Neuroprotective Properties of a Novel Antioxidant (U-101033E) with Improved Blood-Brain Barrier Permeability in Focal Cerebral Ischemia

Abstract

Many efforts have been undertaken to develop antioxidants against free radical induced brain damage, 21-aminosteroids, although accumulating in the cell membrane, thus protecting vascular endothelium from peroxidative damage hardly penetrate the blood-brain barrier. A novel group of antioxidants, the pyrrolopyrimidines, has a markedly improved ability to enter the brain parenchyma. In our current study the neuroprotective potential of the 21-aminosteroid U-74389G was compared with that of the pyrrolopyrimidine U-101033E in a rat model of reversible focal cerebral ischemia. Sprague-Dawley rats were subjected to unilateral occlusion of the middle cerebral artery with assignment to one of three treatment arms (n = 10 each), receiving either vehicle, U-74389G, or U-101033E. Regional CBF was recorded bilaterally by laser Doppler flowmetry. In addition, neurological examination was performed daily, with assessment of infarct volume at day seven. U-101033E reduced the infarct volume significantly by 51%, whereas U-74389G afforded non-significant attenuation only. U-101033E was found to improve neurological recovery promptly; animals with U-74389G began to recover only at the end of the experimental observation period. Differences in the regional CBF were not found in the contralateral hemispheres for either treatment group. We conclude that antioxidative compounds which cross the blood-brain barrier are more effective in focal cerebral ischemia than agents which predominantly act on the endothelium of cerebral microvessels.