Integrin α IIb β 3 Inhibitor Preserves Microvascular Patency in Experimental Acute Focal Cerebral Ischemia

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Abstract
Background and Purpose—Platelets become activated and accumulate in brain microvessels of the ischemic microvascular bed after experimental focal cerebral ischemia. The binding of glycoprotein IIb/IIIa (integrin αIIbβ3) on platelets to fibrinogen is the terminal step in platelet adhesion and aggregation. This study tests the hypothesis that inhibition of platelet-fibrin(ogen) interactions may prevent microvascular occlusion after experimental middle cerebral artery occlusion (MCA:O). Methods—TP9201 is a novel Arg-Gly-Asp (RGD)-containing integrin αIIbβ3 inhibitor. Microvascular patency after 3-hour MCA:O and 1-hour reperfusion within the ischemic and nonischemic basal ganglia was compared in adolescent male baboons who received high-dose TP9201 (group A: IC80 in heparin, n=4), low-dose TP9201 (group B: IC30 in heparin, n=4), or no treatment (group C: n=4) before MCA:O. Results—After MCA:O, microvascular patency decreased significantly in group C. However, in the ischemic zones of groups A and B compared with group C, patencies were significantly greater in the 4.0- to 7.5-μm-diameter (capillary) and 7.5- to 30.0-μm-diameter vessels (2P2 analysis for trend, PConclusions—Platelet activation contributes significantly to ischemic microvascular occlusion. Occlusion formation may be prevented by this RGD–integrin αIIbβ3 inhibitor at a dose that does not produce clinically significant parenchymal hemorrhage. The effect of microvascular patency on neuron recovery can now be tested.

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