Journal of neurotrauma
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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.
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Journal of neurotrauma · Feb 2019
Case ReportsClinical and Neurophysiological Changes after Targeted Intrathecal Injections of Bone Marrow Stem Cells in a C3 Tetraplegic Subject.
High-level quadriplegia is a devastating condition with limited treatment options. Bone marrow derived stem cells (BMSCs) are reported to have immunomodulatory and neurotrophic effects in spinal cord injury (SCI). We report a subject with complete C2 SCI who received three anatomically targeted intrathecal infusions of BMSCs under a single-patient expanded access investigational new drug (IND). ⋯ As a single case, the linkage of the clinical and neurophysiological changes to either natural history or to the BMSC infusions cannot be resolved. Nevertheless, such detailed neurophysiological assessment of high cervical SCI patients is rarely performed. Our findings indicate that electrophysiology studies are sensitive to define both residual connectivity and new plasticity.
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Journal of neurotrauma · Feb 2019
Induced NB-3 Limits Regenerative Potential of Serotonergic Axons after Complete Spinal Transection.
NB-3 (contactin-6) is a member of the contactin family and has a wide range of roles during central nervous system development and disease. Here, we found that NB-3 was simultaneously induced in the serotonergic raphespinal tract (sRST) axons and in the scar-forming cells after spinal cord injury (SCI). ⋯ In vivo evidence also suggested that NB-3 induction in both sRST axons and scar-forming cells was required to mediate NB-3 signaling inhibition of sRST axon regeneration after SCI. Our findings suggest that NB-3 protein is a potential molecular target for future SCI treatments.