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 B(2)R 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.

NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

“…The model of diffuse head injury was elaborated as described previously (Hellal et al, 2003). Briefly, Swiss mice weighing 26 -28 g (Janvier, France) were anesthetized under 2% halothane balanced with air and oxygen.…”

“…Closed head trauma was induced by a 50 g weight dropped along a stainless-steel string. This experimental paradigm creates a pattern of diffuse degeneration into the brain accompanied with a deficit of the functional outcome (Hellal et al, 2003). At the indicated time, mice presenting a significant deficit of the functional outcome were deeply anesthetized with isoflurane and killed, and their brains were immediately removed and briefly rinsed in chilled saline.…”

Blockade of Acute Microglial Activation by Minocycline Promotes Neuroprotection and Reduces Locomotor Hyperactivity after Closed Head Injury in Mice: A Twelve-Week Follow-Up Study

“…Sequelae of TBI include a wide spectrum of effects on the injured brain. TBI causes focal and diffuse brain injury, cerebral inflammation, and hemorrhage, all of which may lead to acute and chronic cell death, and may contribute to functional impairment Hellal et al, 2003;Homsi et al, 2009;Werner and Engelhard, 2007;Zhang et al, 2005). Diffuse axonal injury (DAI) constitutes one of the main consequences of TBI.…”

Up-regulation of bradykinin receptors in rat bronchia via IκB kinase-mediated inflammatory signaling pathway

“…Thus, the up-regulation of B 1 receptor mediated contraction in the present setup may also be regulated by the overexpression of the inflammatory gene. However, the expression of inflammatory genes including IL-6, MMP-9, COX-2 and iNOS were considerably sensitive to repression by bradykinin B 2 receptor antagonists (Hellal et al, 2003;Hsieh et al, 2008;Lee et al, 2008;Zhang et al, 2008), which may suggest an important role of B 2 receptors in regulating of these genes. Although the present study did not provide enough evidence to reveal the relationship between the up-regulation of bradykinin receptors and the overexpression of inflammatory genes, a practical model has been provided here to further studies on airway inflammation and airway hyperresponsivness.…”