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.