Reducing NADPH Oxidative Stress following Acute Neurotrauma

Abstract

1.7 million traumatic brain injuries occur each year in the USA. Utilizing a validated rodent blast model, we investigated how NADPH oxidase expression and associated oxidative stress contributes to cellular apoptosis following blast injuries. We found a visible increase in NADPH Nox4 following single blast injury in Sprague Dawley rats. Interestingly, Nox4 was also increased in post‐mortem human samples obtained from deceased athletes. Nox4 activity led to an increase in superoxide formation. Lipoic acid decreased Nox4 when given i.p. 10mg/kg 5‐minutes after blast exposure. Lipoic acid also significantly decreased the subsequent formation of superoxide. Lipoic acid increased the anti‐apoptotic markers Bcl‐2 (t = 3.079, p<0.05) and heme oxygenase 1 (t = 8.169, p<0.001) compared to blast injured animals. Two weeks following the last blast exposure (6 blasts total over 2 weeks), the lipoic acid treatment group had significantly 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) compared to blast injured animals. Lipoic acid treated animals also had significantly reduced tau hyperphosphorylation. Tissue from the NFL player had increased Bax expression (t=5.424, p<0.01) compared to control. A significant difference in impulsive‐like behavior between experimental animal groups was seen 7 days after repetitive blast injury (F(2,21)=4.327, p<0.05). Rats exposed to repetitive blast displayed increased time in the open arm compared to control (t=3.632, p<0.05), but lipoic acid ameliorated this impulsive‐like behavior (t=3.573, p<0.05). Lipoic acid warrants further investigation as a therapeutic for the treatment of acute neurotrauma.