Morales, D.M. et al. Experimental models of traumatic brain injury: do we really need to build a better mousetrap? Neuroscience 136, 971-989

Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, 3320 Smith Walk, 105C Hayden Hall, Philadelphia, PA 19104, USA.
Neuroscience (Impact Factor: 3.36). 02/2005; 136(4):971-89. DOI: 10.1016/j.neuroscience.2005.08.030
Source: PubMed


Approximately 4000 human beings experience a traumatic brain injury each day in the United States ranging in severity from mild to fatal. Improvements in initial management, surgical treatment, and neurointensive care have resulted in a better prognosis for traumatic brain injury patients but, to date, there is no available pharmaceutical treatment with proven efficacy, and prevention is the major protective strategy. Many patients are left with disabling changes in cognition, motor function, and personality. Over the past two decades, a number of experimental laboratories have attempted to develop novel and innovative ways to replicate, in animal models, the different aspects of this heterogenous clinical paradigm to better understand and treat patients after traumatic brain injury. Although several clinically-relevant but different experimental models have been developed to reproduce specific characteristics of human traumatic brain injury, its heterogeneity does not allow one single model to reproduce the entire spectrum of events that may occur. The use of these models has resulted in an increased understanding of the pathophysiology of traumatic brain injury, including changes in molecular and cellular pathways and neurobehavioral outcomes. This review provides an up-to-date and critical analysis of the existing models of traumatic brain injury with a view toward guiding and improving future research endeavors.

