Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome.

Epstein, Charles J.; Avraham, Karen B.; Lovett, Michael; Smith, Sarah M.; Elroy‐Stein, Orna; Rotman, Galit; Bry, Cheryl G.; Groner, Yoram

doi:10.1073/pnas.84.22.8044

Cited by 407 publications

(217 citation statements)

References 38 publications

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“…Transgenic mice of the TgHS/SF-218 strain, which carries the SOD1 gene with a CD-1 background, were derived from the founder stock (Epstein et al, 1987). There were no observable phenotypic differences between the Tg mice and their wild-type normal littermates.…”

Section: Transient Focal Cerebral Ischemiamentioning

confidence: 99%

Oxidative Stress Transiently Decreases the IKK Complex (IKKα, β, and γ), an Upstream Component of NF-κB Signaling, after Transient Focal Cerebral Ischemia in Mice

Song

Lee

Chan

2005

J Cereb Blood Flow Metab

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Nuclear factor-jB (NF-jB) has a central role in coordinating the expression of a wide variety of genes that control cerebral ischemia. Although there has been intense research on NF-jB, its mechanisms in the ischemic brain have not been clearly elucidated. We investigated the temporal profile of NFjB-related genes using a complementary DNA array method in wild-type mice and human copper/ zinc-superoxide dismutase transgenic (SOD1 Tg) mice that had low-level reactive oxygen species (ROS) by scavenging superoxide. Our DNA array showed that IjB kinase (IKK) complex (IKKa, b, and c) mRNA in the wild-type mice was decreased as early as 1 h after reperfusion, after 30 mins of transient focal cerebral ischemia (tFCI). In contrast, tFCI in the SOD1 Tg mice caused an increase in the IKK complex. The IKK complex protein levels were also drastically decreased at 1 h in the wildtype mice, but did not change in the SOD1 Tg mice throughout the 7 days. Electrophoretic mobility shift assay revealed activation of NF-jB DNA binding after tFCI in the wild-type mice. Nuclear factorjB activation occurred at the same time, as did the phosphorylation and degradation of the inhibitory protein IjBa. However, SOD1 prevented NF-jB activation, and phosphorylation and degradation of IjBa after tFCI. Superoxide production and ubiquitinated protein in the SOD1 Tg mice were also lower than in the wild-type mice after tFCI. These results suggest that ROS are implicated in transient downregulation of IKKa, b, and c in cerebral ischemia.

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Section: Transient Focal Cerebral Ischemiamentioning

confidence: 99%

Oxidative Stress Transiently Decreases the IKK Complex (IKKα, β, and γ), an Upstream Component of NF-κB Signaling, after Transient Focal Cerebral Ischemia in Mice

Song

Lee

Chan

2005

J Cereb Blood Flow Metab

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“…For the gel electrophoresis assay, previously described methods (Epstein et al, 1987) were used. For the measurement of CuZn-SOD-specific activity, supernatant fluids from red blood cell lysates or brain homogenates were assayed by a previously described method based on cytochrome C reduction (McCord and Fridovich, 1969).…”

Section: Methodsmentioning

confidence: 99%

Reduction of CuZn-Superoxide Dismutase Activity Exacerbates Neuronal Cell Injury and Edema Formation after Transient Focal Cerebral Ischemia

Reaume²,

et al. 1997

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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 Ϫ/Ϫ) mice had no detectable CuZn-SOD activity, and heterozygous mutants (Sod1 ϩ/Ϫ) showed a 50% decrease compared with wild-type mice. Sod1 Ϫ/Ϫ mice showed a high level of bloodbrain barrier disruption soon after 1 hr of middle cerebral artery occlusion and 100% mortality at 24 hr after ischemia. Sod1 ϩ/Ϫ mice showed 30% mortality at 24 hr after ischemia, and neurological deficits were exacerbated compared with wildtype controls. The Sod1 ϩ/Ϫ 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. Key words: CuZn-superoxide dismutase; focal cerebral ischemia; blood-brain barrier; Evans blue extravasation; neuronal apoptosis; TUNEL; oxidative stressOxygen-free radicals are believed to be involved in the pathogenesis after cerebral ischemia and reperfusion. During cerebral ischemia, a number of events that predispose the brain to the formation of oxygen-free radicals may occur (Siesjö, 1984;McCord, 1985). After reperfusion, these events can set off a cascade of other biochemical and molecular sequelae such as the xanthine-xanthine oxidase reaction and phospholipase activation, leading to free-radical production (Gaudet and Levine, 1979;Chan et al., 1984;Siesjö, 1984;McCord, 1985). Among these oxygen-free radicals, superoxide anion (O 2 Ϫ ), being directly toxic to neurons (Fridovich, 1986;Patel et al., 1996), may initiate a free radical-mediated chain reaction causing additional CNS damage (Saugstad and Aasen, 1980;Chan, 1994).One of the manifestations of CNS damage after cerebral ischemia is the formation of brain edema caused by the breakdown of the blood-brain barrier (BBB). CuZn-superoxide dismutase (CuZn-SOD), a cytosolic protein, prevents vasogenic brain edema after several kinds of injuries Kinouchi et al., 1991;Shukla et al., 1993), suggesting that O 2 Ϫ is an important factor for BBB disruption. Another manifestation of CNS damage is the direct injury of neuronal cells, including excitatory events that are induced by glutamate release after cerebral ischemia. Glutamate elevates cytosolic free calcium (Ca 2ϩ ) (...

