Oxidative cellular damage and the reduction of APE/Ref-1 expression after experimental traumatic brain injury.
The DNA repair enzyme, apurinic/apyrimidinic endonuclease (or redox effector factor-1, APE/Ref-1), is involved in base excision repair of apurinic/apyrimidinic sites after oxidative DNA damage. We investigated the expression of APE/Ref-1 and its relationship to oxidative stress after severe traumatic brain injury produced by controlled cortical impact in normal mice, and in mice over- or underexpressing copper-zinc superoxide dismutase (SOD1TG and SOD1KO, respectively). Oxygen free radical-mediated cellular injury was visualized with 8-hydroxyguanine immunoreactivity as a marker for DNA oxidation, and in situ hydroethidine oxidation as a marker for superoxide production. After trauma there was a reduced expression of APE/Ref-1 in the ipsilateral cortex and hippocampus that correlated with the gene dosage levels of cytosolic superoxide dismutase. The decrease in APE/Ref-1 expression preceded DNA fragmentation. There was also a close correlation between APE/Ref-1 protein levels 4 h after trauma and the volume of the lesion 1 week after injury. Our data have demonstrated that reduction of APE/Ref-1 protein levels correlates closely with the level of oxidative stress after traumatic brain injury. We suggest that APE/Ref-1 immunoreactivity is a sensitive marker for oxidative cellular injury.
Lewén
A
A
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305-5487, USA.
Sugawara
T
T
Gasche
Y
Y
Fujimura
M
M
Chan
P H
PH
D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D019757:Carbon-Oxygen Lyases / Q000032:analysis / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000032:analysis / Q000378:metabolism
D013481:Superoxides; D004247:DNA; D013482:Superoxide Dismutase; D019757:Carbon-Oxygen Lyases; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase