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Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2016 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 43, no 8, 1016-1033 p.Article in journal (Refereed) PublishedText
Abstract [en]

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)-1 has not been established in TAI. An IL-1-neutralizing or a control antibody was administered intraperitoneally at 30min 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-1 antibody reached the target brain regions in adequate therapeutic concentrations (up to similar to 30g/brain tissue) at 24h post-injury in both cFPI (n=5) and sham-injured (n=3) mice, with lower concentrations at 72h post-injury (up to similar to 18g/g brain tissue in three cFPI mice). Functional outcome was analysed with the multivariate concentric square field (MCSF) test at 2 and 9days post-injury, and the Morris water maze (MWM) at 14-21days post-injury. Following TAI, the IL-1-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-1-neutralizing treatment did not influence cerebral ventricle size or the number of microglia/macrophages. These findings support the hypothesis that IL-1 is an important contributor to the processes causing complex cognitive and behavioural disturbances following TAI.

Place, publisher, year, edition, pages
2016. Vol. 43, no 8, 1016-1033 p.
Keyword [en]
axonal injury, behavioural outcome, central fluid percussion injury, interleukin-1, traumatic brain injury
National Category
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-297130DOI: 10.1111/ejn.13190ISI: 000374645700004PubMedID: 27091435OAI: oai:DiVA.org:uu-297130DiVA: diva2:941127
Funder
Swedish Research Council
Available from: 2016-06-22 Created: 2016-06-21 Last updated: 2016-06-22Bibliographically approved

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Ekmark-Lewén, SaraFlygt, JohannaLewen, AndersClausen, FredrikHillered, LarsMarklund, Niklas
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