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Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity
Author(s) -
Guo Huang,
Singh Itender,
Wang Yaoming,
Deane Rashid,
Barrett Theresa,
Fernández José A.,
Chow Nienwen,
Griffin John H.,
Zlokovic Berislav V.
Publication year - 2009
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2009.06664.x
Subject(s) - endothelial protein c receptor , neuroprotection , protein c , pharmacology , receptor , apoptosis , chemistry , medicine , microbiology and biotechnology , thrombin , biology , biochemistry , platelet
The anticoagulant activated protein C (APC) protects neurons and endothelium via protease activated receptor (PAR)1, PAR3 and endothelial protein C receptor. APC is neuroprotective in stroke models. Bleeding complications may limit the pharmacologic utility of APC. Here, we compared the 3K3A‐APC mutant with 80% reduced anticoagulant activity and wild‐type (wt)‐APC. Murine 3K3A‐APC compared with wt‐APC protected mouse cortical neurons from N ‐methyl‐D‐aspartate‐induced apoptosis with twofold greater efficacy and more potently reduced N ‐methyl‐D‐aspartate excitotoxic lesions in vivo . Human 3K3A‐APC protected human brain endothelial cells (BECs) from oxygen/glucose deprivation with 1.7‐fold greater efficacy than wt‐APC. 3K3A‐APC neuronal protection required PAR1 and PAR3, as shown by using PAR‐specific blocking antibodies and PAR1‐ and PAR3‐deficient cells and mice. BEC protection required endothelial protein C receptor and PAR1. In neurons and BECs, 3K3A‐APC blocked caspase‐9 and ‐3 activation and induction of p53, and decreased the Bax/Bcl‐2 pro‐apoptotic ratio. After distal middle cerebral artery occlusion (dMCAO) in mice, murine 3K3A‐APC compared with vehicle given 4:00 h after dMCAO improved the functional outcome and reduced the infarction volume by 50% within 3 days. 3K3A‐APC compared with wt‐APC multi‐dosing therapy at 12:00 h, 1, 3, 5 and 7 days after dMCAO significantly improved functional recovery and reduced the infarction volume by 75% and 38%, respectively, within 7 days. The wt‐APC, but not 3K3A‐APC, significantly increased the risk of intracerebral bleeding as indicated by a 50% increase in hemoglobin levels in the ischemic hemisphere. Thus, 3K3A‐APC offers a new approach for safer and more efficacious treatments of neurodegenerative disorders and stroke with APC.