Inhibition of Bradykinin Receptor B1 Protects Mice from Focal Brain Injury by Reducing Blood–Brain Barrier Leakage and Inflammation

Abstract

Kinins are proinflammatory and vasoactive peptides that are released during tissue damage and may contribute to neuronal degeneration, inflammation, and edema formation after brain injury by acting on discrete bradykinin receptors, B1R and B2R. We studied the expression of B1R and B2R and the effect of their inhibition on lesion size, blood-brain barrier (BBB) disruption, and inflammatory processes after a focal cryolesion of the right parietal cortex in mice. B1R and B2R gene transcripts were significantly induced in the lesioned hemispheres of wild-type mice (P<0.05). The volume of the cortical lesions and neuronal damage at 24 h after injury in B1R(-/-) mice were significantly smaller than in wild-type controls (2.5+/-2.6 versus 11.5+/-3.9 mm(3), P<0.001). Treatment with the B1R antagonist R-715 1 h after lesion induction likewise reduced lesion volume in wild-type mice (2.6+/-1.4 versus 12.2+/-6.1 mm(3), P<0.001). This was accompanied by a remarkable reduction of BBB disruption and tissue inflammation. In contrast, genetic deletion or pharmacological inhibition of B2R had no significant impact on lesion formation or the development of brain edema. We conclude that B1R inhibition may offer a novel therapeutic strategy after acute brain injuries.

Blockade of the kinin receptor B1 protects from autoimmune CNS disease by reducing leukocyte trafficking

“…Previous studies have shown that B1R is critically involved in the regulation of leukocyte transmigration across endothelial barriers and the disruption of the BBB under inflammatory conditions [13,14,35,36]. For that reason we analyzed the mRNA expression pattern of characteristic adhesion molecules in pure endothelial cells freshly isolated from the CNS of B1R À/À mice at disease maximum of EAE.…”

“…These observations are in agreement with previous reports [4,11,12,26] and suggest that the KKS is of functional importance in autoimmune CNS inflammation. Whether neuronal or glial B1R which are relevant in ischemic and traumatic brain lesion models [13,14,28,37] also play a role in EAE needs to be further established.…”

“…The KKS plays an important role in the regulation of vascular permeability and all components of the KKS have been identified in the brain [16e18]. Only recently, its suitability as an endogenous target to combat CNS inflammation [11,19e22] and other neurological disease states [13,14,23] has been recognized.…”

Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

“…B1R is another key member of the kallikrein-kinin system which acts downstream of KNG. Blocking of B1R dramatically reduced inflammatory processes and edema formation in models of acute ischemic stroke, 13 traumatic brain injury, 12 and multiple sclerosis. 11 The corresponding findings in different mouse models bearing genetic defects in the contact-kinin system suggest that thrombosis and inflammation are closely intertwined during focal cerebral ischemia.…”

“…The contact-kinin system occupies a central position in the pathophysiology of different neurologic disease models that mimic, for example, multiple sclerosis 11 or traumatic brain injury. 12 In acute ischemic stroke activation of the contactkinin system fosters vascular permeability and stroke-related inflammation by the formation of short-lived kinins, while at the same time it is linked to thrombus formation via the FXII-driven intrinsic coagulation cascade. 4,5,13 Therefore, the contact-kinin system represents a promising multifunctional target for potential stroke therapies.…”