Abstract
Blast-induced traumatic brain injury (bTBI) has been recognized as the common mode of neurotrauma amongst military and civilian personnel due to an increased insurgent activity domestically and abroad. Previous studies from our laboratory have identified enhanced blood-brain barrier (BBB) permeability as a significant, sub-acute (four hours post-blast) pathological change in bTBI. We also found that NADPH oxidase (NOX)-mediated oxidative stress occurs at the same time post-blast when the BBB permeability changes. We therefore hypothesized that oxidative stress is a major causative factor in the BBB breakdown in the sub-acute stages. This work therefore examined the role of NOX1 and its downstream effects on BBB permeability in the frontal cortex (a region previously shown to be the most vulnerable) immediately and four hours post-blast exposure. Rats were injured by primary blast waves in a compressed gas-driven shock tube at 180 kPa and the BBB integrity was assessed by extravasation of Evans blue and changes in tight junction proteins (TJPs) as well as translocation of macromolecules from blood to brain and vice versa. NOX1 abundance was also assessed in neurovascular endothelial cells. Blast injury resulted in increased extravasation and reduced levels of TJPs in tissues consistent with our previous observations. NOX1 levels were significantly increased in endothelial cells followed by increased superoxide production within 4 hours of blast. Blast injury also increased the levels/activation of matrix metalloproteinase 3 and 9. To test the role of oxidative stress, rats were administered apocynin, which is known to inhibit the assembly of NOX subunits and arrests its function. We found apocynin completely inhibited dye extravasation as well as restored TJP levels to that of controls and reduced matrix metalloproteinase activation in the sub-acute stages following blast. Together these data strongly suggest that NOX-mediated oxidative stress contributes to enhanced BBB permeability in bTBI through a pathway involving increased matrix metalloproteinase activation.
Highlights
Oxidative stress has been implicated in multiple modes of TBI11,12 and is mainly induced by reactive oxidative species (ROS)
We examined the levels of NOX1 in the vascular endothelial cells in the frontal cortex
This work aims to investigate the role of NADPH oxidase (NOX)-mediated oxidative stress as a mechanism for increased blood-brain barrier (BBB) permeability in blast-induced traumatic brain injury, immediately following blast and further increase between blast and 4 hours post-blast
Summary
Oxidative stress has been implicated in multiple modes of TBI11,12 and is mainly induced by reactive oxidative species (ROS) These include, but are not limited to, superoxide (O2⋅−), hydroxyl radical (HO⋅), and hydrogen peroxide (H2O2)[13,14]. Since our recent studies indicate blast injury results in disruption of BBB and activation of factors conducive to oxidative stress[17,18], we sought to examine the interaction of these two well-known pathogenic factors in BINT. We hypothesize that while BBB is acutely disrupted immediately following blast injury through biomechanical means, and enhanced BBB disruption in later stages (zero to four hours) is due, at least in part, to the activation of NADPH oxidase (NOX) and associated increase in oxidative stress. Apocynin was used to examine the role of NOX on BBB disruption and not as a therapeutic agent though such a treatment possibility exists; that is not the purpose of the present study
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