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  • 1
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Huntington's disease is an autosomal-dominant progressive neurodegenerative disorder resulting in specific neuronal loss and dysfunction in the striatum and cortex. The disease is universally fatal, with a mean survival following onset of 15–20 years and, at present, there is no ...
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 60 (1993), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Quantitative autoradiography of [3H]MK-801 binding was used to characterize regional differences in N-methyl-d-aspartate (NMDA) receptor pharmacology in rat CNS. Regionally distinct populations of NMDA receptors were distinguished on the basis of regulation of [3H]MK-801 binding by the NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). CPP inhibited [3H]MK-801 binding in outer cortex (OC) and medial cortex (MC) with apparent Ki values of 0.32-0.48 μM, whereas in the medial striatum (MS), lateral striatum (LS), CA1, and dentate gyrus (DG) of hippocampus, apparent Ki values were 1.1-1.6 μM. In medial thalamus (MT) and lateral thalamus (LT) the apparent Ki values were 0.78 μM. In the presence of added glutamate (3 μM), the relative differences in apparent Ki values between regions maintained a similar relationship with the exception of the OC. Inhibition of [3H]MK-801 binding by the glycine site antagonist 7-chlorokynurenic acid (7-ClKyn) distinguished at least two populations of NMDA receptors that differed from populations defined by CPP displacement. 7-ClKyn inhibited [3H]MK-801 binding in OC, MC, MS, and LS with apparent Ki values of 6.3-8.6 μM, whereas in CA1, DG, LT, and MT, Ki values were 11.4-13.6 μM. In the presence of added glycine (1 μM), the relative differences in apparent Ki values were maintained. Under conditions of differential receptor activation, regional differences in NMDA receptor pharmacology can be detected using [3H]MK-801 binding.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 45 (1985), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Quantitative autoradiography was used to ascertain alterations in [3H]muscimol, [3H]flunitrazepam (FLU), [3H]naloxone, [3H]d-alanine-d-leucine-enkephalin (DADL), and [3H]spiroperidol binding in basal ganglia 1 week, 4 weeks, and 5 months after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB) in the rat. At 1 and 4 weeks following lesions, [3H]spiroperidol binding increased 33% in striatum. At 5 months, [3H]spiroperidol was only nonsignificantly increased above control. At 1 week, [3H]muscimol binding decreased 39% in ipsilateral globus pallidus (GP), but increased 41% and 11% in entopeduncular nucleus (EPN) and substantia nigra pars reticulata (SNr), respectively. At 4 weeks, [3H]muscimol binding was reduced 19% in striatum and 44% in GP and remained enhanced by 32% in both EPN and SNr. These changes in [3H]muscimol binding persisted at 5 months. [3H]FLU binding was altered in the same direction as [3H]muscimol binding; however, changes were slower in onset and became significant (and remained so) only at 4 weeks after lesions. Decreases in [3H]naloxone and [3H]DADL binding were seen in striatum, GP, EPN, and SNr. Scatchard analyses revealed that only receptor numbers were altered. This study provides biochemical evidence for differential regulation of striatal GABAergic output to GP and EPN/SNr.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 48 (1987), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Glutamate or a related excitatory amino acid is thought to be the major excitatory neurotransmitter of hippocampal afferents, intrinsic neurons, and efferents. We have used an autoradiographic technique to investigate the status of excitatory amino acid receptors in the hippocampal formation of patients dying with dementia of the Alzheimer type (DAT). We examined l-[3H]glutamate binding to sections from the hippocampal formation of six patients dying of DAT and six patients without DAT and found marked reductions in total [3H]glutamate binding in all regions of hippocampus and adjacent parahippocampal cortex in DAT brains as compared to controls. When subtypes of excitatory amino acid receptors were assayed, it was found that binding to the N-methyl-d-aspartate (NMDA)-sensitive receptor was reduced by 75–87%, with the greatest loss found in stratum moleculare and stratum pyramidale of CA1. Binding to quisqualate (QA)-sensitive receptors was reduced by 45–69%. There were smaller reductions (21–46%) in GABAA receptors in DAT cases. Muscarinic cholinergic receptors assayed in adjacent sections of hippocampal formation were unchanged in DAT. Benzodiazepine receptors were reduced significantly only in parahippocampal cortex by 44%. These results suggest that glutamatergic neurotransmission within the hippocampal formation is likely to be severely impaired in Alzheimer's disease. Such impairment may account for some of the cognitive decline and memory deficits that characterize DAT.