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

Kondo, Takeo; Reaume, Andrew G.; Huang, Ting; Carlson, Elaine J.; Murakami, Kensuke; Chen, Sylvia F.; Hoffman, Edward L.; Scott, Richard W.; Epstein, Charles J.; Chan, Pak H.

doi:10.1523/jneurosci.17-11-04180.1997

Cited by 421 publications

(304 citation statements)

References 50 publications

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“…Superoxide dismutases are known to have a protective role against focal ischemic injury by counteracting the deleterious effects of ROS (Kinouchi et al, 1991;Chan, 1996;Kondo et al, 1997;Murakami et al, 1998). It is well established that astrocyte cultures from SOD1 Tg mice show increased resistance to xanthine oxidase/hypoxanthine and the superoxide generator, menadione Figure 3 Reverse transcriptase-polymerase chain reaction analysis of NF-kB p50 mRNA and Western blot analysis of WT and SOD1 Tg astrocytes transfected with NF-kB p50 siRNA.…”

Section: Discussionmentioning

confidence: 99%

Biphasic Role of Nuclear Factor-k B on Cell Survival and COX-2 Expression in SOD1 Tg Astrocytes after Oxygen Glucose Deprivation

Lee

Song

Giffard

et al. 2005

J Cereb Blood Flow Metab

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In cytoplasm, nuclear factor-jB (NF-jB) is associated with the inhibitory protein, IjBa. On activation by H 2 O 2 , IjBa is phosphorylated and degraded, exposing the nuclear localization signals on the NFjB heterodimer. Cyclooxygenase-2 (COX-2), which mediates prostaglandin synthesis during inflammation, is induced by oxidative stress mediated by NF-jB. We investigated whether the NFjB signaling pathway affected cell death and COX-2 expression after hypoxia-induced oxidative stress in wild-type (WT) and copper/zinc-superoxide dismutase transgenic (SOD1 Tg) astrocytes. In WT astrocytes, phospho-IjBa was highly expressed after oxygen-glucose deprivation (OGD) and 2 h of reperfusion, concomitant with the decrease in IjBa. The NF-jB p50 level increased similarly in WT and SOD1 Tg astrocytes (1.2-/1.4-fold) after OGD. Electrophoretic mobility shift assay showed higher DNA-binding activity of NF-jB p50 in WT than in SOD1 Tg astrocytes 6 h after 4 h of OGD. The COX-2 level was induced by 2.7-and 1.3-fold after OGD in WT and SOD1 Tg astrocytes, and an antioxidant protected both groups against OGD injury. Superoxide dismutase transgenic cells were 23% more protective against OGD injury than WTs when assessed by lactate dehydrogenase release. However, transfection of NF-jB small interfering RNAs in SOD1 Tg astrocytes aggravated cell death and increased COX-2 expression. These results suggest that the NF-jB signaling pathway induced COX-2 expression and promoted cell death in WTs after OGD injury; however, NF-jB activation protected cells and decreased COX-2 expression in SOD1 Tg astrocytes. This biphasic role of NF-jB might be coordinately regulated by reactive oxygen species levels in astrocytes, thereby functioning as a regulator of cell death/survival.

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Section: Discussionmentioning

confidence: 99%

Biphasic Role of Nuclear Factor-k B on Cell Survival and COX-2 Expression in SOD1 Tg Astrocytes after Oxygen Glucose Deprivation

Lee

Song

Giffard

et al. 2005

J Cereb Blood Flow Metab

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“…ROS production was determined using in vivo hydroethidine microfluorography (Kondo et al, 1997), as described previously (Cho et al, 2005a;Kunz et al, 2007). Hydroethidine is a cell-permeant dye that is oxidized to ethidium and related products by superoxide (Robinson et al, 2006).…”

Section: Quantification Of Ros Production and 3-nitrotyrosine Immunormentioning

confidence: 99%

Neurovascular Protection by Ischemic Tolerance: Role of Nitric Oxide and Reactive Oxygen Species

