Nuclear Factor-κB Contributes to Excitotoxin-Induced Apoptosis in Rat Striatum

Abstract

Excitotoxin-induced destruction of striatal neurons, proposed as a model of Huntington's disease, involves a process having the biochemical stigmata of apoptosis. Recent studies suggested that transcription factor nuclear factor (NF)-kappa B may be involved in excitotoxicity. To further analyze the contribution of NF kappa B to excitotoxic neuronal death in vivo, changes in binding activities of NF kappa B and other transcription factors as well as the consequences of inhibiting NF kappa B nuclear translocation were measured after the infusion of quinolinic acid (120 nmol) into rat striatum. Internucleosomal DNA fragmentation and terminal transferase-mediated dUTP digoxigenin nick end labeling-positive nuclei appeared 12 hr later and intensified over the next 12 hr. NF kappa B binding activity increased several-fold from 2 to 12 hr, then gradually declined during the next 12 hr. Other transcription factor changes included AP-1, whose binding peaked about 6 hr after quinolinic acid administration, and E2F-1, which was only modestly and transiently elevated. In contrast, quinolinic acid lead to a reduction in OCT-1, beginning after 12 hr, and briefly in SP-1 binding. The NF kappa B, AP-1, and OCT-1 changes were attenuated both by the N-methyl-D-aspartate receptor antagonist MK-801 and the protein synthesis inhibitor cycloheximide. Moreover, quinolinic acid-induced internucleosomal DNA fragmentation and striatal cell death were significantly reduced by the intrastriatal administration of NF kappa B SN50, a cell-permeable recombinant peptide that blocks NF kappa B nuclear translocation. These results illustrate the complex temporal pattern of transcription factor change attending the apoptotic destruction produced in rat striatum by quinolinic acid. They further suggest that NF kappa B activation contributes to the excitotoxin-induced death of striatal neurons.

Induction of Nitric-oxide Synthase and Activation of NF-κB by Interleukin-12 p40 in Microglial Cells

“…Third, SN50, a cell-permeable peptide carrying the nuclear localization sequence of p50 NF-B, but not mutant SN50 (SN50M) inhibits p40 2 -mediated activation of NF-B and expression of iNOS. It has been demonstrated that SN50 specifically blocks the nuclear translocation of NF-B, but does not affect the activity of AP-1, SP-1 factor, and OCT-1 transcriptional factors (48) suggesting that SN50 inhibits the expression of iNOS in p40 2 -stimulated microglial cells by inhibiting the activation of NF-B. In addition, these results also suggest that IL-12 p40 2 is biologically active and that p40 2 alone can activate microglial cells.…”

Nuclear factor kappa B-mediated kainate neurotoxicity in the rat and hamster hippocampus

“…20 This is further supported by a recent finding that a selective peptide inhibitor of NF-kB attenuates excitotoxin-induced neuronal death in the striatum. 35 It becomes evident that necrosis is a predominant pattern of excitotoxic neuronal death according to morphology, biochemical events and interventional criteria. 18 Systemic injections of kainate into the adult rat also induced degeneration of hippocampal neurons exclusively via necrosis (q99%), marked by swelling of the cell body and mitochondria, rapid collapse of the plasma membrane and scattering of nuclear chromatin (Huh K. and Sohn S., unpublished observation).…”

Inhibition of intimal hyperplasia after balloon injury in rat carotid artery model using cis-element ‘decoy’ of nuclear factor-kB binding site as a novel molecular strategy

“…3,[6][7][8] Although little is known about the mechanisms that regulate apoptotic pathways in VSMC, recent studies suggest that the transcription factor nuclear factor-B (NF B) plays a crucial role in the regulation of apoptosis. 9,10 In situ detection of nuclear p65 and p50 has revealed NF B activity within human atheroma, eg in intimal VSMC but not in undiseased arteries. 11,12 Moreover, NF B was induced in VSMC after arterial balloon injury.…”