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  • 1
    Digitale Medien
    Digitale Medien
    Synthesis and biological activity of 8a-phenyldecahydroquinolines as probes of PCP's binding conformation. A new PCP-like compound with increased in vivo potency (1992)
    s.l. : American Chemical Society
    Journal of medicinal chemistry 35 (1992), S. 1634-1638 
    Details
    ISSN: 1520-4804
    Quelle: ACS Legacy Archives
    Thema: Chemie und Pharmazie
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1021/jm00087a020
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  • 2
    Digitale Medien
    Digitale Medien
    [3H] CGP 39653 Binding to the Agonist Site of the N-Methyl- D-Aspartate Receptor Is Modulated by Mg2+ and Polyamines Independently of the Arcaine-Sensitive Polyamine Site (1994)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 62 (1994), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: This study investigated the binding of [3H] CGP 39653, a novel high-affinity antagonist of the N-methyl-D- aspartate (NMDA) recognition site of the NMDA receptor complex. [3H] CGP 39653 bound to the NMDA receptor in well washed rat brain membranes with an affinity of about 15 nM. Other NMDA site drugs inhibited [3H] CGP 39653 binding with the following order of potency: DL-(tetrazol-5- yl)glycine 〉 glutamate 〉 CGS 19755 〉 DL-2-amino-5- phosphonovalerate (DL-AP5) 〉 NMDA. Glycine and 5, 7- dichlorokynurenate partially inhibited binding. The poly-amines spermine and spermidine increased [3H] CGP 39653 binding (EC50 values of 10 and 22 μM, respectively). This effect was mimicked by arcaine, 1, 5-diethylaminopiperidine, diaminodecane, diethylenetriamine, and Mg2+. The increase in [3H] CGP 39653 was a result of an increased affinity of the binding site for the ligand with very little effect on binding site density. Spermine and Mg2+also increased the affinity of the antagonists DL-AP5 and CGS 19755, but had only minor effects on the affinity of glutamate and NMDA. Arcaine did not reverse the enhancement of [3H] CGP 39653 binding by spermine, spermidine, or Mg2+. Channel-blocking dissociative anesthetics, including dizocilpine and ketamine, did not alter basal or Mg2+-stimulated [3H] CGP 39653 binding. Spermine did not alter either the enhancement of [3H]- dizocilpine by glutamate or the inhibition of [3H]dizocilpine by DL-AP5 or CGS 19755. These studies show that poly-amines and divalent cations selectively enhance the affinity of antagonists for the agonist binding site on the NMDA receptor complex. However, this effect is mediated by a site independent of the primary polyamine site defined using [3H] dizocilpine binding.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1046/j.1471-4159.1994.62010054.x
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  • 3
    Digitale Medien
    Digitale Medien
    Regional Variations in [3H]MK801 Binding to Rat Brain N-Methyl-D-Aspartate Receptors (1991)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 56 (1991), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: This study examined (+)-[3H]5-methyl-10,11-di-hydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate ([3H]MK801) binding to the N-methyl-D-aspartate (NMDA) receptor in membranes prepared from six regions of rat brain. Highest levels of binding were found in hippocampus and cortex, whereas much lower densities were found in brainstem and cerebellum. NMDA receptors in cerebellum exhibited a significantly lower affinity for [3H]MK801 than cortical NMDA receptors. To determine whether forebrain and hindbrain NMDA receptors were distinct, the actions of glutamate, NMDA, ibotenate, quinolinate, glycine, and spermine were investigated. These agents increased [3H]MK801 binding in all brain regions examined. However, agonists were uniformly less efficacious in hindbrain compared to forebrain regions. NMDA mimetics and spermine were less potent in cerebellum compared to cortex whereas glycine was equipotent. Antagonists that act at the various modulatory sites on the NMDA receptor were also examined. DL-Amino-phosphonopentanoic acid and 7-chlorokynurenate were approximately equipotent in cortex and cerebellum. However, antagonists that are believed to act inside the NMDA-operated ion channel, including Mg2+ and phencyclidine, were approximately threefold less potent in cerebellum. The diminished regulation of [3H]MK801 binding by glutamate and glycine in the cerebellum was associated with a smaller effect of these agonists on the dissociation of [3H]MK801 from its binding site. The levels of glutamate, aspartate, glycine, serine, and glutamine in the membrane preparations were determined. However, variations in the levels of endogenous amino acids were not sufficient to account for the regional differences in [3H]MK801 binding. These results do not support the hypothesis that a distinct NMDA receptor exists in hindbrain regions of the rat CNS. However, the extent to which NMDA receptors in the cerebellum can be activated by agonists and positive allosteric modulators may be significantly reduced compared to NMDA receptors in cortex.