This study was performed to examine the neuroprotective action of bifemelane against glutamate cytotoxicity in cultured cortical neurons obtained from fetal rats. Cell viability was markedly reduced by a brief exposure to glutamate. Glutamate cytotoxicity was reduced by exposing cultures to bifemelane at concentrations of 1-10 microM for 24 hr prior to glutamate exposure. In contrast, glutamate cytotoxicity was not affected by adding bifemelane to the glutamate-containing-medium without pretreatment. Bifemelane did not affect N-methyl-D-aspartate (NMDA)-induced currents, although the higher concentration (100 microM) of the drug reduced them. These findings suggest that bifemelane protects against glutamate neurotoxicity without affecting NMDA receptors.