Zinc in traumatic brain injury

Morris, Deborah R.; Levenson, Cathy W.

doi:10.1097/mco.0b013e328364f39c

Cited by 25 publications

(12 citation statements)

References 15 publications

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“…Specifically, our finding of a reduction in the membrane-associated ring finger (C3HC4) 8, E3 ubiquitin protein ligase ( MARCH8 ) as well as tripartite motif containing 58 (TRIM58) in military personnel with blast-TBI suggest that adequate functionality of the ubiquitin proteasome is essential for recovery from blast-TBI. Protein ubiquitination protects neurons from the detrimental impact of accumulating reactive oxygen, nitrogen species, and free release of zinc initiates ( 28 ) by initiating the removal of oxidized or misfolded proteins that result following injury ( 18 ). In fact, higher concentrations of the protein encoded by UBC-terminal hydrolase-L1 is one of the primary proteomic biomarkers of acute TBI ( 29 – 31 ), with high concentrations being related to the onset of chronic symptoms in pediatric patients ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Military Personnel with Chronic Symptoms Following Blast Traumatic Brain Injury Have Differential Expression of Neuronal Recovery and Epidermal Growth Factor Receptor Genes

et al. 2014

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Objective: Approximately one-quarter of military personnel who deployed to combat stations sustained one or more blast-related, closed-head injuries. Blast injuries result from the detonation of an explosive device. The mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI), and place military personnel at high risk for chronic symptoms of post-concussive disorder (PCD), post-traumatic stress disorder (PTSD), and depression are not elucidated.Methods: To investigate the mechanisms of persistent blast-related symptoms, we examined expression profiles of transcripts across the genome to determine the role of gene activity in chronic symptoms following blast-TBI. Active duty military personnel with (1) a medical record of a blast-TBI that occurred during deployment (n = 19) were compared to control participants without TBI (n = 17). Controls were matched to cases on demographic factors including age, gender, and race, and also in diagnoses of sleep disturbance, and symptoms of PTSD and depression. Due to the high number of PCD symptoms in the TBI+ group, we did not match on this variable. Using expression profiles of transcripts in microarray platform in peripheral samples of whole blood, significantly differentially expressed gene lists were generated. Statistical threshold is based on criteria of 1.5 magnitude fold-change (up or down) and p-values with multiple test correction (false discovery rate <0.05).Results: There were 34 transcripts in 29 genes that were differentially regulated in blast-TBI participants compared to controls. Up-regulated genes included epithelial cell transforming sequence and zinc finger proteins, which are necessary for astrocyte differentiation following injury. Tensin-1, which has been implicated in neuronal recovery in pre-clinical TBI models, was down-regulated in blast-TBI participants. Protein ubiquitination genes, such as epidermal growth factor receptor, were also down-regulated and identified as the central regulators in the gene network determined by interaction pathway analysis.Conclusion: In this study, we identified a gene-expression pathway of delayed neuronal recovery in military personnel a blast-TBI and chronic symptoms. Future work is needed to determine if therapeutic agents that regulate these pathways may provide novel treatments for chronic blast-TBI-related symptoms.

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Section: Discussionmentioning

confidence: 99%

Military Personnel with Chronic Symptoms Following Blast Traumatic Brain Injury Have Differential Expression of Neuronal Recovery and Epidermal Growth Factor Receptor Genes

et al. 2014

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“…The role of Zn in TBI has been heavily scrutinized over the past several years [16,27,31,60,61], with studies indicating both protective [25,26,62] and toxic [63] roles in TBI outcomes. Although trehalose revealed no observable modulation of Zn, it should be noted that while LA-ICPMS imaging provides informative quantitation of metals on the mesoscale, it is likely that a higher resolution of analysis than the one utilized may be required to visualize the cellular translocation of Zn, that is an observed consequence of TBI [63,64].…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, the biological transition metals iron (Fe) [17,18,22], copper (Cu) [18,23], and zinc (Zn) [16,24–28] have been implicated as having critical roles in TBI. Moreover, these metals have also been proposed to have integral roles in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD) [29–31], Parkinson’s disease (PD) [32] and Amyotrophic Lateral Sclerosis (ALS) [33], conditions which may all be predated by a history of TBI [34–36].…”

