Targeting group II Metabotropic Glutamate (mGlu) receptors for the treatment of psychosis associated with alzheimer's disease: Selective activation of mGlu2 receptors amplifies β-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective (782 views)
Mol Pharmacol (ISSN: 0026-895x), 2011 Mar; 79(3): 618-626.
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Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 4.883, 5-year impact factor: 4.58
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-79951975389&partnerID=40&md5=4d22666774d7ce51cae97a212cc9b001
Keywords: 1 (5 Bromopyrimidin 2 Yl) N (2, 4 Dichlorobenzyl)pyrrolidin 3 Amine Methanesulfonate Hydrate, 2 Amino 2 (2 Carboxycyclopropyl) 3 (xanthen 9 Yl)propionic Acid, 4 Amino 2 Oxabicyclo[3 1 0]hexane 4, 6 Dicarboxylic Acid, Amyloid Beta Protein, Ly 2389575, Ly 566332, Metabotropic Receptor 2, Metabotropic Receptor Agonist, Metabotropic Receptor Antagonist, Cyano Biphenyl 3 Yl) N (3 Pyridinylmethyl)ethanesulfonamide, Transforming Growth Factor Beta1, Unclassified Drug, Alzheimer Disease, Animal Cell, Animal Experiment, Animal Model, Article, Astrocyte, Cell Viability, Drug Antagonism, Drug Targeting, Gene Expression, Mouse, Nerve Cell Culture, Nerve Degeneration, Neuroprotection, Neurotoxicity, Nonhuman, Priority Journal, Psychosis, Amino Acids, Amyloid Beta-Peptides, Antipsychotic Agents, Bicyclo Compounds, Heterocyclic, Knockout, Neuroprotective Agents, Psychotic Disorders, Sprague-Dawley, Metabotropic Glutamate, Reverse Transcriptase Polymerase Chain Reaction, Alzheimer Disease Complications Drug Therapy Metabolism, Amino Acids Pharmacology, Amyloid Beta-Peptides Drug Effects Metabolism, Antipsychotic Agents Pharmacology, Astrocytes Drug Effects Metabolism, Heterocyclic Pharmacology, Neurons Drug Effects Metabolism, Neuroprotective Agents Pharmacology, Psychotic Disorders Drug Therapy Etiology Metabolism, Pyridines Pharmacology, Metabotropic Glutamate Drug Effects Metabolism Physiology, Sulfonamides Pharmacology, Transforming Growth Factor Beta1 Pharmacology, Xanthenes Pharmacology, 4 Dichlorobenzyl) Pyrrolidin 3 Amine Methanesulfonate Hydrate, 2 Amino 2 (2 Carboxycyclopropyl) 3 (xanthen 9 Yl) Propionic Acid, 4 Amino 2 Oxabicyclo [3 1 0] Hexane 4, Cyano Biphenyl 3 Yl) N (3 Pyridinylmethyl) Ethanesulfonamide,
Affiliations:
*** IBB - CNR ***
Department of Pharmaceutical Sciences, University of Catania, Catania, Italy
Experimental and Clinical Pharmacology, University of Catania, Catania, Italy
Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy
Istituto Nazionale Biostrutture e Biosistemi, Rome, Italy
Institute of Biostructure and Bioimaging, National Research Council, Catania, Italy
Department of Physiology and Pharmacology, University of Rome Sapienza, Piazzale Aldo Moro 6, 00185, Rome, Italy
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
References:
Not available.
Mol Pharmacol (ISSN: 0026-895x), 2011 Mar; 79(3): 618-626.
