The NF-κB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia

Hill, W. David; Hess, David C.; Carroll, James E.; Wakade, Chandramohan; Howard, Eugene F.; Chen, Qiang; Cheng, Charles Y.; Martin-Studdard, Angeline; Waller, Jennifer L.; Beswick, Richard A.

doi:10.1016/s0361-9230(01)00503-2

Cited by 55 publications

(39 citation statements)

References 51 publications

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“…The absence of a significant ischemia-induced increase in NFκB activation is in contrast to findings from the majority of experimental global and focal brain ischemia studies [5,[7][8][9][10][11][12][13][14]. Our result is most likely accounted for by the inconsistent ischemic severity demonstrated in our model.…”

Section: Discussioncontrasting

confidence: 99%

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Protein–energy malnutrition increases activation of the transcription factor, nuclear factor κB, in the gerbil hippocampus following global ischemia☆

Nazarali

Paterson

2008

The Journal of Nutritional Biochemistry

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Protein-energy malnutrition (PEM) exacerbates functional impairment caused by brain ischemia. This is correlated with reactive gliosis, which suggests an increased inflammatory response. The objective of the current study was to investigate if PEM increases hippocampal activation of nuclear factor κB (NFκB), a transcription factor that amplifies the inflammatory response involved in ischemic brain injury. Mongolian gerbils (11-12 weeks old) were randomly assigned to control diet (12.5% protein) or protein-deficient diet (2%) for 4 weeks. The 2% protein group had a 15% decrease in voluntary food intake (P<.001; unpaired t test), resulting in PEM. Body weight after 4 weeks was 20% lower in the PEM group (P<.001). Gerbils were then exposed to sham surgery or global ischemia induced by 5-min bilateral common carotid artery occlusion. PEM independently increased hippocampal NFκB activation detected by electrophoretic mobility shift assay at 6 h after surgery (P=.014; 2-factor ANOVA). Ischemia did not significantly affect NFκB activation nor was there interaction between diet and ischemia. Serum glucose and cortisol concentrations at 6 h postischemia were unaltered by diet or ischemia. A second experiment using gerbils of the same age and feeding paradigm demonstrated that PEM also increases hippocampal NFκB activation in the absence of surgery. These findings suggest that PEM, which exists in 16% of elderly patients at admission for stroke, may worsen outcome by increasing activation of NFκB. Since PEM increased NFκB activation independent of ischemia or surgery, the data also have implications for the inflammatory response of the many individuals affected globally by PEM.

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Section: Discussioncontrasting

confidence: 99%

“…Nuclear factor κB (NFκB) is a transcription factor that is key in amplifying the inflammatory response involved in stroke pathophysiology [3,4]. Increased NFκB activation has been demonstrated in human stroke [5,6] and experimental models of brain ischemia [5,[7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Protein–energy malnutrition increases activation of the transcription factor, nuclear factor κB, in the gerbil hippocampus following global ischemia☆

Nazarali

Paterson

2008

The Journal of Nutritional Biochemistry

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“…158 Others, however, have observed deleterious effects of NF-B inhibition: constitutive activation of I B kinase to promote nuclear translocation of NF-B increased infarct size, 157 and rats given diethyldithiocarbamate, an NF-B inhibitor, also had larger infarct size, compared with controls. 159 The reasons for these discrepancies are not clear, but may stem from the fact that NF-B has prosurvival effects in neurons and other cell types. 160 Nevertheless, microglial NF-B activation in brain ischemia appears to be largely neurotoxic.…”

Section: Nf-b and Ap-1mentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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“…To study the sensitivity of breast cancer stem-like cell to NF-κB pathway inhibitors, 11 compounds targeting different steps of the NF-κB pathway, including antioxidants Curcumin [32]; PDTC [33]; DETC [34]; Quercetin [35], NF-κB phosphorylation inhibitors Sulfasalazine [36]; Sulindac [37]; Ibuprofen [38]; PTL [39] and NF-κB degradation inhibitors MG-132 [40]; Cyclosporin A [41]; Genistein [42], were tested in this study. MCF7 sphere cells were used as a model of breast cancer stem-like cells [16,43].…”

Section: Ptl Pdtc and Detc Preferentially Inhibit Mcf7 Sphere Cell Pmentioning

confidence: 99%

NF-κB pathway inhibitors preferentially inhibit breast cancer stem-like cells

Zhou

Zhang

et al. 2007

Breast Cancer Res Treat

197

157

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Accumulating evidence indicates that breast cancer is caused by cancer stem cells and cure of breast cancer requires eradication of breast cancer stem cells. Previous studies with leukemia stem cells have shown that NF-κB pathway is important for leukemia stem cell survival. In this study, by using MCF7 sphere cells as model of breast cancer stem-like cells, we evaluated the effect of NF-κB pathway specific inhibitors on human breast cancer MCF7 sphere cells. Three inhibitors including parthenolide (PTL), pyrrolidinedithiocarbamate (PDTC) and its analog diethyldithiocarbamate (DETC) were found to preferentially inhibit MCF7 sphere cell proliferation. These compounds also showed preferential inhibition in term of proliferation and colony formation on MCF7 side population (SP) cells, a small fraction of MCF7 cells known to enrich in breast cancer stem-like cells. The preferential inhibition effect of these compounds was due to inhibition of the NF-κB activity in both MCF7 sphere and MCF7 cells, with higher inhibition effect on MCF7 sphere cells than on MCF7 cells. PDTC was further evaluated in vivo and showed significant tumor growth inhibition alone but had better tumor growth inhibition in combination with paclitaxel in the mouse xenograft model than either PDTC or paclitaxel alone. This study suggests that breast cancer stem-like cells could be selectively inhibited by targeting signaling pathways important for breast cancer stem-like cells.

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The NF-κB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia

Cited by 55 publications

References 51 publications

Protein–energy malnutrition increases activation of the transcription factor, nuclear factor κB, in the gerbil hippocampus following global ischemia☆

Protein–energy malnutrition increases activation of the transcription factor, nuclear factor κB, in the gerbil hippocampus following global ischemia☆

Microglial Activation in Stroke: Therapeutic Targets

NF-κB pathway inhibitors preferentially inhibit breast cancer stem-like cells

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