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 mm(3) vs 50.1+/-9.1 mm(3), 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 mm(3) vs 50.1+/-9.1 mm(3), 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.
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 mm(3) vs 50.1+/-9.1 mm(3), 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 mm(3) vs 50.1+/-9.1 mm(3), 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.
Authors: Sigurdur T Sigurdsson; Olaf B Paulson; Arne Høj Nielsen; Svend Strandgaard Journal: J Cereb Blood Flow Metab Date: 2013-12-11 Impact factor: 6.200
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Authors: Christoph Kleinschnitz; Henrike Grund; Kirstin Wingler; Melanie E Armitage; Emma Jones; Manish Mittal; David Barit; Tobias Schwarz; Christian Geis; Peter Kraft; Konstanze Barthel; Michael K Schuhmann; Alexander M Herrmann; Sven G Meuth; Guido Stoll; Sabine Meurer; Anja Schrewe; Lore Becker; Valérie Gailus-Durner; Helmut Fuchs; Thomas Klopstock; Martin Hrabé de Angelis; Karin Jandeleit-Dahm; Ajay M Shah; Norbert Weissmann; Harald H H W Schmidt Journal: PLoS Biol Date: 2010-09-21 Impact factor: 8.029
Authors: Evi X Stavrou; Chao Fang; Kara L Bane; Andy T Long; Clément Naudin; Erdem Kucukal; Agharnan Gandhi; Adina Brett-Morris; Michele M Mumaw; Sudeh Izadmehr; Alona Merkulova; Cindy C Reynolds; Omar Alhalabi; Lalitha Nayak; Wen-Mei Yu; Cheng-Kui Qu; Howard J Meyerson; George R Dubyak; Umut A Gurkan; Marvin T Nieman; Anirban Sen Gupta; Thomas Renné; Alvin H Schmaier Journal: J Clin Invest Date: 2018-01-29 Impact factor: 14.808