title: 2016 Scientific Sessions Sol Sherry Distinguished Lecturer in Thrombosis: Thrombotic Stroke: Neuroprotective Therapy by Recombinant-Activated Protein C.
abstract: APC (activated protein C), derived from the plasma protease zymogen, is antithrombotic and anti-inflammatory. In preclinical injury models, recombinant APC provides neuroprotection for multiple injuries, including ischemic stroke. APC acts directly on brain endothelial cells and neurons by initiating cell signaling that requires multiple receptors. Two or more major APC receptors mediate APC's neuroprotective cell signaling. When bound to endothelial cell protein C receptor, APC can cleave protease-activated receptor 1, causing biased cytoprotective signaling that reduces ischemia-induced injury. Pharmacological APC alleviates bleeding induced by tissue-type plasminogen activator in murine ischemic stroke studies. Remarkably, APC's signaling promotes neurogenesis. The signaling-selective recombinant variant of APC, 3K3A-APC, was engineered to lack most of the APC's anticoagulant activity but retain APC's cell signaling actions. Recombinant 3K3A-APC is in ongoing National Institutes of Health (NIH)-funded clinical trials for ischemic stroke.
authors.affiliation: From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (J.H.G., L.O.M., J.A.F.); Division of Hematology/Oncology, Department of Medicine, University of California, San Diego (J.H.G.); and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles (B.V.Z.). jgriffin@scripps.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.affiliation: From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (J.H.G., L.O.M., J.A.F.); Division of Hematology/Oncology, Department of Medicine, University of California, San Diego (J.H.G.); and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles (B.V.Z.).
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Mosnier
authors.affiliation: From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (J.H.G., L.O.M., J.A.F.); Division of Hematology/Oncology, Department of Medicine, University of California, San Diego (J.H.G.); and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles (B.V.Z.).
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.affiliation: From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (J.H.G., L.O.M., J.A.F.); Division of Hematology/Oncology, Department of Medicine, University of California, San Diego (J.H.G.); and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles (B.V.Z.).
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000074283:Endothelial Protein C Receptor; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D020767:Intracranial Thrombosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D011486:Protein C / Q000009:adverse effects / Q000627:therapeutic use*; D020239:Receptor Cross-Talk / Q000187:drug effects; D044463:Receptor, PAR-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015912:Thrombolytic Therapy / Q000009:adverse effects*
chemical_list: C000591161:3K3A-APC protein; D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D018696:Neuroprotective Agents; C478370:PROCR protein, human; D011486:Protein C; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins
keywords: anticoagulant; endothelial cells; neurogenesis; neurons; stroke