Activation of metabotropic glutamate receptors coupled to inositol phospholipid hydrolysis amplifies NMDA-induced neuronal degeneration in cultured cortical cells

Bruno, Valeria; Copani, Agata; Knöpfel, Thomas; Kühn, Rainer; Casabona, G.; Albani, P. Dell'; Condorelli, D. F.; Nicoletti, Ferdinando

doi:10.1016/0028-3908(95)00077-j

Cited by 149 publications

(82 citation statements)

References 38 publications

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“…140 Accordingly, its activation may actually enhance NMDA receptor-mediated neuronal degradation. 150 Finally, chronic treatment with the tricyclic antidepressant imipramine caused functional downregulation of mGluR1in the CA1 region of mouse hippocampi. 151 Interestingly, acute imipramine had no effect on attenuating mGluR1 response to an agonist; after 7 days, however, an effect emerged that was maximized at 14 days and further unchanged at 21 days, somewhat paralleling the time course of action of imipramine in humans.…”

Section: Metabotropic Glutamate Receptorsmentioning

confidence: 99%

Advances in the treatment of anxiety: Targeting glutamate

Simon

Gorman

2006

NeuroRX

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Our current psychopharmacological treatments for anxiety disorders evince a number of shortcomings, including troublesome side effects and lack of primary effects. Whereas many new drugs have been developed in the past few decades, most are based on outmoded theories of the pathogenesis of these disorders (i.e., monoamine hypotheses), thus frustrating our ability to create more specific and effective interventions. Recently, however, the neurobiological literature has shown a convergence of findings focusing on the glutamatergic system in anxiety disorders, and the growth of pharmacological tools targeting these receptors has led to the development of novel treatments having anxiolytic effects in humans and animals alike. Additionally, as this system is showing promise as a final common pathway in the pathogenesis of anxiety disorders, we may be able to employ glutamate-specific neuroimaging techniques (e.g., N-acetyl-aspartate, GLX) to both guide treatment decisions and present reliable objective biomarkers for treatment efficacy.

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Section: Metabotropic Glutamate Receptorsmentioning

confidence: 99%

Advances in the treatment of anxiety: Targeting glutamate

Simon

Gorman

2006

NeuroRX

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“…In general, non subtype-specific inhibition of group I mGluRs tends to be neuroprotective. In animal models of head injury, NMDA toxicity and global ischemia, as well as in vitro models of trauma and ischemia the activation of group I mGluR is neurotoxic (1,6,36,37,63,110,123,188).…”

Section: Mglurs and Neuroprotectionmentioning

confidence: 99%

“…Endogenous activation of group I mGluRs induces multifactorial processes underlying neurotoxicity (1,6,36,37,63,110,123,188) including: 1) amplification of neuronal degeneration through iGluR-induced zinc flux and concomitant production of reactive oxygen species (40,42,44,56,72,73,166,168,170,171,191);…”

Section: Mglurs and Neuroprotectionmentioning

confidence: 99%

“…In relation to cell death phenotype and the pathophysiologicallyinduced position within the apoptosis/necrosis continuum, this separation is especially important (104). Multiple models of CNS injury, including stroke, brain trauma and spinal cord injury (36,63,110,114,119), suggest that activation of mGluR1 (124) can exacerbate necrosis (1,36,37,63,122,123,135,188). In contrast, the mGluR5 subtype (122) appears to attenuate apoptosis (5,6,52).…”

Section: Mglurs and Neuroprotectionmentioning

confidence: 99%

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Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP

2006

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Glutamate regulates the function of central nervous system (CNS), in part, through the cAMP and/or IP3/DAG second messenger-associated metabotropic glutamate receptors (mGluRs). The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) has been extensively used to elucidate potential physiological and pathophysiological functions of mGluR5. Unfortunately, recent evidence indicates significant non-specific actions of MPEP, including inhibition of NMDA receptors. In contrast, in vivo and in vitro characterization of the newer mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) indicates that it is more highly selective for mGluR5 over mGluR1, has no effect on other mGluR subtypes, and has fewer off-target effects than MPEP. This article reviews literature on both of these mGluR5 antagonists, which suggests their possible utility in neurodegeneration, addiction, anxiety and pain management.

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“…Presynaptic Group III mGluRs act as autoreceptors to inhibit the release of L-glutamate from glutamatergic nerve terminals (4 -6), and ␥-aminobutyric acid release via glutamate spillover onto GABAergic synapses expressing mGluRs (7). The ability of agonists at Group III mGluRs to inhibit L-glutamate release appears to underlie the neuroprotective properties of this class of compounds in models of neurotoxicity (8,9) and epilepsy (10 -14).…”

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confidence: 99%

Molecular Determinants of High Affinity Binding to Group III Metabotropic Glutamate Receptors

Rosemond¹,

Peltekova²,

Naples³

et al. 2002

Journal of Biological Chemistry

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The amino-terminal domain containing the ligand binding site of the G protein-coupled metabotropic glutamate receptors (mGluRs) consists of two lobes that close upon agonist binding. In this study, we explored the ligand binding pocket of the Group III mGluR4 receptor subtype using site-directed mutagenesis and radioligand binding. The selection of 16 mutations was guided by a molecular model of mGluR4, which was based on the crystal structure of the mGluR1 receptor.

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Activation of metabotropic glutamate receptors coupled to inositol phospholipid hydrolysis amplifies NMDA-induced neuronal degeneration in cultured cortical cells

Cited by 149 publications

References 38 publications

Advances in the treatment of anxiety: Targeting glutamate

Advances in the treatment of anxiety: Targeting glutamate

Metabotropic Glutamate Receptor Subtype 5 Antagonists MPEP and MTEP

Molecular Determinants of High Affinity Binding to Group III Metabotropic Glutamate Receptors

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