Abstract 321: Prasugrel, a Platelet P2y 12 Receptor Antagonist, Improves Abnormal Gait in a Novel Murine Model of Thrombotic Hind Limb Ischaemia

Abstract

Background: The efficacy of P2Y 12 inhibition for the prevention of cardiovascular events in patients with peripheral arterial disease (PAD) has been established. However the therapeutic effects on ischaemic limb manifestations are less clear. Accordingly, we developed a novel murine model of thrombotic hind limb ischaemia to reflect that found in patients with PAD exhibiting ischaemic limb symptoms. We further investigated the effects of P2Y 12 inhibition by prasugrel in this model. Methods and Results: Thrombus formation induced by application of ferric chloride to the femoral artery resulted in a significant reduction in blood flow in the injured limb. In gait analysis of the ischaemic limb using the CatWalk system, maximum contact area and stance phase duration were reduced and swing phase duration increased in this model. Blood flow reduction and gait abnormalities gradually recovered over 21 days to levels present before arterial injury. Compared to wild-type (WT) mice, significant increases in blood flow and improvement in gait were observed in P2Y 12 -deficient mice. In addition, daily oral administration of prasugrel (3 mg/kg/day) to WT mice resulted in significant inhibition of blood flow reduction and gait abnormalities to levels found in P2Y 12 deficient mice. Conclusions: In conclusion, acute femoral artery thrombosis resulted in hind limb ischaemia and moderate gait abnormalities in mice. In addition, the present study suggests a therapeutic role for P2Y 12 antagonism in reducing the manifestations of limb ischaemia in PAD.