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  • 1
    Electronic Resource
    Electronic Resource
    Guinea Pig Striatum as a Model of Human Dopamine Deamination: The Role of Monoamine Oxidase Isozyme Ratio, Localization, and Affinity for Substrate in Synaptic Dopamine Metabolism (1985)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 45 (1985), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The kinetic properties of type A and type B monoamine oxidase (MAO) were examined in guinea pig striatum, rat striatum, and autopsied human caudate nucleus using 3,4-dihydroxyphenylethylamine (dopamine, DA) as the substrate. MAO isozyme ratio in guinea pig striatum (28% type A/72% type B) was similar to that in human caudate nucleus (25% type A/75% type B) but different from that in rat striatum (76% type A/24% type B). Additional similarities between guinea pig striatum and human caudate nucleus were demonstrated for the affinity constants (Km) of each MAO isozyme toward DA. Endogenous concentrations of DA, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were also measured in guinea pig and rat striatum following selective type A (clorgyline-treated) and type B (deprenyl-treated) MAO inhibition. In guinea pig, DA metabolism was equally but only partially affected by clorgyline or deprenyl alone. Combined treatment with clorgyline and deprenyl was required for maximal alterations in DA metabolism. By contrast, DA metabolism in rat striatum was extensively altered by clorgyline but unaffected by deprenyl alone. Finally, the deamination of DA in synaptosomes from guinea pig striatum was examined following selective MAO isozyme inhibition. Neither clorgyline nor deprenyl alone reduced synaptosomal DA deamination. However, clorgyline and deprenyl together reduced DA deamination by 94%. These results suggest that the isozyme localization and/or isozyme affinity for DA, rather than the absolute isozyme content, determines the relative importance of type A and type B MAO in synaptic DA deamination. Moreover, based on the enzyme kinetic properties of each MAO isozyme, guinea pig striatum may serve as a suitable model of human DA deamination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1985.tb04086.x
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  • 2
    Electronic Resource
    Electronic Resource
    Neuroprotective Actions of Novel and Potent Agonists of Group II Metabotropic Glutamate Receptors (2000)
    Oxford, UK : Blackwell Publishing Ltd
    CNS drug reviews 6 (2000), S. 0 
    Details
    ISSN: 1527-3458
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3458.2000.tb00180.x
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  • 3
    Electronic Resource
    Electronic Resource
    Potent, stereoselective, and brain region selective modulation of second messengers in the rat brain by (+)LY354740, a novel group II metabotropic glutamate receptor agonist (1998)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 358 (1998), S. 175-180 
    Details
    ISSN: 1432-1912
    Keywords: Key words LY354740 ; cAMP ; Phosphoinositide ; hydrolysis ; Hippocampus ; Metabotropic glutamate ; receptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract LY354740 is a highly potent and selective agonist for recombinant Group II mGlu receptors (mGlu2 and mGlu3), which has anxiolytic and drug withdrawal alleviating properties when administered systemically in rats and mice. The modulation of second messengers by LY354740 in rat brain tissues was investigated to understand the cellular basis for the pharmacological and potential therapeutic actions of LY354740. LY354740 potently decreased forskolin-stimulated cAMP formation in slices of the adult rat hippocampus (EC50=22±3 nM) in a stereoselective manner. LY354740 (at 1 µM) greatly (〉90%) suppressed forskolin-stimulated cAMP in the cerebral cortex, hippocampus, and striatum, while producing only partial suppression (about 50%) in midbrain regions and olfactory bulb, and no significant cAMP alterations in the cerebellum and brainstem regions. Inhibition of forskolin-stimulated cAMP formation was antagonized by (+)-α-methyl-4-carboxyphenylglycine [(+)MCPG], a competitive mGlu receptor antagonist. LY354740 did not alter phosphoinositide hydrolysis in the rat hippocampus per se, but potentiated stimulation of phophoinositide hydrolysis by the Group I mGlu receptor selective agonist 3,5-dihydroxyphenylglycine (DHPG) or stimulation of cAMP formation by the adenosine receptor agonist 5’-N-ethylcarboxamideoadenosine (NECA). These data indicate that LY354740 is a highly potent, efficacious, and selective Group II mGlu receptor (mGlu 2/3) agonist in the rat brain. The potent, stereoselective, and brain region selective actions of LY354740 on mGlu receptor linked second messenger systems likely underlie the in vivo potency and stereoselectivity of this compound in animal models.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00005240
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  • 4
    Electronic Resource
    Electronic Resource
    Attenuation of specific PCP-evoked behaviors by the potent mGlu2/3 receptor agonist, LY379268 and comparison with the atypical antipsychotic, clozapine (2000)
    Springer
    Psychopharmacology 148 (2000), S. 423-429 
    Details
    ISSN: 1432-2072
    Keywords: Key words Metabotropic glutamate receptor ; PCP ; Psychosis ; Behavior ; Clozapine ; LY379268
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Recent studies using phencyclidine (PCP) as a model for psychosis have implicated metabotropic glutamate (mGlu) receptors in schizophrenia. We have shown, using an automated motor activity monitoring system, that selective group II mGlu receptor agonists attenuate PCP (5 mg/kg)-evoked increases in ambulations and fine motor movements with similar profiles to the atypical antipsychotic, clozapine. Objective and methods: Because the automated system does not discriminate between specific PCP-evoked behaviors, in this paper we examined the effects of the potent mGlu2/3 receptor agonist LY379268 on PCP-evoked behaviors as assessed by observational methods. Furthermore, we have compared the actions of LY379268 to the atypical antipsychotic clozapine. Results: LY379268 and clozapine reduced the expression of PCP-induced falling, turning and back pedaling in a dose-dependent manner. Thirty minutes post-PCP administration, 1 mg/kg LY379269 reduced falls and turns by 89% and 53%, respectively, and 1 mg/kg clozapine attenuated turning by 70%. Interestingly, low doses of clozapine increased PCP-elicited falls. Back-pedaling was particularly sensitive to LY379268 and clozapine, with 1 mg/kg of either agent completely abolishing back-pedaling 30 min after PCP administration. However, in contrast to LY379268, attenuation of these behaviors by clozapine only occurred at doses that augmented PCP-evoked ataxia. Furthermore, LY379268 did not affect PCP-evoked forepaw treading. Conclusions: These results indicate that mGlu2/3 receptors do not mediate a generalized reduction in motor activity, but instead selectively modulate specific PCP behaviors, further implicating group II mGlu receptors as viable drug targets in the treatment of schizophrenia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050072
