Protective effect of the metabotropic glutamate receptor agonist, DCG-IV, against excitotoxic neuronal death

Bruno, Valeria; Copani, Agata; Battaglia, Giuseppe; Raffaele, R; Shinozaki, H.; Nicoletti, Ferdinando

doi:10.1016/0014-2999(94)90624-6

Cited by 115 publications

(62 citation statements)

References 8 publications

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“…This dichotomy was resolved in the early 1990s using molecular biology, which identified two families of glutamate binding receptor proteins: ionotropic (iGluR) and metabotropic (mGluR) glutamate receptors 10 . Development of antagonists binding to specific protein subunits is currently enabling precise identification of discrete iGluR or mGluR subtypes 11 that participate in a range of central synaptic processes, including synaptic plasticity [12][13][14] .…”

Section: L O E W I D O U B T E D T H a T Neurotransmitters Operatedmentioning

confidence: 99%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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Seventy years ago it was discovered that glutamate is abundant in the brain and that it plays a central role in brain metabolism. However, it took the scientific community a long time to realize that glutamate also acts as a neurotransmitter. Glutamate is an amino acid and brain tissue contains as much as 5 -15 mM glutamate per kg depending on the region, which is more than of any other amino acid. The main motivation for the ongoing research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning. In this review, the basic biology of the excitatory amino acids glutamate, glutamate receptors, GABA, and glycine will first be explored. In the second part of this review, the known pathophysiology and pathology will be described. (J Toxicol Pathol 2008; 21: 25-51)

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Section: L O E W I D O U B T E D T H a T Neurotransmitters Operatedmentioning

confidence: 99%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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“…Pharmacological activation of group-II or -III mGlu receptors protects neurons against excitotoxic degeneration (Bruno et al, 1994Choi, 1994, 1995;Altemus et al, 1995;Maiese et al, 1995;Orlando et al, 1995;Turetsky et al, 1995;Buisson et al, 1996). Because activation of group-II and -III mGlu receptors is expected to attenuate neuronal degeneration without hampering the efficiency of fast excitatory synaptic transmission, these receptors become potential targets for the experimental therapy of acute and chronic neurodegenerative disorders (for review, see Nicoletti et al, 1996).…”

Section: Abstract: Cortical Cultures; Metabotropic Glutamate Receptomentioning

confidence: 99%

The Neuroprotective Activity of Group-II Metabotropic Glutamate Receptors Requires New Protein Synthesis and Involves a Glial–Neuronal Signaling

et al. 1997

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The group-II metabotropic glutamate (mGlu) receptor agonists (2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), S-4-carboxy-3-hydroxyphenylglycine (4C3HPG), and (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (L-CCG-I) protected mouse cortical neurons grown in mixed cultures against excitotoxic degeneration induced by a 10 min pulse with NMDA. Protection was observed not only when agonists were added in combination with NMDA but also when they were transiently applied to cultures 6–20 hr before the NMDA pulse. In both cases, neuroprotection was reduced by the group-II mGlu receptor antagonist (2S,1′S,2′S,3′R)-2-(2′-carboxy-3′-phenylcyclopropyl)glycine (PCCG-IV), as well as by the protein synthesis inhibitor cycloheximide (CHX). Both neurons and astrocytes in mixed cultures were immunostained with an antibody that recognized mGlu2 and mGlu3 receptors in recombinant cells. To determine whether astrocytes played any role in the neuroprotection mediated by group-II mGlu receptors, we exposed pure cultures of cortical astrocytes to DCG-IV, 4C3HPG, or L-CCG-I for 10 min. The astrocyte medium collected 2–20 hr after the exposure to any of these drugs was highly neuroprotective when transferred to mixed cultures treated with NMDA. This protective activity was reduced when CHX was applied to astrocyte cultures immediately after the transient exposure to group-II mGlu receptor agonists. We conclude that neuroprotection mediated by group-II mGlu receptors in cultured cortical cells requires new protein synthesis and involves an interaction between neurons and astrocytes.

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“…Of the eight known mGlu receptor subtypes, mGlu2 and mGlu3 receptors are the best candidates as "neuroprotective receptors," because their activation inhibits glutamate release (Lovinger, 1991;Lovinger and McCool, 1995;Battaglia et al, 1997;Cozzi et al, 1997), inhibits voltage-gated calcium channels (for review, see Pin and Duvoisin, 1995), positively modulates potassium channels (Sharon et al, 1997), and stimulates the production of neurotrophic factors in astrocytes and microglia (Bruno et al, 1997(Bruno et al, , 1998bCiccarelli et al, 1999;D'Onofrio et al, 2001;Matarredona et al, 2001). Early in vitro studies have shown that first generation agonists of mGlu2 and mGlu3, such as (2S,1ЈS,2ЈS)-2-(carboxycyclopropyl)glycine and (2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine, are protective against excitotoxicity and other neuronal insults (Pizzi et al, 1993;Bruno et al, 1994Bruno et al, , 1995Ambrosini et al, 1995;Buisson and Choi, 1995;Thomsen et al, 1996). However, these drugs are not selective for mGlu2/3 receptors and cannot be used in in vivo models (Schoepp et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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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Protective effect of the metabotropic glutamate receptor agonist, DCG-IV, against excitotoxic neuronal death

Cited by 115 publications

References 8 publications

A Review of Glutamate Receptors I: Current Understanding of Their Biology

A Review of Glutamate Receptors I: Current Understanding of Their Biology

The Neuroprotective Activity of Group-II Metabotropic Glutamate Receptors Requires New Protein Synthesis and Involves a Glial–Neuronal Signaling

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

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