Synergistic Role of Oxidative Stress and Blood-Brain Barrier Permeability as Injury Mechanisms in the Acute Pathophysiology of Blast-induced Neurotrauma

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.

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

“…Given the increasing awareness that neuroinflammation can interact with other aspects of TBI pathophysiology, it is likely that alterations or manipulation of the NLRP3 inflammasome will have multiple pathophysiological consequences. For example, recent studies have found that a relationship exists between neuroinflammation, oxidative stress, and blood-brain barrier permeability after TBI [84,108,109]. The involvement of the NLRP3 inflammasome in these interactions is not yet known; however, MCC950 treatment TBI was found to reduce the extent of blood-brain barrier damage and apoptosis in the acute stages after in TBI mice [70].…”

Does Blast Exposure to the Torso Cause a Blood Surge to the Brain?

“…In our study, we investigate whether the kinetic energy transferred to the brain (i.e., a body internal structure) through the blood (i.e., the fluid medium) could potentially damage the brain vessels and tissues. Surprisingly, despite extensive experimental evidence supporting varying degrees of cerebrovascular pathology in animals exposed to whole-body blast (Gama Sosa et al, 2013Kuriakose et al, 2018Kuriakose et al, , 2019Logsdon et al, 2018;Heyburn et al, 2019), the existence of such a blood surge has not been thoroughly investigated, possibly because of the challenges in measuring hemodynamic parameters, such as mass flow rate and flow-velocity fields, in the cerebral vasculature during a blast exposure. As an alternative, and complementary to animal experimentation, high-fidelity, fluidstructure interaction (FSI) computational models allow for the characterization of such hemodynamic parameters and the estimation of biomechanical responses (e.g., the wall shear stress) in the cerebral vasculature, which could help elucidate whether blast exposure targeting only the torso can generate a noticeable blood surge to the brain.…”

Nutritional interventions to improve neurophysiological impairments following traumatic brain injury: A systematic review

“…Across the TBI spectrum, mitochondrial dysfunction and impaired cell membrane homeostasis within neuronal, axonal, and glial cells can exacerbate neurotransmission impairment. Biomechanical forces deforming brain cells during TBI can damage axons and increase BBB permeability, both of which can be further aggravated by unregulated free radicals (Kuriakose et al., 2019; Ljubisavljevic, 2016). Compromised tight junctions between endothelial cells within the BBB results in cerebral edema further compromising neurotransmission (Kenzie et al., 2018; Luissint et al., 2012).…”