Abstract WP278: Effects of Prasugrel on Cerebral Infarction and Neurological Deficits in a Non-human Primate Model of Thrombotic Stroke

Abstract

Introduction: Several clinical trials have demonstrated the benefits of thienopyridine monotherapy in ischemic stroke patients. Non-human primate models of ischemic stroke have been used for various antithrombotic agents; however, to our knowledge, there is no data on the effects of P2Y 12 antagonists in a primate thrombotic middle cerebral artery occlusion (MCAO) model. Accordingly, it remains unclear what level of inhibition of platelet aggregation (IPA) by thienopyridine antiplatelet drugs is required for optimal treatment of ischemic stroke. Hypothesis: We assessed the hypothesis that prasugrel, the third-generation thienopyridine antiplatelet drug, would be effective in a non-human primate model of thrombotic stroke. Methods: Prasugrel hydrochloride was administered orally once daily for 3 d to cynomolgus monkeys. Ex vivo platelet aggregation induced by 5 μM ADP in platelet-rich plasma was determined before the 1st dose and 4, 5, 8 and 24 h after the final dose (N=4 per group). Thrombotic MCAO was induced photochemically by employing rose bengal 4 h after the final dose (N=8 per group). Cerebral infarct volume and neurological deficit score were determined 24 h after the MCAO. Results: Prasugrel showed significant and stable antiplatelet effects. The IPA on Day 3 ranged from 31.4% ± 8.0% to 36.4% ± 5.5% at 0.3 mg/kg/d and from 43.8% ± 6.6% to 49.8% ± 5.6% at 1 mg/kg/d. In the thrombotic MCAO model, prasugrel increased MCA patency in a dose-dependent manner. Prasugrel significantly reduced ischemic infarction to 755.1 ± 293.3 mm 3 ( P <0.01) at 0.3 mg/kg/d and 333.2 ± 187.7 mm 3 ( P <0.01) at 1 mg/kg/d compared to control (2641.8 ± 480.5 mm 3 ) without increasing hemorrhagic infarction. Prasugrel also significantly reduced neurological deficit scores to 14 ± 4 ( P <0.05) at 0.3 mg/kg/d and 6 ± 3 ( P <0.01) at 1 mg/kg/d compared to control (33 ± 3). Conclusions: Prasugrel is effective in the primate model of thrombotic stroke. These data suggest that prasugrel monotherapy would be beneficial in thrombotic stroke patients. In addition, this non-human primate model of photochemically induced MCA thrombosis is a useful model for stroke research.