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- Ekmark-Lewén, Sara, et al.
(författare)
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Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β
- 2016
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 43:8, s. 1016-1033
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Tidskriftsartikel (refereegranskat)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)-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.
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| 3. |
- Ekmark-Lewén, Sara, et al.
(författare)
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Traumatic axonal injury in the mouse is accompanied by a dynamic inflammatory response, astroglial reactivity and complex behavioral changes
- 2013
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 10:1, s. 44-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDiffuse traumatic axonal injury (TAI), a common consequence of traumatic brain injury, is associated with high morbidity and mortality. Inflammatory processes may play an important role in the pathophysiology of TAI. In the murine central fluid percussion injury (cFPI) TAI model, the neuroinflammatory and astroglial response and behavioral changes are unknown.MethodsTwenty cFPI-injured and nine sham-injured mice were used, and the neuroinflammatory and astroglial response was evaluated by immunohistochemistry at 1, 3 and 7 days post-injury. The multivariate concentric square field test (MCSF) was used to compare complex behavioral changes in mice subjected to cFPI (n = 16) or sham injury (n = 10). Data was analyzed using non-parametric statistics and principal component analysis (MCSF data).ResultsAt all post-injury time points, beta-amyloid precursor protein (beta-APP) immunoreactivity revealed widespread bilateral axonal injury and IgG immunostaining showed increased blood--brain barrier permeability. Using vimentin and glial fibrillary acidic protein (GFAP) immunohistochemistry, glial cell reactivity was observed in cortical regions and important white matter tracts peaking at three days post-injury. Only vimentin was increased post-injury in the internal capsule and only GFAP in the thalamus. Compared to sham-injured controls, an increased number of activated microglia (MAC-2), infiltrating neutrophils (GR-1) and T-cells (CD3) appearing one day after TAI (P<0.05 for all cell types) was observed in subcortical white matter. In the MCSF, the behavioral patterns including general activity and exploratory behavior differed between cFPI mice and sham-injured controls.ConclusionsTraumatic axonal injury in mice resulted in marked bilateral astroglial and neuroinflammatory responses and complex behavioral changes. The cFPI model in mice appears suitable for the study of injury mechanisms, including neuroinflammation, and the development of treatments targeting traumatic axonal injury.
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| 4. |
- Israelsson, Charlotte, et al.
(författare)
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Altered expression of myelin-associated inhibitors and their receptors after traumatic brain injury in the mouse
- 2014
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Ingår i: Restorative Neurology and Neuroscience. - 0922-6028 .- 1878-3627. ; 32:5, s. 717-731
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: When central nervous system axons are injured, regeneration is partly inhibited by myelin-associated inhibitors (MAIs). Following traumatic brain injury (TBI) in the rat, pharmacological neutralisation of the MAIs Nogo-A and myelin-associated glycoprotein (MAG) resulted in improved functional outcome. In contrast, genetic or pharmacological neutralization of the MAI receptors Nogo-66 receptor 1 (NgR1) or paired-immunoglobulin like receptor-B (PirB) showed an unaltered or impaired outcome following TBI in mice. The aim of the present study was thus to evaluate the MAI expression levels following TBI in mice. Methods: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure total RNA isolated from brains of young adult male C57BL/6 mice at one, three or seven days following controlled cortical impact TBI or sham injury. Hippocampal and neocortical tissue ipsi- and contralateral to the injury was analyzed for Nogo-A, oligodendrocyte-myelin glycoprotein (OMgp), MAG, and the MAI receptors PirB and NgR1, including its co-receptor Lingo1. Results: Compared to sham-injured controls, PirB neocortical expression was significantly upregulated at one day and NgR1 expression downregulated at seven days post-TBI. In the hippocampus, transcriptional upregulation was observed in Nogo-A (one day post-injury), MAG and PirB at seven days post-injury. In contrast, the hippocampal transcripts of NgR1 and Lingo1 were decreased at seven days post-injury. The expression of OMgp was unaltered at all time points post-injury. Conclusion: These results suggest that early dynamic changes in MAI gene expression occur following TBI in the mouse, particularly in the hippocampus, which may play an inhibitory role for post-injury regeneration and plasticity.
