title: Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor and Plasminogen Activator Inhibitor-1 Reduces Ischemic Brain Damage in Mice.
abstract: Cerebral ischemia and reperfusion is associated with activation of the coagulation cascade and fibrin deposition in cerebral microvessels. Both thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) attenuate fibrinolysis and are therefore attractive targets for the treatment of ischemic stroke.
  
  
  
  TAFI and PAI-1 were inhibited by monoclonal antibodies in a mouse model of transient middle cerebral artery occlusion. Twenty-four hours after stroke, mice were neurologically scored, cerebral thrombotic burden was assessed, and brain infarct sizes were calculated.
  
  
  
  Inhibition of TAFI or PAI-1 significantly decreased cerebral infarct sizes by 50% 24 hours after stroke. This reduction in cerebral damage was associated with a significant decrease in fibrin(ogen) deposition in the ischemic brain. Concurrently, functional recovery of the animals was improved. Interestingly, combined targeting of TAFI and PAI-1 using low, and by themselves inactive, doses of antibodies improved cerebral blood flow and reduced cerebral fibrin(ogen) deposition and infarct sizes by 50%. When dual treatment was delayed to 1 hour after the start of reperfusion, it still reduced brain injury; however, this was not statistically significant.
  
  
  
  Targeting of PAI-1 and TAFI is protective in an ischemic stroke model by attenuating fibrin(ogen) deposition, thereby improving reperfusion. Combined inhibition has a co-operative effect that could become useful in ischemic stroke therapy.
authors.affiliation: From the Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (F.D., N.V., H.D., K.V., S.F.D.M.); and Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (T.W., M.P., A.G., P.J.D.).
authors.forename: Frederik
authors.initials: F
authors.lastname: Denorme
authors.affiliation: From the Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (F.D., N.V., H.D., K.V., S.F.D.M.); and Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (T.W., M.P., A.G., P.J.D.).
authors.forename: Tine
authors.initials: T
authors.lastname: Wyseure
authors.affiliation: From the Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (F.D., N.V., H.D., K.V., S.F.D.M.); and Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (T.W., M.P., A.G., P.J.D.).
authors.forename: Miet
authors.initials: M
authors.lastname: Peeters
authors.affiliation: From the Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (F.D., N.V., H.D., K.V., S.F.D.M.); and Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (T.W., M.P., A.G., P.J.D.).
authors.forename: Nele
authors.initials: N
authors.lastname: Vandeputte
authors.affiliation: From the Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (F.D., N.V., H.D., K.V., S.F.D.M.); and Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (T.W., M.P., A.G., P.J.D.).
authors.forename: Ann
authors.initials: A
authors.lastname: Gils
authors.affiliation: From the Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (F.D., N.V., H.D., K.V., S.F.D.M.); and Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (T.W., M.P., A.G., P.J.D.).
authors.forename: Hans
authors.initials: H
authors.lastname: Deckmyn
authors.affiliation: From the Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (F.D., N.V., H.D., K.V., S.F.D.M.); and Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (T.W., M.P., A.G., P.J.D.).
authors.forename: Karen
authors.initials: K
authors.lastname: Vanhoorelbeke
authors.affiliation: From the Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (F.D., N.V., H.D., K.V., S.F.D.M.); and Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (T.W., M.P., A.G., P.J.D.).
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Declerck
authors.affiliation: From the Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (F.D., N.V., H.D., K.V., S.F.D.M.); and Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (T.W., M.P., A.G., P.J.D.). simon.demeyer@kuleuven.be.
authors.forename: Simon F
authors.initials: SF
authors.lastname: De Meyer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy*; D025901:Carboxypeptidase B2 / Q000276:immunology*; D004195:Disease Models, Animal; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000276:immunology*; D020521:Stroke / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D017395:Plasminogen Activator Inhibitor 1; D025901:Carboxypeptidase B2; C585365:Cpb2 protein, mouse
keywords: fibrinolysis; plasminogen activator inhibitor-1; reperfusion injury; stroke; thrombin-activatable fibirinolysis inhibitor