Article

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.

0 Followers
 · 
61 Views
 · 
0 Downloads
  • Source
    • "In the ischemic brain, a wide range of stimuli may trigger activation of NF-κB including, among others, the following: hypoxia [155]; IL-1, and TNF-α [156]; OS [157]; glutamate [158], and NOS activity, such as nNOS and iNOS [159]. Overactivation of NF-κB after ischemia has been documented in neurons [147], astrocytes [53], microglia [160], and in endothelial cells [149]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerebral ischemia initiates a cascade of detrimental events including glutamate-associated excitotoxicity, intracellular calcium accumulation, formation of Reactive oxygen species (ROS), membrane lipid degradation, and DNA damage, which lead to the disruption of cellular homeostasis and structural damage of ischemic brain tissue. Cerebral ischemia also triggers acute inflammation, which exacerbates primary brain damage. Therefore, reducing oxidative stress (OS) and downregulating the inflammatory response are options that merit consideration as potential therapeutic targets for ischemic stroke. Consequently, agents capable of modulating both elements will constitute promising therapeutic solutions because clinically effective neuroprotectants have not yet been discovered and no specific therapy for stroke is available to date. Because of their ability to modulate both oxidative stress and the inflammatory response, much attention has been focused on the role of nitric oxide donors (NOD) as neuroprotective agents in the pathophysiology of cerebral ischemia-reperfusion injury. Given their short therapeutic window, NOD appears to be appropriate for use during neurosurgical procedures involving transient arterial occlusions, or in very early treatment of acute ischemic stroke, and also possibly as complementary treatment for neurodegenerative diseases such as Parkinson or Alzheimer, where oxidative stress is an important promoter of damage. In the present paper, we focus on the role of NOD as possible neuroprotective therapeutic agents for ischemia/reperfusion treatment.
    Oxidative Medicine and Cellular Longevity 04/2013; 2013:297357. DOI:10.1155/2013/297357 · 3.36 Impact Factor
  • Source
    • "Overexpression of ROS-scavenging enzymes, or superoxide dismutases (SOD) 1, protected against ischemic cell death in transgenic mice. In mice overexpressing SOD1, the activation of NF-κB in the ischemic brain is suppressed when compared with wild-type mice [49]. Moreover, cumulative evidence suggests that NF-κB is activated in cerebral ischemia, mainly in neurons, and contributes to neuronal cell death [50], [51]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress plays an important role in the pathological processes of ischemic brain damage. Many antioxidants have been shown to protect against cerebral ischemia injury by inhibiting oxidative stress both in vitro and in vivo. 20-Hydroxyecdysone (20E), an ecdysteroid hormone, exhibits antioxidative effects. For the work described in this paper, we used an in vitro oxidative damage model and an in vivo ischemic model of middle cerebral artery occlusion (MCAO) to investigate the neuroprotective effects of 20E and the mechanisms related to these effects. Treatment of cells with H(2)O(2) led to neuronal injury, intracellular ROS/RNS generation, mitochondrial membrane potential dissipation, cellular antioxidant potential descent, an increase in malondialdehyde (MDA) and an elevation of intracellular [Ca(2+)], all of which were markedly attenuated by 20E. Inhibition of the activation of the ASK1-MKK4/7-JNK stress signaling pathway and cleaved caspase-3 induced by oxidative stress were involved in the neuroprotection afforded by 20E. In addition, 20E reduced the expression of iNOS protein by inhibition of NF-κB activation. The neuroprotective effect of 20E was also confirmed in vivo. 20E significantly decreased infarct volume and the neurological deficit score, restored antioxidant potential and inhibited the increase in MDA and TUNEL-positive and cleaved caspase-3-positive cells in the cerebral cortex in MCAO rats. Together, these results support that 20E protects against cerebral ischemia injury by inhibiting ROS/RNS production and modulating oxidative stress-induced signal transduction pathways.
    PLoS ONE 12/2012; 7(12):e50764. DOI:10.1371/journal.pone.0050764 · 3.23 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study is to investigate the neuroprotective effects and relevant mechanism of GW0742, an agonist of PPAR-β, after global cerebral ischemia-reperfusion injury (GCIRI) in rats. The rats showed memory and cognitive impairment and cytomorphological change in the hippocampus neurons following GCIRI. These effects were significantly improved by pretreatment with GW0742 in the dose-dependent manner. The expressions of IL-1β, IL-6, and TNF-α were increased after GCIRI, while the increases in these proinflammatory cytokines by GCIRI were inhibited by GW0742 pretreatment. Similarly, GW0742 pretreatment also improved the GCIRI-induced decrease in the expression of IL-10, which can act as an inhibitory cytokine to reduce cerebral ischemic injury. For another, NF-κB p65 expression was significantly increased in hippocampal neurons with apparent nuclear translocation after global cerebral IRI, and these phenomena were also largely attenuated by GW0742 pretreatment. Moreover, the mRNA and protein expressions of PPAR-β were significantly decreased in GCIRI + GW0742 groups when compared with those in GCIRI group. Our data suggests that the PPAR-β agonist GW0742 can exert significant neuroprotective effect against GCIRI in rats via PPAR-β activation and its anti-inflammation effect mediated by the inhibition of expression and activation of NF-κB in the hippocampus.
    PPAR Research 09/2012; 2012:209794. DOI:10.1155/2012/209794 · 1.64 Impact Factor
Show more