Combination of a free radical scavenger and heparin reduces cerebral hemorrhage after heparin treatment in a rabbit middle cerebral artery occlusion model

Background and Purpose - We sought to investigate the effects of EPC-K1, a free radical scavenger, on reducing heparin-produced cerebral hemorrhage in a rabbit model of middle cerebral artery (MCA) photothrombosis and to investigate whether the combination of EPC-K1 and heparin enhances neuroprotection from cerebral ischemic damage. Methods - In the heparin-alone group (n=8), heparin was administered intravenously for 24 hours, starting from 3 hours after MCA occlusion. In the EPC-Kl-alone group (n=8), EPC-K1 was administered as a bolus injection (10 mg/kg) twice at 3 and 6 hours after MCA occlusion. In the combination group (n=8), EPC-K1 and heparin both were administered as in the single-drug procedures. In the vehicle group (n=10), saline were infused for 24 hours. Results - Heparin prolonged activated partial thromboplastin time by ≅3 times that of control animals. In the heparin-treated animals, the hemorrhage size was significantly increased (P<0.0001) and neurological symptoms were significantly worse (P<0.01) than in control animals at 48 hours. The combination of EPC-K1 and heparin dramatically reduced heparin-produced cerebral hemorrhage (P<0.0001), with a significant reduction in infarct volume (reduction by 63.2% and 57.2% of heparin-alone and control animals, respectively, P<0.0001) and a significant improvement in neurological symptoms (P<0.01 versus heparin-alone and control animals, respectively). Conclusions - These data indicate that free radical formation may play a key role in intracerebral hemorrhage exacerbated by heparin treatment and that the combination of a free radical scavenger and heparin augmented neuroprotection from acute brain ischemia. The results of the present study may suggest a potential clinical approach for the treatment of acute stroke.