Detrimental Role of Bradykinin B2Receptor in a Murine Model of Diffuse Brain Injury

Abstract

Inhibition of the bradykinin B₂ receptor type (B₂R) has been shown to improve neurological outcome in models of focal traumatic brain injury. However, the involvement of B₂R in trauma-induced diffuse injury has not yet been explored. This is an important point, since in humans a pattern of diffuse injury is commonly found in severely injured patients and has been associated with a poor neurological outcome and prognosis. Using the non-peptide B₂R antagonist LF 16-0687 Ms and B₂R null (B₂R^-/-) mice, we investigated the role of B₂R in a model of closed head trauma (CHT). LF 16-0687 Ms given 30 min after injury reduced the neurological deficit by 26% and the cerebral edema by 22% when evaluated 4 h after CHT. Neurological function after CHT was improved in B₂R^-/- mice compared to B₂R^+/+ mice, although there was no difference in the development of brain edema. Treatment with LF 16-0687 Ms and B₂R gene deletion decreased the accumulation of neutrophils at 24 h after CHT (50% and 36%, respectively). In addition, the inducible NO synthase (iNOS) mRNA level increased markedly, and this was reduced by LF 16-0687 Ms. Taken together, these data support a detrimental role of B₂R in the development of the neurological deficit and of the inflammatory secondary damage resulting from diffuse traumatic brain injury. Therefore, blockade of bradykinin B₂ receptors might represent an attractive therapeutic approach in the pharmacological treatment of traumatic brain injury.