Kainic acid-induced apoptosis in rat striatum is associated with nuclear factor-κB activation

The present study evaluated whether nuclear factor-kappa B (NF-kappa B) activation contributes to the apoptotic-like death of striatal neurons induced by kainic acid (KA) receptor stimulation. Intrastriatally infused KA (1.25-5.0 nmol) produced substantial neuronal loss as indicated by an 8-73% decrease in 67-kDa glutamic acid decarboxylase (p < 0.05), KA (1.25-5.0 nmol) elicited internucleosomal DNA fragmentation that was inhibited by the AMPA/KA receptor antagonist NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dibenzo[f]quinoxaline-7-sulfonamide) but not by the NMDA receptor antagonist MK-801. A decrease in I kappa B-alpha. protein levels, which was accompanied by an increase in NF-kappa B binding activity, was found from 6 to 72 h after KA (2.5 nmol) infusion. NF-kappa B was composed mainly of p65 and c-Rel as revealed by supershift assay. In addition, c-Myc and p53 increased from five- to sevenfold from 24 to 72 h after KA (2.5 nmol) administration. Immunohistochemistry revealed high levels of c-Myc and p53 immunoreactivity, mainly in medium-sized striatal neurons. Pretreatment with the cell-permeable recombinant peptide NF-kappa B SN50 (5-20 mu g) blocked NF-kappa B nuclear translocation, but had no effect on AP-I binding. NF-kappa B SN50 also inhibited the KA-induced up-regulation of c-Myc and p53, as well as internucleosomal DNA fragmentation. The apoptotic-like destruction of rat striatal neurons induced by KA receptor stimulation thus appears to involve biochemical mechanisms similar to those mediating: the excitotoxic response to NMDA receptor stimulation. The present results provide additional support for the view that NF-kappa B activation contributes to c-Myc and p53 induction and subsequent apoptosis in an excitotoxic model of Huntington's disease.