Experimental models of traumatic brain injury: Do we really need to build a better mousetrap?

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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    • ") 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
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    • "For instance, mFPI is administered by a fluid-filled pulse directly to the brain at the midline causing equally distributed undulation of the brain and leaves the dura intact. This causes mild neuronal pathology including diffuse axonal injury (Lifshitz et al., 2007a) and transient neurological deficits (Morales et al., 2005) that recapitulate complications after mild to moderate concussive head injuries in humans (Lifshitz, 2009). A moderate mFPI in rodents caused activated microglia and an altered phenotype of microglia that persisted up to 1 month after injury. "
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    ABSTRACT: Glia of the central nervous system (CNS) help to maintain homeostasis in the brain and support efficient neuronal function. Microglia are innate immune cells of the brain that mediate responses to pathogens and injury. They have key roles in phagocytic clearing, surveying the local microenvironment and propagating inflammatory signals. An interruption in homeostasis induces a cascade of conserved adaptive responses in glia. This response involves biochemical, physiological and morphological changes and is associated with the production of cytokines and secondary mediators that influence synaptic plasticity, cognition and behavior. This reorganization of host priorities represents a beneficial response that is normally adaptive but may become maladaptive when the profile of microglia is compromised. For instance, microglia can develop a primed or pro-inflammatory mRNA, protein and morphological profile with aging, traumatic brain injury and neurodegenerative disease. As a result, primed microglia exhibit an exaggerated inflammatory response to secondary and sub-threshold challenges. Consequences of exaggerated inflammatory responses by microglia include the development of cognitive deficits, impaired synaptic plasticity and accelerated neurodegeneration. Moreover, impairments in regulatory systems in these circumstances may make microglia more resistant to negative feedback and important functions of glia can become compromised and dysfunctional. Overall, the purpose of this review is to discuss key concepts of microglial priming and immune-reactivity in the context of aging, traumatic CNS injury and neurodegenerative disease. Copyright © 2014. Published by Elsevier Ltd.
    Neuropharmacology 11/2014; 96(Pt A). DOI:10.1016/j.neuropharm.2014.10.028 · 5.11 Impact Factor
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    • "Symptoms induced by a bilateral medial frontal cortex (mFC) CCI injury include prolonged cognitive deficits and impaired forelimb coordination (Hoffman et al., 1994). The physiological consequences include gross reductions in grey and white matter, focal cellular necrosis, apoptosis in the adjacent structures, followed by glial scar formation (Morales et al., 2005). The brain's ability to create new neural pathways through the ongoing process of neural plasticity has been observed in both intact and injured brains (Allred et al., 2008). "
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    ABSTRACT: Purpose: Despite advances towards potential clinically viable therapies there has been only limited success in improving functional recovery following traumatic brain injury (TBI). In rats, exposure to an enriched environment (EE) improves learning and fosters motor skill development. Induced pluripotent stem cells (iPSC) have been shown to survive transplantation and influence the recovery process. The current study evaluated EE and iPSC as a polytherapy for remediating cognitive deficits following medial frontal cortex (mFC) controlled cortical impact (CCI) injury. Methods: Sixty adult male rats received a midline mFC CCI or sham injury and were randomly placed in either EE or standard environment (SE). Seven days post-injury rats received bilateral transplantation of iPSCs or media. Behavioral measures were conducted throughout the remainder of the study. Following behavioral analysis, brains were extracted and prepared for histological analysis. Results: Open-field data revealed that combined therapy resulted in typical Sham/EE activity rearing patterns by the conclusion of the study. On the Vermicelli Handling task, rats with EE/iPSC polytherapy performed better than media-treated rats. Furthermore, rats treated with polytherapy performed equivalently to Sham/EE rats on the Morris water maze. Proficiency on the Rotarod was consistently better in EE when compared to SE counterparts. Confocal microscopy confirmed that iPSCs survived and migrated away from the transplantation site. Conclusions: Overall, EE or iPSC therapy improved cognition and motor performance, however, full cognitive restoration was seen only with the EE/iPSC treatment. These data suggest that EE/iPSC therapy should be explored as a potential, clinically relevant, treatment for TBI.
    Restorative neurology and neuroscience 07/2014; 32(5). DOI:10.3233/RNN-140408 · 2.49 Impact Factor
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