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.
Previously, we showed preventive effects of prasugrel, a P2Y12 antagonist, in a non-human primate model of thrombotic middle cerebral artery occlusion (MCAO); however, it remains unclear if P2Y12 inhibition after MCAO reduces cerebral injury and dysfunction. Here we investigated the effects of R-138727, the major active metabolite of prasugrel, on ex vivo platelet aggregation at 5min, 15min, 60min, and 24h after administration to non-human primates (n=3). A single intravenous dose of R-138727 (0.03-0.3mg/kg) resulted in significant and sustained dose-related effects on platelets for up to 24h. R-138727 was administered 1h 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 increased 1h 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 overall 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 P2Y12 inhibition during early-onset MCAO to limit the progression and degree of cerebral ischaemia and infarction and also associated neurological deficits.
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. Electronic address: sugidachi.atsuhiro.r7@daiichisankyo.co.jp.
Atsuhiro
A
Sugidachi
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Makoto
M
Mizuno
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Kousaku
K
Ohno
Lilly Research Laboratories, Indianapolis, IN, USA.
Joseph A
JA
Jakubowski
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Atsuyuki
A
Tomizawa
D000208:Acute Disease; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D020520:Brain Infarction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008252:Macaca fascicularis; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D000068799:Prasugrel Hydrochloride / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010879:Piperazines; C510685:R-138727; D058925:Receptors, Purinergic P2Y12; D000098662:Vasodilator-Stimulated Phosphoprotein; D000068799:Prasugrel Hydrochloride
Ischaemic stroke; Non-human primate; P2Y(12) antagonist; Platelet; Prasugrel; R-138727; R-138727 (PubChem CID: 10405534)