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

Abstract

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.

• Authors: Dong Liu, Huang Guo, John H Griffin, Jose A Fernández, Berislav V Zlokovic
• Journal: Circulation (Circulation) Vol. 107 Issue 13 Pg. 1791-6 (Apr 08 2003) ISSN: 1524-4539 [Electronic] United States
• PMID: 12665496 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticoagulants
• Neuroprotective Agents
• Protein S

Topics

• Animals
• Anticoagulants (therapeutic use)
• Apoptosis
• Brain Ischemia (drug therapy, pathology)
• Cell Hypoxia
• Cells, Cultured
• Cerebral Cortex (blood supply, drug effects)
• Hypoxia-Ischemia, Brain (drug therapy)
• Infarction, Middle Cerebral Artery (drug therapy, pathology, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Motor Skills Disorders (diagnosis)
• Neurons (cytology, drug effects)
• Neuroprotective Agents (therapeutic use)
• Protein S (therapeutic use)
• Regional Blood Flow (drug effects)
• Stroke (drug therapy, pathology, physiopathology)