Bradykinin 2 receptors (B2R) mediate long term neurocognitive deficits after experimental traumatic brain injury.

The kallikrein-kinin system is one of the first inflammatory pathways to be activated following traumatic brain injury (TBI) and has been shown to exacerbate brain edema formation in the acute phase through activation of Bradykinin-2-receptors (B2R). However, the influence of B2 receptors on chronic posttraumatic damage and outcome is unclear. In the current study we assessed long term effects of B2R-knockout after experimental traumatic brain injury. B2R knockout mice (heterozygous, homozygous) and wildtype littermates (n=10/group) were subjected to controlled cortical impact TBI. Lesion size was evaluated by MRI up to 90 days after CCI. Motor and memory function were regularly assessed by Neurological severity Score (NSS), Beam Walk (BW), and Barnes Maze test. 90 days after TBI, brains were harvested for immunohistochemical analysis. There was no difference in cortical lesion size between B2R deficient and wildtype animals three months after injury, however, hippocampal damage was reduced in B2R KO mice (p=0.03). Protection of hippocampal tissue was accompanied by a significant improvement of learning and memory function three months after TBI (p=0.02 WT vs. KO), whereas motor function was not influenced. Scar formation and astrogliosis were unaffected, but bradykinin-2-receptor deficiency led to a gene-dose dependent attenuation of microglial activation and a reduction of CD45+ cells three months after TBI in cortex (p=0.0003) and hippocampus (p< 0.0001). These results suggest that chronic hippocampal neurodegeneration and subsequent cognitive impairment is mediated by prolonged neuroinflammation and bradykinin-2-receptors. Inhibition of B2-receptors may therefore represent a novel strategy to reduce long-term neurocognitive deficits after TBI.