The role of bradykinin B(1) and B(2) receptors for secondary brain damage after traumatic brain injury in mice.
Inflammatory mechanisms are known to contribute to the pathophysiology of traumatic brain injury (TBI). Since bradykinin is one of the first mediators activated during inflammation, we investigated the role of bradykinin and its receptors in posttraumatic secondary brain damage. We subjected wild-type (WT), B(1)-, and B(2)-receptor-knockout mice to controlled cortical impact (CCI) and analyzed tissue bradykinin as well as kinin receptor mRNA and protein expression up to 48 h thereafter. Brain edema, contusion volume, and functional outcome were assessed 24 h and 7 days after CCI. Tissue bradykinin was maximally increased 2 h after trauma (P<0.01 versus sham). Kinin B(1) receptor mRNA was upregulated up to four-fold 24 h after CCI. Immunohistochemistry showed that B(1) and B(2) receptors were expressed in the brain and were significantly upregulated in the traumatic penumbra 1 to 24 h after CCI. B(2)R(-/-) mice had significantly less brain edema (-51% versus WT, 24 h; P<0.001), smaller contusion volumes ( approximately 50% versus WT 24 h and 7 d after CCI; P<0.05), and better functional outcome 7 days after TBI as compared with WT mice (P<0.05). The present results show that bradykinin and its B(2) receptors play a causal role for brain edema formation and cell death after TBI.
Department for Neurosurgery, University of Munich Medical Center-Grosshadern, Munich, Germany.
Raimund
R
Trabold
Christian
C
Erös
Klaus
K
Zweckberger
Jane
J
Relton
Heike
H
Beck
Juerg
J
Nussberger
Werner
W
Müller-Esterl
Michael
M
Bader
Eric
E
Whalley
Nikolaus
N
Plesnila
D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D001929:Brain Edema / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology*; D003288:Contusions / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043783:Receptor, Bradykinin B1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D001920:Bradykinin