Exposure of primary cultures of cerebellar granule cells for 15 min to micromolar concentrations of glutamate results in cell death of both necrotic and apoptotic types. Among the intracellular events triggered by glutamate, we identified two transcriptional factors: the p50 member of the NF-kappaB family and the tumor suppressor phosphoprotein p53. Pretreatment of the cultures with aspirin, which inhibits NF-kappaB activation, or with specific p53 antisense oligonucleotide, which inhibits p53 transcription, resulted in a complete prevention of glutamate-induced p53 induction and apoptosis. These findings suggest the existence of a transcriptional program activated by glutamate receptor stimulation in which p50 and p53 play a relevant role. Then, we studied the expression of two p53 downstream genes that could participate in the glutamate-induced pro-apoptotic pathway: p21, which codes for an inhibitor of different cyclin dependent kinases, and MSH2, which codes for a protein involved in the recognition and repair of DNA mismatches. We found that primary cerebellar neurons expressed p21 and MSH2 at very low levels in basal conditions. However, very soon after a brief exposure of the cells to glutamate, the expression of both proteins was dramatically enhanced.On these bases, we propose NF-kappaB, p53, p21 and MSH2 as relevant contributors of the glutamate-induced pro-apoptotic pathway. Understanding this cascade of nuclear events may unravel specific targets for pharmacological intervention for those neurological diseases in which excitatory amino acid-induced apoptosis plays a relevant role.