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(Stroke. 1999;30:2408-2415.)
© 1999 American Heart Association, Inc.

Original Contributions

Copper-Zinc Superoxide Dismutase Prevents the Early Decrease of Apurinic/Apyrimidinic Endonuclease and Subsequent DNA Fragmentation After Transient Focal Cerebral Ischemia in Mice

Miki Fujimura, MD; Yuiko Morita-Fujimura, MS; Purnima Narasimhan, PhD; Jean-Christophe Copin, PhD; Makoto Kawase, MD Pak H. Chan, PhD

From the Departments of Neurosurgery, Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Palo Alto, Calif.

Correspondence to Pak H. Chan, PhD, Neurosurgical Laboratories, Stanford University, 701B Welch Rd, #148, Palo Alto, CA 94304. E-mail phchan{at}leland.stanford.edu

Background and Purpose—DNA damage and its repair mechanism are thought to be involved in ischemia/reperfusion injury in the brain. We have previously shown that apurinic/apyrimidinic endonuclease (APE/Ref-1), a multifunctional protein in the DNA base excision repair pathway, rapidly decreased after transient focal cerebral ischemia (FCI) before the peak of DNA fragmentation. To further investigate the role of reactive oxygen species in APE/Ref-1 expression in vivo, we examined the expression of APE/Ref-1 and DNA damage after FCI in wild-type and transgenic mice overexpressing copper-zinc superoxide dismutase.

Methods—Transgenic mice overexpressing copper-zinc superoxide dismutase and wild-type littermates were subjected to 60 minutes of transient FCI by intraluminal blockade of the middle cerebral artery. APE/Ref-1 protein expression was analyzed by immunohistochemistry and Western blot analysis. DNA damage was evaluated by gel electrophoresis and terminal deoxynucleotidyl transferase–mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL).

Results—A similar level of APE/Ref-1 was detected in the control brains from both groups. APE/Ref-1 was significantly reduced 1 hour after transient FCI in both groups, whereas the transgenic mice had less reduction than that seen in wild-type mice 1 and 4 hours after FCI. DNA laddering was detected 24 hours after FCI and was decreased in transgenic mice. Double staining with APE/Ref-1 and TUNEL showed that the neurons that lost APE/Ref-1 immunoreactivity became TUNEL positive.

Conclusions—These results suggest that reactive oxygen species contribute to the early decrease of APE/Ref-1 and thereby exacerbate DNA fragmentation after transient FCI in mice.

Editorial Comment

Chung Y. Hsu, MD, PhD Arif Y. Shaikh, BS

Guest Editors, Department of Neurology, Washington University School of Medicine, St Louis, Missouri

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