scholarly journals Oxidative Stress Increases Phosphorylation of IκB Kinase-α by Enhancing NF-κB-Inducing Kinase after Transient Focal Cerebral Ischemia

2010 ◽  
Vol 30 (7) ◽  
pp. 1265-1274 ◽  
Author(s):  
Yun Seon Song ◽  
Min-Soo Kim ◽  
Hyun-Ae Kim ◽  
Bo-In Jung ◽  
Jiwon Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Nuclear Factor Κb ◽  
Nuclear Accumulation ◽  
Brain Endothelial Cells ◽  
Iκb Kinase ◽  
Transient Focal Cerebral Ischemia ◽  
Mouse Brain Endothelial Cells

The IκB kinase (IKK) complex is a central component in the classic activation of the nuclear factor-κB (NF-κB) pathway. It has been reported to function in physiologic responses, including cell death and inflammation. We have shown that IKK is regulated by oxidative status after transient focal cerebral ischemia (tFCI) in mice. However, the mechanism by which oxidative stress influences IKKs after tFCI is largely unknown. Nuclear accumulation and phosphorylation of IKKα (pIKKα) were observed 1 h after 30 mins of tFCI in mice. In copper/zinc-superoxide dismutase knockout mice, levels of NF-κB-inducing kinase (NIK) (an upstream kinase of IKKα), pIKKα, and phosphorylation of histone H3 (pH3) on Ser10 were increased after tFCI and were higher than in wild-type mice. Immunohistochemistry showed nuclear accumulation and pIKKα in mouse brain endothelial cells after tFCI. Nuclear factor-κB-inducing kinase was increased, and it enhanced pH3 by inducing pIKKα after oxygen–glucose deprivation (OGD) in mouse brain endothelial cells. Both NIK and pH3 interactions with IKKα were confirmed by coimmunoprecipitation. Treatment with IKKα small interfering RNA significantly reduced cell death after OGD. These results suggest that augmentation of NIK, IKKα, and pH3 in response to oxidative stress is involved in cell death after cerebral ischemia (or stroke).

scholarly journals 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

2005 ◽  
Vol 25 (10) ◽  
pp. 1301-1311 ◽  
Author(s):  
Yun S Song ◽  
Yong-Sun Lee ◽  
Pak H Chan
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Dna Array ◽  
Wild Type ◽  
Iκb Kinase ◽  
Transient Focal Cerebral Ischemia ◽  
Ikk Complex ◽  
In The Wild

Nuclear factor-κB (NF-κB) 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-κB, its mechanisms in the ischemic brain have not been clearly elucidated. We investigated the temporal profile of NF-κB-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 IκB kinase (IKK) complex (IKKα, β, and γ) 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 wild-type mice, but did not change in the SOD1 Tg mice throughout the 7 days. Electrophoretic mobility shift assay revealed activation of NF-κB DNA binding after tFCI in the wild-type mice. Nuclear factor-κB activation occurred at the same time, as did the phosphorylation and degradation of the inhibitory protein κBα. However, SOD1 prevented NF-κB activation, and phosphorylation and degradation of IκBα 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 IKKα, β, and γ in cerebral ischemia.

Changes in oxidative stress, iNOS activity and neutrophil infiltration in severe transient focal cerebral ischemia in rats

2002 ◽  
Vol 958 (1) ◽  
pp. 166-175 ◽  
Author(s):  
Dominique Lerouet ◽  
Virginie Beray-Berthat ◽  
Bruno Palmier ◽  
Michel Plotkine ◽  
Isabelle Margaill
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Neutrophil Infiltration ◽  
Inos Activity ◽  
Transient Focal Cerebral Ischemia

scholarly journals Interaction between XIAP and Smac/DIABLO in the Mouse Brain after Transient Focal Cerebral Ischemia

2003 ◽  
Vol 23 (9) ◽  
pp. 1010-1019 ◽  
Author(s):  
Atsushi Saito ◽  
Takeshi Hayashi ◽  
Shuzo Okuno ◽  
Michel Ferrand-Drake ◽  
Pak H. Chan
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Early Period ◽  
Neuronal Cell ◽  
Caspase 9 ◽  
Transient Focal Cerebral Ischemia ◽  
Apoptosis Protein ◽  
Caspase Cascade

The X chromosome–linked inhibitor-of-apoptosis protein (XIAP) contributes to apoptosis regulation after a variety of cell death stimuli. XIAP inhibits the caspase reaction via binding to caspases, and is inhibited via binding to the second mitochondria-derived activator of caspase (Smac)/DIABLO to tightly control apoptotic cell death. However, the interaction among XIAP, Smac/DIABLO, and caspases after in vivo cerebral ischemia is not well known. To clarify this issue, the authors examined time-dependent expression and interaction among XIAP, Smac/DIABLO, and activated caspase-9 by immunohistochemistry, Western blot analysis, and immunoprecipitation using an in vivo transient focal cerebral ischemia model. To examine the relationship of the XIAP pathway to the caspase cascade, a pan-caspase inhibitor was administered. XIAP increased concurrently with the release of Smac/DIABLO and the appearance of activated caspase-9 during the early period after reperfusion injury. The bindings of XIAP to Smac/DIABLO and to caspase-9 and the binding of Smac/DIABLO to caspase-9 reached a peak simultaneously after transient focal cerebral ischemia. Neither XIAP nor Smac/DIABLO expression was affected by caspase inhibition. These results suggest that the XIAP pathway was activated upstream of the caspase cascade and that interaction among XIAP, Smac/DIABLO, and caspase-9 plays an important role in the regulation of apoptotic neuronal cell death after transient focal cerebral ischemia.

