title: Altering endoplasmic reticulum stress in a model of blast-induced traumatic brain injury controls cellular fate and ameliorates neuropsychiatric symptoms.
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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University Morgantown, WV, USA ; Center for Neuroscience, Health Sciences Center, West Virginia University, Morgantown WV, USA ; Department of Neurosurgery, School of Medicine, West Virginia University, Morgantown WV, USA.
authors.forename: Aric Flint
authors.initials: AF
authors.lastname: Logsdon
authors.affiliation: Center for Neuroscience, Health Sciences Center, West Virginia University, Morgantown WV, USA ; Department of Neurosurgery, School of Medicine, West Virginia University, Morgantown WV, USA.
authors.forename: Ryan Coddington
authors.initials: RC
authors.lastname: Turner
authors.affiliation: Center for Neuroscience, Health Sciences Center, West Virginia University, Morgantown WV, USA ; Department of Neurosurgery, School of Medicine, West Virginia University, Morgantown WV, USA.
authors.forename: Brandon Peter
authors.initials: BP
authors.lastname: Lucke-Wold
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University Morgantown, WV, USA ; Department of Pharmacology, School of Medicine, Vanderbilt University Nashville, TN, USA.
authors.forename: Matthew James
authors.initials: MJ
authors.lastname: Robson
authors.affiliation: Department of Neurosurgery, School of Medicine, West Virginia University, Morgantown WV, USA.
authors.forename: Zachary James
authors.initials: ZJ
authors.lastname: Naser
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University Morgantown, WV, USA.
authors.forename: Kelly Elizabeth
authors.initials: KE
authors.lastname: Smith
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University Morgantown, WV, USA ; Dean's Office, College of Pharmacy, Touro University California Vallejo, CA, USA.
authors.forename: Rae Reiko
authors.initials: RR
authors.lastname: Matsumoto
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University Morgantown, WV, USA ; Center for Neuroscience, Health Sciences Center, West Virginia University, Morgantown WV, USA ; Department of Neurosurgery, School of Medicine, West Virginia University, Morgantown WV, USA.
authors.forename: Jason Delwyn
authors.initials: JD
authors.lastname: Huber
authors.affiliation: Center for Neuroscience, Health Sciences Center, West Virginia University, Morgantown WV, USA ; Department of Neurosurgery, School of Medicine, West Virginia University, Morgantown WV, USA.
authors.forename: Charles Lee
authors.initials: CL
authors.lastname: Rosen
keywords: CHOP; apoptosis; blast-induced traumatic brain injury; blood-brain barrier; endoplasmic reticulum stress; prefrontal cortex; salubrinal