title: Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer's disease: selective activation of mGlu2 receptors amplifies beta-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Catania, Catania, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Caraci
authors.forename: Gemma
authors.initials: G
authors.lastname: Molinaro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Giuffrida
authors.forename: Barbara
authors.initials: B
authors.lastname: Riozzi
authors.forename: Anna
authors.initials: A
authors.lastname: Traficante
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.forename: Milena
authors.initials: M
authors.lastname: Cannella
authors.forename: Sara
authors.initials: S
authors.lastname: Merlo
authors.forename: Xushan
authors.initials: X
authors.lastname: Wang
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Heinz
authors.forename: Eric S
authors.initials: ES
authors.lastname: Nisenbaum
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Britton
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Sortino
authors.forename: Agata
authors.initials: A
authors.lastname: Copani
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C114624:LY 341495; C118218:LY 379268; C542802:N-(4'-cyanobiphenyl-3-yl)-N-(3-pyridinylmethyl)ethanesulfonamide; D018696:Neuroprotective Agents; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3