scholarly journals Endonuclease G does not play an obligatory role in poly(ADP-ribose) polymerase-dependent cell death after transient focal cerebral ischemia

2010 ◽  
Vol 299 (1) ◽  
pp. R215-R221 ◽  
Author(s):  
Zhenfeng Xu ◽  
Jian Zhang ◽  
Karen K. David ◽  
Zeng-Jin Yang ◽  
Xiaoling Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Nuclear Translocation ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Wild Type ◽  
Endonuclease G ◽  
Transient Focal Cerebral Ischemia ◽  
Apoptosis Inducing Factor

Activation of poly(ADP-ribose) polymerase (PARP) and subsequent translocation of apoptosis-inducing factor contribute to caspase-independent neuronal injury from N-methyl-d-aspartate, oxygen-glucose deprivation, and ischemic stroke. Some studies have implicated endonuclease G in the DNA fragmentation associated with caspase-independent cell death. Here, we compared wild-type and endonuclease G null mice to investigate whether endonuclease G plays a role in the PARP-dependent injury that results from transient focal cerebral ischemia. Latex casts did not reveal differences in the cerebral arterial distribution territory or posterior communicating arterial diameter, and the decrease in laser-Doppler flux during middle cerebral artery occlusion was similar in wild-type and endonuclease G null mice. After 90 min of occlusion and 1 day of reperfusion, similar degrees of nuclear translocation of apoptosis-inducing factor and DNA degradation were evident in male wild-type and null mice. At 3 days of reperfusion, infarct volume and neurological deficit scores were not different between male wild-type and endonuclease G null mice or between female wild-type and endonuclease G null mice. These data demonstrate that endonuclease G is not required for the pathogenesis of transient focal ischemia in either male or female mice. Treatment with a PARP inhibitor decreased infarct volume and deficit scores equivalently in male wild-type and endonuclease G null mice, indicating that the injury in endonuclease G null mice remains dependent on PARP. Thus endonuclease G is not obligatory for executing PARP-dependent injury during ischemic stroke.

Quercetin Protects Against Oxidative Stress Associated Damages in a Rat Model of Transient Focal Cerebral Ischemia and Reperfusion

2011 ◽  
Vol 36 (8) ◽  
pp. 1360-1371 ◽  
Author(s):  
Ajmal Ahmad ◽  
Mohd. Moshahid Khan ◽  
Md. Nasrul Hoda ◽  
Syed Shadab Raza ◽  
M. Badruzzaman Khan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Rat Model ◽  
Focal Cerebral Ischemia ◽  
Ischemia And Reperfusion ◽  
Transient Focal Cerebral Ischemia ◽  
Cerebral Ischemia And Reperfusion

Dietary genistein and equol (4′, 7 isoflavandiol) reduce oxidative stress and protect rats against focal cerebral ischemia

2010 ◽  
Vol 299 (3) ◽  
pp. R871-R877 ◽  
Author(s):  
Yulin Ma ◽  
Jennifer C. Sullivan ◽  
Derek A. Schreihofer
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Hormone Replacement ◽  
Cerebral Injury ◽  
Female Rats ◽  
Neurological Deficits ◽  
Soy Isoflavone ◽  
Transient Focal Cerebral Ischemia ◽  
The Brain

High soy diets reduce injury in rat models of focal cerebral ischemia and are proposed as alternatives to hormone replacement therapy for postmenopausal women. The present study tests the hypothesis that the major soy isoflavone genistein and the daidzein metabolite equol are neuroprotective in transient focal cerebral ischemia in male and ovariectomized (OVX) female rats by inhibiting oxidative stress. Genistein is the primary circulating soy isoflavone in humans, whereas equol is the primary circulating isoflavone in rats. Male and OVX female Sprague-Dawley rats were fed an isoflavone-reduced diet alone or supplemented with genistein (500 ppm) or equol (250 ppm) for 2 wk prior to 90-min transient middle cerebral artery occlusion followed by reperfusion under isoflurane anesthesia. Indices of oxidative stress were determined 24 h after reperfusion, and cerebral injury was evaluated 3 days after reperfusion. Genistein and equol significantly reduced infarct size in both sexes. Further studies in OVX female rats revealed that this neuroprotection was accompanied by a decrease in NAD(P)H oxidase activity and superoxide levels in the brain. In addition, equol reduced plasma thiobarbituric acid reactive substances, and neurological deficits up to 7 days after injury. There were no significant differences in cerebral blood flow among treatment groups. In conclusion, dietary soy isoflavones are neuroprotective in transient focal cerebral ischemia in male and OVX female rats. These isoflavones may protect the brain via increases in endogenous antioxidant mechanisms and reduced oxidative stress.

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