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  • 1
    Electronic Resource
    Electronic Resource
    Cytoskeletal Breakdown and Apoptosis Elicited by NO Donors in Cerebellar Granule Cells Require NMDA Receptor Activation (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 67 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We have recently demonstrated that nitric oxide (NO) donors can trigger either apoptosis or necrosis of neurons as a function of the intensity of the exposure. Here, we show that the apoptosis induced by the NO donors S-nitrosocysteine (SNOC) or S-nitroso-N-acetylpenicillamine (SNAP) in cultured cerebellar granule cells (CGCs) depends on NMDA receptor (NMDA-R) activation leading to intracellular Ca2+ overload. Early dissolution of actin filaments followed by breakdown of microtubules and nuclear lamins preceded the appearance of typical apoptotic features. NO donors induced tyrosine nitration in neurons, in a small population of contaminating astrocytes, and in cultures of cerebellar astroglial cells. However, astrocytes neither displayed cytoskeletal alterations nor underwent apoptosis. Competitive and uncompetitive NMDA receptor antagonists, such as d-aminophosphonovaleric acid and MK-801, did not influence tyrosine nitration but prevented the accumulation of intracellular Ca2+, cytoskeletal breakdown, and apoptosis induced by either SNOC or SNAP in CGCs. Taken together, these data strongly suggest that Ca2+ influx through NMDA-R-gated ion channels is a critical event in CGC apoptosis induced by NO donors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.67062484.x
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  • 2
    Electronic Resource
    Electronic Resource
    Involvement of Activated Caspase-3-Like Proteases in N-Methyl-D-Aspartate-Induced Apoptosis in Cerebrocortical Neurons (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: Excessive activation of glutamate receptors mediates neuronal death in a number of neurodegenerative diseases. The intracellular signaling pathways that mediate this type of neuronal death are only partly understood. Following mild insults via NMDA receptor activation, central neurons undergo apoptosis, but with more fulminant insults, necrosis intervenes. Caspases are important in several forms of apoptosis in vivo and in vitro. Previously, we have demonstrated that caspases are important in excitotoxicity-mediated apoptosis of cerebrocortical neurons. To determine the possible activation of caspase-3 in NMDA-induced neuronal apoptosis, we used an affinity-labeling technique: Biotinylated N-acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD.CHO) preferentially labels conformationally active caspase-3-like proteases, allowing us to visualize affinity-labeled caspases with streptavidin-fluorescein isothiocyanate under confocal microscopy. NMDA-induced apoptosis of cerebrocortical neurons was associated with a time-dependent increase in conformationally active caspase-3-like proteases. The activation of caspases was apparent within 20 min of NMDA stimulation and was localized primarily in the cytosol. However, following incubation of neurons for 18-24 h, conformationally active caspase-3-like proteases were also detectable in nuclei. Double labeling with propidium iodide to detect chromatin condensation indicated that affinity-labeled caspase-3-like proteases were specifically expressed in apoptotic cells. To further confirm this, we used an antibody specific for the conformationally active fragment of caspase-3 and found largely concordant results. Moreover, preincubation with DEVD.CHO prevented NMDA-induced apoptosis. Our results suggest that caspase-3-like proteases play a major role in excitotoxin-induced neuronal apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0740134.x
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  • 3
    Electronic Resource
    Electronic Resource
    Role of Caspases in N-Methyl-d-Aspartate-Induced Apoptosis in Cerebrocortical Neurons (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: Overactivation of glutamate receptors mediates neuronal death in several acute and chronic neurodegenerative diseases. The intracellular processes underlying this form of death, however, remain poorly understood. Depending on the severity of insult, N-methyl-d-aspartate (NMDA) receptor activation induces either apoptosis or necrosis. Cysteine proteases related to interleukin-1β-converting enzyme (ICE), recently termed caspases, appear necessary for neuronal apoptosis in vivo and in vitro. To determine whether caspases play a role in NMDA-induced apoptosis, we used two functionally distinct approaches to decrease substrate cleavage by caspases. One is a novel peptide (V-ICEinh) that contains the caspase catalytic site and acts as a pseudoenzyme that binds caspase substrates and prevents their cleavage. The other is a pseudosubstrate peptide (Z-VAD·fmk) that inhibits caspase activity. Pretreatment with either V-ICEinh or Z-VAD·fmk protects cerebrocortical neurons from NMDA-induced apoptosis, suggesting a role for caspases in NMDA-induced apoptosis. To explore the signaling pathways involved, we looked at the effects of NMDA receptor activation on Ca2+ influx, production of reactive oxygen species (ROS), mitochondrial membrane potential, and lipid peroxidation. Neither NMDA-induced Ca2+ influx nor the initial collapse of mitochondrial membrane potential could be prevented by pretreatment with V-ICEinh or Z-VAD·fmk. In contrast, ROS formation and lipid peroxidation were completely blocked by both V-ICEinh and Z-VAD·fmk. Taken together, our results suggest that Ca2+ influx and mitochondrial depolarization occur upstream from caspase activation, whereas ROS formation and lipid peroxidation may be downstream events in the cascade leading to cortical neuronal apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71030946.x
