Citation

Lucke-Wold BP, Logsdon A, Turner RC, Huber JD, Rosen CL. J. Neurotrauma 2017; 34(S1): S62-S70.

Affiliation

West Virginia University, Neurosurgery , 1 Medical Center Drive , Morgantown, West Virginia, United States , 26506-9183 ; crosen@hsc.wvu.edu.

Copyright

(Copyright © 2017, Mary Ann Liebert Publishers)

DOI

10.1089/neu.2016.4680

PMID

28077004

Abstract

Blast traumatic brain injury (bTBI) has been shown to contribute to progressive neurodegenerative disease. Recent evidence suggests that endoplasmic reticulum (ER) stress is a mechanistic link between acute neurotrauma and progressive tauopathy. We propose that ER stress contributes to extensive behavioral changes associated with a CTE-like phenotype. Targeting ER stress is a promising option for the treatment of neurotrauma related neurodegeneration warranting investigation. Utilizing our validated and clinically relevant Sprague-Dawley blast model, we investigated a time course of mechanistic changes that occur following bTBI (50 PSI) including: ER stress activation, iron mediated toxicity, and tauopathy via western blot and immunohistochemistry. These changes were associated with behavioral alterations measured by Elevated Plus Maze (EPM), Forced Swim Test (FST), and Morris Water Maze (MWM). Following characterization, salubrinal, an ER stress modulator, was given at a concentration of 1mg/kg post-blast and its mechanism of action determined in vitro. bTBI significantly increased markers of injury in the cortex of the left hemisphere: p-PERK and p-eIF2α at 30 min, p-T205 tau at 6h, and iron at 24h. bTBI animals spent more time immobile on the FST at 72h and more time in the open arm of the EPM at 7d. Furthermore, bTBI caused a significant learning disruption measured with MWM at 21d post-blast with persistent tau changes. Salubrinal successfully reduced ER stress markers in vivo and in vitro while significantly improving performance on the EPM. bTBI causes robust biochemical changes that contribute to neurodegeneration, but these changes may be targeted with ER stress modulators.

Language: en

Keywords

INFLAMMATION; NEURODEGENERATIVE DISORDERS; TRAUMATIC BRAIN INJURY