title: Thrombin mutant W215A/E217A treatment improves neurological outcome and attenuates central nervous system damage in experimental autoimmune encephalomyelitis.
abstract: Multiple sclerosis (MS) is a neuroinflammatory disease characterized by demyelination and axonal damage of the central nervous system. The pathogenesis of MS has also been linked to vascular inflammation and local activation of the coagulation system, resulting in perivascular fibrin deposition. Treatment of experimental autoimmune encephalomyelitis (EAE), a model of human MS, with antithrombotic and antiinflammatory activated protein C (APC) reduces disease severity. Since recombinant APC (Drotecogin alfa), originally approved for the treatment of severe sepsis, is not available for human MS studies, we tested the hypothesis that pharmacologic activation of endogenous protein C could likewise improve the outcome of EAE. Mice were immunized with murine myelin oligodendrocyte glycoprotein (MOG) peptides and at the onset of EAE symptoms, were treated every other day with either WE thrombin (25 μg/kg; i.v.), a selective recombinant protein C activator thrombin analog, or saline control. Mice were monitored for changes in disease score until euthanized for ex vivo analysis of inflammation. Administration of WE thrombin significantly ameliorated clinical severity of EAE, reduced inflammatory cell infiltration and demyelination, suppressed the activation of macrophages comprising the CD11b + population and reduced accumulation of fibrin (ogen) in the spinal cord. These data suggest that symptomatic MS may respond to a treatment strategy that involves temporal pharmacological enhancement of endogenous APC generation.
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR, 97239, USA, verboutn@ohsu.edu.
authors.forename: Norah G
authors.initials: NG
authors.lastname: Verbout
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Yu
authors.forename: Laura D
authors.initials: LD
authors.lastname: Healy
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Phillips
authors.forename: Erik I
authors.initials: EI
authors.lastname: Tucker
authors.forename: András
authors.initials: A
authors.lastname: Gruber
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004789:Enzyme Activation; D005337:Fibrin / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D009103:Multiple Sclerosis; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D017354:Point Mutation; D011486:Protein C / Q000819:agonists* / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013917:Thrombin / Q000235:genetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D066127:White Matter / Q000473:pathology
chemical_list: D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011486:Protein C; D014409:Tumor Necrosis Factor-alpha; C445081:myelin oligodendrocyte glycoprotein (35-55); D018799:Intercellular Adhesion Molecule-1; D005337:Fibrin; D005340:Fibrinogen; D013917:Thrombin