Modeling clinically relevant blast parameters based on scaling principles produces functional &amp; histological deficits in rats

Turner, Ryan C.; Naser, Zachary J.; Logsdon, Aric F.; DiPasquale, Kenneth; Jackson, Garrett J.; Robson, Matthew J.; Gettens, Robert; Matsumoto, Rae R.; Huber, Jason D.; Rosen, Charles L.

doi:10.1016/j.expneurol.2013.07.008

Cited by 59 publications

(86 citation statements)

References 40 publications

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“…Vascular pathology is a well-recognized component of nb-TBI [24] and high-level blast exposure seems particularly prone to inducing hemorrhagic lesions in humans [25, 26]. Intracranial hemorrhage, altered blood/brain permeability or other forms of vascular pathology have been commented on in a number of studies of experimental blast exposure in animals [6, 10, 27–42]. Elevation of serum and CSF biomarkers of vascular related factors have also been described [38, 43–45].…”

Section: Discussionmentioning

confidence: 99%

Selective vulnerability of the cerebral vasculature to blast injury in a rat model of mild traumatic brain injury

Sosa

Gasperi

Janssen

et al. 2014

acta neuropathol commun

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BackgroundBlast-related traumatic brain injury (TBI) is a common cause of injury in the military operations in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. The aim of the present study was to examine whether blast exposure affects the cerebral vasculature in a rodent model. We analyzed the brains of rats exposed to single or multiple (three) 74.5 kPa blast exposures, conditions that mimic a mild TBI. Rats were sacrificed 24 hours or between 6 and 10 months after exposure. Blast-induced cerebral vascular pathology was examined by a combination of light microscopy, immunohistochemistry, and electron microscopy.ResultsWe describe a selective vascular pathology that is present acutely at 24 hours after injury. The vascular pathology is found at the margins of focal shear-related injuries that, as we previously showed, typically follow the patterns of penetrating cortical vessels. However, changes in the microvasculature extend beyond the margins of such lesions. Electron microscopy revealed that microvascular pathology is found in regions of the brain with an otherwise normal neuropil. This initial injury leads to chronic changes in the microvasculature that are still evident many months after the initial blast exposure.ConclusionsThese studies suggest that vascular pathology may be a central mechanism in the induction of chronic blast-related injury.

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Section: Discussionmentioning

confidence: 99%

Selective vulnerability of the cerebral vasculature to blast injury in a rat model of mild traumatic brain injury

Sosa

Gasperi

Janssen

et al. 2014

acta neuropathol commun

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“…Using our clinically relevant and validated blast model [29], we observed statistically significant acute changes in BBB permeability 6 h after a single blast exposure. Interestingly, the PKC modulator bryostatin-1 reduced BBB permeability, decreased levels of the detrimental PKCα isozyme, and increased the beneficial PKCε isozyme.…”

Section: Introductionmentioning

confidence: 99%

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury

et al. 2014

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Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the ‘signature injury’ of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague–Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan’s blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan’s blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t=4.808, p<0.05), and a reduction back toward control levels when bryostatin-1 was administered (t=5.113, p<0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t=4.559, p<0.01) and increased the neuroprotective isozyme PKCε (t=6.102, p<0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.

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“…41,54 Briefly, to remove paraffin, slides were washed for 5 minutes in xylene, 100% EtOH, and 95% EtOH followed by 5-minute rehydration in dH 2 O. The slides were then quenched with 10% methanol and 10% H 2 O 2 in Dulbecco's phosphate-buffered saline (PBS) for 15 minutes.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Blast exposures were generated using a novel shock tube described in our prior work. 54 The shock tube was designed with a short driver section to generate a shortduration wave, a characteristic deemed clinically relevant based on extensive work demonstrating scaling principles associated with blast across species. The overpressure was recorded using piezoelectric sensors (Model 102AO5; PCB Piezotronics) placed in the reflected and incident positions at the exit of the shock tube.…”

Section: Blast Exposurementioning

confidence: 99%

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

Lucke‐Wold

Turner

Logsdon

et al. 2016

JNS

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abbreviatioNs ATF6 = activating transcription factor 6; BiP = binding immunoglobulin protein; CHOP = C/EBP homology protein; CTE = chronic traumatic encephalopathy; DAB = diaminobenzidine; DHA = docosahexaenoic acid; ER = endoplasmic reticulum; GADD34 = growth arrest and DNA damage-inducible protein 34; GSK3b = glycogen synthase kinase-3b; IHC = immunohistochemistry; IRE1a = inositol requiring enzyme 1a; JNK = c-Jun N-terminal kinase; NFL = National Football League; PBS = phosphate-buffered saline; PERK = protein kinase RNA-like ER kinase; PHF = paired helical filament; p-eIF2a = phosphorylated eukaryotic initiation factor 2a; TBI = traumatic brain injury; WWE = World Wrestling Entertainment; XBP1 = X-box binding protein 1. obJective Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. methods The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. results The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3b. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p < 0.05), improved cognition (t = 6.532, p < 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p < 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy. coNclusioNs Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.

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Modeling clinically relevant blast parameters based on scaling principles produces functional & histological deficits in rats

Cited by 59 publications

References 40 publications

Selective vulnerability of the cerebral vasculature to blast injury in a rat model of mild traumatic brain injury

Selective vulnerability of the cerebral vasculature to blast injury in a rat model of mild traumatic brain injury

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

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