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)-κB may be involved in excitotoxicity. To further analyze the contribution of NFκB to excitotoxic neuronal death in vivo, changes in binding activities of NFκB and other transcription factors as well as the consequences of inhibiting NFκB 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. NFκB binding activity increased severalfold 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 NFκB, 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 NFκB SN50, a cell-permeable recombinant peptide that blocks NFκB 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 NFκB activation contributes to the excitotoxin-induced death of striatal neurons.