Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin‐1β. (11th March 2016)

• Record Type: Journal Article
• Authors: Ekmark‐Lewén, Sara; Flygt, Johanna; Fridgeirsdottir, Gudrun A.; Kiwanuka, Olivia; Hånell, Anders; Meyerson, Bengt J.; Mir, Anis K.; Gram, Hermann; Lewén, Anders; Clausen, Fredrik; Hillered, Lars; Marklund, Niklas
• Editors: Chan, Ying‐Shing
• Is Part Of: European journal of neuroscience. Volume 43:Number 8(2016:Apr.)
• Page Start: 1016
• Page End: 1033
• Publication Date: 2016-03-11
• Subjects: axonal injury -- behavioural outcome -- central fluid percussion injury -- interleukin‐1β -- traumatic brain injury; Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.13190
• Languages: English
• ISSNs: 0953-816X

Abstract

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. Abstract : In this study, a mouse model of widespread traumatic axonal injury (TAI) was used to study the role of interleukin (IL)‐1β on post‐traumatic behavioral changes. Following TAI, administration of an IL‐1β neutralizing antibody resulted in improved behavioral outcome, including an improved performance in the Morris Water maze memory trial (left in Figure) and normalized behavioral profiles in the multivariate concentric square filed test (MCSF; right in Figure), up to three weeks post‐injury.