title: Activated protein C promotes neuroprotection: mechanisms and translation to the clinic.
abstract: Activated protein C (APC) is a plasma serine protease that is capable of antithrombotic, anti-inflammatory, anti-apoptotic, and cell-signaling activities. Animal injury studies show that recombinant APC and some of its mutants are remarkably therapeutic for a wide range of injuries. In particular, for neurologic injuries, APC reduces damage caused by ischemia/reperfusion in the brain, by acute brain trauma, and by chronic neurodegenerative conditions. For these neuroprotective effects, APC requires endothelial cell protein C receptor. APC activates cell signaling networks with alterations in gene expression profiles by activating protease activated receptors 1 and 3. To minimize APC-induced bleeding risk, APC variants were engineered to lack > 90% anticoagulant activity but retain normal cell signaling. The neuroprotective APC mutant, 3K3A-APC which has Lys191-193 mutated to Ala191-193, is very neuroprotective and it is currently in clinical trials for ischemic stroke.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA; Department of Medicine, Division of Hematology/Oncology, University of California San Diego, San Diego, CA, USA. Electronic address: jgriffin@scripps.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.affiliation: Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Lyden
authors.affiliation: Department of Neurosurgery, University of Southern California, Keck School of Medicine, Los Angeles, CA; Department of Neurosurgery, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D055495:Neurogenesis / Q000187:drug effects; D000066829:Neuroprotection / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000925:Anticoagulants; D018696:Neuroprotective Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated
keywords: activated protein C (APC); neurogenesis; neuroprotection; stroke; traumatic brain injury