Protection of both grey and white matter is important for improvement in stroke outcome. In the present study the ability of a competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonist to protect axons, oligodendrocytes, and neuronal perikarya, was examined in a rodent model of transient focal cerebral ischemia. SPD 502 (8-methyl-5-(4-( -dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-o(4-hydroxybutyricacid-2-yl)oxime) was administered as an intravenous bolus (16 mg/kg) 15 minutes before transient (3-hour) middle cerebral artery (MCA) occlusion, followed by an intravenous infusion (16 mg kg(-1) hr(-1)) of the drug for 4 hours. Twenty-one hours after ischemia, axonal damage was reduced by 45% (P = 0.006) in the SPD 502-treated group compared with the vehicle. The anatomic extent of ischemically damaged oligodendrocytes, determined by Tau1 immunoreactivity, was reduced in the cerebral cortex by 53% (P = 0.024) in SPD 502-treated rats compared with vehicle-treated rats, but there was minimal effect in the subcortex. The volume of neuronal perikaryal damage after MCA occlusion was significantly reduced by SPD 502 in the cerebral cortex (by 68%; P = 0.005), but there was minimal change in the subcortex with drug treatment. The AMPA receptor antagonist significantly reduced the anatomic extent of lipid peroxidation (assessed as the volume of 4-hydroxynonenol immunoreactivity), and this may have contributed to its ability to protect multiple cell types in ischemia. The data demonstrate that AMPA blockade protects both grey and white matter from damage induced by transient focal ischemia.