Fifteen minute exposure of primary cultures of cerebellar granule cells to micromolar concentrations of glutamate results in apoptotic cell death. Among the intracellular events triggered by glutamate, we identified two transcriptional factors, i.e. the p50 member of the NF-kappaB family and the tumor suppressor phosphoprotein p53, that are apparently linked by a sequential trascriptional program. We found that pretreatment of the cultures with aspirin (ASA), which inhibits NF-kappaB activation, resulted in a complete prevention of glutamate-induced p53 immunoreactivity. The same results were obtained pretreating the cells with a specific p53 antisense oligonucleotide. Both ASA and p53 antisense abolished glutamate-induced apoptosis. We also found that two other proteins, the cyclin dependent kinase inhibitor p21 and DNA mismatches repair MSH2, whose encoding genes are well known target of p53, were upregulated by glutamate. On these bases, we propose NF-kappaB, p53, p21 and MSH2 as relevant contributors of the glutamate-induced pro-apoptotic pathway.