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Using quantitative autoradiography, we have investigated the binding sites for the potent competitive non-N-methyl-D-aspartate (non-NMDA) glutamate receptor antagonist [3H]6-cyano-7-nitro-quinoxaline-2,3-dione ([3H]-CNQX) in rat brain sections. [3H]CNQX binding was regionally distributed, with the highest levels of binding present in hippocampus in the stratum radiatum of CA1, stratum lucidum of CA3, and molecular layer of dentate gyrus. Scatchard analysis of [3H]CNQX binding in the cerebellar molecular layer revealed an apparent single binding site with a KD= 67 ± 9.0 nM and Bmax= 3.56 ± 0.34 pmol/mg protein. In displacement studies, quisqualate, L-glutamate, and kainate also appeared to bind to a single class of sites. However, (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) displacement of [3H]CNQX binding revealed two binding sites in the cerebellar molecular layer. Binding of [3H]AMPA to quisqualate receptors in the presence of potassium thiocyanate produced curvilinear Scatchard plots. The curves could be resolved into two binding sites with KD1= 9.0 ± 3.5 nM, Bmax= 0.15 ± 0.05 pmol/mg protein, KD2= 278 ± 50 nM, and Bmax= 1.54 ± 0.20 pmol/mg protein. The heterogeneous anatomical distribution of [3H]CNQX binding sites correlated to the binding of L-[3H]glutamate to quisqualate receptors and to sites labeled with [3H]AMPA. These results suggest that the non-NMDA glutamate receptor antagonist [3H]CNQX binds with equal affinity to two states of quisqualate receptors which have different affinities for the agonist [3H]AMPA.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Quisqualate, a glutamate analogue, displaced L-[3H]glutamate binding in a biphasic manner, corresponding to “high-affinity” and “low-affinity” binding sites. High-affinity quisqualate sites were termed “quisqualate-sensitive L-[3H]glutamate” binding sites. Quisqualate-sen-sitive L-[3H]glutamate binding was regionally distributed, with the highest levels present in the cerebellar molecular layer. This binding was stimulated by millimolar concentrations of chloride and calcium. The stimulatory effects of calcium required the presence of chloride ions, whereas chloride's stimulatory effects did not require calcium. All of the L-[3H]glutamate binding stimulated by chloride/calcium was quisqualate sensitive and only weakly displaced by N-methyl-D-aspartate, L-aspartate, or kainate. At high concentrations (1 mM), the anion blockers 4-acetamido-4′-isothiocyanostilbene-2,2′-disulfonic acid and4,4′-diisothio-cyanatostilbene-2,2′-disulfonic acid both reduced, by 41 and 43%, respectively, the stimulatory effects of chloride. At concentrations of 100 μM, kynurenate, L-aspartate, (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and L-2-amino-4-phosphonobutyric acid (L-APB) failed to displace quisqualate-sensitive L-[3H]-glutamate binding in the cerebellar molecular layer. In the presence of KSCN, however, 100 μM AMPA displaced 44% of binding. Quisqualate-sensitive L-[3H]glutamate binding was not sensitive to freezing, and, in contrast to other chloride- and calcium-dependent L-[3H]glutamate binding sites that have been reported, quisqualate-sensitive binding observed by autoradiography was enhanced at 4°C compared with 37°C. Quisqualate-sensitive L-[3H]glutamate binding likely represents binding to the subclass of postsynaptic neuronal glutamate receptors known as quisqualate receptors, rather than binding to previously described APB receptors, chloride-driven sequestration into vesicles, or binding to astrocytic membrane binding sites.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 21 (1973), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We have developed a sensitive and specific assay for homocarnosine in tissues. Homocarnosine is separated from GABA by ion exchange chromatography. After hydrolysis of homocarnosine with swine kidney carnosinase, the evolved GABA is measured by an enzymatic-fluorometric procedure. As little as 0.1 nmol of tissue homocarnosine can be detected by this procedure. Homoanserine, which would be detected by this assay, can be separated from homocarnosine by thin layer chromatography. No homoanserine could be detected in any tissues examined. There are marked regional variations in levels of homocarnosine in guinea-pig brain that do not correspond to regional differences in GABA levels.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Molecular and cellular biochemistry 38 (1981), S. 147-162 
    ISSN: 1573-4919
