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Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity

Academic Article
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Overview

authors

  • Guo, H.
  • Singh, I.
  • Wang, Y. M.
  • Deane, R.
  • Barrett, T.
  • Fernandez, J. A.
  • Chow, N.
  • Griffin, John
  • Zlokovic, B. V.

publication date

  • 2009

journal

  • European Journal of Neuroscience  Journal

abstract

  • 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.

subject areas

  • Analysis of Variance
  • Animals
  • Anoxia
  • Antibodies
  • Anticoagulants
  • Apoptosis
  • Brain
  • Caspase 3
  • Caspase 9
  • Cells, Cultured
  • Embryo, Mammalian
  • Endothelial Cells
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Female
  • Glucose
  • Hemoglobins
  • Humans
  • In Situ Nick-End Labeling
  • Infarction, Middle Cerebral Artery
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • N-Methylaspartate
  • Neurons
  • Neuroprotective Agents
  • Pregnancy
  • Protein C
  • Receptors, Proteinase-Activated
  • Time Factors
  • Tumor Suppressor Protein p53
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Research

keywords

  • endothelial injury
  • endothelial protein C receptor
  • neuronal injury
  • permanent ischemic injury
  • protease activated receptor
  • protein C mutant
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Identity

PubMed Central ID

  • PMC2692517

International Standard Serial Number (ISSN)

  • 0953-816X

Digital Object Identifier (DOI)

  • 10.1111/j.1460-9568.2009.06664.x

PubMed ID

  • 19302148
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Additional Document Info

start page

  • 1119

end page

  • 1130

volume

  • 29

issue

  • 6

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