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1111/j.1471-4159.1991.tb02074.x
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  • 4
    Digitale Medien
    Digitale Medien
    Cyclothiazide Modulates AMPA Receptor-Mediated Increases in Intracellular Free Ca2+ and Mg2+ in Cultured Neurons from Rat Brain (1995)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 64 (1995), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: We investigated the modulation of (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-induced increases in intracellular free Ca2+ ([Ca2+]i) and intracellular free Mg2+ ([Mg2+]i) by cyclothiazide and GYKI 52466 using microspectrofluorimetry in single cultured rat brain neurons. AMPA-induced changes in [Ca2+]i were increased by 0.3–100 µM cyclothiazide, with an EC50 value of 2.40 µM and a maximum potentiation of 428% of control values. [Ca2+]i responses to glutamate in the presence of N-methyl-d-aspartate (NMDA) receptor antagonists were also potentiated by 10 µM cyclothiazide. The response to NMDA was not affected, demonstrating specificity of cyclothiazide for non-NMDA receptors. Almost all neurons responded with an increase in [Ca2+]i to both kainate and AMPA in the absence of extracellular Na+, and these Na+-free responses were also potentiated by cyclothiazide. GYKI 52466 inhibited responses to AMPA with an IC50 value of 12.0 µM. Ten micromolar cyclothiazide significantly decreased the potency of GYKI 52466. However, the magnitude of this decrease in potency was not consistent with a competitive interaction between the two ligands. Cyclothiazide also potentiated AMPA- and glutamate-induced increases in [Mg2+]i. These results are consistent with the ability of cyclothiazide to decrease desensitization of non-NMDA glutamate receptors and may provide the basis for the increase in non-NMDA receptor-mediated excitotoxicity produced by cyclothiazide.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1046/j.1471-4159.1995.64052049.x
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  • 5
    Digitale Medien
    Digitale Medien
    Effects of Monovalent and Divalent Cations on 3-(+)[125I]Iododizocilpine Binding to the N-Methyl-d-Aspartate Receptor of Rat Brain Membranes (1992)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 58 (1992), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: We have investigated the binding of 3-[125I]iododizocilpine ([125I]iodo-MK-801) to the N-methyl-d-aspartate (NMDA) receptor in well-washed rat brain membranes. [125I]Iododizocipline binding was displaced by the following: dizocilpine 〉 thienylphencyclidine 〉 phencyclidine 〉 ketamine. Binding of [125I]iododizocilpine was enhanced by glutamate, glycine, and spermidine, whose actions could be reversed by CGS-19755, 7-chlorokynurenate, and arcaine, respectively. [125I]Iododizocilpine binding was also enhanced by a number of divalent cations, including Ba2+, Ca2+, Mg2+, Mn2+, and Sr2+, and several monovalent cations, including Na+ and K+. These cations enhanced [125I]iododizocilpine binding by an action at the polyamine site. In addition, the inhibitory effects associated with high concentrations of these cations was markedly reduced compared to those found in previous studies with [3H]dizocilpine. Analysis of the ability of spermidine, Mg2+, and Sr2+ to alter the inhibition of [125I]iododizocilpine by arcaine gave pA2 values of 5.41, 4.47, and 4.93, corresponding to EC50 concentrations of 3.9, 34.7, and 12.0 μM, respectively, suggesting that physiological concentrations of Mg2+ may occupy the polyamine site. These results demonstrate that [125I]-iododizocilpine is a useful probe for the NMDA receptor. Moreover, its high specific activity and relative insensitivity to the inhibitory actions of divalent cations should make [125I]iododizocilpine a valuable ligand for the study of NMDA receptors in intact cellular systems.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1111/j.1471-4159.1992.tb11366.x
