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Ferroptosis Contributes to Neuronal Death and Functional Outcome After Traumatic Brain Injury.

ABSTRACT: OBJECTIVES:Traumatic brain injury triggers multiple cell death pathways, possibly including ferroptosis-a recently described cell death pathway that results from accumulation of 15-lipoxygenase-mediated lipid oxidation products, specifically oxidized phosphatidylethanolamine containing arachidonic or adrenic acid. This study aimed to investigate whether ferroptosis contributed to the pathogenesis of in vitro and in vivo traumatic brain injury, and whether inhibition of 15-lipoxygenase provided neuroprotection. DESIGN:Cell culture study and randomized controlled animal study. SETTING:University research laboratory. SUBJECTS:HT22 neuronal cell line and adult male C57BL/6 mice. INTERVENTIONS:HT22 cells were subjected to pharmacologic induction of ferroptosis or mechanical stretch injury with and without administration of inhibitors of ferroptosis. Mice were subjected to sham or controlled cortical impact injury. Injured mice were randomized to receive vehicle or baicalein (12/15-lipoxygenase inhibitor) at 10-15 minutes postinjury. MEASUREMENTS AND MAIN RESULTS:Pharmacologic inducers of ferroptosis and mechanical stretch injury resulted in cell death that was rescued by prototypical antiferroptotic agents including baicalein. Liquid chromatography tandem-mass spectrometry revealed the abundance of arachidonic/adrenic-phosphatidylethanolamine compared with other arachidonic/adrenic acid-containing phospholipids in the brain. Controlled cortical impact resulted in accumulation of oxidized phosphatidylethanolamine, increased expression of 15-lipoxygenase and acyl-CoA synthetase long-chain family member 4 (enzyme that generates substrate for the esterification of arachidonic/adrenic acid into phosphatidylethanolamine), and depletion of glutathione in the ipsilateral cortex. Postinjury administration of baicalein attenuated oxidation of arachidonic/adrenic acid-containing-phosphatidylethanolamine, decreased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells in the hippocampus, and improved spatial memory acquisition versus vehicle. CONCLUSIONS:Biomarkers of ferroptotic death were increased after traumatic brain injury. Baicalein decreased ferroptotic phosphatidylethanolamine oxidation and improved outcome after controlled cortical impact, suggesting that 15-lipoxygenase pathway might be a valuable therapeutic target after traumatic brain injury.

SUBMITTER: Kenny EM

PROVIDER: S-EPMC6449247 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Ferroptosis Contributes to Neuronal Death and Functional Outcome After Traumatic Brain Injury.

Kenny Elizabeth M EM Fidan Emin E Yang Qin Q Anthonymuthu Tamil S TS New Lee Ann LA Meyer Elizabeth A EA Wang Hong H Kochanek Patrick M PM Dixon C Edward CE Kagan Valerian E VE Bayir Hülya H

Critical care medicine 20190301 3

<h4>Objectives</h4>Traumatic brain injury triggers multiple cell death pathways, possibly including ferroptosis-a recently described cell death pathway that results from accumulation of 15-lipoxygenase-mediated lipid oxidation products, specifically oxidized phosphatidylethanolamine containing arachidonic or adrenic acid. This study aimed to investigate whether ferroptosis contributed to the pathogenesis of in vitro and in vivo traumatic brain injury, and whether inhibition of 15-lipoxygenase pr ...[more]

PMID: 30531185

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Project description:ProblemUninterrupted nighttime sleep is associated with better cognition and functional outcomes in healthy adults, but the relationship between sleep and functional outcome in individuals hospitalized with severe traumatic brain injury (TBI) remains to be clarified.ObjectiveThe aims of this study were to (1) describe nighttime rest-activity variables-wake bouts (counts), total wake time (minutes), and sleep efficiency (SE) (percentage; time asleep/time in bed)-in people on a neuroscience step-down unit (NSDU) post-TBI and (2) describe the association between injury and nighttime rest-activity on post-TBI functional outcome (using Functional Independence Measure [FIM] at discharge from inpatient care).MethodsThis study is a cross-sectional, descriptive pilot study. We recruited participants from the NSDU (n = 17 [age: mean (SD), 63.4 (17.9)]; 82% male, 94% white) who wore wrist actigraphy (source of nighttime rest-activity variables) for up to 5 nights. For injury variables, we used Glasgow Coma Scale (GCS) score and Injury Severity Score (ISS). We used Spearman ρ and regression to measure associations.ResultsGlasgow Coma Scale mean (SD) score was 8.8 (4.9), ISS mean (SD) score was 23.6 (6.7), and FIM mean (SD) score was 48 (14.5). Averages of nighttime rest-activity variables (8 PM-7 AM) were as follows: SE, 73% (SD, 16); wake bouts, 41 counts (SD, 18); total wake time, 74 minutes (SD, 47). Correlations showed significance between FIM and GCS (P = .005) and between SE and GCS (P = .015). GCS was the only statistically significant variable associated with FIM (P = .013); we eliminated other variables from the model as nonsignificant (P > .10). Sleep efficiency and FIM association was nonsignificant (P = .40). In a separate model (ISS, GCS, and SE [dependent variable]), GCS was significant (P = .04), but ISS was not (P = .25).ConclusionPatients with severe TBI on the NSDU have poor actigraphic sleep at night. GCS has a stronger association to functional outcome than nighttime rest-activity variables.

Project description:ImportanceIntracranial pressure (ICP) monitoring is a mainstay of therapy for children with traumatic brain injury (TBI), but its overall association with patient outcome is unclear.ObjectiveTo test the hypothesis that ICP monitoring is associated with improved functional survival of children with severe TBI.Design, setting, and participantsA propensity-weighted effectiveness analysis was conducted using 2 linked national databases with data from 30 US children's hospitals from January 1, 2007, to December 31, 2012, on 3084 children with severe TBI. Clinical events including neurosurgical procedures were identified using validated computable phenotypes. Data analysis was conducted from September 1, 2016, to March 1, 2017.ExposurePlacement of an ICP monitor.Main outcomes and measuresA composite of hospital mortality, discharge to hospice, or survival with placement of new tracheostomy and gastrostomy tubes.ResultsOf the 3084 children in the study (1128 girls and 1956 boys; mean [SD] age, 7.03 [5.44] years), 1002 (32.4%) underwent ICP monitoring, with substantial hospital variation (6% to 50% by hospital). Overall, 484 children (15.7%) experienced the primary composite outcome. A propensity approach using matching weights generated good covariate balance between those who did and those who did not undergo ICP monitoring. Using a propensity-weighted logistic regression model clustered by hospital, no statistically significant difference was found in functional survival between monitored and unmonitored patients (odds ratio of poor outcome among those who underwent ICP monitoring, 1.31; 95% CI, 0.99-1.74). In a prespecified secondary analysis, no difference in mortality was found (odds ratio, 1.16; 95% CI, 0.89-1.50). Prespecified subgroup analyses of children younger and older than 2 years of age and among those with unintentional and inflicted (intentional) injuries also showed no difference in outcome with ICP monitoring.Conclusions and relevanceWith the use of linked national data and validated computable phenotypes, no evidence was found of a benefit from ICP monitoring on functional survival of children with severe TBI. Intracranial pressure monitoring is a widely but inconsistently used technology with incompletely demonstrated effectiveness. A large prospective cohort study or randomized trial is needed.

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Ferroptosis Contributes to Neuronal Death and Functional Outcome After Traumatic Brain Injury.

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Ferroptosis Contributes to Neuronal Death and Functional Outcome After Traumatic Brain Injury.

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