Journal of neurotrauma
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Journal of neurotrauma · Jun 2019
A Novel Role for the Endocannabinoid System in Ameliorating Motivation for Alcohol Drinking and Negative Behavioral Affect Following Traumatic Brain Injury in Rats.
Traumatic brain injury (TBI) is associated with psychiatric dysfunction-including pain, cognitive impairment, anxiety, and increased alcohol use. We previously demonstrated that inhibiting endocannabinoid degradation post-TBI with JZL184 attenuates neuroinflammation and neuronal hyperexcitability at the site of injury and improves neurobehavioral recovery. This study aimed to determine the effect of JZL184 on post-TBI behavioral changes related to psychiatric dysfunction and post-TBI neuroadaptations in brain regions associated with these behaviors. ⋯ JZL184 attenuated post-TBI GR phosphorylation in the CeA. These findings suggest that TBI produces comorbid cognitive dysfunction, increased alcohol motivation, and anxiety-like behavior, possibly related to amygdala dysfunction, and these changes are prevented by systemic post-TBI endocannabinoid degradation inhibition. Thus, boosting endocannabinoid tone post-TBI may represent a viable therapeutic strategy for TBI-related psychiatric comorbidities such as alcohol use disorder and anxiety.
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Journal of neurotrauma · Jun 2019
4-Phenylbutyrate Ameliorates Anxiety Disorder by Inhibiting Endoplasmic Reticulum Stress after Diffuse Axonal Injury.
Diffuse axonal injury (DAI) is accompanied frequently by adverse sequelae and psychiatric disorders, such as anxiety, leading to a decreased quality of life, social isolation, and poor outcomes in patients. The mechanisms regulating psychiatric disorders post-DAI are not well elucidated, however. Previous studies showed that endoplasmic reticulum (ER) stress functions as a pivotal factor in neurodegeneration disease. ⋯ Treatment with 4-phenylbutyrate (4-PBA) is able to inhibit the UPR and cell apoptosis and relieve the anxiety disorder in our DAI model. Later (14 days post-DAI) 4-PBA treatment, however, can restore only the related gene expression of ER stress and UPR but not the psychiatric disorder. Therefore, the early (5 min after DAI) administration of 4-PBA might be a therapeutic approach for blocking the ER stress/UPR-induced cell death and anxiety disorder after DAI.
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Journal of neurotrauma · Jun 2019
Inhibition of Glycogen Synthase Kinase 3β as a Treatment for the Prevention of Cognitive Deficits after a Traumatic Brain Injury.
Traumatic brain injury (TBI) has many long-term consequences, including impairment in memory and changes in mood. Glycogen synthase kinase 3β (GSK-3β) in its phosphorylated form (p-GSK-3β) is considered to be a major contributor to memory problems that occur post-TBI. We have developed an antisense that targets the GSK-3β (GAO) gene. ⋯ Mice were euthanized at 4 and 72 h post-TBI. Analysis of p-ser9GSK-3β, p-tyr216GSK-3β, and phospho-tau (p-tau)404 showed that mice that received a TBI+RAO had significantly higher p-ser9GSK-3β, p-tyr216GSK-3β, and p-tau404 levels than the mice that received TBI+GAO and the Sham+RAO mice. The current finding suggests that inhibiting GSK-3β increase after TBI with an antisense directed at GSK-3β prevents learning and memory impairments.
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Journal of neurotrauma · Jun 2019
Quantifying the Effect of Repeated Impacts and Lateral Tip Movements on Brain Responses during Controlled Cortical Impact.
Controlled cortical impact (CCI) is a widely used laboratory neurotrauma model to study traumatic brain injury. During CCI, the brain is damaged by an impactor tip, which travels along its axial direction to a pre-defined depth at a pre-set speed. A recent study, however, using high-speed imaging analysis demonstrated that the impactor tip of an electromagnetically driven CCI device experienced repeated impacts and lateral movements, rather than a single axial impact. ⋯ We found that the repeated impacts had minimal effect on peak strains. The lateral movements of the tip, however, greatly increased brain strains and affected large brain regions. Hence, it is necessary to monitor and control lateral movements to ensure the accuracy and reproducibility of CCI.
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Journal of neurotrauma · Jun 2019
ReviewHow to Translate Time; the Temporal Aspects of Rodent and Human Pathobiological Processes in Traumatic Brain Injury.
Traumatic brain injury (TBI) triggers multiple pathobiological responses with differing onsets, magnitudes, and durations. Identifying the therapeutic window of individual pathologies is critical for successful pharmacological treatment. Dozens of experimental pharmacotherapies have been successfully tested in rodent models, yet all of them (to date) have failed in clinical trials. ⋯ Limitations toward determining conversion rates for various pathobiological processes include the use of differing outcome measures in experimental and clinical TBI studies and the rarity of longitudinal studies. In order to better translate time and close the translational gap, we suggest 1) using clinically relevant outcome measures, primarily in vivo imaging and blood-based proteomics, in experimental TBI studies and 2) collecting data at multiple post-injury time points with a frequency exceeding the expected information content by two or three times. Combined with a big data approach, we believe these measures will facilitate the translation of promising experimental treatments into clinical use.