Species-dependent neuroprotection by activated protein C mutants with reduced anticoagulant activity.
Activated protein C (APC) is a protease with anticoagulant and cytoprotective activities. APC is neuroprotective in rodent models of stroke. But, an APC variant with reduced anticoagulant activity, 3K3A-APC, compared to wild-type APC shows greater neuroprotection with no risk for bleeding in stroke models. To determine whether 3K3A-APC exhibits species-dependent neuroprotection similar to that as seen with wild-type APC, we studied murine and human recombinant 3K3A-APC mutants which show approximately 80% reduced anticoagulant activity. Murine 3K3A-APC (0.2 mg/kg i.v.) administered at 4 h after embolic stroke improved substantially functional outcome and reduced by 80% the infract volume 7 days after stroke. Human 3K3A-APC was neuroprotective after embolic stroke in mice, but at significantly higher concentrations (i.e. 2 mg/kg i.v.). Species-dependent neuroprotection, i.e. murine > human 3K3A-APC, was confirmed in a mouse model of permanent middle cerebral artery occlusion. Human 3K3A-APC had by fivefold greater cytoprotective activity than murine 3K3A-APC in oxygen-glucose deprivation model in human brain endothelial cells, whereas murine 3K3A-APC was by 2.5-fold more potent than human 3K3A-APC in a mouse model of NMDA-induced neuronal apoptosis. Thus, 3K3A-APC exhibits species-dependent neuroprotection which should be taken into account when designing human trials for ischemic stroke with APC mutants.
Guo
Huang
H
Department for Neurosurgery and Neurology, Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, Rochester, New York 14642, USA.
Wang
Yaoming
Y
Singh
Itender
I
Liu
Dong
D
Fernández
José A
JA
Griffin
John H
JH
Chow
Nienwen
N
Zlokovic
Berislav V
BV
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism* / Q000627:therapeutic use; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000627:therapeutic use; D011247:Pregnancy; D011486:Protein C / Q000235:genetics* / Q000378:metabolism* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D013045:Species Specificity; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control
D000925:Anticoagulants; D018696:Neuroprotective Agents; D011486:Protein C; D011994:Recombinant Proteins