Antithrombotic Effects of FK419, a Novel Nonpeptide Platelet GPIIb/IIIa Antagonist, in a Guinea Pig Photochemically Induced Middle Cerebral Artery Thrombosis Model: Comparison with Ozagrel and Argatroban

Abstract

Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin ␣ IIb ␤3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)- [1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A 2 synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.

FK419, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Ameliorates Brain Infarction Associated with Thrombotic Focal Cerebral Ischemia in Monkeys: Comparison with Tissue Plasminogen Activator

“…FK419 significantly improved both MCA patency and ischemic brain damage, whereas rt-PA improved MCA blood flow but minimally improved neurologic deficits and caused petechial intracerebral hemorrhaging. We recently reported that FK419 dose-dependently prevented the reocclusion of MCA after recanalization in photothrombotic MCA occlusion model in guinea-pigs (Moriguchi et al , 2004 a ). FK419 was found not only to prevent reocclusion but also to thrombolyse the obstructive thrombus in a similar model (Moriguchi et al , 2004 b ; Moriguchi et al , 2005).…”

FK419, a Novel Nonpeptide GPIIb/IIIa Antagonist, Restores Microvascular Patency and Improves Outcome in the Guinea-Pig Middle Cerebral Artery Thrombotic Occlusion Model: Comparison with Tirofiban

“…The left MCA was photochemically occluded according to the method of Moriguchi et al (2004a,b). Briefly, animals were anesthetized with isoflurane (2% for induction, 1% for maintenance) in a mixture of air and 30% O 2 .…”

“…This model involves a photochemical reaction between rose bengal and transluminal light irradiation, leading to endothelial injury followed by platelet adhesion, aggregation, and a formation of occlusive platelet-rich thrombus at the irradiated site (Saniabadi et al , 1995). FK419 improved brain damage not only by preventing reocclusion of MCA but also by lysing the obstructive thrombus in both the guinea-pig and primate photochemical thrombosis model (Moriguchi et al , 2004a,b; Maeda et al , 2005). FK419 showed a superior profile in the MCA thrombosis models compared with that of common antithrombotic agents, including recombinant tissue plasminogen activator, aspirin, ozagrel, heparin, and argatroban.…”

Progress in the Research of GPIIb/IIIa Antagonists

“…Its mechanism is to inhibit the biosynthesis of thromboxane A 2 from arachidonic acid in platelets through acetylation of the crucial enzyme: cyclooxygenase. Though specific inhibitors of the thromboxane A 2 , thromboxane synthase and the enzyme have been developed, these drugs reduce prostaglandin I 2 production in the endothelium, which may lead to the decreasing of cerebral blood flow [7].…”