Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke.
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.


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.
Department of Neurosurgery, University of Southern California, Los Angeles, USA.
M
M
Shibata
S R
SR
Kumar
A
A
Amar
J A
JA
Fernandez
F
F
Hofman
J H
JH
Griffin
B V
BV
Zlokovic
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001929:Brain Edema / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D016177:Macrophage-1 Antigen / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009897:Optic Chiasm / Q000737:chemistry / Q000378:metabolism; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate
D000893:Anti-Inflammatory Agents; D005343:Fibrinolytic Agents; D006454:Hemoglobins; D016177:Macrophage-1 Antigen; D018696:Neuroprotective Agents; D011486:Protein C; D018799:Intercellular Adhesion Molecule-1; D005337:Fibrin