Prevention of occlusive arterial thrombus formation by a single loading dose of prasugrel suppresses neointimal hyperplasia in mice.
The present study examined the effects of prasugrel in a mouse model of thrombosis-induced neointimal hyperplasia. Following carotid artery injury by application of ferric chloride solution, thrombus formation was assessed on Day 1 and neointimal thickening was assessed on Day 21. Single administrations of prasugrel at 0.3-3mg/kg (p.o.) resulted in a dose-related and sustained inhibition of ADP-induced platelet aggregation through 24h. Single and multiple (1 and 3 weeks) administration of prasugrel (3mg/kg loading and 1mg/kg/day maintenance doses) resulted in a marked inhibition of neointimal thickening in the injured artery. In the dose-response study, a single administration of prasugrel at 0.3-3mg/kg (p.o.) dose-relatedly inhibited thrombus formation and neointimal thickening on Days 1 and 21, respectively. The degree of neointimal hyperplasia in the injured artery correlated significantly with the thrombus indices, time to occlusion and patency rate. To explore possible mechanisms of inhibition of neointimal hyperplasia by prasugrel, mRNA expression levels of inflammatory and fibrosis markers were determined in injured arteries. Prasugrel treatment resulted in reduced MCP-1, ICAM-1 and TGF-β mRNA levels on Day 2 (24h after the injury) and Day 8 (1 week after the injury) in the target arteries. In conclusion, we found that a single oral loading dose of prasugrel markedly prevented neointimal hyperplasia by inhibiting platelet activation and thrombus formation and was associated with inhibition of the expression of inflammatory and fibrosis markers, including MCP-1, ICAM-1 and TGF-β, in the injured arteries.
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Kousaku
K
Ohno
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Atsuyuki
A
Tomizawa
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Joseph A
JA
Jakubowski
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Makoto
M
Mizuno
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. Electronic address: sugidachi.atsuhiro.r7@daiichisankyo.co.jp.
Atsuhiro
A
Sugidachi
D000244:Adenosine Diphosphate / Q000737:chemistry; D000818:Animals; D001011:Aorta / Q000473:pathology; D001157:Arterial Occlusive Diseases / Q000188:drug therapy / Q000517:prevention & control*; D001158:Arteries / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D002712:Chlorides; D005290:Ferric Compounds; D006965:Hyperplasia / Q000517:prevention & control; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000473:pathology; D010974:Platelet Aggregation / Q000187:drug effects; D000068799:Prasugrel Hydrochloride / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control* / Q000628:therapy; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D002712:Chlorides; D005290:Ferric Compounds; C090509:Icam1 protein, mouse; D011725:Pyridines; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C446540:thienopyridine; D018799:Intercellular Adhesion Molecule-1; D000244:Adenosine Diphosphate; D000068799:Prasugrel Hydrochloride; C024555:ferric chloride
Neointimal hyperplasia; P2Y(12) receptor; Platelet aggregation; Prasugrel; Thienopyridine; Thrombosis