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Winning Abstracts from the 2015 Medical Student Abstract Competition: Targeting NADPH-Mediated Oxidative Stress Reduces Cell Death and Improves Behavior following Neurotrauma
First Author: Brandon P. Lucke-Wold, West Virigina University School of Medicine, Class of 2019
1.7 million traumatic brain injuries (TBIs) occur each year in the United States. Recent evidence suggests that repetitive TBIs can lead to chronic neurodegenerative changes over time. Currently, available pharmacologic options for the treatment of acute neurotrauma are limited. Oxidative stress is an important secondary mechanism of injury that can lead to cellular apoptosis and behavioral changes such as impulsivity. Utilizing a clinically relevant and validated rodent blast model, we investigated how NADPH oxidase expression and associated oxidative stress contributes to cellular apoptosis following single and repeat blast injuries.
Nox4 forms a complex with p22phox following injury, both of which are important subunits of the NADPH oxidase system found within the brain. Using immunohistochemical-staining methods, we found a visible increase in Nox4 following single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in post-mortem human samples obtained from athletes diagnosed with chronic traumatic encephalopathy (CTE). Nox4 activity correlated with an increase in superoxide formation. Alpha lipoic acid, an oxidative stress inhibitor, prevented the development of superoxide acutely, and increased anti-apoptotic markers Bcl-2 (t = 3.079, p<0.05) and heme oxygenase 1 (t = 8.169, p< 0.001) after single blast exposure. Subacutely, alpha lipoic acid treatment reduced pro-apoptotic 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) following repetitive blast, and reduced tau hyperphosphorylation indicated by decreased CP-13 and PHF staining.
Alpha lipoic acid ameliorated impulsive-like behavior 7 days after repetitive blast injury (t=3.573, p<0.05) compared to blast exposed animals without treatment. TBI can cause debilitating symptoms, disability, and psychiatric disorders. Secondary mechanisms of injury, such as oxidative stress, are ideal targets for neuropharmacologic intervention. Alpha lipoic acid warrants further investigation as a therapeutic for the treatment of acute neurotrauma and prevention of chronic neurodegeneration.