Journal of neurotrauma
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Journal of neurotrauma · Aug 2016
Resuscitation With Valproic Acid Alters Inflammatory Genes in a Porcine Model of Combined Traumatic Brain Injury and Hemorrhagic Shock.
Traumatic brain injury and hemorrhagic shock (TBI+HS) elicit a complex inflammatory response that contributes to secondary brain injury. There is currently no proven pharmacologic treatment for TBI+HS, but modulation of the epigenome has been shown to be a promising strategy. The aim of this study was to investigate whether valproic acid (VPA), a histone deacetylase inhibitor, modulates the expression of cerebral inflammatory gene profiles in a large animal model of TBI+HS. ⋯ DAVID analysis indicated that a cluster of inflammatory pathways held the highest rank and gene enrichment score. Real-time PCR data confirmed that VPA significantly down-expressed genes that ultimately regulate nuclear factor-kB (NF-kB)-mediated production of cytokines, such as TYROBP, TREM2, CCR1, and IL-1β. This high-throughput analysis of cerebral gene expression shows that addition of VPA to the resuscitation protocol significantly modulates the expression of inflammatory pathways in a clinically realistic model of TBI+HS.
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Journal of neurotrauma · Aug 2016
Outcome after Repetitive Mild Traumatic Brain Injury is Temporally Related to Glucose Uptake Profile at Time of Second Injury.
Repeated mild traumatic brain injury (rmTBI) results in worsened outcomes, compared with a single injury, but the mechanism of this phenomenon is unclear. We have previously shown that mild TBI in a rat lateral fluid percussion model results in globally depressed glucose uptake, with a peak depression at 24 h that resolves by 16 days post-injury. The current study investigated the outcomes of a repeat injury conducted at various times during this period of depressed glucose uptake. ⋯ The level of microglial and astrocytic activation also was associated with the timing of the second impact. Finally, rmTBI with latencies of 24 h and 5 days showed significant alterations in [(18)F]fluorodeoxyglucose uptake, compared with baseline scans. Therefore, we conclude that the state of the metabolic environment, as indicated by FDG-PET at the time of the repeat injury, significantly influences neurological outcomes.
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Journal of neurotrauma · Aug 2016
Autophagy modulation by lanthionine ketimine ethyl ester improves long-term outcome following central fluid percussion injury in the mouse.
Diffuse axonal injury is recognized as a progressive and long-term consequence of traumatic brain injury. Axonal injury can have sustained negative consequences on neuronal functions such as anterograde and retrograde transport and cellular processes such as autophagy that depend on cytoarchitecture and axon integrity. These changes can lead to somatic atrophy and an inability to repair and promote plasticity. ⋯ Lanthionine ketimine ethyl ester, a bioavailable derivative of a natural sulfur amino acid metabolite, has demonstrated effects on autophagy both in vitro and in vivo. Thirty minutes after a moderate central fluid percussion injury and throughout the survival period, lanthionine ketimine ethyl ester was administered, and mice were subsequently evaluated for learning and memory impairments and biochemical and histological changes over a 5-week period. Lanthionine ketimine ethyl ester, which we have shown previously to modulate autophagy markers and alleviate pathology and slow cognitive decline in the 3 × TgAD mouse model, spared cognition and pathology after central fluid percussion injury through a mechanism involving autophagy modulation.
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Journal of neurotrauma · Aug 2016
Intravenous Administration of Simvastatin improves Cognitive Outcome following Severe Traumatic Brain Injury in Rats.
Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor commonly used to reduce serum cholesterol. The beneficial effects of oral simvastatin have been reported in pre-clinical models of traumatic brain injury (TBI). The current study was designed to evaluate the potential beneficial effects of simvastatin in a model of severe penetrating TBI using an intravenous (IV) route of administration. ⋯ Biomarker and cytokine analysis showed that IV simvastatin significantly reduced GFAP, interleukin (IL)-1α, and IL-17 serum levels by 4.0-, 2.6-, and 7.0-fold, respectively, at 4 h post-injury. Collectively, our results demonstrate that IV simvastatin provides significant protection against injury-induced cognitive dysfunction and reduces TBI-specific biomarker levels. Further research is warranted to identify the optimal dose and therapeutic window for IV delivery of simvastatin in models of severe TBI.
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Journal of neurotrauma · Aug 2016
The Economic Burden of Autonomic Dysreflexia during Hospitalization for Individuals with Spinal Cord Injury.
We sought to determine the economic burden of autonomic dysreflexia (AD) from the perspective of the Canadian healthcare system in a case series of individuals with spinal cord injury (SCI) presenting to emergency care. In doing so, we sought to illustrate the potential return on investments in the translation of evidence-informed practices and developments in the prevention, diagnosis, and management of AD. Activity-based costing methodology was employed to estimate the direct healthcare or hospitalization costs of AD following presentation to the emergency department. ⋯ Emergency room admissions resulting from AD can result in dramatic healthcare costs. Delayed diagnosis and inefficient management of AD may lead to further complications, adding to the strain on already limited healthcare resources. Prompt recognition of AD; broader translation of evidence-informed practices; and novel diagnosis, self-management, and/or therapeutic/pharmaceutical applications may prove to mitigate the burden of AD and improve patient well-being.