Cerebellar granule cells in culture, which are extremely vulnerable to excitotoxin glutamate or N-methyl-D-aspartate (NMDA), were used to study mechanisms of neuronal cell death and protection. Paradoxically, pretreatment of these cells with subtoxic concentrations of NMDA markedly blocked the neurotoxicity resulting from subsequent exposure to glutamate or NMDA. The NMDA-mediated neuroprotection can be antagonized by pretreatment of these cells with protein synthesis inhibitors, suggesting an involvement of protein(s) with neuroprotectant properties, most likely neurotrophic factors. Because basic fibroblast growth factor (BFGF) is well known to prevent neuronal cell death following mechanical or chemical injury, we have tested whether NMDA increases the synthesis of bFGF in cerebellar granule cells. NMDA elicited a rapid and time-dependent increase in bFGF mRNA, suggesting that availability of this trophic factor may play a role in the NMDA-mediated neuroprotection.