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Complex behavioral alterations after diffuse traumatic axonal injury in mice are normalized by post-injury neutralization of interleukin-1β

Ekmark-Lewen, S and Fridgeirsdottir, A and Kiwanuka, O and Hanell, A and Meyerson , B and Mir, Anis Khusro and Gram, Hermann and Lewen , A and Clausen, F and Hillered, L and Marklund, N (2016) Complex behavioral alterations after diffuse traumatic axonal injury in mice are normalized by post-injury neutralization of interleukin-1β. European Journal of Neuroscience, 43 (8). pp. 1016-1033. ISSN 0953816X

Abstract

Abstract
Wide-spread traumatic axonal injury (TAI), clinically known as diffuse axonal injury, results in brain network dysfunction which commonly leads to persisting cognitive and behavioral 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-1β (IL-1β) in TAI has not been established. An IL-1β-neutralizing or a control antibody was administered intraperitoneally at 30 min following central fluid percussion injury (cFPI) in mice, a model of wide-spread TAI. Animals subjected to moderate cFPI (n=41) were compared to sham-injured controls (n=20) and untreated, naive animals (n=9). The anti-IL-1β antibody reached the target brain regions in adequate therapeutic concentrations (up to ~30µg /g brain tissue) at 24h post-injury in both cFPI-injured (n=5) and sham-injured animals (n=3) whereas at 72 h post-injury (n=3 cFPI-injured), the antibody concentration was lower (up to ~18µg /g brain tissue). Functional outcome was analyzed using 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 behavioral outcome, including normalized behavioral profiles in the MCSF test, and improved performance in the MWM probe (memory) trial, although without influencing MWM learning. The IL1β neutralizing treatment did not influence cerebral ventricle size or the number of activated microglia at 21 days post- injury. These findings support the hypothesis that IL-1β is an important contributor to the processes causing complex cognitive and behavioral disturbances following TAI.

Keywords: Interleukin 1β, central fluid percussion injury, mice, multivariate concentric square field test, Morris water maze, microglia, traumatic brain injury, traumatic axonal injury, diffuse axonal injury, behavioral outcome

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/24433

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