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| 2. |
- Bolouri, Hayde, 1957
(författare)
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An animal model of sport related concussive brain injury
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A new animal model for concussion of the type seen in professional football was developed, since current animal models did not simulate these conditions. The model is characterized by a high velocity-low mass impact to the head of a freely moving object. Structural damages and functional effects of the model have been investigated. Paper I describes the rat model. A pneumatically driven projectile impacted the temporal region of the head. A 50 g projectile matches the concussions in football players scaled to the rat. Exposures were also performed with a 100 g impactor. The pressure accelerated the projectile to velocities of 7.4 m/s, 9.3 m/s and 11.2 m/s. The head was protected with a padded aluminum helmet. A small accelerometer was attached on the opposite side of the head, inline with the impact, for recording the acceleration of the head. Rats were exposed to a single or repeated (3, with 6 hour intervals) impacts and were sacrificed 1, 4 or 10 days later. Peak head acceleration, ?V, duration and energy transfer were determined. Brains were perfused and surface injuries identified. Skull fractures were never found. Impact velocity and head ?V and acceleration were within 1% and 3% of the target. In paper II, neuronal injury was assessed with immunohistochemistry for NF-200, the heaviest neurofilament subunit, and GFAP, an intermediate filament protein in astrocytes. Hemorrhages were visualized with unspecific peroxidase. NF-200 immunoreactivity was accumulated in neuronal perikarya and was reduced in the axons 10 days after impact. Reactive astrocytes were found in the midline regions of the cerebral cortex and periventricularly. Erythrocyte-loaded blood capillaries indicated brain edema in regions of the cerebral cortex, brain stem and cerebellum. A single impact at 7.4 and 9.3 m/s with the 50 g projectile resulted in minimal neuronal injury and astrocytosis. Repeated impacts with the 100 g projectile at 11.2 m/s and 9.3 m/s led to injury bilaterally in the cerebral cortex, subcortical white matter, hippocampus CA1, corpus callosum and the striatum. The pattern of injury is suggestive of Diffuse Neuronal Injury (DAI). In paper III, cognitive function and exploratory behavior were investigated following repeated head impacts. Rats were trained daily for 6 days in the Morris Water Maze. The time of latency to find a hidden platform was reduced from 50 secs on day 1 to 15 secs on day 6. They were then exposed with the 50 g or the 100 g projectile at 9.3 or 11.2 m/s. Spontaneous exploratory activity was assessed with the open field test 2-4 days and 1 and 2 weeks after impacts with the 50 g projectile at 9.3 and 11.2 m/s. The results showed that rats exposed at 11.2 m/s (x3) with the 50 g projectile or 9.3 m/s (x3) and 11.2 m/s (x2) with the 100 g projectile had a significantly increased time of latency to the platform, while those exposed with the 50 g at 9.3 m/s did not differ from the controls. Rats impacted with 50 g (x3) at 9.3 or 11.2 m/s showed a significant decrease in spontaneous exploratory activity. In conclusion, the model fulfilled the conditions of concussion in the freely moving animal, without preparatory surgery, still with good reproducibility. Some aspects of the neuropathology and functional effects were investigated and both showed dose-response effects. The functional changes were cognitive deficits and reduced exploratory activity. Key words: Animal model, football, concussion, brain injury, neuropathology, cognitive function. ISBN Gothenburg 2008
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| 4. |
- Bolouri, Hayde, 1957, et al.
