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Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β
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) Published
Resource type
Text
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: 2017-03-07Bibliographically approved
In thesis
1. Oligodendrocyte pathology following Traumatic Brain Injury: Experimental and clinical studies
Open this publication in new window or tab >>Oligodendrocyte pathology following Traumatic Brain Injury: Experimental and clinical studies
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI) caused by traffic and fall accidents, sports-related injuries and violence commonly results in life-changing disabilities. Cognitive impairments following TBI may be due to disruption of axons, stretched by the acceleration/deceleration forces of the initial impact, and their surrounding myelin in neuronal networks. The primary injury, which also results in death to neuronal and glial cells, is followed by a cascade of secondary injury mechanisms including a complex inflammatory response that will exacerbate the white matter injury.

Axons are supported and protected by the ensheathing myelin, ensuring fast conduction velocity. Myelin is produced by oligodendrocytes (OLs), a cell type vulnerable to many of the molecular processes, including several inflammatory mediators, elicited by TBI. Since one OL extends processes to several axons, the protection of OLs is an important therapeutic target post-TBI.  During development, OLs mature from oligodendrocyte progenitor cells (OPCs), also present in the adult brain.

The aim of this thesis was to investigate white matter pathology, with a specific focus on the OL population, in experimental and clinical TBI. Since the inflammatory response may contribute to OL cell death and OPC proliferation, neutralization of interleukin-1β (IL-1β) was investigated.

The lateral and central fluid percussion injury models were used in mice and rats where memory, learning and complex behaviors were investigated by two functional tests. Brain tissue, surgically resected due to life-threatening brain swelling or hemorrhage, from TBI patients was also investigated. Axonal injury, myelin damage, microglia alterations and OPCs and OL cell death were investigated by immunohistochemical techniques. In focal and diffuse experimental TBI, OL cell death was observed in important white matter tracts. OL cell death was accompanied by myelin damage, axonal injury and presence of microglia as well as an increased number of OPCs in both the experimental and human setting. OPCs were found to proliferate in diffuse TBI in mice where both complex behavioral changes and impaired memory were observed. Neutralization of IL-1β normalized and improved these behavioral alterations and also lead to a preserved number of mature OLs although without influencing OPC proliferation.

The results provided in this thesis indicate that white matter pathology is a key component of the pathophysiology of TBI. The OPC proliferation may influence regeneration post-injury and might be an important future therapeutic targets for TBI. The present studies also suggest that treatment strategies targeting neuroinflammation may positively influence behavioral outcome and OL cell death in TBI.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1311
Keyword
Traumatic brain injury, oligodendrocytes, oligodendrocyte progenitor cells, interleukin 1-β, central fluid percussion injury
National Category
Natural Sciences
Research subject
Neurosurgery; Neurosurgery
Identifiers
urn:nbn:se:uu:diva-316401 (URN)978-91-554-9846-7 (ISBN)
Public defence
2017-05-05, Hedstrandsalen, Akademiska Sjukhuset, Uppsala, 09:00 (English)
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(Faculty of Medicine)

Available from: 2017-04-11 Created: 2017-03-07 Last updated: 2017-04-21

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