKC effects on NMDA receptors in neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71041471.x
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  • 8
    Electronic Resource
    Electronic Resource
    AMPA Receptor-Mediated Excitotoxicity in Human NT2-N Neurons Results from Loss of Intracellular Ca2+ Homeostasis Following Marked Elevation of Intracellular Na+ (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Human NT2-N neurons express Ca2+-permeable α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPA-GluRs) and become vulnerable to excitotoxicity when AMPA-GluR desensitization is blocked with cyclothiazide. Although the initial increase in intracellular Ca2+ levels ([Ca2+]i) was 1.9-fold greater in the presence than in the absence of cyclothiazide, Ca2+ entry via AMPA-GluRs in an early phase of the exposure was not necessary to elicit excitotoxicity in these neurons. Rather, subsequent necrosis was caused by a 〉40-fold rise in [Na+]i, which induced a delayed [Ca2+]i rise. Transfer of the neurons to a 5 mM Na+ medium after AMPA-GluR activation accelerated the delayed [Ca2+]i rise and intensified excitotoxicity. Low-Na+ medium-enhanced excitotoxicity was partially blocked by amiloride or dizocilpine (MK-801), and completely blocked by removal of extracellular Ca2+, suggesting that Ca2+ entry by reverse operation of Na+/Ca2+ exchangers and via NMDA glutamate receptors was responsible for the neuronal death after excessive Na+ loading. Our results serve to emphasize the central role of neuronal Na+ loading in AMPA-GluR-mediated excitotoxicity in human neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71010112.x
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  • 9
    Electronic Resource
    Electronic Resource
    Cyclic AMP-Elevating Agents Prevent Oligodendroglial Excitotoxicity (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 70 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Previously, we have demonstrated that cells of the oligodendroglial lineage express non-NMDA glutamate receptor genes and are damaged by kainate-induced Ca2+ influx via non-NMDA glutamate receptor channels, representing oligodendroglial excitotoxicity. We find in the present study that agents that elevate intracellular cyclic AMP prevent oligodendroglial excitotoxicity. After oligodendrocyte-like cells, differentiated from the CG-4 cell line established from rat oligodendrocyte type-2 astrocyte progenitor cells, were exposed to 2 mM kainate for 24 h, cell death was evaluated by measuring activity of lactate dehydrogenase released into the culture medium. Released lactate dehydrogenase increased about threefold when exposed to 2 mM kainate. Kainate-induced cell death was prevented by one of the following agents: adenylate cyclase activator (forskolin), cyclic AMP analogues (dibutyryl cyclic AMP and 8-bromo-cyclic AMP), and cyclic AMP phosphodiesterase inhibitors (3-isobutyl-1-methylxanthine, pentoxifylline, propentofylline, and ibudilast). Simultaneous addition of both forskolin and phosphodiesterase inhibitors prevented the kainate-induced cell death in an additive manner. A remarkable increase in Ca2+ influx (∼5.5-fold) also was induced by kainate. The cyclic AMP-elevating agents caused a partial suppression of the kainate-induced increase in Ca2+ influx, leading to a less prominent response of intracellular Ca2+ concentration to kainate. The suppressing effect of forskolin on the kainate-induced Ca2+ influx was partially reversed by H-89, an inhibitor of cyclic AMP-dependent protein kinase. In contrast to this, okadaic acid, an inhibitor of protein phosphatases 1 and 2A, brought about a decrease in the kainate-induced Ca2+ influx. We therefore concluded that cyclic AMP-elevating agents prevented oligodendroglial excitotoxicity by cyclic AMP-dependent protein kinase-dependent protein phosphorylation, resulting in decreased kainate-induced Ca2+ influx.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.70062416.x
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  • 10
    Electronic Resource
    Electronic Resource
    Hypoxic Cell Death in Human NT2-N Neurons: Involvement of NMDA and Non-NMDA Glutamate Receptors (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Human NTera2 teratocarcinoma cells were differentiated into postmitotic NT2-N neurons and exposed to hypoxia for 6 h. The cultures were evaluated microscopically, and percent lactate dehydrogenase (LDH) release after 24 and 48 h was used as an assay for cell death. After 48 h LDH release was 24.3 ± 5.6% versus 13.8 ± 3.7% in controls (p 〈 0.001). Cell death was greatly diminished by MK-801 pretreatment (15.4 ± 5.1%, p 〈 0.001). If glutamate was omitted from the medium, glutamate levels after 6 h of hypoxia were reduced from 101 ± 63 to 2.3 ± 0.3 µM, and cell death at 48 h was also markedly reduced (15.4 ± 4.5%, p 〈 0.001). The α-amino-3-hydroxy-5-methylisoxazole-4-propionate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (18.7 ± 5.1%, p 〈 0.001) and mild hypothermia (33.5–34°C) during hypoxia (19.5 ± 2.75, p 〈 0.05) were moderately protective. Basic fibroblast growth factor (24.1 ± 3.2%), the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (22.8 ± 8.1%), the antioxidant N-tert-butyl-o-phenylnitrone (18.9 ± 5.9%), and the 21-aminosteroid U74389G (24.0 ± 3.4%) did not protect the cells. N-Acetyl-l-cysteine even tended to increase cell death (30.1 ± 2.5%, p = 0.06). Treatment with MK-801 at the end of hypoxia did not reduce cell death (23.3 ± 2.3%). In separate experiments, a 15-min exposure to 1 mM glutamate without hypoxia did not result in significant cell death (14.7 ± 2.4 vs. 12.2 ± 2.1%,p = 0.07). We conclude that, although somewhat resistant to glutamate toxicity when normoxic, NT2-N neurons die via an ionotropic glutamate receptor-mediated mechanism when exposed to hypoxia in the presence of glutamate. As far as we know, this is the first reported analysis of the mechanism of hypoxic cell death in cultured human neuronlike cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71041544.x
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