Dose-response analysis of the effect of 21-aminosteroid tirilazad mesylate (U-74006F) upon neurological outcome and ischemic brain damage in permanent focal cerebral ischemia

Abstract

The protective effects of the 21-aminosteroid tirilazad mesylate (U-74006F), one of the most efficacious inhibitors of free radical-initiated lipid peroxidation, against ischmic brain damage particularly in permanent focal cerebral ischemia still remain controversial. The present study was designed to determine the degree of neuroprotection produced by various doses of U-74006F in permanent middle cerebral artery occlusion. Focal cerebral ischemia was achieved mby permanent occlusion of the left middle cerebral artery in male Sprague-Dawley rats. Four groups of rats were studied: viz. vehicle-administered controls ( n = 7), and U-74006F-treated animals at doses of 0.3 mg/kg ( n = 7), 1.0 mg/kg ( n = 7) and 3.0 mg/kg ( n = 7) (i.v. 15 min, 2 h and 6 h post occlusion, and 3.3 times higher than the first 3 doses, i.p. 12 h post occlusion). Twenty-four hours after surgery, the animals were subjected to neurological examination using a grading scale of 0 to 3, and sacrificed to assess ischemic damage by means of tetrazolium chloride staining. A dose-related attenuation of neurological deficits and ischemic damage was observed. At the two highest doses, the volume of ischemic damage in the cerebral hemisphere was reduced by 25.3% ( P < 0.05) and 32.9% ( P < 0.005), compared to the controls. The neurological deficit score for animals treated with U-74006F (3.0 mg/kg) was also significantly lower than for the controls (1.7 ± 1.1 vs. 2.7 ± 0.8; P < 0.05). This study shows that U-74006F ameliorates postischemic neurologic deficits and provides dose-dependent neuroprotection against ischemic brain damage in focal cerebral infarction.