Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective

Bruno, Valeria; Ksiazek, Iwona; Battaglia, Giuseppe; Lukić, Snežana; Leonhardt, T; Sauer, Dirk; Gasparini, F.; Kühn, Rainer; Nicoletti, Ferdinando; Flor, Peter J.

doi:10.1016/s0028-3908(00)00079-4

Cited by 118 publications

(72 citation statements)

References 17 publications

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“…2 F). The latter finding was entirely unexpected and suggests that the permissive role of mGlu5 receptors on NMDA toxicity (Bruno et al, 2000a) requires the presence of mGlu3 receptors in astrocytes and mGlu2 receptors in neurons. Cultures containing astrocytes from mGlu2 Ϫ/Ϫ mice behaved similarly to cultures containing wt astrocytes because astrocytes did not express mGlu2 receptors (data not shown).…”

Section: Resultsmentioning

confidence: 97%

The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection

Corti

Battaglia²,

Molinaro³

et al. 2007

J. Neurosci.

184

161

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Dual metabotropic glutamate 2/3 (mGlu2/3) receptor agonists have been examined with success in the clinic with positive proof of efficacy in several tests of anxiety and schizophrenia. Moreover, a large body of evidence has accumulated that these drugs have significant neuroprotective potential. An important discussion in the field deals with dissecting effects on mGlu2 versus effects on mGlu3 receptors, which is relevant for the potential use of subtype-selective agonists or allosteric activators. We addressed this issue using mGlu2 and mGlu3 receptor knock-out mice. We used mixed cultures of cortical cells in which astrocytes and neurons were plated at different times and could therefore originate from different mice. Cultures were challenged with NMDA for the induction of excitotoxic neuronal death. The mGlu2/3 receptor agonist, (Ϫ)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), was equally neuroprotective in cultures containing neurons from wild-type, mGlu2 ؊/؊ , or mGlu3 ؊/؊ mice. Neuroprotection was instead abolished when astrocytes lacked mGlu3 receptors, unless neuronal mGlu2 receptors were also absent. The latter condition partially restored the protective activity of LY379268. Cultures in which neurons originated from mGlu2 ؊/؊ mice were also intrinsically resistant to NMDA toxicity. In in vivo experiments, systemic administration of LY379268 protected striatal neurons against NMDA toxicity in wild-type and mGlu2 Ϫ/Ϫ mice but not in mGlu3 ؊/؊ mice. In addition, LY379268 was protective against nigrostriatal degeneration induced by low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only in mice lacking mGlu2 receptors. We conclude that neuroprotection by mGlu2/3 receptor agonists requires the activation of astrocytic mGlu3 receptors, whereas, unexpectedly, activation of mGlu2 receptors might be harmful to neurons exposed to toxic insults.

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Section: Resultsmentioning

confidence: 97%

The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection

Corti

Battaglia²,

Molinaro³

et al. 2007

J. Neurosci.

184

161

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“…The selective mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks NMDA-induced membrane depolarization in striatal spiny neurons and in cortical wedges (Pisani et al, 1997;Attucci et al, 2001). Systemically administered mGlu5 and NMDA receptor antagonists produce similar anxiolytic (Spooren et al, 2000;Chojnacka-Wojcik et al, 2001), neuroprotective (Bruno et al, 2000), anticonvulsant (Chapman et al, 2000), and tolerance blocking (Kozela et al, 2003) effects, and disrupt prepulse inhibition (Henry et al, 2002;Kinney et al, 2002). Therefore, modulation of mGlu5 receptors may be an effective therapeutic strategy for manipulation of NMDA receptor-mediated neurotransmission in disorders such as schizophrenia (Tamminga, 1998;Goff and Coyle, 2001; Krystal et al, 2003;Moghaddam, 2003) and addiction (Wolf, 1998), where NMDA receptor dysfunction is suspected.…”

Section: Introductionmentioning

confidence: 99%

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

Homayoun

Stefani

Adams

et al. 2004

Neuropsychopharmacol

231

182

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Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.

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“…The mGluR5 binds through G-dependent or independent pathways (Heuss et al, 1999) with predominantly couple via Gq to phospholipase C. This yields diacylglycerol, which activates protein kinase C (PKC), and inositol-1,4,5-triphosphate, which releases intracellular Ca 2 + (Conn and Pin, 1997), and this in turn can increase NMDAR-evoked responses in a variety of neuronal tissues (Doherty et al, 1997;Awad et al, 2000), indicating one potential functional link between mGluR5 and NMDAR. Indeed, administration of mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyradine (MPEP) facilitated in vivo effects of NMDAR antagonists in rodents, producing anxiolytic (Spooren et al, 2000), neuroprotective (Bruno et al, 2000), and anticonvulsant (Chapman et al, 2000) effects, disrupting prepulse inhibition (PPI) (Kinney et al, 2003) and enhancing the detrimental effects of MK-801 on cognition and stereotypy (Homayoun et al, 2004). This demonstrates that mGluR5 play a major role in regulating NMDAR-dependent function.…”

Section: Introductionmentioning

confidence: 99%

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

Lipina

Weiss

Roder

2006

Neuropsychopharmacol

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In order to test the possible role of mGluR5 signaling in the behavioral endophenotypes of schizophrenia and other psychiatric disorders, we used genetic engineering to create mice carrying null mutations in this gene. Compared to their mGluR5 + / + littermates, mGluR5 À/À mice have disrupted latent inhibition (LI) as measured in a thirst-motivated conditioned emotional response procedure. Administration of the positive modulator of a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPAR), CX546, during the conditioning phase only, improved the disrupted LI in mGluR5 knockout mice and facilitated LI in control C57BL/6J mice, given extended number of conditioning trails (four conditioning stimulus-unconditioned stimulus). Prepulse inhibition (PPI) was impaired in mGluR5 À/À mice to a level that could not be disrupted further by the antagonist of N-methyl-D-aspartate receptorsFMK-801. PPI deficit of mGluR5 À/À mice was effectively reversed by CX546, whereas aniracetam had a less pronounced effect. These data provide evidence that a potent positive AMPAR modulator can elicit antipsychotic action and represents a new approach for treatment of schizophrenia. Neuropsychopharmacology (2007) 32, 745-756.

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Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective

Cited by 118 publications

References 17 publications

The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection

The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

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