Highlights
- •Prasugrel inhibited ADP-induced platelet aggregation in non-human primates.
- •Prasugrel reduced ischaemic infarct volume in a thrombotic stroke model.
- •Prasugrel also ameliorated neurological deficits in the same model.
- •This non-human primate model of thrombotic stroke is useful for stroke research.
Abstract
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 0.3 mg/kg/day and from 44% to 50% at 1 mg/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 0.3 mg/kg/day and 90% at 1 mg/kg/day without increasing haemorrhagic infarction. Prasugrel also significantly
reduced neurological deficit scores by 60% at 0.3 mg/kg/day and 80% at 1 mg/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.
Keywords
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Article info
Publication history
Published online: September 11, 2015
Accepted:
September 9,
2015
Received in revised form:
September 8,
2015
Received:
July 13,
2015
Identification
Copyright
© 2015 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
