title: Evidence against a permissive role of the metabotropic glutamate receptor 1 in acute excitotoxicity.
abstract: Excitotoxicity has been proposed to contribute to neuronal loss in a broad spectrum of neurodegenerative conditions such as ischemia, hypoglycaemic coma or cerebral trauma. Excitotoxic neuronal injury appears to be mediated mainly by the over-activation of glutamate receptors, especially N-methyl-D-aspartate receptors, with subsequent excessive Ca2+ influx. Concurrent with the activation of glutamate-gated ion channels, metabotropic glutamate receptors (mGluR), which are G-protein coupled receptors, are also expected to be activated. Excessive stimulation of phospholipase C-coupled mGluR, mGluR1 and mGluRS, has been suggested to have neurotoxic consequences. However, the contribution of mGluR activation on excitotoxicity is still unclear and controversial. Here we report that, following ischemic and excitotoxic brain injuries, inactivation of mGluR1 does not prevent excitotoxic neuronal damage. Given the evidence that agonists at this group of mGluR promoted neuronal death in cerebrocortical cultures after oxygen-glucose deprivation or after N-methyl-D-aspartate exposure, our findings suggest that mGluR-mediated excitotoxicity is unlikely associated with mGluR1 but rather with other PLC-coupled mGluR.
authors.affiliation: GlaxoWellcome S.p.A. Medicines Research Centre, Verona, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ferraguti
authors.forename: C
authors.initials: C
authors.lastname: Pietra
authors.forename: E
authors.initials: E
authors.lastname: Valerio
authors.forename: C
authors.initials: C
authors.lastname: Corti
authors.forename: C
authors.initials: C
authors.lastname: Chiamulera
authors.forename: F
authors.initials: F
authors.lastname: Conquet
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D002544:Cerebral Infarction / Q000473:pathology / Q000503:physiopathology*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D019204:GTP-Binding Proteins / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D007276:Injections, Intraventricular; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology*; D007608:Kainic Acid / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009498:Neurotoxins; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D001565:Benzoates; D015415:Biomarkers; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C079694:alpha-methyl-4-carboxyphenylglycine; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D007608:Kainic Acid; D005998:Glycine