Temporal relationship of peroxynitrite-induced oxidative damage, calpain-mediated cytoskeletal degradation and neurodegeneration after traumatic brain injury

Ying Deng, Brian M. Thompson, Xiang Gao, Edward D. Hall

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

Abstract

We assessed the temporal and spatial characteristics of PN-induced oxidative damage and its relationship to calpain-mediated cytoskeletal degradation and neurodegeneration in a severe unilateral controlled cortical impact (CCI) traumatic brain injury (TBI) model. Quantitative temporal time course studies were performed to measure two oxidative damage markers: 3-nitrotyrosine (3NT) and 4-hydroxynonenal (4HNE) at 30 min, 1, 3, 6, 12, 24, 48, 72 h and 7 days after injury in ipsilateral cortex of young adult male CF-1 mice. Secondly, the time course of Ca++-activated, calpain-mediated proteolysis was also analyzed using quantitative western-blot measurement of breakdown products of the cytoskeletal protein α-spectrin. Finally, the time course of neurodegeneration was examined using de Olmos silver staining. Both oxidative damage markers increased in cortical tissue immediately after injury (30 min) and elevated for the first 3-6 h before returning to baseline. In the immunostaining study, the PN-selective marker, 3NT, and the lipid peroxidation marker, 4HNE, were intense and overlapping in the injured cortical tissue. α-Spectrin breakdown products, which were used as biomarker for calpain-mediated cytoskeletal degradation, were also increased after injury, but the time course lagged behind the peak of oxidative damage and did not reach its maximum until 24 h post-injury. In turn, cytoskeletal degradation preceded the peak of neurodegeneration which occurred at 48 h post-injury. These studies have led us to the hypothesis that PN-mediated oxidative damage is an early event that contributes to a compromise of Ca++ homeostatic mechanisms which causes a massive Ca++ overload and calpain activation which is a final common pathway that results in post-traumatic neurodegeneration.

Original languageEnglish
Pages (from-to)154-165
Number of pages12
JournalExperimental Neurology
Volume205
Issue number1
DOIs
StatePublished - May 2007

Keywords

  • Calpain
  • Controlled cortical impact (CCI)
  • Cytoskeletal degradation
  • Neurodegeneration
  • Oxidative damage
  • Peroxynitrite
  • TBI

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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