IKK mediates ischemia-induced neuronal death

Herrmann, Oliver; Baumann, Bernd; Lorenzi, Rossana De; Muhammad, Sajjad; Zhang, Wen; Kleesiek, Jens; Malfertheiner, Maximilian; Köhrmann, Martin; Potrovita, Ioana; Maegele, Ira; Beyer, Cordian; Burke, James R.; Hasan, Mazahir T.; Bujard, Hermann; Wirth, Thomas; Pasparakis, Manolis; Schwaninger, Markus

doi:10.1038/nm1323

Cited by 243 publications

(228 citation statements)

References 48 publications

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“…Likewise, functional parameters of visual acuity and contrast sensitivity were indistinguishable between WT and RelA CNSKO mice (published elsewhere). These findings are in line with previous reports showing that mice with inactivated upstream regulators of NF-kB (IkBa, IKK) in the neuro-glial compartment are indiscernible regarding overall neuro-anatomical and behavioral features 3,4 and, in particular, display normal myelination. 5 Among the NF-kB family members (RelA, RelB, c-Rel, p105/50, p100/52), only deletion of the subunit p50, which lacks a transcriptional activator domain, results in a destructive neuronal phenotype as characterized by precocious aging, neuronal apoptosis and spontaneous demyelination in young adult mice.…”

supporting

confidence: 93%

Dysfunctional NF-κB and brain myelin formation

et al. 2013

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supporting

confidence: 93%

Dysfunctional NF-κB and brain myelin formation

et al. 2013

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“…In addition, it has neuroprotective effects 22,43 . PGD 2 has a short half-life in tissue and is spontaneously converted into the cyclopentenone 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ), which inhibits the IkB kinase (IKK), the main activator of the transcription factor NF-kB and a key player in ischemic brain damage 44,45 . In accordance with this, HCA 2 activation has been shown to inhibit NF-kB activation in bone marrow-derived macrophages 46 .…”

Section: Discussionmentioning

confidence: 99%

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

et al. 2014

Self Cite

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The ketone body b-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA 2 , GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2 À / À mice. We further demonstrate that nicotinic acid, a clinically used HCA 2 agonist, reduces infarct size via a HCA 2 -mediated mechanism, and that noninflammatory Ly-6C Lo monocytes and/or macrophages infiltrating the ischemic brain also express HCA 2 . Using cell ablation and chimeric mice, we demonstrate that HCA 2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA 2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD 2 production by COX1 and the haematopoietic PGD 2 synthase. Our data suggest that HCA 2 activation by dietary or pharmacological means instructs Ly-6C Lo monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

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“…Accordingly, topoisomerase II inhibitors that intercalate into the DNA such as doxorubicin, daunorubicin, and mitoxantrone trigger NF-kB activation before the induction of apoptosis, and NF-kB inhibition significantly reduces apoptosis (24). In addition, a proapoptotic function of NF-kB has been described in several systems of neuronal cell death, for example, induced by ischemia, glutamate, betulinic acid, or NMDA receptors stimulation (25,(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation–Induced Apoptosis

Berger

Jennewein²,

Marschall³

et al. 2011

Molecular Cancer Therapeutics

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Evasion of apoptosis contributes to radioresistance of glioblastoma, calling for novel strategies to overcome apoptosis resistance. In this study, we investigated the potential of the small molecule Smac mimetic BV6 to modulate radiosensitivity of glioblastoma cells. Here, we identify a novel proapoptotic function of NF-kB in g-irradiation-induced apoptosis of glioblastoma cells by showing, for the first time, that NF-kB is critically required for Smac mimetic-mediated radiosensitization. BV6 significantly increases g-irradiation-triggered apoptosis in several glioblastoma cell lines in a dose-and time-dependent manner. Calculation of combination index (CI) reveals that the interaction of BV6 and g-irradiation is highly synergistic (CI < 0.3). Molecular studies show that BV6 stimulates NF-kB activation, which is critical for radiosensitization, because genetic inhibition of NF-kB by overexpression of the dominant-negative superrepressor IkBa-SR significantly decreases BV6-and g-irradiation-induced apoptosis. Also, the BV6-mediated enhancement of g-irradiation-triggered caspase activation, drop of mitochondrial membrane potential, and cytochrome c release is abolished in cells overexpressing IkBa-SR. Similarly, NF-kB inhibition by ectopic expression of a kinase dead mutant of IKKb prevents the BV6-mediated sensitization for g-irradiation. The clinical relevance is underscored by experiments with primary tumor samples showing that BV6 sensitizes primary cultured glioma cells as well as glioblastoma-initiating cancer stem cells derived from surgical specimens for g-irradiation. In conclusion, we identify NF-kB as a critical mediator of Smac mimetic-conferred radiosensitization of glioblastoma cells. These results have important implications for the development of Smac mimetic-based combination protocols for radiosensitization of glioblastoma. Mol Cancer Ther; 10(10); 1867-75. Ó2011 AACR.

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IKK mediates ischemia-induced neuronal death

Cited by 243 publications

References 48 publications

Dysfunctional NF-κB and brain myelin formation

Dysfunctional NF-κB and brain myelin formation

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation–Induced Apoptosis

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