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
Temporal Neurophysiological Dynamics in Traumatic Brain Injury: Role of Pressure Reactivity and Optimal Cerebral Perfusion Pressure for Predicting Outcome.
Intracranial pressure (ICP), cerebral perfusion pressure (CPP), and the pressure reactivity index (PRx) have been shown to correlate with outcome after traumatic brain injury (TBI), but their temporal evolution is less studied. Optimal CPP (CPPopt; i.e., the CPP with the lowest [optimal] PRx value) has been proposed as a dynamic, individualized CPP target. Our aim was to map the temporal course of these parameters and their relation to outcome, in particular the extent and impact of CPP insults based both on fixed CPP thresholds and on divergence from CPPopt. ⋯ PRx was significant when PRx55-15 was excluded. High PRx55-15 and high grade of monitoring time with CPP > CPPopt, but not the traditional fixed CPP thresholds, were strong predictors for worse clinical outcome. The study supports the concept that CPPopt is an important parameter in TBI management.
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Journal of neurotrauma · Jun 2019
Age moderates the effects of traumatic brain injury on beta-amyloid plaque load in APP/PS1 mice.
Traumatic brain injury (TBI) has been identified as a risk factor for Alzheimer's disease (AD). However, how such neural damage contributes to AD pathology remains unclear; specifically, the relationship between the timing of a TBI relative to aging and the onset of AD pathology is not known. In this study, we have examined the effect of TBI on subsequent beta-amyloid (Aβ) deposition in APP/PS1 (APPSWE/PSEN1dE9) transgenic mice either before (3 months of age) or after the onset (6 months of age) of plaque pathology. ⋯ No Aβ plaques were present in any WT mice across these conditions. Glial fibrillary acidic protein immunolabeling of astrocytes and ionized calcium-binding adapter molecule 1 immunolabeling of microglial/macrophages was not significantly different (p < 0.05) in injured animals compared to sham mice, or APP/PS1 mice compared to WT mice. The current data indicate that TBI may have differential effects on Aβ plaque deposition depending on the age and the stage of amyloidosis at the time of injury.
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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
Acute Non-Convulsive Status Epilepticus after Experimental Traumatic Brain Injury in Rats.
Severe traumatic brain injury (TBI) induces seizures or status epilepticus (SE) in 20-30% of patients during the acute phase. We hypothesized that severe TBI induced with lateral fluid-percussion injury (FPI) triggers post-impact SE. Adult Sprague-Dawley male rats were anesthetized with isoflurane and randomized into the sham-operated experimental control or lateral FPI-induced severe TBI groups. ⋯ Interestingly, also a few sham-operated and naïve rats had post-operation seizures, which were not associated with EEG background patterns typical to non-convulsive SE seen in TBI rats. To summarize, our data show that lateral FPI-induced TBI results in non-convulsive SE with subtle behavioral manifestations; this explains why it has remained undiagnosed until now. The lateral FPI model provides a novel platform for assessing the mechanisms of acute symptomatic non-convulsive SE and for testing treatments to prevent post-injury SE in a clinically relevant context.