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  • 4
    Electronic Resource
    Electronic Resource
    Translationally distinct populations of NMDA receptor subunit NR1 mRNA in the developing rat brain (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 87 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The translational activity of the NMDA subunit 1 (NR1) mRNA was examined in the developing rat brain by sucrose gradient fractionation. One translationally-active pool of NR1 mRNA was associated with large polyribosomes (polysomes) over the entire developmental period examined. A second NR1 mRNA pool, approximately half of the NR1 mRNA at post-natal day 4, sedimented only within the two to three ribosome range, indicating that it was translationally blocked during early brain development despite active translation of mRNAs coding for the NR2 subunits of the receptor. At post-natal day 4, both NR1 mRNA pools were distributed throughout the brain and contained similar profiles of NR1 mRNA splice variants, except that NR1-3 appeared to be present only in the translationally-blocked NR1 pool. After post-natal day 8, the translationally-blocked NR1 mRNA pool became progressively active within a background of globally-decreasing brain translational activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.02048.x
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  • 5
    Electronic Resource
    Electronic Resource
    AIDS-Related Dementia and Calcium Homeostasis (1994)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 747 (1994), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1994.tb44411.x
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  • 6
    Electronic Resource
    Electronic Resource
    Neuroprotective and Neurodestructive Effects of Nitric Oxide and Redox Congeners (1994)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 738 (1994), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1994.tb21826.x
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  • 7
    Electronic Resource
    Electronic Resource
    NEURONAL INJURY ASSOCIATED WITH HIV-1: Approaches to Treatment (1998)
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Pharmacology 38 (1998), S. 159-177 
    Details
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Abstract Mounting evidence suggests that cognitive dysfunction developing as a result of HIV-1 infection is mediated at least in part by generation of excitotoxins and free radicals in the brain. This syndrome is currently designated HIV-1-associated cognitive/motor complex, was originally termed the AIDS Dementia Complex, and for simplicity, is called AIDS dementia in this review. Recently, brains of patients with AIDS have been shown to manifest neuronal injury and apoptotic-like cell death. How can HIV-1 result in neuronal damage if neurons themselves are only rarely, if ever, infected by the virus? Experiments from several different laboratories have lent support to the existence of HIV- and immune-related toxins in a variety of in vitro and in vivo paradigms. In one recently defined pathway to neuronal injury, HIV-infected macrophages and microglia, or immune-activated macrophages and astrocytes (activated by the shed HIV-1 envelope protein, gp120, or other viral proteins and cytokines), appear to secrete excitants and neurotoxins. These substances may include arachidonic acid, platelet-activating factor, free radicals (NO. and O2.-), glutamate, quinolinate, cysteine, amines, and as yet unidentified factors emanating from stimulated macrophages and reactive astrocytes. A final common pathway for neuronal susceptibility is operative, similar to that observed in stroke and several neurodegenerative diseases. This mechanism involves excessive activation of N-methyl-d-aspartate (NMDA) receptor-operated channels, with resultant excessive influx of Ca2+ and the generation of free radicals, leading to neuronal damage. With the very recent development of clinically tolerated NMDA antagonists, there is hope for future pharmacological intervention.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1146/annurev.pharmtox.38.1.159
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  • 8
    Electronic Resource
    Electronic Resource
    7-Chlorokynurenate Ameliorates Neuronal Injury Mediated by HIV Envelope Protein gp120 in Rodent Retinal Cultures (1992)
