SOD1 down-regulates NF-κB and c-Myc expression in mice after transient focal cerebral ischemia

Department of Neurosurgery, Stanford University School of Medicine, California, USA.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.34). 03/2001; 21(2):163-73. DOI: 10.1097/00004647-200102000-00008
Source: PubMed

ABSTRACT Reactive oxygen species (ROS) are implicated in reperfusion injury after focal cerebral ischemia (FCI). Reactive oxygen species regulate activity of transcription factors like NF-kappaB. The authors investigated the role of ROS in NF-kappaB activity after FCI using transgenic mice that overexpressed human copper/zinc-superoxide dismutase (SOD1) and that had reduced infarction volume after FCI. Superoxide dismutase transgenic and wild-type mice were subjected to 1 hour of middle cerebral artery occlusion (MCAO) and subsequent reperfusion. Immunohistochemistry showed SOD1 overexpression attenuated ischemia-induced NF-kappaB p65 immunoreactivity. Colocalization of NF-kappaB and the neuronal marker, microtubule-associated proteins (MAPs), showed that NF-kappaB was up-regulated in neurons after FCI. Electrophoretic mobility shift assays showed that SODI overexpression reduced ischemia-induced NF-kappaB DNA binding activity. Supershift assays showed that DNA-protein complexes contained p65 and p50 subunits. Immunoreactivity of c-myc, an NF-kappaB downstream gene, was increased in the ischemic cortex and colocalized with NF-kappaB. Western blotting showed that SOD1 overexpression reduced NF-kappaB and c-Myc protein levels in the ischemic brain. Colocalization of c-Myc and TUNEL staining was observed 24 hours after FCI. The current findings provide the first evidence that SOD1 overexpression attenuates activation of NF-kappaB after transient FCI in mice and that preventing this early activation may block expression of downstream deleterious genes like c-myc, thereby reducing ischemic damage.

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    • "Specifically , a substantial and persistent production of these cytokines can significantly increase the risk and extent of brain injury [10] [14]. For another, NF-κB, an important transcription factor that plays a pivotal role in mediating inflammatory response to proinflammatory cytokines [15], was also upregulated during cerebral IRI [16]. Similar cerebral IRI-induced inflammation reaction and neural damage were reportedly observed in the hippocampus [17] [18]. "
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    • "These results implied that excessive AMPK activation in vitro is deleterious to SH-SY5Y cells and that Sal A acts to decrease the excessive activation of AMPK, which results in neuroprotection, by relieving acidosis and decreasing apoptotic activation. The actions of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in cerebral ischemia have been widely reported [29] [30] [31] "
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    • "The present study suggests that, ROS and RNS produced by ammonia stimulate the intrinsic activity of MMPs in the EC of the cerebral microvessels as well (Fig. 4A,B). While the mechanism by which ONS generated by ammonia activates MMPs in RBE-4 cells remains to be studied in detail, it is likely analogous to that in other CNS cells and includes i) direct activation of pro-MMPs by nitrosylation (Gu et al. 2002) or oxidation (Meli et al. 2003) and/or ii) increased expression of MMPs in response to inflammation (Huang et al., 2001). Nitrosylation and oxidation appear to be directly linked to the observations of the present study, because excess ammonia stimulates nitration and nitrosylation of amino acid residues (mostly of tyrosine or serine) in different CNS proteins (Häussinger et al. 2005). "
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