Export to BibTeX Export to EndNote
Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 4.883, 5-year impact factor: 4.58
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-79951975389&partnerID=40&md5=4d22666774d7ce51cae97a212cc9b001
Keywords: 1 (5 Bromopyrimidin 2 Yl) N (2, 4 Dichlorobenzyl)pyrrolidin 3 Amine Methanesulfonate Hydrate, 2 Amino 2 (2 Carboxycyclopropyl) 3 (xanthen 9 Yl)propionic Acid, 4 Amino 2 Oxabicyclo[3 1 0]hexane 4, 6 Dicarboxylic Acid, Amyloid Beta Protein, Ly 2389575, Ly 566332, Metabotropic Receptor 2, Metabotropic Receptor Agonist, Metabotropic Receptor Antagonist, Cyano Biphenyl 3 Yl) N (3 Pyridinylmethyl)ethanesulfonamide, Transforming Growth Factor Beta1, Unclassified Drug, Alzheimer Disease, Animal Cell, Animal Experiment, Animal Model, Article, Astrocyte, Cell Viability, Drug Antagonism, Drug Targeting, Gene Expression, Mouse, Nerve Cell Culture, Nerve Degeneration, Neuroprotection, Neurotoxicity, Nonhuman, Priority Journal, Psychosis, Amino Acids, Amyloid Beta-Peptides, Antipsychotic Agents, Bicyclo Compounds, Heterocyclic, Knockout, Neuroprotective Agents, Psychotic Disorders, Sprague-Dawley, Metabotropic Glutamate, Reverse Transcriptase Polymerase Chain Reaction, Alzheimer Disease Complications Drug Therapy Metabolism, Amino Acids Pharmacology, Amyloid Beta-Peptides Drug Effects Metabolism, Antipsychotic Agents Pharmacology, Astrocytes Drug Effects Metabolism, Heterocyclic Pharmacology, Neurons Drug Effects Metabolism, Neuroprotective Agents Pharmacology, Psychotic Disorders Drug Therapy Etiology Metabolism, Pyridines Pharmacology, Metabotropic Glutamate Drug Effects Metabolism Physiology, Sulfonamides Pharmacology, Transforming Growth Factor Beta1 Pharmacology, Xanthenes Pharmacology, 4 Dichlorobenzyl) Pyrrolidin 3 Amine Methanesulfonate Hydrate, 2 Amino 2 (2 Carboxycyclopropyl) 3 (xanthen 9 Yl) Propionic Acid, 4 Amino 2 Oxabicyclo [3 1 0] Hexane 4, Cyano Biphenyl 3 Yl) N (3 Pyridinylmethyl) Ethanesulfonamide,
Affiliations:
*** IBB - CNR ***
Department of Pharmaceutical Sciences, University of Catania, Catania, Italy
Experimental and Clinical Pharmacology, University of Catania, Catania, Italy
Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy
Istituto Nazionale Biostrutture e Biosistemi, Rome, Italy
Institute of Biostructure and Bioimaging, National Research Council, Catania, Italy
Department of Physiology and Pharmacology, University of Rome Sapienza, Piazzale Aldo Moro 6, 00185, Rome, Italy
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States
References:
Not available.
Targeting group II Metabotropic Glutamate (mGlu) receptors for the treatment of psychosis associated with alzheimer's disease: Selective activation of mGlu2 receptors amplifies β-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective
Dual orthosteric agonists of metabotropic glutamate 2 (mGlu2) and mGlu3 receptors are being developed as novel antipsychotic agents devoid of the adverse effects of conventional antipsychotics. Therefore, these drugs could be helpful for the treatment of psychotic symptoms associated with Alzheimer's disease (AD). In experimental animals, the antipsychotic activity of mGlu2/3 receptor agonists is largely mediated by the activation of mGlu2 receptors and is mimicked by selective positive allosteric modulators (PAMs) of mGlu2 receptors. We investigated the distinct influence of mGlu2 and mGlu3 receptors in mixed and pure neuronal cultures exposed to synthetic β-amyloid protein (Aβ) to model neurodegeneration occurring in AD. The mGlu2 receptor PAM, N-4′-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride (LY566332), devoid of toxicity per se, amplified Aβ-induced neurodegeneration, and this effect was prevented by the mGlu2/3 receptor antagonist (2S,1′S,2′S)-2-(9-xanthylmethyl)-2-(2′- carboxycyclopropyl)glycine (LY341495). LY566332 potentiated Aβ toxicity regardless of the presence of glial mGlu3 receptors, but it was inactive when neurons lacked mGlu2 receptors. The dual mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]exhane-4,6-dicarboxylic acid (LY379268), was neuroprotective in mixed cultures via a paracrine mechanism mediated by transforming growth factor-β1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against Aβ neurotoxicity was mediated entirely by glial mGlu3 receptors. The selective noncompetitive mGlu3 receptor antagonist, (3S)-1-(5-bromopyrimidin-2-yl)-N-(2,4-dichlorobenzyl)pyrrolidin-3-amine methanesulfonate hydrate (LY2389575), amplified Aβ toxicity on its own, and, interestingly, unmasked a neurotoxic activity of LY379268, which probably was mediated by the activation of mGlu2 receptors. These data indicate that selective potentiation of mGlu2 receptors enhances neuronal vulnerability to Aβ, whereas dual activation of mGlu2 and mGlu3 receptors is protective against Aβ-induced toxicity. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics.
