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 pa thways to generate free radicals under pathological conditions. We evaluate d the neuroprotective efficacy of two different antioxidants, a microvascul arly acting 21-aminosteroid (U-74389G) and a brain-penetrating pyrrolopyrim idine (U-101033E) alone and in combination. Forty Sprague-Dawley rats were randomly assigned to one of four treatment groups: (1) vehicle-treated cont rols, (2) U-74389G, (3) U-101033E, (4) U-74389G + U-101033E. Drugs were adm inistered in a dosage of 3 X 3 mg/kg i.v. before, during, and after ischemi a. All animals were subjected to 90 min of middle cerebral artery occlusion . Local cortical blood flow (LCBF) was continuously recorded by bilateral l aser Doppler flowmetry. Functional deficits were quantified by daily neurol ogical examinations. Infarct volume was assessed after 7 days. There were n o significant differences in LCBF among groups. U-101033E improved neurolog ical function from postoperative day 4 to 7, while U-74389G did not improve neurological recovery. Animals treated with both drugs showed significantl y less deficits from postoperative day 1 to 7. U-101033E and combination th erapy 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 co mbination therapy protected the basal ganglia from infarction. In conclusio n, brain-penetrating antioxidants have superior neuroprotective properties compared to microvascularly acting agents. Combination therapy, affording a ntioxidation plus radical scavenging in blood vessels and brain parenchyma, might yield the highest degree of neuronal protection from peroxidative da mage. The neuroprotective efficacy seems to be independent of CBF. (C) 1999 Elsevier Science B.V. All rights reserved.