CA2-MEDIATED ACTIVATION OF C-JUN N-TERMINAL KINASE AND NUCLEAR FACTORKAPPA-B BY NMDA IN CORTICAL CELL-CULTURES()

We examined the possibility that c-Jun N-terminal kinase (JNK) and nuc lear factor kappa B (NF-kappa B) might be involved in intracellular si gnaling cascades that mediate NMDA-initiated neuronal events. Exposure of cortical neurons to 100 mu M NMDA induced activation of JNK within I min. Activity of JNK was further increased over the next 5 min and then declined by 30 min. Similarly, ionomycin, a selective Ca2+ ionoph ore, induced activation of JNK. The NMDA-induced activation of JNK was abrogated in the absence of extracellular Ca2+, suggesting that Ca2entry is necessary and sufficient for the JNK activation. Immunohistoc hemistry with anti-NF-kappa B antibody demonstrated nuclear translocat ion of NF-kappa B within 5 min following NMDA treatment, NMDA treatmen t also enhanced the DNA binding activity of nuclear NF-kappa B in a Ca 2+-dependent manner. Treatment with 3 mM aspirin blocked the NMDA-indu ced activation of JNK and NF-kappa B. Neuronal death following a brief exposure to 100 mu M NMDA was Ca2+ dependent and attenuated by additi on of aspirin or sodium salicylate. The present study suggests that Ca 2+ influx is required for NMDA-induced activation of JNK and NF-kappa B as well as NMDA neurotoxicity. This study also implies that aspirin may exert its neuroprotective action against NMDA through blocking the NMDA-induced activation of NF-kappa B and JNK.