Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a major cause of death in the young age group and leads to persisting neurological impairment in many of its victims. It may result in permanent functional deficits because of both primary and secondary damages. This review addresses the role of oxidative stress in TBI-mediated secondary damages by affecting the function of the vascular unit, changes in blood-brain barrier (BBB) permeability, posttraumatic edema formation, and modulation of various pathophysiological factors such as inflammatory factors and enzymes associated with trauma. Oxidative stress plays a major role in many pathophysiologic changes that occur after TBI. In fact, oxidative stress occurs when there is an impairment or inability to balance antioxidant production with reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels. ROS directly downregulate proteins of tight junctions and indirectly activate matrix metalloproteinases (MMPs) that contribute to open the BBB. Loosening of the vasculature and perivascular unit by oxidative stress-induced activation of MMPs and fluid channel aquaporins promotes vascular or cellular fluid edema, enhances leakiness of the BBB, and leads to progression of neuroinflammation. Likewise, oxidative stress activates directly the inflammatory cytokines and growth factors such as IL-1β, tumor necrosis factor-α (TNF-α), and transforming growth factor-beta (TGF-β) or indirectly by activating MMPs. In another pathway, oxidative stress-induced degradation of endothelial vascular endothelial growth factor receptor-2 (VEGFR-2) by MMPs leads to a subsequent elevation of cellular/serum VEGF level. The decrease in VEGFR-2 with a subsequent increase in VEGF-A level leads to apoptosis and neuroinflammation via the activation of caspase-1/3 and IL-1β release.

Fig. 1

Induction of oxidative/nitrosative stress and activation of MMP-2 and AQP-4 in primary blast (123-kPa peak overpressure) induced mTBI rat brain microvessels. Immunofluorescent staining of nitrosative stress marker, 3-nitrotyrosine (3NT) in mTBI rat brain cortex (a); matrix metalloproteinases-2 (MMP-2) in mTBI rat in intact brain microvessels (b); aquaporin-4 (AQP-4) (red) and endothelial marker, GLUT1 (green) in brain microvessels of rats exposed to primary blast (c). Cell nuclei were counterstained with DAPI (blue) in c. Scale bar (yellow bar in last panel)=5 μm in all panels. For details, see Abdul-Muneer et al. [9]

Fig. 2

Schematic representation of oxidative stress-induced BBB disruption and neuroinflammation in traumatic brain injury. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the main sources of oxidative stress in brain injury. ROS include superoxide (O_2^•−), hydroxyl radical (HO•), hydrogen peroxide (H₂O₂), and hypochlorous acid (HOCl). RNS refer to various nitric oxide (NO)-derived compounds, such as peroxynitrite (⁻OONO) and nitrogen dioxide (NO₂). Superoxide (O_2^•−) causes tissue damage by promoting hydroxyl radicals from hydrogen peroxide (H₂O₂) and peroxynitrite (−ONOO) when combined with nitric oxide (NO). ROS activate matrix metalloproteinases (MMPs) that further exacerbate the condition and lead to BBB disruption via degradation of the extracellular matrix and tight junction proteins. Further, MMPs are involved in degradation of vascular endothelial growth factor (VEGFR) and lead to an increase in the level of VEGF that in turn causes ROS and activates caspase-1/3, which leads to cell death. At the same time, ROS or RNS also activate different inflammatory cytokines and growth factors such as IL-1β, TNF-α, and TGF-β, which cause BBB disruption and neuroinflammation