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  • 6
    Digitale Medien
    Digitale Medien
    Muscarinic Agonists Cause Calcium Influx and Calcium Mobilization in Forebrain Neurons In Vitro (1989)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 53 (1989), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: We have examined the effects of the muscarinic agonist carbachol on the intracellular free Ca2+ concentration ([Ca2+]i) in primary cultures of neurons from rat forebrain using the Ca2+-sensitive fluorescent dye fura-2. Addition of carbachol increased the [Ca2+]i in ∼60% of cells studied. Oxotremorine-M, but not pilocarpine, mimicked the effects of carbachol. The response was reduced by 60% on removal of extracellular Ca2+, a finding suggesting that muscarinic receptor activation causes Ca2+ influx in addition to intracellular Ca2+ mobilization. Tetrodotoxin and nitrendipine also significantly reduced the response to carbachol. These studies suggest that the changes in [Ca2+]i produced by activation of muscarinic receptors result in part from mobilization of intracellular Ca2+ and that influx through voltage-sensitive Ca2+ channels also provides a significant contribution to the net [Ca2+]i change observed
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1111/j.1471-4159.1989.tb07318.x
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  • 7
    Digitale Medien
    Digitale Medien
    Calcium-Sensitive Fluorescent Dyes Can Report Increases in Intracellular Free Zinc Concentration in Cultured Forebrain Neurons (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: High concentrations of Zn2+ are found in presynaptic terminals of excitatory neurons in the CNS. Zn2+ can be released during synaptic activity and modulate postsynaptic receptors, but little is known about the possibility that Zn2+ may enter postsynaptic cells and produce dynamic changes in the intracellular Zn2+ concentration ([Zn2+]i). We used fura-2 and magfura-2 to detect the consequences of Zn2+ influx in cultured neurons under conditions that restrict changes in intracellular Ca2+ and Mg2+ concentrations. The resulting ratio changes for both dyes were reversed completely by the Zn2+ chelator, N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine, indicating that these dyes are measuring changes in [Zn2+]i. We found that fura-2 was useful in measuring small increases in [Zn2+]i associated with exposure to Zn2+ alone that may be mediated by a Na+/Ca2+ exchanger. Magfura-2, which has a lower affinity for Zn2+, was more useful in measuring larger agonist-stimulated increases in [Zn2+]i. The coapplication of 300 µM Zn2+ and 100 µM glutamate/10 µM glycine resulted in a [Zn2+]i increase that was ∼40–100 nM in magnitude and could be inhibited by the NMDA receptor antagonist, MK-801 (30 µM), or extracellular Na+. This suggests that Zn2+ influx can occur through at least two different pathways, leading to varying increases in [Zn2+]i. These findings demonstrate the feasibility of measuring changes in [Zn2+]i in neurons.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71062401.x
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  • 8
    Digitale Medien
    Digitale Medien
    Alkalinization Prolongs Recovery from Glutamate-Induced Increases in Intracellular Ca2+ Concentration by Enhancing Ca2+ Efflux Through the Mitochondrial Na+/Ca2+ Exchanger in Cultured Rat Forebrain Neurons (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: Increasing extracellular pH from 7.4 to 8.5 caused a dramatic increase in the time required to recover from a glutamate (3 µM, for 15 s)-induced increase in intracellular Ca2+ concentration ([Ca2+]i) in indo-1-loaded cultured cortical neurons. Recovery time in pH 7.4 HEPES-buffered saline solution (HBSS) was 126 ± 30 s, whereas recovery time was 216 ± 19 s when the pH was increased to 8.5. Removal of extracellular Ca2+ did not inhibit the prolongation of recovery caused by increasing pH. Extracellular alkalinization caused rapid intracellular alkalinization following glutamate exposure, suggesting that pH 8.5 HBSS may delay Ca2+ recovery by affecting intraneuronal Ca2+ buffering mechanisms, rather than an exclusively extracellular effect. The effect of pH 8.5 HBSS on Ca2+ recovery was similar to the effect