The active metabolite of prasugrel, R-138727, improves cerebral blood flow and reduces cerebral infarction and neurologic deficits in a non-human primate model of acute ischaemic stroke

摘要

Previously, we showed preventive effects of prasugrel, a P2Y(12) antagonist, in a non-human primate model of thrombotic middle cerebral artery occlusion (MCAO); however, it remains unclear if P2Y(12) inhibition after MCAO reduces cerebral injury and dysfunction. Here we investigated the effects of R-138727, the major active metabolite of prasugrel, on e chi vivo platelet aggregation at 5 min, 15 min, 60 min, and 24 h after administration to non-human primates (n=3). A single intravenous dose of R-138727(0.03-0.3 mg/kg) resulted in significant and sustained dose-related effects on platelets for up to 24 h. R-138727 was administered 1 h after MCAO induction, and its effects on thrombosis, cerebral infarction, and neurological deficits were determined (n=8-10). R-138727 (0.3mg/kg) significantly increased total patency rate of the MCA (P=0.0211). Although there was no effect on the patency rate before R-138727 dosing (P=0.3975), it increased1 h after dosing (P=0.0114). R-138727 significantly reduced total ischaemic infarction volumes (P=0.0147), including those of basal ganglia (P=0.0028), white matter (P=0.0393), and haemorrhagic infarction (P=0.0235). Additionally, treatment with R-138727 reduced over all neurological deficits (P=0.0019), including the subcategories of consciousness (P=0.0042), sensory system (P=0.0045), motor system (P=0.0079) and musculoskeletal coordination (P=0.0082). These findings support the possible utility of P2Y(12) inhibition during early-onset MCAO to limit the progression and degree of cerebral ischaemia and infarction and also associated neurological deficits. (C) 2016 Elsevier B.V. All rights reserved.