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“…In the dismutation reaction the enzyme exhibits a bell-shaped protective effect against free radicals, at higher as well as lower concentrations giving way for increased lipid peroxidation (72,73). The Superoxide dismutase also catalyzes the formation of hydroxyl radical from hydrogen peroxide (74), and the generation of peroxynitrite from nitric oxide and Superoxide which decomposes to the highly reactive hydroxyl free radical (75). These paradoxical effects of Superoxide dismutase may be of significance in porphyric neuropathy, as a high expression of mutant Superoxide dismutase in mice has been observed Eur J Clijn Chem Clin Biochem 1995; 33 (No 4) to cause damages to the ventral «horn neurons of the spinal cord, i. e. the part of the nervous system taking the brunt of the damage in human acute porphyria (76,77).…”

Section: Discussionmentioning

confidence: 99%

Markers for Vulnerability in Acute Porphyria. A Hypothesis Paper

Thunell¹,

Andersson²,

Carlmark³

et al. 1995

CCLM

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Summary:Previously symptomatic and permanently asymptomatic carriers of a gene mutation for acute intermittent porphyria as well as matched controls were screened with regard to a series of variables of possible relevance to the development of porphyric symptoms. The basis for the study was a concept of acute porphyria as a condition of a permanent system overload of oxidative stress, with long term effects on hepatic and renal tissue, and with instances of periodic overload of free radicals giving rise to acute neurologic involvement.Leukocyte concentrations of manganese, calcium, iron and zinc, as well as erythrocyte calcium differed between the groups, acute intermittent porphyria gene carriers, irrespective of previous porphyric illness, showing significantly higher levels than the controls.Manganese was found to be the most discriminative component of all the 78 variables investigated, accounting for about 98 per cent of the variance between the groups. An increment, by a factor of four, in cellular manganese is suggestive of an increase, in acute intermittent porphyria, of a manganese associated enzyme, e. g. glutamine synthetase, pyruvate carboxylase or mitochondrial Superoxide dismutase. The best fit into the model considered is provided by a theory focused on Superoxide dismutase, induced in response to Superoxide anion radical produced from aminolaevulinic acid. In porphyria gene carriers seemingly resistent to porphyric manifestations, an increase in potentially prooxidant cellular iron is matched by a proportional increment in manganese, i.e. presumably by a corresponding mitochondrial Superoxide dismutase induction. This mechanism is not operative in porphyric individuals prone to development of neuropsychiatric symptoms.In acute intermittent poiphyria with a history of porphyric illness there is a positive correlation between erythrocyte manganese and serum folate and a negative correlation between leukocyte ferrochelatase activity and serum cobalamin concentration. This may mirror a role of the cobalamin-folate system in the acute porphyric process.

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Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome.

Cited by 407 publications

References 38 publications

Oxidative Stress Transiently Decreases the IKK Complex (IKKα, β, and γ), an Upstream Component of NF-κB Signaling, after Transient Focal Cerebral Ischemia in Mice

Oxidative Stress Transiently Decreases the IKK Complex (IKKα, β, and γ), an Upstream Component of NF-κB Signaling, after Transient Focal Cerebral Ischemia in Mice

Reduction of CuZn-Superoxide Dismutase Activity Exacerbates Neuronal Cell Injury and Edema Formation after Transient Focal Cerebral Ischemia

Markers for Vulnerability in Acute Porphyria. A Hypothesis Paper

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