(författare)
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ANIMAL MODELS FOR CONCUSSION: MOLECULAR AND COGNITIVE ASSESSMENTS - RELEVANCE TO SPORT AND MILITARY CONCUSSIONS
- 2014
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Ingår i: Brain Neurotrauma: Molecular, Neuropsychological and Rehabilitation. Firas H. Kobeissy (Ed.). - USA : Taylor & Francis. - 9781466565982 ; , s. 643-656
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Bokkapitel (refereegranskat)abstract
- Abstract Mild traumatic brain injury (mTBI) or concussion, the most common form of brain injury, results in a complex cascade of injurious and reparative events in the brain and is not always as mild in nature as the mTBI term would imply. Over the last decades it has become clear that repeated mTBIs may give rise to chronic and sometimes progressive brain changes that may lead to a broad range of psychiatric and neurological symptoms. Presently, there is a convention to categorize TBI into three groups: mild, moderate, and severe, based on initial presentation. At the more severe end of the injury spectrum, the correlation between initial injury severity rating and various outcome measures is relatively robust. At the milder end of the spectrum, this correlation is less tight, and over the last 100 years this has generated confusion with regards to the typical presentation and outcome of milder injuries. For a successful translation of basic science knowledge to the clinic to occur, further techniques and models are needed that better reflect mTBI in humans. The purpose of this chapter is to overview the underlying evidence for the necessity of animal models for mTBI in sports and other high risk activities such as military service.
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| 5. |
- Bolouri, Hayde, 1957, et al.
(författare)
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Innate defence regulator peptide 1018 protects against perinatal brain injury.
- 2014
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Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 75:3, s. 395-410
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Tidskriftsartikel (refereegranskat)abstract
- Objective: There is currently no pharmacological treatment that provides protection against brain injury in neonates. It is known that activation of an innate immune response is a key, contributing factor in perinatal brain injury, therefore, the neuroprotective therapeutic potential of innate defence regulator peptides (IDRs) was investigated. Methods: The anti-inflammatory effects of three IDRs was measured in LPS-activated murine microglia. IDRs were then assessed for their ability to confer neuroprotection in vivo when given 3h after neonatal brain injury in a clinically relevant model that combines an inflammatory challenge (LPS) with hypoxia-ischemia (HI). To gain insight into peptide-mediated effects on LPS-induced inflammation and neuroprotective mechanisms, global cerebral gene expression patterns were analyzed in pups that were treated with IDR-1018 either 4 h before LPS or 3h after LPS+HI. Results: IDR-1018 reduced inflammatory mediators produced by LPS-stimulated microglia cells in vitro and modulated LPS-induced neuroinflammation in vivo. When administered 3h after LPS+HI, IDR-1018 exerted effects on regulatory molecules of apoptotic (for e.g. Fadd and Tnfsf9) and inflammatory (for e.g. IL-1, TNF-α, chemokines and cell adhesion molecules) pathways and showed marked protection of both white and grey brain matter. Interpretation: IDR-1018 supresses pro-inflammatory mediators and cell injurious mechanisms in the developing brain, and post-insult treatment is efficacious in reducing LPS-induced hypoxic-ischemic brain damage. IDR-1018 is effective in the brain when given systemically, confers neuroprotection of both grey and white matter, and lacks significant effects on the brain under normal conditions. Thus this peptide provides the features of a promising neuroprotective agent in newborns with brain injury. ANN NEUROL 2013. © 2013 American Neurological Association.
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| 6. |
- Dean, Justin M, et al.
(författare)
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Delayed cortical impairment following lipopolysaccharide exposure in preterm fetal sheep.
- 2011
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Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 70:5, s. 846-856
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Preterm infants exhibit chronic deficits in white matter (WM) and cortical maturation. Although fetal infection/inflammation may contribute to WM pathology, the factors contributing to cortical changes are largely unknown. We examined the effect of fetal lipopolysaccharide (LPS) exposure on WM and cortical development as assessed by magnetic resonance imaging (MRI), electroencephalography (EEG), and histopathology in fetal sheep at preterm human equivalent age. METHODS: LPS was administered to fetal sheep at 102.5 ± 0.5 days of gestation. Continuous biophysical recordings were analyzed for 10 days after LPS. At postmortem, measurement of cerebral WM and cortical tissue volumes was achieved by stereological techniques. Specific effects of LPS on MRI-assessed T(1) -weighted and T(2) -weighted images, and immunohistochemical expression of oligodendrocytes, proliferating cells, cortical NeuN-positive and Nurr1-positive neurons (subplate marker), and cell death mechanisms were examined. RESULTS: We observed reductions in WM (∼21%; LPS, 1.19 ± 0.04 vs control, 1.51 ± 0.07cm(3) ; p < 0.001) and cortical (∼18%; LPS, 2.34 ± 0.10 vs control, 2.85 ± 0.07cm(3) ; p < 0.001) volumes, associated with overt and diffuse WM injury, T(1) -/T(2) -weighted signal alterations, and reduced numbers of WM oligodendrocytes (LPS, 485 ± 31 vs control, 699 ± 69 cells/mm(2) ; p = 0.0189) and NeuN-positive (LPS, 421 ± 71 vs control 718 ± 92 cells/mm(2) ; p = 0.04) and Nurr1-positive (control, 2.5 ± 0.6 vs LPS, 0.6 ± 0.1 cells/mm(2) ; p = 0.007) cortical neurons after LPS. Moreover, there was loss of the normal maturational increase in cortical EEG amplitude, which correlated with reduced cortical volumes. INTERPRETATION: Fetal exposure to LPS prior to myelination onset can impair both white matter and cortical development in a preclinical large animal model, supporting a role for maternal/fetal infection in the pathogenesis of preterm brain injury. ANN NEUROL 2011.
