Nuclear factor-κB activation during cerebral reperfusion: effect of attenuation with N-acetylcysteine treatment

Carroll, James E.; Howard, Eugene F.; Hess, David C.; Wakade, Chandramohan; Chen, Qiang; Cheng, Charles Y.

doi:10.1016/s0169-328x(98)00045-x

Cited by 81 publications

(44 citation statements)

References 27 publications

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“…In earlier publications, inhibition of NFB activation after middle cerebral artery occlusion has been described to decrease neuronal damage (9,10,12,23). How can we explain the results of several studies showing neuroprotection after NFB inhibition?…”

Section: Discussionmentioning

confidence: 96%

“…However, inhibition of the proteasome pathway may also alter the availability of other proteins that are involved in neuronal damage. N-acetylcysteine inhibits NFB activation but also has antioxidant activity, which may contribute to neuroprotection (23). Therefore, it is difficult to conclude from these studies whether the observed neuroprotective effects are mediated via inhibition of NFB alone or are also dependent on the additional effects of these drugs.…”

Section: Discussionmentioning

confidence: 99%

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Selective Inhibition of Nuclear Factor-κB Activation After Hypoxia/Ischemia in Neonatal Rats Is Not Neuroprotective

et al. 2006

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Activated nuclear factor-B (NFB) has been shown to increase transcription of several genes that could potentially contribute to neuronal damage, such as proinflammatory cytokines, chemokines, and inducible nitric oxide synthase. The aim of our study was to investigate whether inhibition of NFB activation could prevent hypoxia/ischemia (HI)-induced cerebral damage in neonatal rats. We used a cell permeable peptide (NEMO binding domain [NBD] peptide) that is known to prevent the association of the regulatory protein NEMO with IKK, the kinase that activates NFB. Via this mechanism, the NBD peptide can specifically block the activation of NFB, without inhibiting basal NFB activity. Cerebral HI was induced in neonatal rats by occlusion of the right carotid artery followed by 90 min of hypoxia (FiO 2 ϭ 0.08). Immediately upon reoxygenation, as well as 6 and 12 h later, rats were treated with vehicle or NBD peptide (20 mg/kg i.p.). Histologic analysis of brain damage was performed at 6 wk after HI. To assess NFB activation, electromobility shift assays (EMSAs) were performed on brain nuclear extracts obtained 6 h after reoxygenation. Increased NFB activity could be shown at 6 h after HI in both hemispheres. Peripheral administration of NBD peptide prevented this HI-induced increase in NFB activity in both hemispheres. Histologic analysis of long-term cerebral damage revealed that inhibition of NFB activation by administration of NBD peptide at 0, 6, and 12 h after HI resulted in an increment of neuronal damage. In conclusion, our data suggest that inhibition of NFB activation using NBD peptide early after HI increases brain damage in neonatal rats. (Pediatr Res 59: 232-236, 2006) P erinatal HI is a common cause of neonatal mortality and morbidity. Long-term effects can be cerebral palsy and/or impaired neurodevelopmental outcome (1,2). During HI and in particular upon reperfusion and reoxygenation, a cascade of potentially destructive pathways is activated eventually leading to neuronal cell death (3,4).Activation of the transcription factor NFB regulates the production of pro-and anti-inflammatory cytokines, chemokines, and inducible nitric oxide synthase and of adhesion molecules, which together will promote apoptosis and neuronal cell death (5,6). In resting cells, the heterodimeric NFB, consisting of a p50 and a p65 protein, is retained in the cytoplasm through interaction with the inhibitory protein IB. Activation of NFB requires phosphorylation of IB by the I-kinase complex, consisting of IKK␣, IKK␤, and the regulatory protein NEMO. Phosphorylated IB will be ubiquitinated and degraded via the proteasome pathway. The free or activated NFB can then translocate to the nucleus of the cell and will bind to the promoter sequences of many target genes (7).Evidence of a role for NFB activation in HI-induced cerebral damage comes from animal models. In NFB-p50 knockout mice, neuronal damage was significantly reduced in an adult model of stroke by occlusion of the middle cerebral artery (8). Similarly, inhibitio...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Nuclear Factor-κB Activation After Hypoxia/Ischemia in Neonatal Rats Is Not Neuroprotective

et al. 2006

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“…Several synthetic free radical scavengers have been evaluated in animal models of cerebral ischemia and reperfusion and have been shown to be protective. For example, antioxidants, N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate have important neuroprotective effects against I/R-induced injury through downregulating the activation of NF-κB [25,26,27] . Therefore, our present study is designed to further investigate the protective effects of selenite, an antioxidant, during reperfusion after 15 min of global brain ischemia in rat hippocampi.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection of selenite against ischemic brain injury through negatively regulating early activation of ASK1/JNK cascade via activation of PI3K/AKT pathway

Wang

Zhang

et al. 2007

Acta Pharmacologica Sinica

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Aim: To investigate whether selenite, a known antioxidant, could decrease the activation of apoptosis signal regulating kinase 1/c-jun N-terminal kinase (ASK1/ JNK) signaling cascade in cerebral ischemia/reperfusion (I/R) by activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in rat hippocampi, and the neuroprotective effect of selenite against ischemic injury after 15 min of transient brain ischemia. Methods: Transient global brain ischemia was induced by 4-vessel occlusion into adult male Sprague-Dawley rats weighing 250-300 g. The rats were pretreated only with selenite (0.3 mg/kg dissolved in 0.9% saline) every 24 h for 7 d by means of intravenous injection of the tail or combined with LY294002 from d 5 by left cerebral ventricle injection before surgery. Results: Selenite significantly increased AKT1 activation and decreased the activation of ASK1/ JNK cascade via phosphorylating ASK1 at Ser-83 residue by AKT1 during early reperfusion after 15 min transient global brain ischemia. On the contrary, combined pretreatment of the rats with LY294002 (a specific PI3K inhibitor) and selenite significantly inhibited the effects solely with selenite. Conclusion: The activation of the pro-apoptotic ASK1/JNK cascade, which is closely associated with oxidative stress, could be suppressed by selenite through activating the antiapoptotic PI3K/AKT pathway during early reperfusion after cerebral ischemia in rat hippocampi.

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“…Ischemic damage was significantly reduced in p50 knockout mice. There are reports of activation of NF-kB after tFCI and global cerebral ischemia (Salminen et al, 1995;Clemens et al, 1997;Gabriel et al, 1999;Stephenson et al, 2000;Huang et al, 2001) and of the neuroprotective role of antioxidants (Carroll et al, 1998;Clemens, 2000). However, Irving et al (2000) showed a decrease in NF-kB 6 h after an initial increase at 3 h in permanent FCI.…”

Section: Introductionmentioning

confidence: 97%

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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Nuclear factor-κB activation during cerebral reperfusion: effect of attenuation with N-acetylcysteine treatment

Cited by 81 publications

References 27 publications

Selective Inhibition of Nuclear Factor-κB Activation After Hypoxia/Ischemia in Neonatal Rats Is Not Neuroprotective

Selective Inhibition of Nuclear Factor-κB Activation After Hypoxia/Ischemia in Neonatal Rats Is Not Neuroprotective

Neuroprotection of selenite against ischemic brain injury through negatively regulating early activation of ASK1/JNK cascade via activation of PI3K/AKT pathway

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

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