Journal
EXPERIMENTAL NEUROLOGY
Volume 205, Issue 1, Pages 154-165Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2007.01.023
Keywords
peroxynitrite; oxidative damage; calpain; cytoskeletal degradation; neurodegeneration; controlled cortical impact (CCI); TBI
Categories
Funding
- NINDS NIH HHS [R01 NS046566, P30 NS051220-029005, P30 NS051220-019005, P30 NS051220-01, R01 NS046566-03, R01 NS046566-01A1, R01 NS046566-02, R01 NS046566-04, P30 NS051220, P30 NS051220-02] Funding Source: Medline
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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- I 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 alpha-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. alpha-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. (C) 2007 Elsevier Inc. All rights reserved.
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