Journal of neurotrauma
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Journal of neurotrauma · Mar 2014
Reversal of established traumatic brain injury-induced anxiety-like behavior in rats following delayed, post-injury neuroimmune suppression.
Abstract Traumatic brain injury (TBI) increases the risk of neuropsychiatric disorders, particularly anxiety disorders. Yet, there are presently no therapeutic interventions to prevent the development of post-traumatic anxiety or effective treatments once it has developed. This is because, in large part, of a lack of understanding of the underlying pathophysiology. ⋯ We examined the efficacy of an anti-inflammatory treatment in decreasing anxiety-like behavior and reactive gliosis when introduced at 1 month after injury. Delayed treatment substantially reduced established LFPI-induced freezing behavior and reactive gliosis in brain regions associated with anxiety and continued neuroprotective effects were evidenced 6 months post-treatment. These results support the conclusion that neuroinflammation may be involved in the development and maintenance of anxiety-like behaviors after TBI.
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Journal of neurotrauma · Mar 2014
The Cysteine Protease Cathepsin B is a Key Drug Target and Cysteine Protease Inhibitors are Potential Therapeutics for Traumatic Brain Injury.
There are currently no effective therapeutic agents for traumatic brain injury (TBI), but drug treatments for TBI can be developed by validation of new drug targets and demonstration that compounds directed to such targets are efficacious in TBI animal models using a clinically relevant route of drug administration. The cysteine protease, cathepsin B, has been implicated in mediating TBI, but it has not been validated by gene knockout (KO) studies. Therefore, this investigation evaluated mice with deletion of the cathepsin B gene receiving controlled cortical impact TBI trauma. ⋯ E64d treatment was effective even when administered 8 h after injury, indicating a clinically plausible time period for acute therapeutic intervention. These data demonstrate that a cysteine protease inhibitor can be orally efficacious in a TBI animal model when administered at a clinically relevant time point post-trauma, and that E64d-mediated improvement of TBI is primarily the result of inhibition of cathepsin B activity. These results validate cathepsin B as a new TBI therapeutic target.
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Journal of neurotrauma · Mar 2014
Correlations between blood-brain barrier disruption and neuroinflammation in an experimental model of penetrating ballistic-like brain injury.
Abstract Blood-brain barrier (BBB) disruption is a pathological hallmark of severe traumatic brain injury (TBI) and is associated with neuroinflammatory events contributing to brain edema and cell death. The goal of this study was to elucidate the profile of BBB disruption after penetrating ballistic-like brain injury (PBBI) in conjunction with changes in neuroinflammatory markers. Brain uptake of biotin-dextran amine (BDA; 3 kDa) and horseradish peroxidase (HRP; 44 kDa) was evaluated in rats at 4 h, 24 h, 48 h, 72 h, and 7 days post-PBBI and compared with the histopathologic and molecular profiles for inflammatory markers. ⋯ This profile was most closely associated with markers for adhesion (mRNA for intercellular adhesion molecule-1) and infiltration of peripheral granulocytes (mRNA for matrix metalloproteinase-9 [MMP-9] and myeloperoxidase staining). Improvement of BBB dysfunction coincided with increased expression of markers implicated in tissue remodeling and repair. The results of this study reveal a uniphasic and gradient opening of the BBB after PBBI and suggest MMP-9 and resident inflammatory cell activation as candidates for future neurotherapeutic intervention after PBBI.
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Journal of neurotrauma · Mar 2014
Infection Rates and Associated Factors In Pediatric Severe Traumatic Brain Injury.
Abstract Infections can increase medical costs and worsen patient outcomes. Our aims in pediatric severe traumatic brain injury (sTBI) patients were to determine the infection and fever rates, and to report on associated clinical, imaging, treatment, and outcome factors. We included 180 sTBI patients (presedation Glasgow Coma Scale ≤ 8 and Maximum Abbreviated Injury Scale ≥ 4) admitted to our pediatric intensive care unit. ⋯ In summary, infections were prevalent in sTBI patients and were associated with greater head-imaging abnormalities and use of ICP-lowering therapies. Hypertonic saline administration was strongly associated with infection, but further analyses are required to determine the nature of this relationship. Fever was a poor indicator of infection after sTBI.