Relationship of nitric oxide synthase induction to peroxynitrite-mediated oxidative damage during the first week after experimental traumatic brain injury

Edward D. Hall, Juan A. Wang, Darren M. Miller

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


We have previously shown the pathophysiological importance of the reactive nitrogen species peroxynitrite (PN) formed from the reaction of nitric oxide (•NO) and superoxide (O2•-) radicals and its involvement in lipid peroxidation (LP) and protein nitration damage in brain tissue following traumatic brain injury (TBI). Nitric oxide is produced by at least three isoforms of the enzyme nitric oxide synthase (NOS) including: endothelial NOS (eNOS) in the CNS vasculature, neuronal NOS (nNOS), and inducible NOS (iNOS) in macrophages/microglia. In view of the requirement of •NO synthesis for PN formation, we sought to address the time course of NOS expression (mRNA by real time quantitative PCR and protein by western blot) after TBI in comparison with the time course of PN-mediated protein nitration (3-nitrotyrosine, 3-NT) in ipsilateral cortex (CTX) and hippocampus (HIPP) between 3hours and 1week post-injury using a controlled cortical impact (CCI) mouse model of TBI in young adult CF-1 mice. Protein nitration showed a progressive posttraumatic increase that became significant in CTX at 24hours and then peaked at 72hours in both CTX and HIPP. During the increase in PN-derived 3-NT, there was no increase in either CTX or HIPP eNOS mRNA levels, whereas eNOS protein levels were significantly (p<0.05) increased at 48 and 72hours in both brain regions. There was a significant decrease in HIPP, but not CTX nNOS mRNA; however, nNOS protein did not change except for a significant increase in CTX at 1week. There was significantly increased CTX and HIPP iNOS mRNA levels at 24, 48, and 72hours (p<.05) post-injury. In contrast, no change was seen in CTX or HIPP iNOS protein at any timepoint. Taken together, eNOS protein expression and iNOS mRNA appear to bear a coincident temporal relationship to the time course of PN-mediated protein nitrative damage after CCI-TBI suggesting that both constitutive and inducible NOS isoforms contribute •NO for PN formation and 3-NT protein modification after BI.

Original languageEnglish
Pages (from-to)176-182
Number of pages7
JournalExperimental Neurology
Issue number2
StatePublished - Dec 2012

Bibliographical note

Funding Information:
This work was supported by 1R01 NS046566, 2P01 NS058484, 5P30 NS051220 and the Kentucky Spinal Cord and Head Injury Research Trust . Darren M. Miller was supported by fellowship funds from the NIH Blueprint Translational Neuroscience Training Grant 1T32 DA022738 .


  • 3-Nitrotyrosine
  • Nitric oxide synthase
  • Oxidative damage
  • Peroxynitrite
  • Traumatic brain injury

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience


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