Journal of neurotrauma
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Journal of neurotrauma · Apr 2022
Dysfunctional ER-mitochondrion coupling is associated with ER stress-induced apoptosis and neurological deficits in a rodent model of severe head injury.
Cellular homeostasis requires critical communications between the endoplasmic reticulum (ER) and mitochondria to maintain the viability of cells. This communication is mediated and maintained by the mitochondria-associated membranes and may be disrupted during acute traumatic brain injury (TBI), leading to structural and functional damage of neurons and supporting cells. To test this hypothesis, we subjected male C57BL/6 mice to severe TBI (sTBI) using a controlled cortical impact device. ⋯ This enhanced coupling correlated closely with increases in the expression of the Ca2+ regulatory proteins (inositol 1,4,5-trisphosphate receptor type 1 [IP3R1], voltage-dependent anion channel 1 [VDAC1], glucose-regulated protein 75 [GRP75], Sigma 1 receptor [Sigma-1R]), production of ROS, degree of ER stress, levels of UPR, and release of proinflammatory cytokines. Further, the neurological function of sTBI mice was significantly improved by silencing the gene for the ER-mitochondrion tethering factor PACS2, restoring the IP3R1-GRP75-VDAC1 axis of Ca2+ regulation, alleviating mitochondria-derived oxidative stress, suppressing inflammatory response through the PERK/eIF2α/ATF4/CHOP pathway, and inhibiting ER stress and associated apoptosis. These results indicate that dysfunctional ER-mitochondrion coupling might be primarily involved in the neuronal apoptosis and neurological deficits, and modulating the ER-mitochondrion crosstalk might be a novel therapeutic strategy for sTBI.
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Journal of neurotrauma · Apr 2022
Review Meta AnalysisThe Renin Angiotensin System as a potential treatment target for Traumatic Brain Injury.
Traumatic brain injury (TBI) is a major health concern and leading cause of death and disability in young adults in the United Kingdom and worldwide; however, there is a paucity of disease modifying therapies for the treatment of TBI. This review investigates the potential of the renin-angiotensin system (RAS) as a treatment pathway for TBI in adults. Relevant electronic databases were searched on December 18, 2019, and updated May 16, 2021. ⋯ We conclude that angiotensin-receptor blockers, especially candesartan, show positive outcomes post-TBI in pre-clinical studies with moderate quality of evidence (Grading of Recommendations Assessment, Development and Evaluation [GRADE]). More research into the effect of regulatory-RAS targeting drugs is needed. Clinical trials of candesartan following TBI are recommended, because there is strong and consistent evidence of neuroprotection shown by these pre-clinical studies.
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Journal of neurotrauma · Apr 2022
ReviewA Framework to Advance Biomarker Development in the Diagnosis, Outcome Prediction, and Treatment of Traumatic Brain Injury.
Multi-modal biomarkers (e.g., imaging, blood-based, physiological) of unique traumatic brain injury (TBI) endophenotypes are necessary to guide the development of personalized and targeted therapies for TBI. Optimal biomarkers will be specific, sensitive, rapidly and easily accessed, minimally invasive, cost effective, and bidirectionally translatable for clinical and research use. For both uses, understanding how TBI biomarkers change over time is critical to reliably identify appropriate time windows for an intervention as the injury evolves. ⋯ Prognostic biomarkers that reliably predict outcomes and recovery windows to assess neurodegenerative change and guide decisions for return to play or duty are also important. TBI biomarkers that fill these needs will transform clinical practice and could reduce the patient's risk for long-term symptoms and lasting deficits. This article summarizes biomarkers currently under investigation and outlines necessary steps to achieve short- and long-term goals, including how biomarkers can advance TBI treatment and improve care for patients with TBI.
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Journal of neurotrauma · Apr 2022
Randomized Controlled TrialCervicovestibular Rehabilitation in Adults with Mild Traumatic Brain Injury: A Randomised Clinical Trial.
The objective of this study was to compare the effects of a cervicovestibular rehabilitation program combined with symptom-limited aerobic exercise (SLAE) program to a SLAE program alone in adults with persistent symptoms after mild traumatic brain injury (mTBI) on severity of symptoms and other indicators of clinical recovery. In this single-blind, parallel-group randomized controlled trial, 60 adults with persistent symptoms after mTBI were randomly assigned to: (1) a 6-week SLAE program or (2) a 6-week cervicovestibular rehabilitation program combined with a SLAE program. All participants took part in four evaluation sessions (baseline, week 6, 12, and 26) performed by a blinded evaluator. ⋯ For PCSS, NPRS, NDI, HDI, DHI, and return to function, there were no group-by-time interactions at any time points follow-up (p > 0.05); clinically significant time effects were, however, observed (p < 0.05). There were group-by-time interactions at weeks 6 and 12 for vestibulo-ocular reflex (p < 0.003) and the craniovertebral mobility (p < 0.001) measures in favor of the cervicovestibular rehabilitation group. The study indicates that a cervicovestibular rehabilitation program combined with SLAE was not superior to a SLAE program alone in term of symptoms and functional level improvement but resulted in improved physical cervical and vestibular function.
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Journal of neurotrauma · Apr 2022
Randomized Controlled TrialBrain Injury Effects on Neuronal Activation and Synaptic Transmission in the Basolateral Amygdala (BLA) of Adult Male and Female Wistar Rats.
Traumatic brain injury (TBI) is defined as brain damage produced by an external mechanical force that leads to behavioral, cognitive, and psychiatric sequelae. The basolateral amygdala (BLA) is involved in emotional regulation, and its function and morphology are altered following TBI. Little is known about potential sex-specific effects of TBI on BLA neuronal function, but it is critical for the field to identify potential sex differences in TBI effects on brain and behavior. ⋯ Further, TBI increased spontaneous excitatory and inhibitory postsynaptic current (sEPSC and sIPSC) amplitude in BLA neurons of females relative to all other groups. TBI increased sEPSC frequency in BLA neurons of females relative to males but did not alter sIPSC frequency. In summary, lateral fluid percussion produced different physiological responses in male and female rats, as well as sex-specific alterations in BLA neuronal activation, excitability, and synaptic transmission 1 h after injury.