title: The novel and systemically active metabotropic glutamate 1 (mGlu1) receptor antagonist 3-MATIDA reduces post-ischemic neuronal death.
abstract: We examined the pharmacological properties of 3-methyl-aminothiophene dicarboxylic acid (3-MATIDA) by measuring second messenger responses in baby hamster kidney cells stably transfected with mGlu1a, mGlu2, mGlu4a or mGlu5a receptors and ionotropic glutamate receptor agonist-induced depolarizations in mouse cortical wedges. 3-MATIDA was a potent (IC(50)=6.3 microM, 95% confidence limits 3-15) and relatively selective mGlu1 receptor antagonist. When tested on mGlu2, mGlu4 or mGlu5 receptors its IC(50) was >300 microM. When tested in cortical wedges, however, 3-MATIDA was also able to antagonize AMPA or NMDA responses with an IC(50) of 250 microM. When present in the incubation medium of cultured murine cortical cells, 3-MATIDA (1-100 microM) significantly reduced the death of neurons induced by 60 min of oxygen and glucose deprivation (OGD), even when added up to 60 min after OGD. A similar neuroprotective activity was observed when 3-MATIDA was present at 10-100 microM in the medium of rat organotypic hippocampal slice cultures exposed to 30 min OGD. Systemic administration of 3-MATIDA (3-10 mg/kg, immediately and 1 h after the onset of ischemia) reduced the volume of brain infarcts following permanent middle cerebral artery occlusion in rats. Our results show that 3-MATIDA is a potent and possibly selective mGlu 1 receptor antagonist that may be considered as a novel prototype neuroprotective agent.
authors.affiliation: Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy. fmoroni@pharm.unifi.it
authors.forename: Flavio
authors.initials: F
authors.lastname: Moroni
authors.forename: Sabina
authors.initials: S
authors.lastname: Attucci
authors.forename: Andrea
authors.initials: A
authors.lastname: Cozzi
authors.forename: Elena
authors.initials: E
authors.lastname: Meli
authors.forename: Roberta
authors.initials: R
authors.lastname: Picca
authors.forename: Mark A
authors.initials: MA
authors.lastname: Scheideler
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: Christian
authors.initials: C
authors.lastname: Noe
authors.forename: Iran
authors.initials: I
authors.lastname: Sarichelou
authors.forename: Domenico E
authors.initials: DE
authors.lastname: Pellegrini-Giampietro
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000502:physiology; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C465380:3-methyl-aminothiophene dicarboxylic acid; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D013876:Thiophenes; C104077:metabotropic glutamate receptor type 1