Journal of neurotrauma
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Journal of neurotrauma · May 2013
Detection of structural and metabolic changes in traumatically injured hippocampus by quantitative differential proteomics.
Traumatic brain injury (TBI) is a complex and common problem resulting in the loss of cognitive function. In order to build a comprehensive knowledge base of the proteins that underlie these cognitive deficits, we employed unbiased quantitative mass spectrometry, proteomics, and bioinformatics to identify and quantify dysregulated proteins in the CA3 subregion of the hippocampus in the fluid percussion model of TBI in rats. Using stable isotope 18O-water differential labeling and multidimensional tandem liquid chromatography (LC)-MS/MS with high stringency statistical analyses and filtering, we identified and quantified 1002 common proteins, with 124 increased and 76 decreased. ⋯ Western blotting confirmed that the calcineurin regulatory subunit, CANB1, and its catalytic binding partner PP2BA, were decreased without changes in other calcineurin subunits. CANB1 plays a critical role in downregulated networks of calcium signaling and homeostasis through calmodulin and calmodulin-dependent kinase II to highly interconnected structural networks dominated by tubulins. This large-scale knowledge base lays the foundation for the identification of novel therapeutic targets for cognitive rescue in TBI.
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Journal of neurotrauma · May 2013
Design of poly(ethylene glycol)-functionalized hydrophilic carbon clusters for targeted therapy of cerebrovascular dysfunction in mild traumatic brain injury.
Traumatic brain injury (TBI) involves the elaboration of oxidative stress that causes cerebrovascular dysfunction, including impairment of autoregulation of cerebral blood flow. Currently, there is no clinically effective antioxidant treatment for these pathologies. Most currently available antioxidants act through mechanisms in which the antioxidant either transfers the radical or requires regeneration, both of which are impaired in the toxic post-TBI environment. ⋯ Here we report that PEG-HCCs possess innate antioxidant activity and can be rapidly targeted via an antibody to the P-selectin antigen in a model of injured cultured brain endothelial cells. One immediate application of this therapy is to vascular dysfunction that accompanies TBI and worsens outcome in the face of systemic hypotension. These in vitro results support the need for further investigation in animal models.
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Journal of neurotrauma · May 2013
Inflammatory consequences in a rodent model of mild traumatic brain injury.
Mild traumatic brain injury (mTBI), particularly mild "blast type" injuries resulting from improvised exploding devices and many sport-caused injuries to the brain, result in long-term impairment of cognition and behavior. Our central hypothesis is that there are inflammatory consequences to mTBI that persist over time and, in part, are responsible for resultant pathogenesis and clinical outcomes. ⋯ Our mild LFP injury resulted in acute increases in interleukin-1α/β and tumor necrosis factor alpha levels, macrophage/microglial and astrocytic activation, evidence of heightened cellular stress, and blood-brain barrier (BBB) dysfunction that were evident as early as 3-6 h postinjury. Both glial activation and BBB dysfunction persisted for 18 days postinjury.
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Journal of neurotrauma · May 2013
Analysis of functional pathways altered after mild traumatic brain injury.
Concussive injury (or mild traumatic brain injury; mTBI) can exhibit features of focal or diffuse injury patterns. We compared and contrasted the cellular and molecular responses after mild controlled cortical impact (mCCI; a focal injury) or fluid percussion injury (FPI; a diffuse injury) in rats. The rationale for this comparative analysis was to investigate the brain's response to mild diffuse versus mild focal injury to identify common molecular changes triggered by these injury modalities and to determine the functional pathways altered after injury that may provide novel targets for therapeutic intervention. ⋯ We therefore examined changes in the protein levels of a panel of 23 cytokines and chemokines in cortical extracts using a Luminex-based bead immunoassay and detected significant increases in macrophage inflammatory protein (MIP)-1α (CCL3), GRO-KC (CXCL1), interleukin (IL)-1α, IL-1β, and IL-6. Immunohistochemical localization of MIP-1α and IL-1β showed marked increases at 3 h postinjury in the cortical vasculature and microglia, respectively, that were largely resolved by 24 h postinjury. Our findings demonstrate that both focal and diffuse mTBI trigger many shared pathobiological processes (e.g., inflammatory responses) that could be targeted for mechanism-based therapeutic interventions.
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Journal of neurotrauma · May 2013
Blast wave exposure impairs memory and decreases axon initial segment length.
Exposure to a blast wave has been proposed to cause mild traumatic brain injury (mTBI), with symptoms including altered cognition, memory, and behavior. This idea, however, remains controversial, and the mechanisms of blast-induced brain injury remain unknown. To begin to resolve these questions, we constructed a simple compressed air shock tube, placed rats inside the tube, and exposed them to a highly reproducible and controlled blast wave. ⋯ Intriguingly, we also observed a significant shortening of the axon initial segment (AIS) in both the cortex and hippocampus of blast-exposed rats, suggesting altered neuronal excitability after exposure to a blast. A computational model showed that shortening the AIS increased both threshold and the interspike interval of repetitively firing neurons. These results support the conclusion that exposure to a single blast wave can lead to mTBI with accompanying cognitive impairment and subcellular changes in the molecular organization of neurons.