Role of peroxynitrite in secondary oxidative damage after spinal cord injury

Yiqin Xiong, Alexander G. Rabchevsky, Edward D. Hall

Research output: Contribution to journalArticlepeer-review

170 Scopus citations

Abstract

Peroxynitrite (PON, ONOO-), formed by nitric oxide synthase-generated nitric oxide radical (̇NO) and superoxide radical (O 2̇-), is a crucial player in post-traumatic oxidative damage. In the present study, we determined the spatial and temporal characteristics of PON-derived oxidative damage after a moderate contusion injury in rats. Our results showed that 3-nitrotyrosine (3-NT), a specific marker for PON, rapidly accumulated at early time points (1 and 3 h) and a significant increase compared with sham rats was sustained to 1 week after injury. Additionally, there was a coincident and maintained increase in the levels of protein oxidation-related protein carbonyl and lipid peroxidation-derived 4-hydroxynonenal (4-HNE). The peak increases of 3-NT and 4-HNE were observed at 24 h post-injury. In our immunohistochemical results, the co-localization of 3-NT and 4-HNE results indicates that PON is involved in lipid peroxidative as well as protein nitrative damage. One of the consequences of oxidative damage is an exacerbation of intracellular calcium overload, which activates the cysteine protease calpain leading to the degradation of several cellular targets including cytoskeletal protein (α-spectrin). Western blot analysis of α-spectrin breakdown products showed that the 145-kDa fragments of α-spectrin, which are specifically generated by calpain, were significantly increased as soon as 1 h following injury although the peak increase did not occur until 72 h post-injury. The later activation of calpain is most likely linked to PON-mediated secondary oxidative impairment of calcium homeostasis. Scavengers of PON, or its derived free radical species, may provide an improved antioxidant neuroprotective approach for the treatment of post-traumatic oxidative damage in the injured spinal cord.

Original languageEnglish
Pages (from-to)639-649
Number of pages11
JournalJournal of Neurochemistry
Volume100
Issue number3
DOIs
StatePublished - Feb 2007

Keywords

  • Calpain
  • Oxidative damage
  • Peroxynitrite
  • Reactive oxygen species
  • Spinal cord injury
  • α-spectrin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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