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| 7. |
- Hamberger, Anders, 1937, et al.
(författare)
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Concussion in Professional Football: Morphology of Brain Injuries in the Nfl Concussion Model-Part 16
- 2009
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Ingår i: Neurosurgery. - 0148-396X. ; 64:6, s. 1174-1182
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: An animal model of concussions in National Football League players has been described in a previous study. It involves a freely moving 300-g Wistar rat impacted on the side of the head at velocities of 7.4 to 11.2 m/s with a 50-g impactor. The impact causes a 6% to 28% incidence of meningeal hemorrhages and 0.1- to 0.3-mm focal petechiae depending on the impact velocity. This study addresses the immunohistochemical responses of the brain. METHODS: Twenty-seven tests were conducted with a 50-g impactor and velocities of 7.4, 9.3, or 11.2 m/s. The left temporal region of the helmet-protected head was hit 1 or 3 times. Thirty-one additional tests were conducted with a 100-g impactor. Diffuse axonal injury in distant regions of the brain was assessed with immunohistochemistry for NF-200, the heaviest neurofilament subunit, and glial fibrillary acidic protein, an intermediate filament protein in astrocytes. Hemorrhages were analyzed by unspecific peroxidase. There were 10 controls. RESULTS: A single impact at 7.4 and 9.3 m/s velocity with the 50-g impactor causes minimal neuronal injury and astrocytosis. Repeat impacts with 11.2 m/s velocity and more than 9.3-m/s impacts with 100 g cause diffuse axonal injury and distant injury bilaterally in the cerebral cortex, the subcortical, the white matter, the hippocampus CA1, the corpus callosum, and the striatum, as indicated by NF-200 accumulation in neuronal perikarya 10 days after impact. It also causes reactive astrocytosis in the midline regions of the cerebral cortex and periventricularly. Regions with erythrocyte-loaded blood capillaries indicated brain edema in regions of the cerebral cortex, the brainstem, and the cerebellum. CONCLUSION: When the immunohistochemical results are extrapolated to professional football players, concussions result in no or minimal brain injury. Repeat impacts at higher velocity or with a heavier mass impactor cause extensive and distant diffuse axonal injury. Based on this model, the threshold for diffuse axonal injury is above even the most severe conditions for National Football League concussion. Copyright (C) by the Congress of Neurological Surgeons
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| 8. |
- Keller, Matthias, et al.
