Oxidative damage mechanisms in traumatic brain injury and antioxidant neuroprotective approaches

Edward D. Hall, Indrapal N. Singh, John E. Cebak

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

3 Scopus citations


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.

Original languageEnglish
Title of host publicationAcute Neuronal Injury
Subtitle of host publicationThe Role of Excitotoxic Programmed Cell Death Mechanisms: Second Edition
Number of pages23
ISBN (Electronic)9783319774954
StatePublished - Jan 1 2018


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

ASJC Scopus subject areas

  • Medicine (all)
  • Neuroscience (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Agricultural and Biological Sciences (all)


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