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(Stroke. 2009;40:285.)
© 2009 American Heart Association, Inc.

Original Contributions

Blockade of Bradykinin Receptor B1 but Not Bradykinin Receptor B2 Provides Protection From Cerebral Infarction and Brain Edema

Madeleine Austinat, PhD; Stefan Braeuninger, MD; João B. Pesquero, PhD; Marc Brede, MD; Michael Bader, PhD; Guido Stoll, MD; Thomas Renné, MD, PhD Christoph Kleinschnitz, MD

From Department of Neurology (M.A., S.B., G.S., C.K.), Department of Anesthesiology (M.Brede), and Institute for Clinical Biochemistry and Pathobiochemistry (T.R.), University of Würzburg, Würzburg, Germany; Departamento de Biofisica (J.B.P.), Universidade Federal de São Paulo, São Paulo, Brazil; Max-Delbrück-Center for Molecular Medicine (M.Bader), Berlin-Buch, Germany.

Correspondence to Christoph Kleinschnitz, MD, Department of Neurology, Julius-Maximilians-University of Würzburg, Josef-Schneider Strasse 11, D-97080 Würzburg, Germany. E-mail christoph.kleinschnitz{at}mail.uni-wuerzburg.de

Background and Purpose— Brain edema is detrimental in ischemic stroke and its treatment options are limited. Kinins are proinflammatory peptides that are released during tissue injury. The effects of kinins are mediated by 2 different receptors (B1 and B2 receptor [B1R and B2R]) and comprise induction of edema formation and release of proinflammatory mediators.

Methods— Focal cerebral ischemia was induced in B1R knockout, B2R knockout, and wild-type mice by transient middle cerebral artery occlusion. Infarct volumes were measured by planimetry. Evan’s blue tracer was applied to determine the extent of brain edema. Postischemic inflammation was assessed by real-time reverse-transcriptase polymerase chain reaction and immunohistochemistry. To analyze the effect of a pharmacological kinin receptor blockade, B1R and B2R inhibitors were injected.

Results— B1R knockout mice developed significantly smaller brain infarctions and less neurological deficits compared to wild-type controls (16.8±4.7 mm³ vs 50.1±9.1 mm³, respectively; P<0.0001). This was accompanied by a dramatic reduction of brain edema and endothelin-1 expression, as well as less postischemic inflammation. Pharmacological blockade of B1R likewise salvaged ischemic tissue (15.0±9.5 mm³ vs 50.1±9.1 mm³, respectively; P<0.01) in a dose-dependent manner, even when B1R inhibitor was applied 1 hour after transient middle cerebral artery occlusion. In contrast, B2R deficiency did not confer neuroprotection and had no effect on the development of tissue edema.

Conclusions— These data demonstrate that blocking of B1R can diminish brain infarction and edema formation in mice and may open new avenues for acute stroke treatment in humans.

Expanded Materials and Methods

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