title: The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats.
abstract: OBJECTIVE
  Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach.
  
  
  METHODS
  For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation.
  
  
  RESULTS
  Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis.
  
  
  CONCLUSIONS
  With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury.
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Krupka
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: May
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weimer
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Pragst
authors.affiliation: University of Würzburg, Department of Neurology, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.affiliation: University of Würzburg, Department of Neurology, Würzburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.affiliation: CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
authors.forename: Con
authors.initials: C
authors.lastname: Panousis
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Nolte
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D016466:CHO Cells; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D015956:Factor XIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D019476:Insect Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000517:prevention & control*; D045442:Rotarod Performance Test; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012709:Serum Albumin / Q000494:pharmacology* / Q000627:therapeutic use; D000075462:Serum Albumin, Human
chemical_list: D019476:Insect Proteins; D011993:Recombinant Fusion Proteins; D015842:Serine Proteinase Inhibitors; D012709:Serum Albumin; C000609004:rHA-infestin-4 protein; D015956:Factor XIIa; D000075462:Serum Albumin, Human
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