Journal of neurotrauma
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Journal of neurotrauma · Feb 2019
Inhaled Nitric Oxide Protects Cerebral Autoregulation and Reduces Hippocampal Neuronal Cell Necrosis after Traumatic Brain Injury in Newborn and Juvenile Pigs.
Traumatic brain injury (TBI) contributes to morbidity in children, and boys are disproportionately represented. Cerebral blood flow (CBF) is reduced and autoregulation is impaired after TBI, contributing to poor outcome. Cerebral perfusion pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP). ⋯ Protection lasted for at least 2 h after iNO administration was stopped. Papaverine-induced dilation was unchanged by TBI and iNO. These data indicate that iNO offers the opportunity to have a single therapeutic that uniformly protects autoregulation and limits hippocampal neuronal cell necrosis across both ages and sexes.
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Journal of neurotrauma · Feb 2019
Chronic White Matter Degeneration, but No Tau Pathology at One-Year Post-Repetitive Mild Traumatic Brain Injury in a Tau Transgenic Model.
Tau pathology associated with chronic traumatic encephalopathy has been documented in the brains of individuals with a history of repetitive mild traumatic brain injury (r-mTBI). At this stage, the pathobiological role of tau in r-mTBI has not been extensively explored in appropriate pre-clinical models. Here, we describe the acute and chronic behavioral and histopathological effects of single and repetitive mild TBI (five injuries given at 48 h intervals) in young adult (3 months old) hTau mice that express all six isoforms of hTau on a null murine tau background. ⋯ Histopathological analyses revealed that hTau mice developed axonal injury, thinning of the corpus callosum, microgliosis and astrogliosis in the white matter at acute and chronic time points after injury. Tau immunohistochemistry and enzyme-linked immunosorbent assay data suggest, however, only transient, injury-dependent increases in phosphorylated tau in the cerebral cortex beneath the impact site and in the CA1/CA3 subregion of the hippocampus after single or r-mTBI. This study implicates white matter degeneration as a prominent feature of survival from mTBI, while the role of tau pathology in the neuropathological sequelae of TBI remains elusive.
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Journal of neurotrauma · Feb 2019
Chemogenomics Systems Pharmacology Mapping of Potential Drug Targets for Treatment of Traumatic Brain Injury.
Traumatic brain injury (TBI) is associated with high mortality and morbidity. Though the death rate of initial trauma has dramatically decreased, no drug has been developed to effectively limit the progression of the secondary injury caused by TBI. TBI appears to be a predisposing risk factor for Alzheimer's disease (AD), whereas the molecular mechanisms remain unknown. ⋯ In particular, our results indicated that TRPV4, NEUROD1, and HPRT1 were among the top therapeutic target candidates for TBI, which are congruent with literature reports. Our analyses also suggested the strong associations between TBI and AD, as perturbations on AD-related genes, such as APOE, APP, PSEN1, and MAPT, can induce similar gene expression patterns as those of TBI. To the best of our knowledge, this is the first CSP-based gene expression profile analyses for predicting TBI-related drug targets, and the findings could be used to guide the design of new drugs targeting the secondary injury caused by TBI.
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Journal of neurotrauma · Feb 2019
Cerebral Edema and Neurological Recovery after Traumatic Brain Injury Are Worsened if Accompanied by a Concomitant Long Bone Fracture.
Progression of severe traumatic brain injury (TBI) is associated with worsening cerebral inflammation, but it is unknown how a concomitant bone fracture (FX) affects this progression. Enoxaparin (ENX), a low molecular weight heparin often used for venous thromboembolic prophylaxis, decreases penumbral leukocyte (LEU) mobilization in isolated TBI and improves neurological recovery. We investigated if TBI accompanied by an FX worsens LEU-mediated cerebral inflammation and if ENX alters this process. ⋯ IHC demonstrated greatest polymorphonuclear neutrophil (PMN) invasion in CCI+FX in uninjured cerebral territories. A concomitant long bone FX worsens TBI-induced cerebral LEU mobilization, microvascular leakage, and cerebral edema, and impairs neurological recovery at 48 h. ENX suppresses this progression but may increase bleeding.
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Journal of neurotrauma · Feb 2019
Inhibiting High Mobility Group Box-1 Reduces Early Spinal Cord Edema and Attenuates Astrocyte Activation and Aquaporin-4 Expression after Spinal Cord Injury in Rats.
High mobility group box-1 (HMGB1) could function as an early trigger for pro-inflammatory activation after spinal cord injury (SCI). Spinal cord edema contributes to inflammatory response mechanisms and a poor clinical prognosis after SCI, for which efficient therapies targeting the specific molecules involved remain limited. This study was designed to evaluate the roles of HMGB1 on the regulation of early spinal cord edema, astrocyte activation, and aquaporin-4 (AQP4) expression in a rat SCI model. ⋯ HMGB1 inhibition decreased SCI-associated GFAP and AQP4 overexpression in the spinal cord. Further, HMGB1 inhibition also repressed the activation of the toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-kappa B signaling pathway. These results implicate that HMGB1 inhibition improved locomotor function and reduced early spinal cord edema, which was associated with a downregulation of astrocyte activation (GFAP expression) and AQP4 expression in SCI rats.