Neuroprotective effects of the novel brain-penetrating antioxidant U-101033E and the spin-trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN)

Literature on the therapeutic efficacy of free radical scavengers suggests that drugs that are able to cross the blood-brain barrier are more effectiv e in protecting the brain from ischemic damage. However, the exact mechanis ms by which brain-penetrating antioxidants act have yet not been delineated We compared the neuroprotective potential of the newly discovered pyrrolop yrimidine U-101033E with that of alpha-phenyl-N-tert-butyl nitrone (PBN) an d investigated their influence on cerebral blood flow. Thirty male Sprague- Dawley rats were subjected to 90 min of middle cerebral artery (MCA) occlus ion by an intraluminal filament. Lo cal cerebral blood flow (LCBF) was bila terally recorded by laser Doppler flowmetry. Neurological deficits were qua ntified daily. Infarct volume was assessed after 7 days. MCA occlusion redu ced ipsilateral LCBF to 20-30% of baseline. After reperfusion, postischemic hyperemia was followed by a decrease in LCBF to about 70% of baseline. The re was no difference in LCBF among groups. U-101033E improved neurological function and reduced infarct volume by 52% (P<0.05). Improvement of neurolo gical function and reduction of infarct volume (-25%) in animals treated wi th PEN was not significant. We conclude that U-101033E has superior neuropr otective properties compared with PEN. Neither drug improves blood flow dur ing ischemia and 1 h of reperfusion. The mechanisms by which these brain-pe netrating antioxidants act remain to be clarified.