title: The AMPA receptor/Na(+) channel blocker BIIR 561 CL is protective in a model of global cerebral ischaemia.
abstract: In this study, we investigated whether the novel neuroprotective compound dimethyl-[2-[2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-phenoxy]-ethyl]-amine hydrochloride, BIIR 561 CL, a combined non-competitive antagonist of AMPA receptors and blocker of voltage-gated Na+ channels, is protective in a rat model of severe global ischaemia. BIIR 561 CL administered immediately after 10 min of ischaemia (occlusion of both carotid arteries plus reduction of arterial blood pressure to 38-40 mm Hg) significantly reduced hippocampal damage at 4 x 26.8 mg/kg (subcutaneous injections). The competitive AMPA receptor antagonist 2,3-dihydro-6-nitro-7-sulfamoyl-benz(F)quinoxaline, NBQX, was used as a reference compound and was protective at 3x30 mg/kg (intraperitoneal and/or subcutaneous administration). BIIR 561 CL significantly reduced the ischaemia-induced premature mortality from 33.6% in the controls to 14.3%, whereas NBQX treatment had no statistically significant effect.Thus, BIIR 561 CL could be shown to reduce hippocampal damage and premature mortality in a model of severe global ischaemia. A compound with these properties might be an interesting candidate for the treatment of disorders related to global cerebral ischaemia in man.
authors.affiliation: Department of CNS Research, Boehringer Ingelheim Pharma KG, D-52218 Ingelheim, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Weiser
authors.forename: M
authors.initials: M
authors.lastname: Wienrich
authors.forename: M
authors.initials: M
authors.lastname: Brenner
authors.forename: R
authors.initials: R
authors.lastname: Kubiak
authors.forename: G
authors.initials: G
authors.lastname: Weckesser
authors.forename: R
authors.initials: R
authors.lastname: Palluk
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000401:mortality / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D026941:Sodium Channel Blockers; D015996:Survival Rate
chemical_list: D018696:Neuroprotective Agents; D010069:Oxadiazoles; D011810:Quinoxalines; D018091:Receptors, AMPA; D026941:Sodium Channel Blockers; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C119322:irampanel