This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kawase, M. Articles by Wolin, M. S. Search for Related Content PubMed PubMed Citation Articles by Kawase, M. Articles by Wolin, M. S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Transient Ischemic Attack Related Collections Animal models of human disease Transient Ischemic Attacks Gene therapy Oxidant stress

(Stroke. 1999;30:1962-1968.)
© 1999 American Heart Association, Inc.

Original Contributions

Exacerbation of Delayed Cell Injury After Transient Global Ischemia in Mutant Mice With CuZn Superoxide Dismutase Deficiency

Makoto Kawase, MD; Kensuke Murakami, MD; Miki Fujimura, MD; Yuiko Morita-Fujimura, MS; Yvan Gasche, MD; Takeo Kondo, MD; Richard W. Scott, PhD Pak H. Chan, PhD

From the Departments of Neurosurgery, Neurology and Neurological Sciences and the Program in Neurosciences, Stanford University School of Medicine, Palo Alto, Calif (M.K., M.F., Y.M-F., Y.G., P.H.C.); Departments of Neurological Surgery and Neurology, CNS Injury and Edema Research Center, University of California, San Francisco (M.K., K.M., M.F., Y.M-F., T.K., P.H.C.); and Department of Molecular Biology, Cephalon, Inc, West Chester, Pa (R.W.S.).

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

Background and Purpose—We have demonstrated that copper-zinc superoxide dismutase (CuZn-SOD), a cytosolic isoenzyme of SODs, has a protective role in the pathogenesis of superoxide radical–mediated brain injury. Using mice bearing a disruption of the CuZn-SOD gene (Sod1), the present study was designed to clarify the role of superoxide anion in the pathogenesis of selective vulnerability after transient global ischemia.

Methods—Sod1 knockout homozygous mutant mice (Sod1 -/-) with a complete absence of endogenous CuZn-SOD activity, heterozygous mutant mice (Sod1 +/-) with a 50% decrease in the activity, and littermate wild-type mice (male, 35 to 45 g) were subjected to global ischemia. Since the plasticity of the posterior communicating artery (PcomA) has been reported to influence the outcome of hippocampal injury, we assessed the relation between the plasticity of PcomAs and the decrease of regional cerebral blood flow in global ischemia.

Results—The fluorescence intensity of hydroethidine oxidation, a measurement of ethidium fluorescence for superoxide radicals, was increased in mutant mice 1 day after both 5 and 10 minutes of global ischemia, compared with wild-type mice. Hippocampal injury in the PcomA hypoplastic brains showed significant exacerbation in mutant mice compared with wild-type littermates 3 days after 5 minutes of global ischemia, although a marked difference was not observed at 1 day.

Conclusions—These data suggest that superoxide radicals play an important role in the pathogenesis of delayed injury in the vulnerable hippocampal CA1 subregion after transient global ischemia.

Editorial Comment

Michael S. Wolin, PhD, Guest Editor

Department of Physiology, New York Medical College, Valhalla, New York

This article has been cited by other articles:

				D. P. D'Agostino, R. W. Putnam, and J. B. Dean Superoxide ({middle dot}O2 ) Production in CA1 Neurons of Rat Hippocampal Slices Exposed to Graded Levels of Oxygen J Neurophysiol, August 1, 2007; 98(2): 1030 - 1041. [Abstract] [Full Text] [PDF]

				J.-H. Zhu, X. Zhang, J. P. McClung, and X. G. Lei Impact of Cu,Zn-Superoxide Dismutase and Se-Dependent Glutathione Peroxidase-1 Knockouts on Acetaminophen-Induced Cell Death and Related Signaling in Murine Liver Experimental Biology and Medicine, December 1, 2006; 231(11): 1726 - 1732. [Abstract] [Full Text] [PDF]

				J. W. Park, W.-N. Qi, Y. Cai, I. Zelko, J. Q. Liu, L.-E. Chen, J. R. Urbaniak, and R. J. Folz Skeletal muscle reperfusion injury is enhanced in extracellular superoxide dismutase knockout mouse Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H181 - H187. [Abstract] [Full Text] [PDF]

				H. Tummala, C. Jung, A. Tiwari, C. M. J. Higgins, L. J. Hayward, and Z. Xu Inhibition of Chaperone Activity Is a Shared Property of Several Cu,Zn-Superoxide Dismutase Mutants That Cause Amyotrophic Lateral Sclerosis J. Biol. Chem., May 6, 2005; 280(18): 17725 - 17731. [Abstract] [Full Text] [PDF]

				H. Zhao, J. Joseph, H. M. Fales, E. A. Sokoloski, R. L. Levine, J. Vasquez-Vivar, and B. Kalyanaraman Detection and characterization of the product of hydroethidine and intracellular superoxide by HPLC and limitations of fluorescence PNAS, April 19, 2005; 102(16): 5727 - 5732. [Abstract] [Full Text] [PDF]

				S.-R. Lee, K. Tsuji, S.-R. Lee, and E. H. Lo Role of Matrix Metalloproteinases in Delayed Neuronal Damage after Transient Global Cerebral Ischemia J. Neurosci., January 21, 2004; 24(3): 671 - 678. [Abstract] [Full Text] [PDF]

				S. P. Didion, M. J. Ryan, L. A. Didion, P. E. Fegan, C. D. Sigmund, and F. M. Faraci Increased Superoxide and Vascular Dysfunction in CuZnSOD-Deficient Mice Circ. Res., November 15, 2002; 91(10): 938 - 944. [Abstract] [Full Text] [PDF]