Molecular Neurobiology

, Volume 51, Issue 3, pp 966–979 | Cite as

Interactions of Oxidative Stress and Neurovascular Inflammation in the Pathogenesis of Traumatic Brain Injury

  • P. M. Abdul-MuneerEmail author
  • Namas Chandra
  • James HaorahEmail author


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.


Traumatic brain injury Oxidative stress Blood-brain barrier Matrix metalloproteinases Vascular endothelial growth factor Neuroinflammation Edema 



This work was supported by NIH/NIAAA Grant R21AA020370-01A1 to J.H. and by the U.S. Army Research Office project “Army–UNL Center of Trauma Mechanics” (Contract W911NF-08-10483) to N.C.

Conflict of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of Biomedical EngineeringNew Jersey Institute of TechnologyNewarkUSA
  3. 3.New Jersey Neuroscience InstituteJFK Medical CenterEdisonUSA

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