(Circulation. 2001;103:1799.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Anti-Inflammatory, Antithrombotic, and Neuroprotective Effects of Activated Protein C in a Murine Model of Focal Ischemic Stroke
From the Department of Neurosurgery (M.S., S.R.K., A.A.) and the Department of Pathology (F.H.), University of Southern California, Los Angeles; the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla (J.A.F., J.H.G.), Calif; and the Division of Neurovascular Biology and the Department of Neurosurgery, Center for Aging and Developmental Biology, University of Rochester Medical Center (B.V.Z.), Rochester, NY.
Correspondence to Berislav V. Zlokovic, MD, PhD, Arthur Kornberg Medical Research Bldg, 601 Elmwood Ave, Box 645, Rochester, NY 14642. E-mail berislav_zlokovic{at}urmc.rochester.edu
Background—Activated protein C (APC) contributes to systemic anticoagulant and anti-inflammatory activities. APC may reduce organ damage by inhibiting thrombin generation and leukocyte activation. Neutrophils and cerebrovascular thrombosis contribute to ischemic neuronal injury, suggesting that APC may be a potential protective agent for stroke.
Methods and Results—We examined the effects of APC in a murine model of focal ischemia. After middle cerebral artery occlusion/reperfusion, the average survival time in controls was 13.6 hours. Animals that received purified human plasma–derived APC 2 mg/kg IV either 15 minutes before or 10 minutes after stroke induction survived 24 hours and were killed for neuropathological analysis. APC 2 mg/kg given before or after onset of ischemia restored cerebral blood flow, reduced brain infarct volume (59% to 69%; P<0.003) and brain edema (50% to 61%; P<0.05), eliminated brain infiltration with neutrophils, and reduced the number of fibrin-positive cerebral vessels by 57% (P<0.05) and 25% (nonsignificant), respectively. The neuroprotective effect of APC was dose-dependent and associated with significant inhibition of ICAM-1 expression on ischemic cerebral blood vessels (eg, 61% inhibition with 2 mg/kg APC). Intracerebral bleeding was not observed with APC.
Conclusions—APC exerts anti-inflammatory, antithrombotic, and neuroprotective effects in stroke. Central effects of APC are likely to be related to improved maintenance of the blood-brain barrier to neutrophils and to reduced microvascular obstructions and fibrin deposition.
Key Words: proteins • ischemia • blood cells • cerebrovascular disorders • thrombosis • nervous system
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