Blocking of bradykinin receptor B1 protects from focal closed head injury in mice by reducing axonal damage and astroglia activation.

Abstract

The two bradykinin receptors B1R and B2R are central components of the kallikrein-kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration.

• Authors: Christiane Albert-Weissenberger, Christian Stetter, Sven G Meuth, Kerstin Göbel, Michael Bader, Anna-Leena Sirén, Christoph Kleinschnitz
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 32 Issue 9 Pg. 1747-56 (Sep 2012) ISSN: 1559-7016 [Electronic] United States
• PMID: 22569191 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bradykinin B1 Receptor Antagonists
• Bradykinin B2 Receptor Antagonists
• R 715
• Receptor, Bradykinin B1
• Receptor, Bradykinin B2
• Tumor Necrosis Factor-alpha
• Bradykinin

Topics

• Animals
• Apoptosis (drug effects)
• Astrocytes (drug effects)
• Axons (pathology)
• Behavior, Animal (physiology)
• Bradykinin (analogs & derivatives, pharmacology)
• Bradykinin B1 Receptor Antagonists
• Bradykinin B2 Receptor Antagonists
• Head Injuries, Closed (drug therapy, metabolism, pathology)
• Immunohistochemistry
• Macrophage Activation (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Real-Time Polymerase Chain Reaction
• Receptor, Bradykinin B1 (biosynthesis, genetics)
• Receptor, Bradykinin B2 (biosynthesis, genetics)
• Recovery of Function
• Tumor Necrosis Factor-alpha (metabolism)