icatibant and Encephalitis

Brain edema is detrimental in ischemic stroke and its treatment options are limited. Kinins are proinflammatory peptides that are released during tissue injury. The effects of kinins are mediated by 2 different receptors (B1 and B2 receptor [B1R and B2R]) and comprise induction of edema formation and release of proinflammatory mediators.. Focal cerebral ischemia was induced in B1R knockout, B2R knockout, and wild-type mice by transient middle cerebral artery occlusion. Infarct volumes were measured by planimetry. Evan's blue tracer was applied to determine the extent of brain edema. Postischemic inflammation was assessed by real-time reverse-transcriptase polymerase chain reaction and immunohistochemistry. To analyze the effect of a pharmacological kinin receptor blockade, B1R and B2R inhibitors were injected.. B1R knockout mice developed significantly smaller brain infarctions and less neurological deficits compared to wild-type controls (16.8+/-4.7 mm(3) vs 50.1+/-9.1 mm(3), respectively; P<0.0001). This was accompanied by a dramatic reduction of brain edema and endothelin-1 expression, as well as less postischemic inflammation. Pharmacological blockade of B1R likewise salvaged ischemic tissue (15.0+/-9.5 mm(3) vs 50.1+/-9.1 mm(3), respectively; P<0.01) in a dose-dependent manner, even when B1R inhibitor was applied 1 hour after transient middle cerebral artery occlusion. In contrast, B2R deficiency did not confer neuroprotection and had no effect on the development of tissue edema.. These data demonstrate that blocking of B1R can diminish brain infarction and edema formation in mice and may open new avenues for acute stroke treatment in humans.

Topics: Animals; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Brain Edema; Cerebral Arteries; Cerebral Infarction; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Encephalitis; Endothelin-1; Gene Expression; Infarction, Middle Cerebral Artery; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor, Bradykinin B1; Receptor, Bradykinin B2; RNA, Messenger

The role of kinins, well known as peripheral inflammatory mediators, in the modulation of brain inflammation is unclear. The present data show that bradykinin, a bradykinin B(2) receptor agonist, enhanced both basal and lipopolysaccharide-induced prostaglandin E(2) synthesis in rat neonatal glial cells in culture. By contrast, Lys-des-Arg(9)-bradykinin, which is a kinin breakdown product and a selective bradykinin B(1) receptor agonist, attenuated both basal and lipopolysaccharide-induced production of prostaglandin E(2) in glia. These results suggest a feedback regulatory mechanism of kinins on glial cells, in which prostaglandin synthesis is initially enhanced by bradykinin (B(2)) and eventually blocked by the effect of the kinin breakdown product, acting on bradykinin B(1) receptors.

Topics: Animals; Animals, Newborn; Bradykinin; Cells, Cultured; Dinoprostone; Dose-Response Relationship, Drug; Encephalitis; Kallidin; Kinins; Lipopolysaccharides; Neuroglia; Rats; Rats, Wistar; Receptor, Bradykinin B1; Receptor, Bradykinin B2