Superiority of platelet integrin GPIIb–IIIa receptor antagonist over aspirin in preventing cyclic flow reductions in the guinea pig middle cerebral artery

Abstract

We established a photothrombotic occlusion model in the guinea pig middle cerebral artery. In this model, the middle cerebral artery was recanalized within 10 to 20 min after thrombotic occlusion, with subsequent cyclic flow reductions. Cyclic flow reductions in the middle cerebral artery are expected to manage cerebral infarction by modulating arterial patency. Therefore, we evaluated the effect of several antiplatelet agents on the frequency of cyclic flow reductions and subsequent cerebral infarction using this model. A platelet integrin GPIIb–IIIa receptor antagonist, ME3277 (sodium hydrogen [4-[(4,5,6,7-tetrahydrothieno[3,2 c]pyridin-2-yl) carbonylamino] acetyl- o-phenylene] dioxydiacetate, 0.3, 1 and 3 mg/kg i.v.) dose-dependently inhibited the ex vivo platelet aggregation induced by ADP (5 μM), collagen (0.8 and 20 μg/ml) and arachidonic acid (100 μM). While the same doses of ME3277 reduced the frequency of the cyclic flow reductions and increased the total patency time of the middle cerebral artery, time to thrombotic occlusion was prolonged only at the highest dose, 3 mg/kg. ME3277 (0.3–3 mg/kg) significantly reduced the infarct volume and improved the neurological deficit at 24 h. In contrast, aspirin (30 mg/kg) did not affect these variables in spite of complete inhibition of platelet aggregation induced by arachidonic acid and collagen (0.8 μg/ml). A thromboxane A 2 synthetase inhibitor, sodium ozagrel, significantly increased the total patency time and reduced the infarct volume at 30 mg/kg. Inhibition of prostaglandin I 2 generation could explain the effectiveness of sodium ozagrel but not aspirin in this model. These results suggest that platelet integrin GPIIb–IIIa receptor antagonists are more beneficial than aspirin for the treatment of cerebral thrombosis.