title: Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia.
abstract: Apoptotic neuronal cell death has recently been associated with the development of infarction after cerebral ischemia. In a variety of studies, CuZn-superoxide dismutase (CuZn-SOD) has been shown to protect the brain from ischemic injury. A possible role for CuZn-SOD-related modulation of neuronal viability is suggested by the finding that CuZn-SOD inhibits apoptotic neuronal cell death in response to some forms of cellular damage. We evaluated this possibility in the model of transient focal cerebral ischemia in mice bearing a disruption of the CuZn-SOD gene (Sod1). Homozygous mutant (Sod1 -/-) mice had no detectable CuZn-SOD activity, and heterozygous mutants (Sod1 +/-) showed a 50% decrease compared with wild-type mice. Sod1 -/- mice showed a high level of blood-brain barrier disruption soon after 1 hr of middle cerebral artery occlusion and 100% mortality at 24 hr after ischemia. Sod1 +/- mice showed 30% mortality at 24 hr after ischemia, and neurological deficits were exacerbated compared with wild-type controls. The Sod1 +/- animals also had increased infarct volume and brain swelling, accompanied by increased apoptotic neuronal cell death as indicated by the in situ nick-end labeling technique to detect DNA fragmentation and morphological criteria. These results suggest that oxygen-free radicals, especially superoxide anions, are an important factor for the development of infarction by brain edema formation and apoptotic neuronal cell death after focal cerebral ischemia and reperfusion.
authors.affiliation: Department of Neurological Surgery, University of California School of Medicine, San Francisco, California 94143, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.forename: A G
authors.initials: AG
authors.lastname: Reaume
authors.forename: T T
authors.initials: TT
authors.lastname: Huang
authors.forename: E
authors.initials: E
authors.lastname: Carlson
authors.forename: K
authors.initials: K
authors.lastname: Murakami
authors.forename: S F
authors.initials: SF
authors.lastname: Chen
authors.forename: E K
authors.initials: EK
authors.lastname: Hoffman
authors.forename: R W
authors.initials: RW
authors.lastname: Scott
authors.forename: C J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: P H
authors.initials: PH
authors.lastname: Chan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001710:Biotin; D001812:Blood-Brain Barrier / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002544:Cerebral Infarction / Q000503:physiopathology; D053938:DNA Fragmentation; D003856:Deoxyuracil Nucleotides; D004487:Edema / Q000503:physiopathology*; D005070:Evans Blue / Q000493:pharmacokinetics; D002546:Ischemic Attack, Transient / Q000201:enzymology* / Q000401:mortality / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D009460:Neurologic Examination; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D016548:Prosencephalon / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000502:physiology; D013194:Staining and Labeling; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism
chemical_list: D003856:Deoxyuracil Nucleotides; D017382:Reactive Oxygen Species; D005070:Evans Blue; D001710:Biotin; D013482:Superoxide Dismutase