The vascular endothelium and parenchyma of the brain have both potential pathways to generate
free radicals under pathological conditions. We evaluated the neuroprotective efficacy of two different
antioxidants, a microvascularly acting 21-aminosteroid (U-74389G) and a brain-penetrating
pyrrolopyrimidine (U-101033E) alone and in combination. Forty Sprague-Dawley rats were randomly assigned to one of four treatment groups: (1) vehicle-treated controls, (2)
U-74389G, (3)
U-101033E, (4) U-74389G+U-101033E. Drugs were administered in a dosage of 3x3 mg/kg i.v. before, during, and after
ischemia. All animals were subjected to 90 min of
middle cerebral artery occlusion. Local cortical blood flow (LCBF) was continuously recorded by bilateral
laser Doppler flowmetry. Functional deficits were quantified by daily neurological examinations.
Infarct volume was assessed after 7 days. There were no significant differences in LCBF among groups.
U-101033E improved neurological function from postoperative day 4 to 7, while
U-74389G did not improve neurological recovery. Animals treated with both drugs showed significantly less deficits from postoperative day 1 to 7.
U-101033E and combination
therapy reduced total
infarct volume by 53% and 54% (P<0.05).
U-74389G non-significantly reduced total
infarct volume by 25%. Cortical
infarct volume was significantly reduced in all treatment groups but only
U-101033E and combination
therapy protected the basal ganglia from
infarction. In conclusion, brain-penetrating
antioxidants have superior neuroprotective properties compared to microvascularly acting agents. Combination
therapy, affording antioxidation plus radical scavenging in blood vessels and brain parenchyma, might yield the highest degree of neuronal protection from peroxidative damage. The neuroprotective efficacy seems to be independent of CBF.