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Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1.

ABSTRACT: Axonal degeneration is a critical, early event in many acute and chronic neurological disorders. It has been consistently observed after traumatic brain injury, but whether axon degeneration is a driver of traumatic brain injury remains unclear. Molecular pathways underlying the pathology of traumatic brain injury have not been defined, and there is no efficacious treatment for traumatic brain injury. Here we show that mice lacking the mouse Toll receptor adaptor Sarm1 (sterile ?/Armadillo/Toll-Interleukin receptor homology domain protein) gene, a key mediator of Wallerian degeneration, demonstrate multiple improved traumatic brain injury-associated phenotypes after injury in a closed-head mild traumatic brain injury model. Sarm1(-/-) mice developed fewer ?-amyloid precursor protein aggregates in axons of the corpus callosum after traumatic brain injury as compared to Sarm1(+/+) mice. Furthermore, mice lacking Sarm1 had reduced plasma concentrations of the phophorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after traumatic brain injury. Strikingly, whereas wild-type mice exibited a number of behavioural deficits after traumatic brain injury, we observed a strong, early preservation of neurological function in Sarm1(-/-) animals. Finally, using in vivo proton magnetic resonance spectroscopy we found tissue signatures consistent with substantially preserved neuronal energy metabolism in Sarm1(-/-) mice compared to controls immediately following traumatic brain injury. Our results indicate that the SARM1-mediated prodegenerative pathway promotes pathogenesis in traumatic brain injury and suggest that anti-SARM1 therapeutics are a viable approach for preserving neurological function after traumatic brain injury.

SUBMITTER: Henninger N

PROVIDER: S-EPMC5006226 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1.

Henninger Nils N Bouley James J Sikoglu Elif M EM An Jiyan J Moore Constance M CM King Jean A JA Bowser Robert R Freeman Marc R MR Brown Robert H RH

Brain : a journal of neurology 20160211 Pt 4

Axonal degeneration is a critical, early event in many acute and chronic neurological disorders. It has been consistently observed after traumatic brain injury, but whether axon degeneration is a driver of traumatic brain injury remains unclear. Molecular pathways underlying the pathology of traumatic brain injury have not been defined, and there is no efficacious treatment for traumatic brain injury. Here we show that mice lacking the mouse Toll receptor adaptor Sarm1 (sterile α/Armadillo/Toll- ...[more]

PMID: 26912636

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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:Poor outcomes after traumatic brain injury (TBI) are common yet remain difficult to predict. Diffuse axonal injury is important for outcomes, but its assessment remains limited in the clinical setting. Currently, axonal injury is diagnosed based on clinical presentation, visible damage to the white matter or via surrogate markers of axonal injury such as microbleeds. These do not accurately quantify axonal injury leading to misdiagnosis in a proportion of patients. Diffusion tensor imaging provides a quantitative measure of axonal injury in vivo, with fractional anisotropy often used as a proxy for white matter damage. Diffusion imaging has been widely used in TBI but is not routinely applied clinically. This is in part because robust analysis methods to diagnose axonal injury at the individual level have not yet been developed. Here, we present a pipeline for diffusion imaging analysis designed to accurately assess the presence of axonal injury in large white matter tracts in individuals. Average fractional anisotropy is calculated from tracts selected on the basis of high test-retest reliability, good anatomical coverage and their association to cognitive and clinical impairments after TBI. We test our pipeline for common methodological issues such as the impact of varying control sample sizes, focal lesions and age-related changes to demonstrate high specificity, sensitivity and test-retest reliability. We assess 92 patients with moderate-severe TBI in the chronic phase (≥6 months post-injury), 25 patients in the subacute phase (10 days to 6 weeks post-injury) with 6-month follow-up and a large control cohort (n = 103). Evidence of axonal injury is identified in 52% of chronic and 28% of subacute patients. Those classified with axonal injury had significantly poorer cognitive and functional outcomes than those without, a difference not seen for focal lesions or microbleeds. Almost a third of patients with unremarkable standard MRIs had evidence of axonal injury, whilst 40% of patients with visible microbleeds had no diffusion evidence of axonal injury. More diffusion abnormality was seen with greater time since injury, across individuals at various chronic injury times and within individuals between subacute and 6-month scans. We provide evidence that this pipeline can be used to diagnose axonal injury in individual patients at subacute and chronic time points, and that diffusion MRI provides a sensitive and complementary measure when compared to susceptibility weighted imaging, which measures diffuse vascular injury. Guidelines for the implementation of this pipeline in a clinical setting are discussed.

Project description: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.

Project description:BackgroundTraumatic brain injury (TBI) is the leading cause of death and disability in children, but effective tools for predicting outcome remain elusive. Although many pediatric patients receive early magnetic resonance imaging (MRI), data on its utility in prognostication are lacking. Diffuse axonal injury (DAI) is a hallmark of TBI detected on early MRI and was shown previously to improve prognostication in adult patients with TBI. In this exploratory study, we investigated whether DAI grade correlates with functional outcome and improves prognostic accuracy when combined with core clinical variables and computed tomography (CT) biomarkers in pediatric patients with moderate-severe TBI (msTBI).MethodsPediatric patients (≤ 19 years) who were admitted to two regional level one trauma centers with a diagnosis of msTBI (Glasgow Coma Scale [GCS] score < 13) between 2011 and 2019 were identified through retrospective chart review. Patients who underwent brain MRI within 30 days of injury and had documented clinical follow-up after discharge were included. Age, pupil reactivity, and initial motor GCS score were collected as part of the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. Imaging was reviewed to calculate the Rotterdam score (CT) and DAI grade (MRI) and to evaluate for presence of hypoxic-ischemic injury (MRI). The primary outcome measure was the Pediatric Cerebral Performance Category Scale (PCPCS) score at 6 months after TBI, with favorable outcome defined as PCPCS scores 1-3 and unfavorable outcome defined as PCPCS scores 4-6. The secondary outcome measure was discharge disposition to home versus to an inpatient rehabilitation facility.ResultOf 55 patients included in the study, 45 (82%) had severe TBI. The most common mechanism of injury was motor vehicle collision (71%). Initial head CT scans showed acute hemorrhage in 84% of patients. MRI was acquired a median of 5 days after injury, and hemorrhagic DAI lesions were detected in 87% of patients. Each 1-point increase in DAI grade increased the odds of unfavorable functional outcome by 2.4-fold. When controlling for core IMPACT clinical variables, neither the DAI grade nor the Rotterdam score was independently correlated with outcome and neither significantly improved outcome prediction over the IMPACT model alone.ConclusionsA higher DAI grade on early MRI is associated with worse 6-month functional outcome and with discharge to inpatient rehabilitation in children with acute msTBI in a univariate analysis but does not independently correlate with outcome when controlling for the GCS score. Addition of the DAI grade to the core IMPACT model does not significantly improve prediction of poor neurological outcome. Further study is needed to elucidate the utility of early MRI in children with msTBI.

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Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1.

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Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1.

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