(författare)
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Inflammatory-induced hibernation in the fetus:priming of fetal sheep metabolism correlates with developmental brain injury.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- Prenatal inflammation is considered an important factor contributing to preterm birth and neonatal mortality and morbidity. The impact of prenatal inflammation on fetal bioenergetic status and the correlation of specific metabolites to inflammatory-induced developmental brain injury are unknown. We used a global metabolomics approach to examine plasma metabolites differentially regulated by intrauterine inflammation. Preterm-equivalent sheep fetuses were randomized to i.v. bolus infusion of either saline-vehicle or LPS. Blood samples were collected at baseline 2 h, 6 h and daily up to 10 days for metabolite quantification. Animals were killed at 10 days after LPS injection, and brain injury was assessed by histopathology. We detected both acute and delayed effects of LPS on fetal metabolism, with a long-term down-regulation of fetal energy metabolism. Within the first 3 days after LPS, 121 metabolites were up-regulated or down-regulated. A transient phase (4–6 days), in which metabolite levels recovered to baseline, was followed by a second phase marked by an opposing down-regulation of energy metabolites, increased pO2 and increased markers of inflammation and ADMA. The characteristics of the metabolite response to LPS in these two phases, defined as 2 h to 2 days and at 6–9 days, respectively, were strongly correlated with white and grey matter volumes at 10 days recovery. Based on these results we propose a novel concept of inflammatory-induced hibernation of the fetus. Inflammatory priming of fetal metabolism correlated with measures of brain injury, suggesting potential for future biomarker research and the identification of therapeutic targets.
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| 9. |
- Persson, Åsa, 1980, et al.
(författare)
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Radixin expression in microglia after cortical stroke lesion
- 2013
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Ingår i: Glia. - : Wiley. - 0894-1491. ; 61:5, s. 790-799
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Tidskriftsartikel (refereegranskat)abstract
- Stroke induces extensive tissue remodeling, resulting in the activation of several cell types in the brain as well as recruitment of blood-borne leucocytes. Radixin is part of a cytoskeleton linker protein family with the ability to connect transmembrane proteins to the actin cytoskeleton, promoting cell functions involving a dynamic cytoskeleton such as morphological changes, cell division and migration which are common events of different cell types after stroke. In the healthy adult brain radixin is expressed in Olig2+ cells throughout the brain and in neural progenitor cells in the subventricular zone. In the current study, we detected a 2.5 fold increase in the number of radixin positive cells in the peri-infarct cortex two weeks after the induction of cortical stroke by photothrombosis. Similarly, the number of Olig2+ cells increased in the peri-infarct area after stroke; however, the number of radixin+/Olig2+ cells was unchanged. Neural progenitor cells maintained radixin expression on their route to the infarct. More surprising however, was the expression of radixin in activated microglia in the peri-infarct cortex. Seventy percent of Iba1+ cells expressed radixin after stroke, a population which was not present in the control brain. Furthermore, activation of radixin was predominantly detected in the peri-infarct region of oligodendrocyte progenitors and microglia. The specific location of radixin+ cells in the peri-infarct region and in microglia suggests a role for radixin in microglial activation after stroke.
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| 10. |
- Säljö, Annette, et al.
(författare)
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Low-level blast raises intracranial pressure and impairs cognitive function in rats: prophylaxis with processed cereal feed
- 2010
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 27:2, s. 383-389
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Tidskriftsartikel (refereegranskat)abstract
- There is increasing evidence that even low levels of blast cause brain injury, but little is known about their thresholds and mechanisms. Exposure of rats to 10-60 kPa blasts elevate intracranial pressure (ICP) in a dose-dependent manner and impair cognitive function. We have evaluated a prophylactic measure against these brain injuries in a rat animal model, consisting of feeding them processed cereal. This type of feed is known to ameliorate disturbances in secretion of body fluids and to have anti-inflammatory effects. In humans, intake of processed cereals is effective against intestinal diarrhea and also reduces the symptoms of Ménière's disease. Rats were given either standard laboratory feed or processed cereal feed for 2 weeks before exposure to blast in a shock tube. The ICP was monitored at different time points up to 1 week after exposure to a 60-kPa blast, and for up to 24 h after exposure to a 30-kPa blast. Maximal ICP elevation was reached at 10 h in both groups. In the group of rats on standard feed exposed to 60 kPa, an ICP increase of 145% was noted at 10 h, and the corresponding increase in the rats fed processed cereal feed was only 50%. In rats exposed to a 30-kPa blast, those fed standard feed and processed cereal feed demonstrated increases of ICP of 80% and 40%, respectively. Cognitive function as measured by the Morris water maze was assessed in other groups of rats at 2 days after exposure to 10- or 30-kPa blasts. Their performance was significantly impaired at both exposure levels in rats on standard feed, but no functional impairment was seen in rats fed processed cereal feed.
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