Combination of a free radical scavenger and heparin reduces cerebral hemorrhage after heparin treatment in a rabbit middle cerebral artery occlusion model.
OBJECTIVE
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-K1-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 approximately 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.
Zhao
B Q
BQ
Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
Suzuki
Y
Y
Kondo
K
K
Ikeda
Y
Y
Umemura
K
K
D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D001783:Blood Flow Velocity / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D016166:Free Radical Scavengers / Q000008:administration & dosage*; D006493:Heparin / Q000008:administration & dosage* / Q000009:adverse effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008028:Light Coagulation; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000503:physiopathology; D010314:Partial Thromboplastin Time; D011817:Rabbits; D015424:Reperfusion; D016896:Treatment Outcome; D014810:Vitamin E / Q000008:administration & dosage* / Q000031:analogs & derivatives*
D016166:Free Radical Scavengers; D014810:Vitamin E; C066638:potassium ascorbyl tocopheryl phosphate; D006493:Heparin; D001205:Ascorbic Acid