Direct Thrombin Inhibitor Argatroban Reduces Stroke Damage in 2 Different Models

Abstract

Background and Purpose— We showed previously robust neuroprotection with the thrombin inhibitor argatroban and now sought additional support for its neuroprotective potential. Methods— We used behavioral and histological end points; rigorously blinded the study groups; extended the treatment window to 3 hours after ischemia onset; and used 2 separate models. First, 2-hour filament middle cerebral artery occlusion in 64 male Sprague-Dawley rats was followed by learning and memory testing and quantitative histomorphometry. Randomly assigned treatment was 0.45 mg argatroban, saline, or 0.4 U thrombin. Second, we used the quantal bioassay (n=272) after 2-hour middle cerebral artery occlusion to detect the longest time delay after which therapy failed. Results— Argatroban powerfully and significantly reversed learning and memory deficits because of focal ischemia compared with saline or thrombin ( P <0.03; ANOVA). Argatroban was significantly ( P <0.05; t test with Bonferroni) protective when given immediately or after 1, 2, 3, but not 4 hours delay. Conclusions— We obtained supportive evidence for argatroban protection of the neurovascular unit using behavioral and histological measurements at realistic therapeutic time windows.