Several clinical trials have demonstrated the benefits of
thienopyridine monotherapy in
ischaemic stroke patients. Non-human primate models of
ischaemic stroke have been used for various
antithrombotic agents; however, to the best of our knowledge, there is no data on the effects of P2Y12 antagonists in models, such as the thrombotic
middle cerebral artery occlusion (MCAO) monkey model. Accordingly, it remains unclear what level of inhibition of platelet aggregation (IPA) is required for optimal treatment of
ischaemic stroke. In the present study, we investigated the effects of
prasugrel, a third-generation
thienopyridine antiplatelet drug, on platelet aggregation,
thrombus formation and
cerebral infarct volume in a non-human primate model. Daily
oral administration of
prasugrel resulted in significant and stable platelet inhibitory effects on Day 3, with IPA values ranging from 31% to 36% at 0.3mg/kg/day and from 44% to 50% at 1mg/kg/day. These IPA levels encompassed values observed in clinical trials of
clopidogrel, and were thus selected for further study. In the thrombotic MCAO model,
prasugrel increased MCA patency in a dose-dependent manner and significantly reduced ischaemic
infarct volume by approximately 70% at 0.3mg/kg/day and 90% at 1mg/kg/day without increasing haemorrhagic
infarction.
Prasugrel also significantly reduced neurological deficit scores by 60% at 0.3mg/kg/day and 80% at 1mg/kg/day. In conclusion,
prasugrel treatment resulted in effective reduction of ischaemic
infarction and an associated improvement in neurological function without increasing haemorrhagic
infarction. These data suggest that
prasugrel monotherapy would be effective for the prevention of
thrombotic stroke.