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(Stroke. 2001;32:2356.)
© 2001 American Heart Association, Inc.

Original Contributions

Superoxide During Reperfusion Contributes to Caspase-8 Expression and Apoptosis After Transient Focal Stroke

Yuiko Morita-Fujimura, PhD; Miki Fujimura, MD, PhD; Takashi Yoshimoto, MD, PhD Pak H. Chan, PhD

From the Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences (Y.M.-F., M.F., P.H.C.), Stanford University School of Medicine, Stanford, Calif; and the Department of Neurosurgery (M.F., T.Y.), Tohoku University School of Medicine, Sendai, Japan.

Correspondence to Pak H. Chan, PhD, Neurosurgical Labs, Stanford University, MSLS #P304, 1201 Welch Rd., Stanford, CA 94305-5487. E-mail phchan{at}leland.stanford.edu

Background and Purpose—— Reactive oxygen species produced during reperfusion may play a detrimental role in focal cerebral ischemia (FCI). We examined the protein expression of caspase-8, which plays a major role in both Fas-dependent and cytochrome c–dependent apoptotic pathways after FCI with or without reperfusion. Caspase-8 expression after transient FCI was compared between wild-type and transgenic mice that overexpress the cytosolic antioxidant copper/zinc superoxide dismutase (SOD1).

Methods—— Adult male CD-1 mice were subjected to 1 hour of FCI and reperfusion or to permanent FCI by intraluminal blockade of the middle cerebral artery. DNA fragmentation was evaluated by genomic DNA gel electrophoresis. Caspase-8 expression was analyzed by Western blot.

Results—— Caspase-8 was significantly induced 4 hours after transient FCI and remained at an increased level until 24 hours, whereas it was not modified after permanent FCI. Genomic DNA gel electrophoresis showed DNA laddering in a pattern similar to that seen in apoptosis, with a small amount of background smear 24 hours after transient FCI, whereas 25 hours of permanent FCI resulted in less DNA laddering with a strong background smear. Caspase-8 induction was significantly reduced in SOD1 transgenic mice compared with wild-type mice 4 hours after transient FCI.

Conclusions—— The results suggest that increased reactive oxygen species production during reperfusion may contribute to the induction of caspase-8, thereby exacerbating apoptosis after FCI.

Key Words: apoptosis • cerebral ischemia, focal • DNA damage • reperfusion injury • superoxide dismutase • mice

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