Kunz¹,

Park²,

Abe³

et al. 2007

J. Neurosci.

131

117

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Cerebral ischemic preconditioning or tolerance is a powerful neuroprotective phenomenon by which a sublethal injurious stimulus renders the brain resistant to a subsequent damaging ischemic insult. We used lipopolysaccharide (LPS) as a preconditioning stimulus in a mouse model of middle cerebral artery occlusion (MCAO) to examine whether improvements in cerebrovascular function contribute to the protective effect. Administration of LPS 24 h before MCAO reduced the infarct by 68% and improved ischemic cerebral blood flow (CBF) by 114% in brain areas spared from infarction. In addition, LPS prevented the dysfunction in cerebrovascular regulation induced by MCAO, as demonstrated by normalization of the increase in CBF produced by neural activity, hypercapnia, or by the endotheliumdependent vasodilator acetylcholine. These beneficial effects of LPS were not observed in mice lacking inducible nitric oxide synthase (iNOS) or the nox2 subunit of the superoxide-producing enzyme NADPH oxidase. LPS increased reactive oxygen species and the peroxynitrite marker 3-nitrotyrosine in wild-type mice but not in nox2 nulls. The peroxynitrite decomposition catalyst 5,10,15, 20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) attenuated LPS-induced nitration and counteracted the beneficial effects of LPS on infarct volume, ischemic CBF, and vascular reactivity. Thus, LPS preserves neurovascular function and ameliorates CBF in regions of the ischemic territory at risk for infarction. This effect is mediated by peroxynitrite formed from iNOS-derived NO and nox2-derived superoxide. The data indicate that preservation of cerebrovascular function is an essential component of ischemic tolerance and suggest that combining neuroprotection and vasoprotection may be a valuable strategy for treating ischemic brain injury.

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“…In mice, expression of mutant SOD1, but not complete elimination of SOD1, causes ALS. Nonetheless, SOD1 -knockout mice show reduced fertility (Matzuk et al ., 1998), motor axonopathy (Shefner et al ., 1999), age-associated loss of cochlear hair cells (McFadden et al ., 2001) and neuromuscular junction synapses , as well as enhanced susceptibility to a variety of noxious assaults on the nervous system, such as axonal injury (Reaume et al ., 1996), ischaemia (Kondo et al ., 1997;Kawase et al ., 1999), haemolysate exposure (Matz et al ., 2000) and irradiation (Behndig et al ., 2001). Given the toxicity of the mutant protein and the functional importance of the wild-type, the ideal therapy for ALS would selectively block expression of the mutant while retaining expression of wild-type protein.…”

Section: Introductionmentioning

confidence: 99%

Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis

et al. 2003

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SummaryRNA interference (RNAi) can achieve sequence-selective inactivation of gene expression in a wide variety of eukaryotes by introducing double-stranded RNA corresponding to the target gene. Here we explore the potential of RNAi as a therapy for amyotrophic lateral sclerosis (ALS) caused by mutations in the Cu, Zn superoxide dismutase ( SOD1 ) gene. Although the mutant SOD1 is toxic, the wild-type SOD1 performs important functions. Therefore, the ideal therapeutic strategy should be to selectively inhibit the mutant, but not the wild-type SOD1 expression. Because most SOD1 mutations are single nucleotide changes, to selectively silence the mutant requires singlenucleotide specificity. By coupling rational design of small interfering RNAs (siRNAs) with their validation in RNAi reactions in vitro and in vivo , we have identified siRNA sequences with this specificity. A similarly designed sequence, when expressed as small hairpin RNA (shRNA) under the control of an RNA polymerase III (pol III) promoter, retains the single-nucleotide specificity. Thus, RNAi is a promising therapy for ALS and other disorders caused by dominant, gain-of-function gene mutations.

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

Cited by 421 publications

References 50 publications

Biphasic Role of Nuclear Factor-k B on Cell Survival and COX-2 Expression in SOD1 Tg Astrocytes after Oxygen Glucose Deprivation

Biphasic Role of Nuclear Factor-k B on Cell Survival and COX-2 Expression in SOD1 Tg Astrocytes after Oxygen Glucose Deprivation

Neurovascular Protection by Ischemic Tolerance: Role of Nitric Oxide and Reactive Oxygen Species

Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis

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