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    • "Building on the substantial database of clinical, experimental, and pathological findings associated with TBI, biological mechanisms underlying PTE are actively being explored (D'Ambrosio et al., 1999; Norris and Scheff, 2009; Prince et al., 2009; Willmore and Ueda, 2009; Hunt et al., 2010, 2011; Kharatishvili and Pitkänen, 2010a; Mtchedlishvili et al., 2010; Kharlamov et al., 2011; Belousov et al., 2012; D'Ambrosio et al., 2013a,b; Hunt et al., 2013). Experimental models of TBI simulate human TBI with varying degrees of accuracy (Morales et al., 2005). Two of the most commonly used models of TBI are fluid percussion injury (FPI) and controlled cortical impact (CCI). "
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    ABSTRACT: Posttraumatic epilepsy (PTE) has been modeled with different techniques of experimental traumatic brain injury (TBI) using mice and rats at various ages. We hypothesized that the technique of controlled cortical impact (CCI) could be used to establish a model of PTE in young adult rats. A total of 156 male Sprague-Dawley rats of 2-3 months of age (128 CCI-injured and 28 controls) was used for monitoring and/or anatomical studies. Provoked class 3-5 seizures were recorded by video monitoring in 7/57 (12.3%) animals in the week immediately following CCI of the right parietal cortex; none of the 7 animals demonstrated subsequent spontaneous convulsive seizures. Monitoring with video and/or video-EEG was performed on 128 animals at various time points 8-619 days beyond one week following CCI during which 26 (20.3%) demonstrated nonconvulsive or convulsive epileptic seizures. Nonconvulsive epileptic seizures of >10s were demonstrated in 7/40 (17.5%) animals implanted with 2 or 3 depth electrodes and usually characterized by an initial change in behavior (head raising or animal alerting) followed by motor arrest during an ictal discharge that consisted of high-amplitude spikes or spike-waves with frequencies ranging between 1 and 2Hz class 3-5 epileptic seizures were recorded by video monitoring in 17/88 (19%) and by video-EEG in 2/40 (5%) CCI-injured animals. Ninety of 156 (58%) animals (79 CCI-injured, 13 controls) underwent transcardial perfusion for gross and microscopic studies. CCI caused severe brain tissue loss and cavitation of the ipsilateral cerebral hemisphere associated with cell loss in the hippocampal CA1 and CA3 regions, hilus, and dentate granule cells, and thalamus. All Timm-stained CCI-injured brains demonstrated ipsilateral hippocampal mossy fiber sprouting in the inner molecular layer. These results indicate that the CCI model of TBI in adult rats can be used to study the structure-function relationships that underlie epileptogenesis and PTE.
    Epilepsy research 10/2015; 117:104-116. DOI:10.1016/j.eplepsyres.2015.09.009 · 2.02 Impact Factor
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    • ") which could be the reason for increased calcium concentration in the cEND cells incubated in medium of injured C6 cells compared to cEND cells alone . Traumatic brain injury ( TBI ) involves a cascade of morphological and physiological events . Most in vivo models of TBI meet the criteria of reproducing such occurrences ( Morales et al . , 2005 ; Albert - Weissenberger and Sirén , 2010"
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    ABSTRACT: The blood-brain barrier (BBB), made up of endothelial cells of capillaries in the brain, maintains the microenvironment of the central nervous system. During ischemia and traumatic brain injury (TBI), cellular disruption leading to mechanical insult results to the BBB being compromised. Oxygen glucose deprivation (OGD) is the most commonly used in vitro model for ischemia. On the other hand, stretch injury is currently being used to model TBI in vitro. In this paper, the two methods are used alone or in combination, to assess their effects on cerebrovascular endothelial cells cEND in the presence or absence of astrocytic factors. Applying severe stretch and/or OGD to cEND cells in our experiments resulted to cell swelling and distortion. Damage to the cells induced release of lactate dehydrogenase enzyme (LDH) and nitric oxide (NO) into the cell culture medium. In addition, mRNA expression of inflammatory markers interleukin (I L)-6, IL-1α, chemokine (C-C motif) ligand 2 (CCL2) and tumor necrosis factor (TNF)-α also increased. These events could lead to the opening of calcium ion channels resulting to excitotoxicity. This could be demonstrated by increased calcium level in OGD-subjected cEND cells incubated with astrocyte-conditioned medium. Furthermore, reduction of cell membrane integrity decreased tight junction proteins claudin-5 and occludin expression. In addition, permeability of the endothelial cell monolayer increased. Also, since cell damage requires an increased uptake of glucose, expression of glucose transporter glut1 was found to increase at the mRNA level after OGD. Overall, the effects of OGD on cEND cells appear to be more prominent than that of stretch with regards to TJ proteins, NO, glut1 expression, and calcium level. Astrocytes potentiate these effects on calcium level in cEND cells. Combining both methods to model TBI in vitro shows a promising improvement to currently available models.
    Frontiers in Cellular Neuroscience 09/2015; 9:323. DOI:10.3389/fncel.2015.00323 · 4.29 Impact Factor
    • "Lateral fluid percussion injury is one of the most commonly used and well-characterized experimental models of TBI (Morales et al., 2005; Thompson et al., 2005). Here, a voice-coil driven fluid percussion injury device (vcFPI) was designed and built to model TBI Fig. 7. Neurodegeneration and altered electrophysiological function. "
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    ABSTRACT: Injury to the brain can occur from a variety of physical insults and the degree of disability can greatly vary from person to person. It is likely that injury outcome is related to the biomechanical parameters of the traumatic event such as magnitude, direction and speed of the forces acting on the head. To model variations in the biomechanical injury parameters, a voice coil driven fluid percussion injury (FPI) system was designed and built to generate fluid percussion waveforms with adjustable rise times, peak pressures, and durations. Using this system, pathophysiological outcomes in the rat were investigated and compared to animals injured with the same biomechanical parameters using the pendulum based FPI system. Immediate post-injury behavior shows similar rates of seizures and mortality in adolescent rats and similar righting times, toe pinch responses and mortality rates in adult rats. Interestingly, post injury mortality in adult rats was sensitive to changes in injury rate. Fluoro-Jade labeling of degenerating neurons in the hilus and CA2-3 hippocampus were consistent between injuries produced with the voice coil and pendulum operated systems. Granule cell population spike amplitude to afferent activation, a measure of dentate network excitability, also showed consistent enhancement 1wk after injury using either system. Overall our results suggest that this new FPI device produces injury outcomes consistent with the commonly used pendulum FPI system and has the added capability to investigate pathophysiology associated with varying rates and durations of injury. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Neuroscience Methods 03/2015; 248. DOI:10.1016/j.jneumeth.2015.03.010 · 2.05 Impact Factor
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