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| 5. |
- Kiwanuka, Olivia, et al.
(författare)
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Long-term health-related quality of life after trauma with and without traumatic brain injury : a prospective cohort study
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- To purpose was to assess and compare the health-related quality of life (HRQoL) and risk of depression two years after trauma, between patients with and without traumatic brain injury (TBI) in a mixed Swedish trauma cohort. In this prospective cohort study, TBI and non-TBI trauma patients included in the Swedish Trauma registry 2019 at a level II trauma center in Stockholm, Sweden, were contacted two years after admission. HRQoL was assessed with RAND-36 and EQ-5D-3L, and depression with Montgomery Åsberg depression Rating Scale self-report (MADRS-S). Abbreviated Injury Score (AIS) head was used to grade TBI severity, and American Society of Anesthesiologists (ASA) score was used to assess comorbidities. Data were compared using Chi-squared test, Mann Whitney U test and ordered logistic regression, and Bonferroni correction was applied. A total of 170 of 737 eligible patients were included. TBI was associated with higher scores in 5/8 domains of RAND-36 and 3/5 domains of EQ-5D (p < 0.05). No significant difference in MADRS-S. An AIS (head) of three or higher was associated with lower scores in five domains of RAND-36 and two domains of EQ-5D but not for MADRS-S. An ASA-score of three was associated with lower scores in all domains of both RAND-36 (p < 0.05, except mental health) and EQ-5D (p < 0.001, except anxiety/depression), but not for MADRS-S. In conclusion, patients without TBI reported a lower HRQoL than TBI patients two years after trauma. TBI severity assessed according to AIS (head) was associated with HRQoL, and ASA-score was found to be a predictor of HRQoL, emphasizing the importance of considering pre-injury health status when assessing outcomes in TBI patients.
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| 6. |
- Marklund, Niklas, et al.
(författare)
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Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice
- 2009
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522 .- 1873-7544. ; 163:2, s. 540-551
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Tidskriftsartikel (refereegranskat)abstract
- Increasing age is associated with a poor prognosis following traumatic brain injury (TBI). CNS axons may recover poorly following TBI due to expression of myelin-derived inhibitors to axonal outgrowth such as Nogo-A. To study the role of Nogo-A/B in the pathophysiological response of the elderly to TBI, 1-year-old mice deficient in Nogo-A/B (Nogo-A/B homozygous(-/-) mice), Nogo-A/B heterozygous(-/+) mice, and age-matched wild-type (WT) littermate controls were subjected to a controlled cortical impact (CCI) TBI. Sham-injured WT mice (7 months old) and 12 month old naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) served as controls. Neurological motor function was evaluated up to 3 weeks, and cognitive function, hemispheric tissue loss, myelin staining and hippocampal beta-amyloid (A beta) immunohistochemistry were evaluated at 4 weeks post-injury. In WT littermates, TBI significantly impaired learning ability at 4 weeks and neurological motor function up to 2 weeks post-injury and caused a significant loss of hemispheric tissue. Following TBI, Nogo-A/B(-/-) mice showed significantly less recovery from neurological motor and cognitive deficits compared to brain-injured WT mice. Naïve Nogo-A/B(-/-) and Nogo-A/B(-/+) mice quickly learned the MWM task in contrast to brain-injured Nogo-A/B(-/-) mice who failed to learn the MWM task at 4 weeks post-injury. Hemispheric tissue loss and cortical lesion volume were similar among the brain-injured genotypes. Neither TBI nor the absence of NogoA/B caused an increased A beta expression. Myelin staining showed a reduced area and density in the corpus callosum in brain-injured Nogo-A/B(-/-) animals compared to their littermate controls. These novel and unexpected behavioral results demonstrate that the absence of Nogo-A/B may negatively influence outcome, possibly related to hypomyelination, following TBI in mice and suggest a complex role for this myelin-associated axonal growth inhibitor following TBI.
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