title: Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury.
abstract: 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.
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WVa; The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WVa.
authors.forename: Brandon P
authors.initials: BP
authors.lastname: Lucke-Wold
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WVa; The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WVa; Department of Medicine, Professional Studies in Health Sciences, Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Naser
authors.affiliation: The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WVa; Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WVa.
authors.forename: Aric F
authors.initials: AF
authors.lastname: Logsdon
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WVa; The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WVa.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Turner
authors.affiliation: The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WVa; Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WVa.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Smith
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WVa; Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tenn.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Robson
authors.affiliation: Department of Neurosurgery, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, Evanston, Ill.
authors.forename: Julian E
authors.initials: JE
authors.lastname: Bailes
authors.affiliation: Department of Pathology, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, Evanston, Ill.
authors.forename: John M
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WVa; The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WVa.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Rosen
authors.affiliation: The Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WVa; Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WVa. Electronic address: jdhuber@hsc.wvu.edu.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Huber
mesh_terms: D000818:Animals; D017209:Apoptosis; D001753:Blast Injuries / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D001930:Brain Injuries / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D008063:Thioctic Acid / Q000494:pharmacology
chemical_list: D008063:Thioctic Acid; D019255:NADPH Oxidases