Oxidative Damage Mechanisms in Traumatic Brain Injury and Antioxidant Neuroprotective Approaches

  • Edward D. HallEmail author
  • Indrapal N. Singh
  • John E. Cebak


This chapter reviews our current knowledge of the role of oxidative damage mechanisms and pharmacological antioxidant neuroprotective strategies for inhibiting reactive oxygen species (ROS) and reactive nitrogen species (RNS)-mediated secondary injury following traumatic brain injury (TBI). First of all, the chemistry of the main forms of oxidative damage: lipid peroxidation, carbonylation and nitration are presented as well as the interactions of oxidative damage with other secondary injury mechanisms including glutamate-mediated excitotoxicity, intracellular calcium overload and mitochondrial dysfunction. Secondly, the general mechanistic approaches to interrupting oxidative damage are presented: decreasing ROS/RNS formation or scavenging ROS and RNS-derived radicals, inhibition of lipid peroxidation propagation, chelation of iron, which is a potent catalyst of lipid peroxidation reactions, scavenging of neurotoxic aldehydic lipid peroxidation products (‘carbonyls’), and enhancement of the expression of the pleiotopic Nrf2-antioxidant response element (ARE) pathway that controls the synthesis of several endogenous antioxidant enzymes and chemical antioxidants. Pharmacological examples of compounds that effectively inhibit oxidative damage and produce neuroprotective effects in animal TBI models by each of these various approaches are presented. Finally, the results of large phase III clinical trials with the either the radical scavenger polyethylene glycol-coupled superoxide dismutase (PEG-SOD) or the 21-aminosteroid lipid peroxidation inhibitor tirilazad are revisited in which the latter compound was found to selectively improve survival after moderate and severe TBI, particularly in male patients, suggesting that successful clinical translation of neuroprotective antioxidant compounds, or combinations of mechanistically complimentary antioxidants, should be possible.


Glutamate excitotoxicity Calcium overload Reactive oxygen species Lipid peroxidation Antioxidant Neuroprotection Traumatic brain injury 



Portions of the work reviewed in this chapter were supported by funding from 5R01 NS046566, 5P30 NS051220, and 5P01 NS58484 and currently by 5R01 NS083405, 5R01 NS084857 and 1R01 NS100093 and from the Kentucky Spinal Cord & Head Injury Research Trust.


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Edward D. Hall
    • 1
    Email author
  • Indrapal N. Singh
    • 1
  • John E. Cebak
    • 2
  1. 1.Spinal Cord & Brain Injury Research Center (SCoBIRC) and Department of NeuroscienceUniversity of Kentucky Medical CenterLexingtonUSA
  2. 2.Lincoln Memorial University DeBusk College of Osteopathic MedicineHarrogateUSA

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