Extracellular superoxide dismutase deficiency worsens outcome from focal cerebral ischemia in the mouse

Sheng, Huaxin; Brady, Todd C.; Pearlstein, Robert D.; Crapo, James D.; Warner, David S.

doi:10.1016/s0304-3940(99)00316-x

Cited by 85 publications

(46 citation statements)

References 15 publications

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“…We assumed that short telomeres might indicate low antioxidant capacity and thus higher risk of stroke-induced brain damage in vivo (18). Data demonstrating a protective role for EC-SOD against ischemic brain damage (40,41) and age-related deterioration (42) together with the demonstration of a role for EC-SOD in telomere maintenance in human cells (this study) are in agreement with this interpretation.…”

Section: Resultssupporting

confidence: 84%

“…More interestingly, EC-SOD plays an important role in brain function, as both young EC-SODover-expressing and knockout mice are impaired in spatial learning and memory, which has been attributed to a deregulation of nitric oxide catabolism (38,39). Conversely, knockout mice are more sensitive to focal cerebral ischemia (40), and EC-SOD over-expression increases the resistance of mice to global ischemia (41). Furthermore, improved learning and memory performance in aged mice over-expressing EC-SOD has been demonstrated recently (42).…”

Section: Resultsmentioning

confidence: 99%

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Extracellular Superoxide Dismutase Is a Major Antioxidant in Human Fibroblasts and Slows Telomere Shortening

Serra¹,

Zglinicki²,

Lorenz³

et al. 2003

Journal of Biological Chemistry

247

154

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There is good evidence that telomere shortening acts as a biological clock in human fibroblasts, limiting the number of population doublings a culture can achieve. Oxidative stress also limits the growth potential of human cells, and recent data show that the effect of mild oxidative stress is mediated by a stress-related increased rate of telomere shortening. Thus, fibroblast strains have donor-specific antioxidant defense, telomere shortening rate, and growth potential. We used low-density gene expression array analysis of fibroblast strains with different antioxidant potentials and telomere shortening rates to identify gene products responsible for these differences. Extracellular superoxide dismutase was identified as the strongest candidate, a correlation that was confirmed by Northern blotting. Over-expression of this gene in human fibroblasts with low antioxidant capacity increased total cellular superoxide dismutase activity, decreased the intracellular peroxide content, slowed the telomere shortening rate, and elongated the life span of these cells under normoxia and hyperoxia. These results identify extracellular superoxide dismutase as an important antioxidant gene product in human fibroblasts, confirm the causal role of oxidative stress for telomere shortening, and strongly suggest that the senescence-like arrest under mild oxidative stress is telomere-driven.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Extracellular Superoxide Dismutase Is a Major Antioxidant in Human Fibroblasts and Slows Telomere Shortening

Serra¹,

Zglinicki²,

Lorenz³

et al. 2003

Journal of Biological Chemistry

247

154

View full text Add to dashboard Cite

show abstract

“…71 The ECSOD level in the brain is much lower than in other organs, but recent studies have demonstrated that overexpression of this protein provides protection after focal and global ischemia, whereas KO animals showed a larger infarct after focal ischemia. [72][73][74] Results from pharmacological trials and studies using Tg/KO rodents provide strong evidence to support the importance of SODs and superoxide in the pathophysiology of ischemic brain injury.…”

Section: Antioxidant Enzymes and Studies Using Tg And Ko Animalsmentioning

confidence: 95%

Neuronal death/survival signaling pathways in cerebral ischemia

et al. 2004

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Summary:Cumulative evidence suggests that apoptosis plays a pivotal role in cell death in vitro after hypoxia. Apoptotic cell death pathways have also been implicated in ischemic cerebral injury in in vivo ischemia models. Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and the numerous reports suggest the involvement of cell survival/death signaling pathways in the pathogenesis of apoptotic cell death in ischemic lesions. In these models, reoxygenation during reperfusion provides a substrate for numerous enzymatic oxidation reactions. Oxygen radicals damage cellular lipids, proteins and nucleic acids, and initiate cell signaling pathways after cerebral ischemia. Genetic manipulation of intrinsic antioxidants and factors in the signaling pathways has provided substantial understanding of the mechanisms involved in cell death/survival signaling pathways and the role of oxygen radicals in ischemic cerebral injury. Future studies of these pathways may provide novel therapeutic strategies in clinical stroke.

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“…However, its overexpression has been shown to be beneficial in models of cerebral ischemia, 81,82 while mice deficient in this enzyme are more vulnerable to ischemic injury. 83 Pharmacologic variants of SOD have also shown some efficacy in experimental models of TBI. These variants have been generated to increase the blood brain barrier permeability of SOD and thus improve its efficacy.…”

Section: Oxidative Damagementioning

confidence: 99%

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

Potts

Koh

Whetstone

et al. 2006

NeuroRX

143

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Summary: Traumatic brain injury (TBI) is the leading cause of morbidity and mortality among children and both clinical and experimental data reveal that the immature brain is unique in its response and vulnerability to TBI compared to the adult brain. Current therapies for pediatric TBI focus on physiologic derangements and are based primarily on adult data. However, it is now evident that secondary biochemical perturbations play an important role in the pathobiology of pediatric TBI and may provide specific therapeutic targets for the treatment of the head-injured child. In this review, we discuss three specific components of the secondary pathogenesis of pediatric TBIinflammation, oxidative injury, and iron-induced damage -and potential therapeutic strategies associated with each. The inflammatory response in the immature brain is more robust than in the adult and characterized by greater disruption of the blood-brain barrier and elaboration of cytokines. The immature brain also has a muted response to oxidative stress compared to the adult due to inadequate expression of certain antioxidant molecules. In addition, the developing brain is less able to detoxify free iron after TBI-induced hemorrhage and cell death. These processes thus provide potential therapeutic targets that may be tailored to pediatric TBI, including anti-inflammatory agents such as minocycline, antioxidants such as glutathione peroxidase, and the iron chelator deferoxamine.

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Extracellular superoxide dismutase deficiency worsens outcome from focal cerebral ischemia in the mouse

Cited by 85 publications

References 15 publications

Extracellular Superoxide Dismutase Is a Major Antioxidant in Human Fibroblasts and Slows Telomere Shortening

Extracellular Superoxide Dismutase Is a Major Antioxidant in Human Fibroblasts and Slows Telomere Shortening

Neuronal death/survival signaling pathways in cerebral ischemia

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

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