Section: Introductionmentioning

confidence: 99%

Trehalose improves traumatic brain injury-induced cognitive impairment

et al. 2017

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Traumatic brain Injury (TBI) is a significant cause of death and long-term disability for which there are currently no effective pharmacological treatment options. In this study then, we utilized a mouse model of TBI to assess the therapeutic potential of the stable disaccharide trehalose, which is known to protect against oxidative stress, increase levels of chaperone molecules and enhance autophagy. Furthermore, trehalose has demonstrated neuroprotective properties in numerous animal models and has been proposed as a potential treatment for neurodegeneration. As TBI (and associated neurodegenerative disorders) is complicated by a sudden and dramatic change in brain metal concentrations, including iron (Fe) and zinc (Zn), the collective accumulation and translocation of which has been hypothesized to contribute to the pathogenesis of TBI, then we also sought to determine whether trehalose modulated the metal dyshomeostasis associated with TBI. In this study three-month-old C57Bl/6 wildtype mice received a controlled cortical impact TBI, and were subsequently treated for one month with trehalose. During this time animals were assessed on multiple behavioral tasks prior to tissue collection. Results showed an overall significant improvement in the Morris water maze, Y-maze and open field behavioral tests in trehalose-treated mice when compared to controls. These functional benefits occurred in the absence of any change in lesion volume or any significant modulation of biometals, as assessed by laser ablation inductively coupled plasma mass spectrometry. Western blot analysis, however, revealed an upregulation of synaptophysin, doublecortin and brain derived neurotrophic factor protein in trehalose treated mice in the contralateral cortex. These results indicate that trehalose may be efficacious in improving functional outcomes following TBI by a previously undescribed mechanism of action that has relevance to multiple disorders of the central nervous system.

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“…However, it has been shown that excessive release of zinc from synaptic boutons can result in post-synaptic neuronal death, and those neurons in brain regions with high concentrations of free zinc, such as the hippocampus, are thus especially prone to zinc-mediated damage and death. Nevertheless, TBI results in significantly depressed serum zinc levels as well as increased urinary zinc excretion, which is proportional to the severity of brain injury and can reach 14 times normal values, suggesting rapid zinc depletion in sTBI (Morris and Levenson, 2013). As TBI induces various damaging oxidative processes, several studies have shown a role for zinc deficiency in the induction of reactive oxygen species (ROS), thus exacerbating oxidative damage.…”

Section: Nutrition Issuementioning

confidence: 99%

“…After day 15, an oral dose of 22 mg/day was provided. Therefore, considering the scarcity of clinical trials, the existing data strongly suggest that Zn status should be monitored and maintained after a brain injury, not only because of the reported neurocognitive outcomes but also because both Zn deficiency and TBI have been associated with oxidative stress (Cope et al, 2012;Morris and Levenson, 2013).…”

Section: Nutrition Issuementioning

confidence: 99%

Nutrition Therapy, Glucose Control, and Brain Metabolism in Traumatic Brain Injury: A Multimodal Monitoring Approach

Kurtz

Rocha²

2020

Front. Neurosci.

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The goal of neurocritical care in patients with traumatic brain injury (TBI) is to prevent secondary brain damage. Pathophysiological mechanisms lead to loss of body mass, negative nitrogen balance, dysglycemia, and cerebral metabolic dysfunction. All of these complications have been shown to impact outcomes. Therapeutic options are available that prevent or mitigate their negative impact. Nutrition therapy, glucose control, and multimodality monitoring with cerebral microdialysis (CMD) can be applied as an integrated approach to optimize systemic immune and organ function as well as adequate substrate delivery to the brain. CMD allows real-time bedside monitoring of aspects of brain energy metabolism, by measuring specific metabolites in the extracellular fluid of brain tissue. Sequential monitoring of brain glucose and lactate/pyruvate ratio may reveal pathologic processes that lead to imbalances in supply and demand. Early recognition of these patterns may help individualize cerebral perfusion targets and systemic glucose control following TBI. In this direction, recent consensus statements have provided guidelines and recommendations for CMD applications in neurocritical care. In this review, we summarize data from clinical research on patients with severe TBI focused on a multimodal approach to evaluate aspects of nutrition therapy, such as timing and route; aspects of systemic glucose management, such as intensive vs. moderate control; and finally, aspects of cerebral metabolism. Research and clinical applications of CMD to better understand the interplay between substrate supply, glycemic variations, insulin therapy, and their effects on the brain metabolic profile were also reviewed. Novel mechanistic hypotheses in the interpretation of brain biomarkers were also discussed. Finally, we offer an integrated approach that includes nutritional and brain metabolic monitoring to manage severe TBI patients.

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Zinc in traumatic brain injury

Cited by 25 publications

References 15 publications

Military Personnel with Chronic Symptoms Following Blast Traumatic Brain Injury Have Differential Expression of Neuronal Recovery and Epidermal Growth Factor Receptor Genes

Military Personnel with Chronic Symptoms Following Blast Traumatic Brain Injury Have Differential Expression of Neuronal Recovery and Epidermal Growth Factor Receptor Genes

Trehalose improves traumatic brain injury-induced cognitive impairment

Nutrition Therapy, Glucose Control, and Brain Metabolism in Traumatic Brain Injury: A Multimodal Monitoring Approach

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