Protein S confers neuronal protection during ischemic/hypoxic injury in mice.
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.


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.
Liu
Dong
D
Frank P. Smith Neurosurgical Research Laboratory, Division of Neurovascular Biology, University of Rochester Medical Center, 601 Elmwood Ave, Box 645, Rochester, NY 14642, USA.
Guo
Huang
H
Griffin
John H
JH
Fernández
Jose A
JA
Zlokovic
Berislav V
BV
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D017209:Apoptosis; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019957:Motor Skills Disorders / Q000175:diagnosis; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017293:Protein S / Q000627:therapeutic use*; D012039:Regional Blood Flow / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D000925:Anticoagulants; D018696:Neuroprotective Agents; D017293:Protein S