Nuclear Factor-κB Contributes to Infarction After Permanent Focal Ischemia

Abstract

Background and Purpose-Activation of transcription factor nuclear factor-B (NF-B) may induce expression of either proinflammatory/apoptotic genes or antiapoptotic genes. Because a considerable number of middle cerebral artery occlusions (MCAOs) in humans are not associated with reperfusion during the first 24 hours, the role of NF-B after permanent MCAO (pMCAO) was investigated. Methods-Mice transgenic for a NF-B-driven ␤-globin reporter were exposed to pMCAO, and the expression of the reporter gene was quantified with real-time polymerase chain reaction. Mice lacking the p50 subunit of NF-B and wild-type controls were exposed to pMCAO with or without treatment with pyrrolidinedithiocarbamate (PDTC), an NF-B inhibitor. Brain sections of human stroke patients were immunostained for the activated NF-B. Results-pMCAO increased NF-B transcriptional activity to 260% (36.9Ϯ4.5 compared with 14.4Ϯ2.6; nϭ10; PϽ0.01) in the brain; this NF-B activation was completely blocked by PDTC (17.2Ϯ2.6; nϭ9; PϽ0.05). In p50 Ϫ/Ϫ mice, pMCAO resulted in 41% (18Ϯ3.2 mm 3 ; nϭ12) smaller infarcts compared with wild-type controls (32.9Ϯ3.8 mm 3 ; nϭ9; PϽ0.05), which was comparable to the protection achieved with PDTC in wild-type mice (19.6Ϯ4.2 mm 3 ; nϭ8). Pro-DTC, a PDTC analogue that does not cross the blood-brain barrier, had no effect, even though Pro-DTC and PDTC were equally protective in vitro. During the first 2 days of human stroke, NF-B was activated in neurons in the penumbral areas. Conclusions-NF-B is induced in neurons during

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…In models of ischemia, for example, NF-kB activation appears to contribute to brain damage and mice lacking the p50 subunit of NF-kB demonstrate decreased infarct volumes. 63,64 In some cases, however, support for proapoptotic functions of NF-kB has been based upon either associations between NF-kB activity and neuronal death without a causal relationship 65 or on experiments that employed drugs with multiple mechanisms of action such as aspirin and PDTC. 64,66,67 Although it is well documented that NF-kB does under certain conditions actually promote the expression of proapoptotic genes, an alternative mechanism should be considered in the complex cellular milieu of the CNS.…”

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

“…In agreement with the in vivo data, huperzine A is also able to attenuate iNOS, COX-2, and NO overproduction, and it can increase cell survival in oxygen-glucose deprivation (OGD)-treated C6 rat glioma cells [88] . Nuclear factorkappa B (NF-κB) is a principal mediator of the postischemic inflammatory response [89] . Further investigation showed that MCAO/OGD led to increased phosphorylation and degradation of IκB, as well as the nuclear translocation of p65, which indicated activation of NF-κB signaling.…”

Bim and Noxa Are Candidates to Mediate the Deleterious Effect of the NF-κB Subunit RelA in Cerebral Ischemia

“…Surprisingly, in some paradigms, NF-B promotes apoptosis (Kaltschmidt et al, 2000(Kaltschmidt et al, , 2002Pizzi et al, 2002). In a mouse model of stroke, NF-B was associated with neurodegeneration because germline deletion of the gene for the NF-B subunit p50 reduced the infarct size (Schneider et al, 1999;Nurmi et al, 2004). Furthermore, expression of an NF-B superrepressor was neuroprotective (Xu et al, 2002;Zhang et al, 2005), and inhibition or deletion of the upstream kinase I B kinase (IKK) profoundly reduced the infarct size .…”