Title

Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury

Document Type

Article

Publication Date

12-1-2015

Abstract

A total of 1.7 million traumatic brain injuries (TBIs) occur each year in the UnitedStates, but available pharmacologic options for the treatment of acute neurotraumaare limited. Oxidative stress is an important secondary mechanism of injury that canlead to neuronal apoptosis and subsequent behavioral changes. Using a clinicallyrelevant and validated rodent blast model, we investigated how nicotinamideadenine dinucleotide phosphate oxidase (Nox) expression and associated oxida-tive stress contribute to cellular apoptosis after single and repeat blast injuries.Nox4 forms a complex with p22phox after injury, forming free radicals at neuronalmembranes. Using immunohistochemical-staining methods, we found a visible in-crease in Nox4 after single blast injury in Sprague Dawley rats. Interestingly, Nox4was also increased in postmortem human samples obtained from athletes diag-nosed with chronic traumatic encephalopathy. Nox4 activity correlated with an in-crease in superoxide formation. Alpha-lipoic acid, an oxidative stress inhibitor,prevented the development of superoxide acutely and increased antiapoptoticmarkers B-cell lymphoma 2 (t53.079,P,0.05) and heme oxygenase 1(t58.169,P,0.001) after single blast. Subacutely, alpha-lipoic acid treatmentreduced proapoptotic markers Bax (t54.483,P,0.05), caspase 12 (t56.157,P,0.001), and caspase 3 (t54.573,P,0.01) after repetitive blast, and reduced

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