of the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxyphenyl)hydrazone (FCCP; 750 nM). However, pH 8.5 HBSS did not have a quantitative effect on mitochondrial membrane potential comparable to that of FCCP in neurons loaded with a potential-sensitive fluorescent indicator, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolocarbocyanine iodide (JC-1). We found that the effect of pH 8.5 HBSS on Ca2+ recovery was completely inhibited by the mitochondrial Na+/Ca2+ exchange inhibitor CGP-37157 (25 µM). This suggests that increased mitochondrial Ca2+ efflux via the mitochondrial Na2+/Ca2+ exchanger is responsible for the prolongation of [Ca2+]i recovery caused by alkaline pH following glutamate exposure.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71031051.x
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  • 9
    Digitale Medien
    Digitale Medien
    Induction of Neuronal Apoptosis by Thiol Oxidation (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 75 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: The membrane-permeant oxidizing agent 2,2′-dithiodipyridine (DTDP) can induce Zn2+ release from metalloproteins in cell-free systems. Here, we report that brief exposure to DTDP triggers apoptotic cell death in cultured neurons, detected by the presence of both DNA laddering and asymmetric chromatin formation. Neuronal death was blocked by increased extracellular potassium levels, by tetraethylammonium, and by the broad-spectrum cysteine protease inhibitor butoxy-carbonyl-aspartate-fluoromethylketone. N,N,N′,N′-Tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) and other cell-permeant metal chelators also effectively blocked DTDP-induced toxicity in neurons. Cell death, however, was not abolished by the NMDA receptor blocker MK-801, by the intracellular calcium release antagonist dantrolene, or by high concentrations of ryanodine. DTDP generated increases in fluorescence signals in cultured neurons loaded with the zinc-selective dye Newport Green. The fluorescence signals following DTDP treatment also increased in fura-2- and magfura-2-loaded neurons. These responses were completely reversed by TPEN, consistent with a DTDP-mediated increase in intracellular free Zn2+ concentrations. Our studies suggest that under conditions of oxidative stress, Zn2+ released from intracellular stores may contribute to the initiation of neuronal apoptosis.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0751878.x
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  • 10
    Digitale Medien
    Digitale Medien
    Effects of Oxidants and Glutamate Receptor Activation on Mitochondrial Membrane Potential in Rat Forebrain Neurons (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Quelle: Blackwell Publishing Journal Backfiles 1879-2005
    Thema: Medizin
    Notizen: Abstract: Both glutamate and reactive oxygen species have been implicated in excitotoxic neuronal injury, and mitochondria may play a key role in the mediation of this process. In this study, we examined whether glutamate-receptor stimulation and oxidative stress interact to affect the mitochondrial membrane potential (ΔΨ). We measured ΔΨ in rat forebrain neurons with the ratiometric fluorescent dye JC-1 by using laser scanning confocal imaging. Intracellular oxidant levels were measured by using the oxidation-sensitive dyes 2′,7′-dichlorodihydrofluorescein (DCFH2) and dihydroethidium (DHE). Application of hydrogen peroxide (0.3–3 mM) or 1 mM xanthine/0.06 U/ml xanthine oxidase decreased ΔΨ in a way that was independent of the presence of extracellular Ca2+ and was not affected by the addition of cyclosporin A, suggesting the presence of either a cyclosporin A-insensitive form of permeability transition, or a separate mechanism. tert-Butylhydroperoxide (730 µM) had less of an effect on ΔΨ than hydrogen peroxide despite similar effects on intracellular DCFH2 or DHE oxidation. Hydrogen peroxide-, tert-butylhydroperoxide-, and superoxide-enhanced glutamate, but not kainate, induced decreases in ΔΨ. The combined effect of peroxide or superoxide plus glutamate was Ca2+ dependent and was partially inhibited by cyclosporin A. These results suggest that oxidants and glutamate depolarize mitochondria by different mechanisms, and that oxidative stress may enhance glutamate-mediated mitochondrial depolarization.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71062392.x
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