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60th Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Benelux countries and Bulgaria

German Society of Neurosurgery (DGNC)

24 - 27 May 2009, Münster

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Blockade of bradykinin receptor B1 reduces brain injury in a mouse model of neurotrauma

Meeting Abstract

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  • F. Raslan - Neurochirurgische Klinik, Universitätsklinikum Würzburg
  • M. Austinat - Neurologische Klinik, Universitätsklinikum Würzburg
  • T. Schwarz - Neurologische Klinik, Universitätsklinikum Würzburg
  • C. Kleinschnitz - Neurologische Klinik, Universitätsklinikum Würzburg
  • A.L. Sirén - Neurochirurgische Klinik, Universitätsklinikum Würzburg

Deutsche Gesellschaft für Neurochirurgie. 60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit den Benelux-Ländern und Bulgarien. Münster, 24.-27.05.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. DocP09-04

doi: 10.3205/09dgnc344, urn:nbn:de:0183-09dgnc3442

Published: May 20, 2009

© 2009 Raslan et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

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Objective: Development of brain edema worsens outcome after head injury while its treatment options remain limited. Kinins are proinflammatory and vasoactive peptides that are released during tissue injury and may contribute to neuronal damage, inflammation and edema formation after head injury by acting on discrete bradykinin receptors, B1R and B2R. While B2R is constitutively expressed and mediates the physiological effects of bradykinin, the expression of B1R is induced by inflammation and its selective pharmacological or genetic ablation has recently shown to reduce ischemic brain damage (Austinat & al., Stroke 2008, Nov 6 Epub ahead). Here we studied the impact of B1R / B2R inhibition on the pathophysiological sequelae following neurotrauma.

Methods: Focal freezing lesion was applied on the right parietal cortex of 8-week-old male B1R knockout, B2R knockout, and wild-type C57/B6 mice. Lesion volumes were measured by planimetry on 2,3,4-triphenyl-tetrazoliumchloride (TTC)-stained sections and morphology was assessed by H&E staining. The extent of brain edema was quantified by Evans blue leakage and expression of inflammatory markers by real time PCR and immunohistochemistry. To analyze the effect of an acute pharmacological blockade of B1R and B2R in wild-type mice, the selective B1R antagonist R-175 (0.5-1.0 mg/kg, Biomatik Corporation) or the selective B2R antagonist Hoe-140 (0.5 mg/kg, Sigma) was injected intravenously shortly before or 1 h after induction of the cortical lesion.

Results: B1R knockout mice developed significantly smaller brain lesions compared to wild-type controls (2.5±2.6 mm3 vs. 11.5±3.9 mm3, mean±SD respectively; n=7; p=0.0008). Pharmacological blockade of B1R with the selective antagonist R-175 (1.0 mg/kg) likewise salvaged lesioned tissue (2.6±1.4 mm3 vs. 12.2±6.1 mm3, mean±SD respectively; n=7; p=0.0034). In contrast, B2R inhibition was ineffective (p=0.0667). H&E staining revealed significantly less neuronal damage in the cortices of B1R null mice. Preliminary data suggest reduced edema formation and inflammatory responses as underlying mechanisms.

Conclusions: Inhibition of B1R attenuates brain damage in mice and may open new avenues for the management of clinical head injuries.