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

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 ␤-amyloid protein (A␤) to model neurodegeneration occurring in AD. The mGlu2 receptor PAM, N-4Ј-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride (LY566332), devoid of toxicity per se, amplified A␤-induced neurodegeneration, and this effect was prevented by the mGlu2/3 receptor antagonist (2S,1ЈS,2ЈS)-2-(9-xanthylmethyl)-2-(2Ј-carboxycyclopropyl)glycine (LY341495). LY566332 potentiated A␤ toxicity regardless of the presence of glial mGlu3 receptors, but it was inactive when neurons lacked mGlu2 receptors. The dual mGlu2/3 receptor agonist, (Ϫ)-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-␤1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against A␤ 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 A␤ 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 A␤, whereas dual activation of mGlu2 and mGlu3 receptors is protective against A␤-induced toxicity.

A Real-Time Method for Measuring cAMP Production Modulated by Gαi/o-Coupled Metabotropic Glutamate Receptors

“…Group II and group III mGluRs have been implicated as therapeutic targets for treating a variety of cognitive and neurodegenerative diseases, including schizophrenia, stress and anxiety disorders, Parkinson's disease, and Alzheimer's disease (Calabresi et al, 1999;Niswender and Conn, 2010;Caraci et al, 2011). Although the group II and group III mGluRs share a common signaling mechanism, selective activation of just one receptor subtype can have unique physiologic consequences (Corti et al, 2007).…”

“…These clinical setbacks may be attributed to the lack of subtype selectivity, as studies suggest that even within groups, individual mGluR can play opposing physiological roles (Conn and Pin, 1997;Caraci et al, 2011). In turn, agents that preferentially target a single mGluR may demonstrate enhanced clinical efficacy compared with their nonselective counterparts.…”

“…Despite this common signaling mechanism, each receptor has unique cognitive and neurotrophic properties (Lyon et al, 2008;Caraci et al, 2011). At least in part, these differences are attributed to the unique cellular expression profile of each mGlu receptor (mGluR) within the central nervous system and to changes in expression patterns of these receptors during development (Catania et al, 1994).…”

The Role of Mitochondrial Function in Glutamate-Dependent Metabolism in Neuronal Cells

“…Metabotropic glutamate receptors belong to a class of G-protein-linked receptors. The selective activation of metabotropic glutamate 2 receptors amplifies A -induced neurodegeneration in neuronal cultures, whereas the activation of metabotropic glutamate 2 and 3 receptors evokes neuroprotection against A -mediated toxicity [183]. Furthermore, the metabotropic glutamate 2 receptor causes the production and release of A in isolated, intact nerve terminals in TgCRND8 mice [184], corroborating the importance of metabotropic glutamate receptors in AD.…”

Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1–42)-induced toxicity

“…All experiments with TCP were carried out in cultures exposed to Aβ(1-42) oligomers (100 nM) for 48 h. Because Aβ(1-42) is able to potentiate glutamate toxicity (Caraci et al, 2011), the experiments were carried out in the presence of a cocktail of ionotropic glutamate receptor antagonists [MK-801 (10 mM) and DNQX (30 mM)] to exclude the contribution of endogenous excitotoxicity to the overall process of neuronal death. Under these conditions, neurons exposed to Aβ oligomers die showing an apoptotic phenotype (Loo et al, 1993;Gong and Klein, 2003).…”