SELECTIVE POTENTIATION OF NMDA-INDUCED NEURONAL INJURY FOLLOWING INDUCTION OF ASTROCYTIC INOS

Nitric oxide (NO) produced by the constitutive NO synthase (cNOS) in n eurons has been implicated in mediating excitotoxic neuronal death. In our murine cortical cell culture system, NMDA neurotoxicity was not b locked by addition of the NOS inhibitors, N-G-nitro-L-arginine or amin oguanidine. However, following activation of inducible NOS in astrocyt es by interleukin-1 beta plus interferon-gamma, NMDA but not kainate n eurotoxicity was markedly potentiated. This selective potentiation of NMDA neurotoxicity was blocked by NOS inhibition or antioxidants (supe roxide dismutase/catalase or Tempol) and could be mimicked by NO gener ators (SIN-1 or SNAP) or the oxygen radical generator, pyragallol. The se results raise the possibility that NO production by astrocytes may contribute to NMDA receptor-mediated neuronal death, perhaps through i nteraction with oxygen radicals.