Journal ArticleDOI
Neuroprotectant effects of LY274614, a structurally novel systemically active competitive NMDA receptor antagonist.
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TLDR
In adult rats, the neuro-degenerative effects following the intrastriatal infusions of NMDA or quinolinate, but not kainate, were prevented by LY 274614 and is a promising therapeutic agent for conditions where glutamate plays a role in the pathology of neuronal degeneration.Abstract:
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 LY274614, a structurally novel competitive NMDA receptor antagonist, for pharmacological selectivity and neuroprotectant effects following systemic administration. LY274614 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. LY274614. Oral doses showed a delayed but prolonged duration of effect. In adult rats, the neurodegenerative effects (loss of choline acetyltransferase activity) following the intrastriatal infusions of NMDA or quinolinate, but not kainate, were prevented by LY274614 (2.5 to 20 mg/kg i.p.). LY274614 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.read more
Citations
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Journal ArticleDOI
The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids.
Kathryn J. Elliott,Nobuko Minami,Yuri Kolesnikov,Gavril W. Pasternak,Gavril W. Pasternak,Charles E. Inturrisi +5 more
TL;DR: The results suggest that mu‐opioid tolerance but not kappa1‐ or kappa3‐opIOid tolerance involves the mediation of NMDA receptors and the nitric oxide system.
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The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal. Medication development issues for opiate addiction.
TL;DR: The medications with the most immediate clinical appeal are those that could be coadministered with methadone to decrease mu opioid tolerance and dependence; they include DM, MB, 7-NI, ACPC, and ACEA-1328.
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Activation of hippocampal metabotropic excitatory amino acid receptors leads to seizures and neuronal damage.
TL;DR: A highly selective metabotropic EAA agonist was injected into the hippocampus of halothane-anesthetized rats, which resulted in delayed-onset seizures and selective hippocampal neuronal damage that was indirectly mediated by NMDA receptors.
Journal ArticleDOI
The NMDA receptor, NMDA antagonists and epilepsy therapy. A status report.
TL;DR: The 1980s was a period of intensive research on the N-methyl-D-aspartate (NMDA) receptor that culminated with a profound understanding of the physiology and biophysics of the receptor, its role in synaptic integration and plasticity, and its potential importance in a surprisingly diverse group of neurological disorders.
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NMDA Receptors Regulate Nicotine-Enhanced Brain Reward Function and Intravenous Nicotine Self-Administration: Role of the Ventral Tegmental Area and Central Nucleus of the Amygdala
TL;DR: The data suggest that NMDA receptors, including those in the CeA and VTA, gate the magnitude and valence of the effects of nicotine on brain reward systems, thereby regulating motivation to consume the drug.
References
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Dennis W. Choi,Steven M. Rothman +1 more
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Brian S. Meldrum,John Garthwaite +1 more
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Journal ArticleDOI
Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage.
TL;DR: Current efforts to develop an effective therapy for hypoxic-ischemic neuronal injury are appropriately focused onNMDA antagonists; however, it is possible that additional benefit might be gained by combining NMDA antagonists with pharmacological manipulations designed to attenuate Ca 2+ entry through these other routes.
Journal ArticleDOI
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