1. ¹Laboratory of Experimental Neurosurgery, Institute for Surgical Research, University of Munich, Munich, Germany
2. ²Groupe de Pharmacochimie des Récepteurs, Centre de Recherche, Fournier Pharma, Daix, France
3. ³Biogen Idec, Cambridge, Massachusetts, USA
4. ⁴Division of Hypertension and Vascular Medicine, University Hospital Lausanne, Lausanne, Switzerland

Correspondence: Dr N Plesnila, Institut für Chirurgische Forschung, Ludwig-Maximilians Universität, Marchioninistr. 15, 81366 Munich, Germany. E-mail: plesnila@icf.med.uni-muenchen.de

Received 24 September 2004; Revised 22 November 2004; Accepted 23 November 2004; Published online 6 April 2005.

Abstract

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.