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Kainic Acid‐Induced Apoptosis in Rat Striatum Is Associated with Nuclear Factor‐κB Activation
Author(s) -
Nakai Masami,
Qin ZhengHong,
Chen JiangFan,
Wang Yumei,
Chase Thomas N.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.740647.x
Subject(s) - kainic acid , nbqx , biology , dna fragmentation , ampa receptor , apoptosis , receptor , medicine , endocrinology , striatum , stimulation , receptor antagonist , glutamate receptor , antagonist , quinolinic acid , microbiology and biotechnology , programmed cell death , biochemistry , amino acid , tryptophan , dopamine
The present study evaluated whether nuclear factor‐κB (NF‐κB) 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 IκB‐α protein levels, which was accompanied by an increase in NF‐κB binding activity, was found from 6 to 72 h after KA (2.5 nmol) infusion. NF‐κB 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‐κB SN50 (5‐20 μg) blocked NF‐κB nuclear translocation, but had no effect on AP‐1 binding. NF‐κB 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‐κB activation contributes to c‐Myc and p53 induction and subsequent apoptosis in an excitotoxic model of Huntington’s disease.