Nitric oxide (NO) produced by the constitutive NO synthase (cNOS) in neurons has been implicated in mediating excitotoxic neuronal death. In our murine cortical cell culture system, NMDA neurotoxicity was not blocked by addition of the NOS inhibitors, NG-nitro-L-arginine or aminoguanidine. However, following activation of inducible NOS in astrocytes by interleukin-1 beta plus interferon-gamma, NMDA but not kainate neurotoxicity was markedly potentiated. This selective potentiation of NMDA neurotoxicity was blocked by NOS inhibition or antioxidants (superoxide dismutase/catalase or Tempol) and could be mimicked by NO generators (SIN-1 or SNAP) or the oxygen radical generator, pyragallol. These results raise the possibility that NO production by astrocytes may contribute to NMDA receptor-mediated neuronal death, perhaps through interaction with oxygen radicals.