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Summary In this paper it is shown that the postsynaptic GABA-receptor chloride ion channel complex is composed of several functional subunits. There are probably at least two stereospecific locations on the receptor for GABA-binding and both must be occupied to obtain an increase in chloride conductance. The interaction between these sites is uncertain but there could be either positive cooperativity between the sites or only a requirement that both sites are occupied without occupation of either site affecting the affinity for GABA of the other site. There is a chloride conductance channel coupled to the GABA receptor which opens for an average of 20 msec and has an average conductance of 18 pS. The GABA-coupled chloride channel may or may not have the same composition as the glycine coupled chloride channel. In addition to the GABA-recognition site and the chloride ion channel, GABA-receptors must have additional binding sites or modulator sites where drugs can bind to modify GABA activation of the GABA-receptor. The convulsant PICRO binds to a site which is independent of the GABA-recognition site and PICRO reduces GABA responses. Barbiturates and benzodiazepines augment GABA-responses without reducing GABA-binding and thus they must bind to a modulator site independent of the GABA recognition site. Whether or not this is the same site as the PICRO binding site is uncertain. Thus, the GABA-receptorchloride ion channel complex is composed of at least: 1) two GABA-binding sites; 2) a chloride ion channel; 3) a convulsant binding site (PICRO-binding site) and 4) an anticonvulsant binding site. This organization serves several obvious purposes. First, since two GABA-molecules are required to activate GABA-coupled chloride ion channels, the dose-response relationship for GABA is sigmoidal and steep. Thus minor shifts in GABA affinity will produce large alterations in GABA-responses and the GABA receptor can be easily modulated. Second, since the receptor has binding sites for convulsant and anticonvulsant compounds which decrease and increase GABA-responses, GABAergic inhibition can easily be modulated.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1433-0407
    Keywords: Schlüsselwörter Chorea Huntington ; Transgene Mäuse ; Exzitoxizität ; CAG-Tripleterkrankungen ; Neurodegeneration ; Key words Huntington's disease ; Transgenic mice ; Exitotoxicity ; CAG-triplet diseases ; Neurodegeneration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Huntington's disease (HD) is member of a growing family of neurodegenerative diseases which are caused by a CAG-Triplet expansion in the coding region of their respective genes. The results of the research of the last years is very suggestive of a common pathomechanisms of all these diseases even though their clinical appearance may be quite different. The development of new animal models by transferring the human gene defect into the mouse genome has led to the finding of so-called intranuclear inclusion bodies. This new observation allowed to come closer to solving the problem how this genetic defect causes neurodegeneration. Recent studies on transgenic HD mice could also demonstrate a possible connection between the genetic defect and glutamate exitotoxicity in the neurodegenerative process of HD which had been emphasized by earlier animal models of the disease. Transgenic animal models of HD will have an important impact on the understanding of the disease mechanisms and may contribute to a faster development and testing of new therapeutic approaches.
    Notes: Zusammenfassung Chorea Huntington (CH) ist das bisher am besten erforschte Mitglied einer neuen Familie von autosomal dominanten neurodegenerativen Erbkrankheiten, das durch eine Verlängerung von CAG-Tripletwiederholungen im krankheitsspezifischen Gen verursacht wird. Die molekularbiologischen Erkenntnisse der letzten Jahre weisen darauf hin, daß diesen klinisch unterschiedlich in Erscheinung tretenden Erkrankungen gemeinsame Pathomechanismen zugrunde liegen. Dabei hat vor allem die Schaffung neuer Tiermodelle mit Übertragung der menschlichen Gendefekte auf die Maus und die an diesen Modellen erstmals beschriebene Entstehung intranukleärer Einschlußkörper ermöglicht, der Frage näher zu kommen, wie der Gendefekt zur Neurodegeneration führt. Hierbei lassen neuere Arbeiten an transgenen Mäusen darauf schließen, wie ein Zusammenhang zwischen dem Gendefekt und der aus früheren Modellen der CH bereits vermuteten Bedeutung von Glutamat-Exzitoxizität für die Neurodegeneration hergestellt werden kann. Transgene Mausmodelle der CH werden zukünftig nicht nur bei der Untersuchung pathophysiologischer Mechanismen eine Rolle spielen, sondern möglicherweise auch zur schnelleren Validierung von Therapieansätzen beitragen.
    Type of Medium: Electronic Resource
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