Neuroprotective efficacy of combination therapy with two different antioxidants in rats subjected to transient focal ischemia.

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.