Dual orthosteric agonists of metabotropic glutamate 2 (mGlu2) and mGlu3 receptors are being developed as novel antipsychotic agents devoid of the adverse effects of conventional antipsychotics. Therefore, these drugs could be helpful for the treatment of psychotic symptoms associated with Alzheimer's disease (AD). In experimental animals, the antipsychotic activity of mGlu2/3 receptor agonists is largely mediated by the activation of mGlu2 receptors and is mimicked by selective positive allosteric modulators (PAMs) of mGlu2 receptors. We investigated the distinct influence of mGlu2 and mGlu3 receptors in mixed and pure neuronal cultures exposed to synthetic β-amyloid protein (Aβ) to model neurodegeneration occurring in AD. The mGlu2 receptor PAM, N-4′-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride (LY566332), devoid of toxicity per se, amplified Aβ-induced neurodegeneration, and this effect was prevented by the mGlu2/3 receptor antagonist (2S,1′S,2′S)-2-(9-xanthylmethyl)-2-(2′- carboxycyclopropyl)glycine (LY341495). LY566332 potentiated Aβ toxicity regardless of the presence of glial mGlu3 receptors, but it was inactive when neurons lacked mGlu2 receptors. The dual mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]exhane-4,6-dicarboxylic acid (LY379268), was neuroprotective in mixed cultures via a paracrine mechanism mediated by transforming growth factor-β1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against Aβ neurotoxicity was mediated entirely by glial mGlu3 receptors. The selective noncompetitive mGlu3 receptor antagonist, (3S)-1-(5-bromopyrimidin-2-yl)-N-(2,4-dichlorobenzyl)pyrrolidin-3-amine methanesulfonate hydrate (LY2389575), amplified Aβ toxicity on its own, and, interestingly, unmasked a neurotoxic activity of LY379268, which probably was mediated by the activation of mGlu2 receptors. These data indicate that selective potentiation of mGlu2 receptors enhances neuronal vulnerability to Aβ, whereas dual activation of mGlu2 and mGlu3 receptors is protective against Aβ-induced toxicity. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics.
Targeting group II Metabotropic Glutamate (mGlu) receptors for the treatment of psychosis associated with alzheimer's disease: Selective activation of mGlu2 receptors amplifies β-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective
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Targeting group II Metabotropic Glutamate (mGlu) receptors for the treatment of psychosis associated with alzheimer's disease: Selective activation of mGlu2 receptors amplifies β-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective
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* Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system (417 views)
Neuropharm (ISSN: 0028-3908linking, 1873-7064electronic), 2018 Jan; 128: 301-313.
Impact Factor: 3.383
View Export to BibTeX Export to EndNote
Caraci F, Nicoletti F, Copani A
* Metabotropic glutamate receptors: the potential for therapeutic applications in Alzheimer's disease (655 views)
Curr Opin Pharmacol (ISSN: 1471-4892), 2017 Dec 23; 38: 1-7.
Impact Factor: 6.313
View Export to BibTeX Export to EndNote
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* Metabotropic glutamate receptors in neurodegeneration/neuroprotection: Still a hot topic? (876 views)
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Impact Factor: 2.659
View Export to BibTeX Export to EndNote
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Impact Factor: 3.677
View Export to BibTeX Export to EndNote
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5 Records (5 excluding Abstracts).
Total impact factor: 20.563 (20.563 excluding Abstracts).
Total 5 year impact factor: 19.727 (19.727 excluding Abstracts).
Total impact factor: 20.563 (20.563 excluding Abstracts).
Total 5 year impact factor: 19.727 (19.727 excluding Abstracts).
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