Published Online
on March 24, 2003

A more recent version of this article appeared on April 8, 2003

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Submitted on October 28, 2002
Revised on December 19, 2002
Accepted on January 3, 2003

Protein S Confers Neuronal Protection During Ischemic/Hypoxic Injury in Mice

Dong Liu PhD, Huang Guo PhD, John H. Griffin PhD, Jose A. Fernández MD, PhD, and Berislav V. Zlokovic MD, PhD^*

From the Frank P. Smith Neurosurgical Research Laboratory, Division of Neurovascular Biology, University of Rochester Medical Center (D.L., B.V.Z.) and Socratech Laboratories at the University of Rochester (H.G.), Rochester, NY, and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, Calif (J.H.G., J.A.F.).

^* To whom correspondence should be addressed. E-mail: berislav_zlokovic{at}urmc.rochester.edu.

Background--Protein S is an antithrombotic factor that also exhibits mitogenic activity. Thus, we hypothesized that protein S may control cerebrovascular thrombosis in stroke and protect brain tissue from ischemic injury.

Methods and Results--We studied protein S in a murine in vivo model of stroke and an in vitro model of neuronal hypoxia/reoxygenation injury. Animals received purified human plasma-derived protein S or vehicle intravenously 10 minutes after initiation of middle cerebral artery occlusion followed by reperfusion. Protein S at 0.2 to 2 mg/kg significantly improved the motor neurological deficit by 3.8- to 3.2-fold and reduced infarction and edema volumes by 45% to 54% and 45% to 62%, respectively. Protein S at 2 mg/kg improved postischemic cerebral blood flow by 21% to 26% and reduced brain fibrin deposition and infiltration with neutrophils by 40% and 53%, respectively. Intracerebral bleeding was not observed with protein S. Protein S protected ischemic neurons in vivo and cultured neurons from hypoxia/reoxygenation-induced apoptosis in a time- and dose-dependent manner. Recombinant human protein S exerted protective effects from hypoxia-induced damage similar to the plasma-derived protein S both in vivo and in vitro.

Conclusions--Protein S is a significant neuroprotectant during ischemic brain injury with direct effects on neurons and antithrombotic effects. Thus, protein S could be a prototype of a new class of agents for clinical stroke with combined direct neuronal protective effects and systemic antithrombotic and antiinflammatory activities.

Key words: protein S • ischemia • stroke • thrombosis • neurons

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