Abstract
Neuronal injury following blast-induced traumatic brain injury (bTBI) increases the risk for neuropsychiatric disorders, yet the pathophysiology remains poorly understood. Blood-brain-barrier (BBB) disruption, endoplasmic reticulum (ER) stress, and apoptosis have all been implicated in bTBI. Microvessel compromise is a primary effect of bTBI and is postulated to cause subcellular secondary effects such as ER stress. What remains unclear is how these secondary effects progress to personality disorders in humans exposed to head trauma. To investigate this we exposed male rats to a clinically relevant bTBI model we have recently developed. The study examined initial BBB disruption using Evan’s blue (EB), ER stress mechanisms, apoptosis and impulsive-like behavior measured with elevated plus maze (EPM). Large BBB openings were observed immediately following bTBI, and persisted for at least 6 h. Data showed increased mRNA abundance of stress response genes at 3 h, with subsequent increases in the ER stress markers C/EBP homologous protein (CHOP) and growth arrest and DNA damage-inducible protein 34 (GADD34) at 24 h. Caspase-12 and Caspase-3 were both cleaved at 24 h following bTBI. The ER stress inhibitor, salubrinal (SAL), was administered (1 mg/kg i.p.) to investigate its effects on neuronal injury and impulsive-like behavior associated with bTBI. SAL reduced CHOP protein expression, and diminished Caspase-3 cleavage, suggesting apoptosis attenuation. Interestingly, SAL also ameliorated impulsive-like behavior indicative of head trauma. These results suggest SAL plays a role in apoptosis regulation and the pathology of chronic disease. These observations provide evidence that bTBI involves ER stress and that the unfolded protein response (UPR) is a promising molecular target for the attenuation of neuronal injury.
Highlights
Blast-induced traumatic brain injury has been described as the “hallmark injury” of recent wars in Iraq and Afghanistan (Goldstein et al, 2012)
BLAST EXPOSURE IMPARTS APPARENT CONTRA COUP blood-brain barrier (BBB) DISRUPTION The suggestion has been made previously that BBB disruption, or loss of micro-vessel endothelium integrity, may be an inciting event for the molecular changes frequently induced following neurotrauma (Abdul-Muneer et al, 2013; Arun et al, 2013). This may be relevant in models of blast injury in which a pressure wave, and associated surge in vascular flow to the brain, may induce microvascular changes manifested as BBB disruption (Sosa et al, 2013)
Impulsive-like behavior, a neuropsychiatric symptom associated with prefrontal cortex (PFC) damage (Johnson et al, 2013), was demonstrated by rats exposed to Blast-induced traumatic brain injury (bTBI) through their increased exploration in the open arms of the elevated plus maze (EPM)
Summary
Blast-induced traumatic brain injury (bTBI) has been described as the “hallmark injury” of recent wars in Iraq and Afghanistan (Goldstein et al, 2012). Many blast exposures cause concussive or sub-concussive brain damage and are associated with the shearing of axons (Rosenfeld and Ford, 2010) and the compromise of brain micro-vessels (Chen et al, 2013a). Often these injuries go undetected in soldiers and civilians due to poor understanding of the underlying mechanisms of blast injury and the diagnostic limitations preventing the detection of pathophysiologic changes in living patients (Stern et al, 2011).
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