Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β

Research output: Contribution to journalArticle

Abstract

Widespread traumatic axonal injury (TAI) results in brain network dysfunction, which commonly leads to persisting cognitive and behavioural impairments following traumatic brain injury (TBI). TBI induces a complex neuroinflammatory response, frequently located at sites of axonal pathology. The role of the pro-inflammatory cytokine interleukin (IL)-1β has not been established in TAI. An IL-1β-neutralizing or a control antibody was administered intraperitoneally at 30 min following central fluid percussion injury (cFPI), a mouse model of widespread TAI. Mice subjected to moderate cFPI (n = 41) were compared with sham-injured controls (n = 20) and untreated, naive mice (n = 9). The anti-IL-1β antibody reached the target brain regions in adequate therapeutic concentrations (up to ~30 μg/brain tissue) at 24 h post-injury in both cFPI (n = 5) and sham-injured (n = 3) mice, with lower concentrations at 72 h post-injury (up to ~18 μg/g brain tissue in three cFPI mice). Functional outcome was analysed with the multivariate concentric square field (MCSF) test at 2 and 9 days post-injury, and the Morris water maze (MWM) at 14-21 days post-injury. Following TAI, the IL-1β-neutralizing antibody resulted in an improved behavioural outcome, including normalized behavioural profiles in the MCSF test. The performance in the MWM probe (memory) trial was improved, although not in the learning trials. The IL-1β-neutralizing treatment did not influence cerebral ventricle size or the number of microglia/macrophages. These findings support the hypothesis that IL-1β is an important contributor to the processes causing complex cognitive and behavioural disturbances following TAI.

Details

Authors
  • Sara Ekmark-Lewén
  • Johanna Flygt
  • Gudrun A Fridgeirsdottir
  • Olivia Kiwanuka
  • Anders Hånell
  • Bengt J Meyerson
  • Anis K Mir
  • Hermann Gram
  • Anders Lewén
  • Fredrik Clausen
  • Lars Hillered
  • Niklas Marklund
Organisations
External organisations
  • Uppsala University
Research areas and keywords

Keywords

  • Journal Article, Research Support, Non-U.S. Gov't
Original languageEnglish
Pages (from-to)1016-33
Number of pages18
JournalEuropean Journal of Neuroscience
Volume43
Issue number8
Publication statusPublished - 2016 Apr
Publication categoryResearch
Peer-reviewedYes