Pharmacological evidence for a role of peroxynitrite in the pathophysiology of spinal cord injury

Yiqin Xiong, Edward D. Hall

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Evidence suggests that the reactive oxygen species peroxynitrite (PN) is an important player in the pathophysiology of acute spinal cord injury (SCI). In the present study, we examined the ability of tempol, a catalytic scavenger of PN-derived free radicals, to alleviate oxidative damage, mitochondrial dysfunction and cytoskeletal degradation following a severe contusion (200 kdyn force) SCI in female Sprague-Dawley rats. PN-mediated oxidative damage in spinal cord tissue, including protein nitration, protein oxidation and lipid peroxidation was significantly reduced by acute tempol treatment (300 mg/kg, i.p. within 5 min post-injury). Injury-induced mitochondrial respiratory dysfunction, measured after 24 h in isolated mitochondria, was partially reversed by tempol along with an attenuation of oxidative damage to mitochondrial proteins. Mitochondrial dysfunction disrupts intracellular Ca2+ homeostasis contributing to calpain-mediated axonal cytoskeletal protein (α-spectrin, 280 kD) degradation. Increased levels of α-spectrin breakdown proteins (SBDP 145 kD and 150 kD) were significantly decreased at 24 h in tempol-treated rats indicative of spinal axonal protection. However, a therapeutic window analysis showed that the axonal cytoskeletal protective effects require tempol dosing within the first hour after injury. Nevertheless, these findings are the first to support the concept that PN is an important neuroprotective target in early secondary SCI, and that there is a mechanistic link between PN-mediated oxidative compromise of spinal cord mitochondrial function, loss of intracellular Ca2+ homeostasis and calpain-mediated proteolytic axonal damage.

Original languageEnglish
Pages (from-to)105-114
Number of pages10
JournalExperimental Neurology
Volume216
Issue number1
DOIs
StatePublished - Mar 2009

Bibliographical note

Funding Information:
This study was supported by a grant from the Kentucky Spinal Cord and Head Injury Research Trust and by NIH 1P30 NS051220.

Keywords

  • Cytoskeletal breakdown
  • Lipid peroxidation
  • Mitochondrial dysfunction
  • Oxidative damage
  • Peroxynitrite
  • Protein nitration
  • Spinal cord injury
  • Tempol

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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