A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the United
States, but available pharmacologic options for the treatment of acute neurotrauma
are limited. Oxidative stress is an important secondary mechanism of injury that can
lead to neuronal apoptosis and subsequent behavioral changes. Using a clinically relevant
and validated rodent blast model, we investigated how nicotinamide adenine dinucleotide
phosphate oxidase (Nox) expression and associated oxidative stress contribute to cellular
apoptosis after single and repeat blast injuries. Nox4 forms a complex with p22phox
after injury, forming free radicals at neuronal membranes. Using immunohistochemical-staining
methods, we found a visible increase in Nox4 after single blast injury in Sprague
Dawley rats. Interestingly, Nox4 was also increased in postmortem human samples obtained
from athletes diagnosed with chronic traumatic encephalopathy. Nox4 activity correlated
with an increase in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor,
prevented the development of superoxide acutely and increased antiapoptotic markers
B-cell lymphoma 2 (t = 3.079, P < 0.05) and heme oxygenase 1 (t = 8.169, P < 0.001) after single blast. Subacutely, alpha-lipoic acid treatment reduced proapoptotic
markers Bax (t = 4.483, P < 0.05), caspase 12 (t = 6.157, P < 0.001), and caspase 3 (t = 4.573, P < 0.01) after repetitive blast, and reduced tau hyperphosphorylation indicated by
decreased CP-13 and paired helical filament staining. Alpha-lipoic acid ameliorated
impulsive-like behavior 7 days after repetitive blast injury (t = 3.573, P < 0.05) compared with blast exposed animals without treatment. TBI can cause debilitating
symptoms and psychiatric disorders. Oxidative stress is an ideal target for neuropharmacologic
intervention, and alpha-lipoic acid warrants further investigation as a therapeutic
for prevention of chronic neurodegeneration.
Abbreviations:
CTE (chronic traumatic encephalopathy), CTRL (control), EPM (elevated plus maze), HO-1 (heme oxygenase 1), LA (lipoic acid), NADPH (nicotinamide adenine dinucleotide phosphate), Nox (NADPH oxidase), NFL (professional football player), PHF (paired helical filament), RB (repeat blast), ROS (free radical oxygen species), SB (single blast), TBI (traumatic brain injury), WWE (professional wrestler), NIH (National Institutes of Health), mRNA (messenger ribonucleic acid), IHC (immunohistochemistry), DNPH (2,4-dinitrophenylhydrazine), DAB (diaminobenzadine), ANOVA (analysis of variance), PET (positron emission tomography), Std (standard), C (control)To read this article in full you will need to make a payment
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Biography
Brandon P. Lucke-Wold is an MD, PhD candidate in the Department of Neurosurgery at West Virginia University School of Medicine. His article is based on a presentation given at the Combined Annual Meeting of the Central Society for Clinical and Translational Research and the Midwestern Section American Federation for Medical Research, held in Chicago, Ill, on April 2015.
Article info
Publication history
Published online: September 08, 2015
Accepted:
August 12,
2015
Received in revised form:
July 29,
2015
Received:
May 18,
2015
Footnotes
Brandon P. Lucke-Wold and Zachary J. Naser have equal authorship contribution.
Identification
Copyright
© 2015 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