    Oxford, UK : Blackwell Publishing Ltd
    European journal of neuroscience 4 (1992), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Prior studies with in vitro model systems have suggested that at least part of the neurological manifestations of AIDS may stem from neuronal injury involving the HIV-1 coat protein gp120. This form of neuronal damage is most probably mediated indirectly by a complex set of cellular interactions among macrophages, astrocytes, and neurons, resulting in a final common pathway of overstimulation of N-methyl-d-aspartate (NMDA) receptors. We studied the neuroprotective effect from gp120-induced neuronal injury of an antagonist of the glycine site of the NMDA receptor, 7-chlorokynurenate. In identified rat retinal ganglion cells in culture, we found that 50 μM 7-chlorokynurenate significantly abrogated the injury engendered by 20 pM gp120. Addition of 300 μM exogenous glycine prevented this protective effect of 50 μM 7-chlorokynurenate. These data suggest that glycine site antagonists of the NMDA receptor may have therapeutic potential for ameliorating neuronal damage associated with gp120.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1460-9568.1992.tb00167.x
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  • 9
    Electronic Resource
    Electronic Resource
    Expression of GABAC receptor ρ1 and ρ2 subunits during development of the mouse retina (2000)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 12 (2000), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Retinal γ-aminobutyric acid type C (GABAC) receptors consist of ρ subunits. Here we report our results from a competitive PCR and patch-clamp electrophysiology study quantifying ρ subunit message and characterizing GABAC receptor-mediated currents at different stages of mouse retinal development. Mouse ρ1 message is first detected at postnatal day 6 (P6), increases significantly until P9 and remains at this level through adulthood, whereas mouse ρ2 message does not appear until P9, peaks at P15 and remains at this level through adulthood. There is an approximate twofold excess of ρ1 compared to ρ2 message at most stages of development, which persists in adulthood. Functional GABAC receptors are detected in acutely dissociated bipolar cells of P9 or older mouse retina. Early in development (P9–10), GABAC receptors are composed solely of ρ1 subunits, but subsequently contain ρ1 and/or ρ2 subunits (by P11 and later). These findings are intriguing because the onset and rapid increase in ρ subunit transcription and functional expression match the initiation and active period of bipolar cell differentiation in retinal development as well as the stage of eye opening and initial visual experience in the rodent. The investigation of mouse ρ subunits here forms a basis for future studies on the role of GABAC receptors in retinal development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1460-9568.2000.00247.x
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  • 10
    Electronic Resource
    Electronic Resource
    Evidence for coassembly of mutant GABACρ1 with GABAAγ2S, glycine α1 and glycine α2 receptor subunits in vitro (2000)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 12 (2000), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Functional coassembly of γ-aminobutyric acid (GABA)Cρ1 subunits with GABAA (α1, β2, and γ2S) or glycine (α1, α2, and β) subunits was examined using two-electrode voltage-clamp recordings in the Xenopus laevis oocyte expression system. To facilitate this study, we took advantage of the unique gating and pharmacological properties of two mutant ρ1 subunits, ρ1(T314A) and ρ1(T314A/L317A). When the ρ1(T314A) subunit was coexpressed with GABA γ2S, glycine α1 or glycine α2 subunits, GABA response properties were different from those of homomeric ρ1(T314A) receptors. Additionally, the sensitivity of heteromeric ρ1(T314A) and γ2S receptors to picrotoxinin (PTX) blockade of GABA-evoked responses was altered compared to that of homomeric ρ1(T314A) receptors. Changes in GABA response properties and picrotoxinin sensitivity were also observed when ρ1(T314A) subunits were coexpressed with wild-type ρ1 subunits. When ρ1(T314A/L317A) subunits were coexpressed with GABA γ2S, glycine α1 or glycine α2 subunits, suppression by GABA of spontaneously active current was reduced compared to that of homomeric ρ1(T314A/L317A) receptors. Recovery of the spontaneous current from inhibition by GABA for GABA ρ1(T314A/L317A)/γ2S heteromeric receptors displayed an additional component. Coinjection of wild-type ρ1 with γ2S cRNAs at a ratio of 1 : 1 resulted in a 〉 10-fold reduction in GABA-evoked current. Furthermore, coexpression of wild-type ρ1 and γ2S subunits was found to shift the GABA dose–response curve. Our results provide functional evidence that the GABACρ1 subunit can coassemble with the GABAAγ2S subunit, and, at least in its mutated form, ρ1 can also form heteromeric receptors with glycine α1 or α2 subunits in vitro.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1460-9568.2000.00198.x
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