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  • 5
    Electronic Resource
    Electronic Resource
    Selective protection against AMPA- and kainate-evoked neurotoxicity by (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) and its racemate (LY215490) (1996)
    Springer
    Journal of neural transmission 103 (1996), S. 905-916 
    Details
    ISSN: 1435-1463
    Keywords: AMPA ; NMDA ; kainate ; glutamate receptor ; LY293558 ; excitotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glutamate receptor-mediated excitotoxicity is linked to the activation of multiple receptors including those activated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate. In this study, the novel glutamate receptor antagonist, as its active isomer (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahydroisoquinoline-3-carboxylic acid ((−)LY293558) and it's ± racemate (LY215490), was examined for neuroprotectant effects against excitotoxic injury in vitro and in vivo. This agent selectively protected against AMPA and kainate injury in cultured primary rat hippocampal neurons, an in vivo rat striatal neurotoxicity model, and against agonist-evoked seizures in mice. Thus, (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisguinoline-3-carboxylic acid represents a novel receptor selective and potent systemically active AMPA/kainate receptor antagonist for exploring neuroprotection via non-NMDA receptor mechanisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01291781
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  • 6
    Electronic Resource
    Electronic Resource
    Neuroprotectant effects of LY 274614, a structurally novel systemically active competitive NMDA receptor antagonist (1991)
    Springer
    Journal of neural transmission 85 (1991), S. 131-143 
    Details
    ISSN: 1435-1463
    Keywords: NMDA ; neuronal degeneration ; excitatory amino acid ; excitotoxicity ; glutamate ; quirolinic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Antagonists for the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor may have therapeutic potential as neuroprotectant agents in conditions of neuronal degeneration that include brain ischemia, Huntington's chorea, and Alzheimer's disease. Here we have investigated the pharmacological actions of LY 274614, a structurally novel competitive NMDA receptor antagonist, for pharmacological selectivity and neuroprotectant effects following systemic administration. LY 274614 potently displaced NMDA receptor ([3H]CGS19755) binding (IC50=58.8±10.3 nM), but had no appreciable affinity at [3H]AMPA or [3H]kainate receptor sites at up to 10,000 nM. NMDA-induced convulsions in neonatal rats or NMDA-induced lethality in mice are potently and selectively antagonized by i.p. or p.o. LY 274614. Oral doses showed a delayed but prolonged duration of effect. In adult rats, the neuro-degenerative effects (loss of choline acetyltransferase activity) following the intrastriatal infusions of NMDA or quinolinate, but not kainate, were prevented by LY 274614 (2.5 to 20mg/kg i.p.). LY 274614 is an effective neuroprotectant agent against NMDA receptor-induced toxicity when administered systemically and is a promising therapeutic agent for conditions where glutamate plays a role in the pathology of neuronal degeneration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01244705
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  • 7
    Electronic Resource
    Electronic Resource
    CGS-19755 and MK-801 selectively prevent rat striatal cholinergic and gabaergic neuronal degeneration induced by N-methyl-D-aspartate and ibotenate in vivo (1989)
    Springer
    Journal of neural transmission 78 (1989), S. 183-193 
    Details
    ISSN: 1435-1463
    Keywords: CGS-19755 ; MK-801 ; ibotenate ; N-methyl-D-aspartate ; excitotoxicity ; excitatory amino acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The in vivo efficacies and potencies of various excitatory amino acid agonists in inducing cholinergic neuronal degeneration were compared following unilateral injections into the rat striatum. Kainic acid (KA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), ibotenic acid (IBO), and N-methyl-D-aspartic acid (NMDA) all produced dose-related decreases in choline acetyltransferase (ChAT) activity. The relative order of potency was KA〉AMPA〉IBO〉NMDA. Quisqualic acid (QUIS) was about as potent as NMDA, but the maximal decrease in ChAT activity was less (36%). N-acetylaspartyl-L-glutamate (NAAG) did not significantly decrease ChAT activity when up to 1,000 nmoles was injected. Approximate equitoxic doses of agonists were then used to examine the ability of i.p. administered CGS-19755 and MK-801 to prevent in vivo excitatory amino acid-induced cholinergic and GABAergic neuronal degeneration. NMDA-induced decreases in ChAT and glutamic acid decarboxylase (GAD) activities were prevented by CGS-19755 (10–40 mg/kg) and MK-801 (1–10 mg/kg). CGS-19755 (40 mg/kg) and MK-801 (10 mg/kg) did not prevent loss of ChAT or GAD induced by KA or AMPA, but did prevent the degenerative effects of IBO. This study shows that CGS-19755 and MK-801, two NMDA receptor antagonists that act by different mechanisms, are completely selective following systemic administration. Moreover, the in vivo excitotoxic effects of IBO are mediated at NMDA receptor sites that are blocked by these compounds.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01249228
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