Release of bradykinin and expression of kinin B2 receptors in the brain: role for cell death and brain edema formation after focal cerebral ischemia in mice.
Pharmacological studies using bradykinin B2 receptor antagonists suggest that bradykinin, an early mediator of inflammation and the main metabolite of the kallikrein-kinin system, is involved in secondary brain damage after cerebral ischemia. However, the time-course of bradykinin production and kinin receptor expression as well as the conclusive role of bradykinin B2 receptors for brain damage after experimental stroke have not been elucidated so far. C57/Bl6 mice were subjected to 45 mins of middle cerebral artery occlusion (MCAO) and 2, 4, 8, 24, and 48 h later brains were removed for the analysis of tissue bradykinin concentration and kinin B2 receptor mRNA and protein expression. Brain edema, infarct volume, functional outcome, and long-term survival were assessed in WT and B2-/- mice 24 h or 7 days after MCAO. Tissue bradykinin was maximally increased 12 h after ischemia (three-fold), while kinin B2 receptor mRNA upregulation peaked 24 to 48 h after MCAO (10- to 12-fold versus naïve brain tissue). Immunohistochemistry revealed that kinin B2 receptors were constitutively and widely expressed in mouse brain, were upregulated 2 h after ischemia in cells showing signs of ischemic damage, and remained upregulated in the penumbra up to 24 h after ischemia. B2-/- mice had improved motor function (P<0.05), smaller infarct volumes (-38%; P<0.01), developed less brain edema (-87%; P<0.05), and survived longer (P<0.01) as compared with wild-type controls. The current results show that bradykinin is produced in the brain, kinin B2 receptors are upregulated on dying cells, and B2 receptors are involved in cell death and brain edema formation after experimental stroke.
Gröger
Moritz
M
Laboratory of Experimental Neurosurgery, Institute for Surgical Research, University of Munich, Munich, Germany.
Lebesgue
Diane
D
Pruneau
Didier
D
Relton
Jane
J
Kim
Seong-Woong
SW
Nussberger
Jürg
J
Plesnila
Nikolaus
N
D000818:Animals; D015153:Blotting, Western; D001920:Bradykinin / Q000097:blood / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology*; D001929:Brain Edema / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D016923:Cell Death / Q000502:physiology; D002544:Cerebral Infarction / Q000473:pathology; D007150:Immunohistochemistry; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D043782:Receptor, Bradykinin B2 / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D001920:Bradykinin