Bradykinin 2 Receptors Mediate Long-Term Neurocognitive Deficits After Experimental Traumatic Brain Injury
Publication: Journal of Neurotrauma
Abstract
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 B2R on chronic post-traumatic damage and outcome is unclear. In the current study, we assessed long-term effects of B2R-knockout (KO) after experimental TBI. B2R KO mice (heterozygous, homozygous) and wild-type (WT) littermates (n = 10/group) were subjected to controlled cortical impact (CCI) TBI. Lesion size was evaluated by magnetic resonance imaging up to 90 days after CCI. Motor and memory function were regularly assessed by Neurological Severity Score, Beam Walk, and Barnes maze test. Ninety days after TBI, brains were harvested for immunohistochemical analysis. There was no difference in cortical lesion size between B2R-deficient and WT animals 3 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 3 months after TBI (p = 0.02 WT vs. KO), whereas motor function was not influenced. Scar formation and astrogliosis were unaffected, but B2R deficiency led to a gene-dose-dependent attenuation of microglial activation and a reduction of CD45+ cells 3 months after TBI in cortex (p = 0.0003) and hippocampus (p < 0.0001). These results suggest that chronic hippocampal neurodegeneration and subsequent cognitive impairment are mediated by prolonged neuroinflammation and B2R. Inhibition of B2R may therefore represent a novel strategy to reduce long-term neurocognitive deficits after TBI.
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Transparency, Rigor, and Reproducibility Summary
All animal experiments were reviewed and approved by the Ethical Review Board of the Government of Upper Bavaria. Results are reported in accordance with the ARRIVE guidelines.40 Animal husbandry, health, and hygiene management checks were performed in accordance with Federation of European Laboratory Animal Science Association’s guidelines and recommendations.41 All surgical procedures, behavioral testing, imaging, and data analysis were performed in a randomized manner by a researcher blinded to genotype and group allocation of the animals. Genotyping and group allocation were obtained by a third party not involved in the study or data acquisition or analysis. Sample size was calculated with the following parameters: alpha error = 0.05, beta error = 0.2, calculated standard deviation ranged from 15% to 20% (depending on the parameter investigated), and biologically relevant difference = 30%. All data are given as mean ± SD. For comparison between groups, Student’s t-test was used for normally distributed data and Mann–Whitney Rank Sum test for non-normally distributed data according to the result of Kolmogorov–Smirnov normality test. Measurements over time were tested between groups using one-way or two-way ANOVA with repeated measurements, followed by Tukey’s multiple comparisons test for normally and Sidak’s multiple comparisons test for non-normally distributed data as post hoc test. Calculations were performed with SigmaPlot version 14.0 (Systat Software GmbH). All animals were genotyped before inclusion into the study to ascertain B2R status. Thirty mice (15 male, 15 female) were subjected to experimental TBI, of which none had to be excluded. MRI-based evaluation of lesion volume and functional assessments were performed in all 30 animals. For immunohistochemical analyses and histopathological staining, 3 male and 2 female animals per group (total 9 males and 6 females) were analyzed. All raw data are provided in the supplementary material.
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Journal of Neurotrauma
PubMed: 38818807
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Copyright 2024, Mary Ann Liebert, Inc., publishers.
History
Published online: 27 June 2024
Published ahead of production: 31 May 2024
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Authors’ Contributions
Conception or design of the study: A.C.W., I.K., N.P., and N.A.T. Acquisition, analysis, or interpretation of the data: A.C.W., I.K., S.H., X.M., S.C., N.P., and N.A.T. Drafting the article or revising it critically for important intellectual content: all authors. All authors gave final approval of the current article version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Author Disclosure Statement
Data used for the dissertation thesis of A.C.W. were generated with the same methodology as in the present article (DOI: 10.5282/edoc.31972). Therefore, CrossRef/iThenticate analysis shows similarity of this article to the thesis; similarities, however, are only found in the description of materials and methods. No data of the present publication were published anywhere.
Funding Information
This research was funded by Munich Medical School’s Förderung für Forschung und Lehre (A.C.W., N.P., N.A.T.) program, the Friedrich Baur Foundation (N.A.T.), and the Munich Cluster of Systems Neurology (Project ID EXC 2145/ID 390857198).
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