NF-κB is activated and promotes cell death in focal cerebral ischemia

Schneider, Armin; Martín-Villalba, Ana; Weih, Falk; Vogel, Johannes; Wirth, Thomas; Schwaninger, Markus

doi:10.1038/8432

Cited by 528 publications

(488 citation statements)

References 42 publications

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“…The NF-kB pathway plays an important role in the immune system and is generally thought to exacerbate brain damage in ischaemic stroke. In mouse cerebral cortex, the NF-kB inhibitory protein IkBa was induced by OEA treatment ( Figure 4b) and thus would be expected to restrict activity in the NF-kB pathway, inhibition of which has been demonstrated to reduce brain damage in several ischaemic stroke models (Salminen et al, 1995;Yang et al, 1995;Schneider et al, 1999). Consistent with these findings, expression of the NF-kB-regulated COX-2 gene was found to be reduced by OEA treatment.…”

Section: Ppara Activity Of Synthetic and Endogenous Cannabinoidssupporting

confidence: 66%

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Sun

Alexander

Garle

et al. 2007

British Journal of Pharmacology

205

172

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Background and purpose: Although CB 1 receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPARa and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection. Experimental approach: Assays of PPARa occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPARa activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPARa gene-disrupted mice. Key results: The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPARa ligand binding domain and to increase PPARa-driven transcriptional activity. The high affinity synthetic CB 1/2 cannabinoid agonist WIN 55212-2 bound to PPARa equipotently with the PPARa agonist fenofibrate, and stimulated PPARa-mediated gene transcription. The phytocannabinoid D 9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPARa-null mice. OEA treatment also led to increased expression of the NFkB-inhibitory protein, IkB, in mouse cerebral cortex, while expression of the NFkB-regulated protein COX-2 was inhibited. Conclusions and implications: These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPARa and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.

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Section: Ppara Activity Of Synthetic and Endogenous Cannabinoidssupporting

confidence: 66%

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Sun

Alexander

Garle

et al. 2007

British Journal of Pharmacology

205

172

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“…22 Mice deficient in the NF-B p50 subunit have reduced brain injury after experimental stroke. 156 Similar observations were made using deletion of the I B kinase. 157 In global ischemia, neuronal damage was significantly attenuated by introducing NF-B decoy oligodeoxynucleotides into rat brain neurons through the carotid artery.…”

Section: Nf-b and Ap-1supporting

confidence: 58%

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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“…An antiapoptotic role of NF-kB was reported in many different cellular systems, and its activation was linked to cellular resistance to apoptosis induced by radiation and chemotherapeutic treatment in several cancers (reviewed in (Garg and Aggarwal, 2002)). However, in addition to the more common antiapoptotic role, NFkB was also reported to play a proapoptotic role under several biological conditions (Abbadie et al, 1993;Qin et al, 1999;Schneider et al, 1999). The opposing effects of NF-kB probably reflect cell type-specific function of this signaling pathway, and/or dependency of its outcome on the inducing signal (Shishodia and Aggarwal, 2004).…”

Section: Discussionmentioning

confidence: 99%

Parallel induction of ATM-dependent pro- and antiapoptotic signals in response to ionizing radiation in murine lymphoid tissue

Rashi-Elkeles

Elkon

Weizman³

et al. 2005

Oncogene

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The ATM protein kinase, functionally missing in patients with the human genetic disorder ataxia-telangiectasia, is a master regulator of the cellular network induced by DNA double-strand breaks. The ATM gene is also frequently mutated in sporadic cancers of lymphoid origin. Here, we applied a functional genomics approach that combined gene expression profiling and computational promoter analysis to obtain global dissection of the transcriptional response to ionizing radiation in murine lymphoid tissue. Cluster analysis revealed a prominent pattern characterizing dozens of genes whose response to irradiation was Atm-dependent. Computational analysis identified significant enrichment of the binding site signatures of NF-jB and p53 among promoters of these genes, pointing to the major role of these two transcription factors in mediating the Atm-dependent transcriptional response in the irradiated lymphoid tissue. Examination of the response showed that pro-and antiapoptotic signals were simultaneously induced, with the proapoptotic pathway mediated by p53 targets, and the prosurvival pathway by NF-jB targets. These findings further elucidate the molecular network induced by IR, point to novel putative NF-jB targets, and suggest a mechanistic model for cellular balancing between pro-and antiapoptotic signals induced by IR in lymphoid tissues, which has implications for cancer management. The emerging model suggests that restoring the p53-mediated apoptotic arm while blocking the NF-jB-mediated prosurvival arm could effectively increase the radiosensitivity of lymphoid tumors.

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NF-κB is activated and promotes cell death in focal cerebral ischemia

Cited by 528 publications

References 42 publications

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Microglial Activation in Stroke: Therapeutic Targets

Parallel induction of ATM-dependent pro- and antiapoptotic signals in response to ionizing radiation in murine lymphoid tissue

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