title: Blocking of plasma kallikrein ameliorates stroke by reducing thromboinflammation.
abstract: OBJECTIVE
  Recent evidence suggests that ischemic stroke is a thromboinflammatory disease. Plasma kallikrein (PK) cleaves high-molecular-weight kininogen to release bradykinin (BK) and is a key constituent of the proinflammatory contact-kinin system. In addition, PK can activate coagulation factor XII, the origin of the intrinsic coagulation cascade. Thus, PK triggers 2 important pathological pathways of stroke formation, thrombosis and inflammation.
  
  
  METHODS
  We investigated the consequences of PK inhibition in transient and permanent models of ischemic stroke.
  
  
  RESULTS
  PK-deficient mice of either sex challenged with transient middle cerebral artery occlusion developed significantly smaller brain infarctions and less severe neurological deficits compared with controls without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarctions as well as after permanent stroke. Reduced intracerebral thrombosis and improved cerebral blood flow could be identified as underlying mechanisms. Moreover, blood-brain barrier function was maintained in mice lacking PK, and the local inflammatory response was reduced. PK-deficient mice reconstituted with PK or BK again developed brain infarctions similar to wild-type mice. Important from a translational perspective, inhibition of PK in wild-type mice using a PK-specific antibody was likewise effective even when performed in a therapeutic setting up to 3 hours poststroke.
  
  
  CONCLUSIONS
  PK drives thrombus formation and inflammation via activation of the intrinsic coagulation cascade and the release of BK but appears to be dispensable for hemostasis. Hence, PK inhibition may offer a safe strategy to combat thromboembolic disorders including ischemic stroke.
authors: Department of Neurology, University Hospital Würzburg, Würzburg.
authors: Eva
authors: E
authors: Göb
authors: Stephan
authors: S
authors: Reymann
authors: Friederike
authors: F
authors: Langhauser
authors: Michael K
authors: MK
authors: Schuhmann
authors: Peter
authors: P
authors: Kraft
authors: Ina
authors: I
authors: Thielmann
authors: Kerstin
authors: K
authors: Göbel
authors: Marc
authors: M
authors: Brede
authors: György
authors: G
authors: Homola
authors: László
authors: L
authors: Solymosi
authors: Guido
authors: G
authors: Stoll
authors: Christian
authors: C
authors: Geis
authors: Sven G
authors: SG
authors: Meuth
authors: Bernhard
authors: B
authors: Nieswandt
authors: Christoph
authors: C
authors: Kleinschnitz
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000097:blood / Q000235:genetics / Q000517:prevention & control; D005260:Female; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020842:Plasma Kallikrein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020521:Stroke / Q000097:blood* / Q000235:genetics / Q000517:prevention & control*; D013927:Thrombosis / Q000097:blood* / Q000235:genetics / Q000517:prevention & control*
chemical_list: D020842:Plasma Kallikrein