title: C1-inhibitor protects from brain ischemia-reperfusion injury by combined antiinflammatory and antithrombotic mechanisms.
abstract: OBJECTIVE
  Inflammation and thrombosis are pathophysiological hallmarks of ischemic stroke still unamenable to therapeutic interventions. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is involved in stroke development. C1-inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-inhibitor in models of ischemic stroke.
  
  
  METHODS
  Male and female C57Bl/6 mice and rats of different ages were subjected to middle cerebral artery occlusion and treated with C1-inhibitor after 1 hour or 6 hours. Infarct volumes and functional outcomes were assessed between day 1 and day 7, and findings were validated by magnetic resonance imaging. Blood-brain barrier damage, thrombus formation, and the local inflammatory response were determined poststroke.
  
  
  RESULTS
  Treatment with 15.0 U C1-inhibitor, but not 7.5 U, 1 hour after stroke reduced infarct volumes by ≈60% and improved clinical scores in mice of either sex on day 1. This protective effect was preserved at later stages of infarction as well as in elderly mice and in another species, ie, rats. Delayed C1-inhibitor treatment still improved clinical outcome. Blood-brain barrier damage, edema formation, and inflammation were significantly lower compared with controls. Moreover, C1-inhibitor showed strong antithrombotic effects.
  
  
  CONCLUSIONS
  C1-inhibitor is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings.
authors: Department of Neurology, University of Würzburg, Josef-Schneider Strasse 11, 97080 Würzburg, Germany.
authors: Nadine
authors: N
authors: Heydenreich
authors: Marc W
authors: MW
authors: Nolte
authors: Eva
authors: E
authors: Göb
authors: Friederike
authors: F
authors: Langhauser
authors: Marion
authors: M
authors: Hofmeister
authors: Peter
authors: P
authors: Kraft
authors: Christiane
authors: C
authors: Albert-Weissenberger
authors: Marc
authors: M
authors: Brede
authors: Csanad
authors: C
authors: Varallyay
authors: Kerstin
authors: K
authors: Göbel
authors: Sven G
authors: SG
authors: Meuth
authors: Bernhard
authors: B
authors: Nieswandt
authors: Gerhard
authors: G
authors: Dickneite
authors: Guido
authors: G
authors: Stoll
authors: Christoph
authors: C
authors: Kleinschnitz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D001812:Blood-Brain Barrier / Q000187:drug effects; D015153:Blotting, Western; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D050718:Complement C1 Inhibitor Protein / Q000627:therapeutic use*; D005260:Female; D005343:Fibrinolytic Agents; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D020767:Intracranial Thrombosis / Q000188:drug therapy / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009460:Neurologic Examination; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D012727:Sex Characteristics; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D050718:Complement C1 Inhibitor Protein; D005343:Fibrinolytic Agents