Time dependency of the action of nitric oxide in lipopolysaccharide-interferon-gamma-induced neuronal cell death in murine primary neuron-glia co-cultures

We investigated the time-dependency of the action of nitric oxide (NO) on g lia-mediated neuronal cell death. Cortical neuron-glia co-cultures were tre ated with lipopolysaccharide and interferon gamma (LPS/LFN gamma). The prod uction of NO was first detectable 9 h after the exposure to LPS/IFN gamma a nd increased for up to 48 h. A significant neuronal cell death was observed 36-48 h after treatment with LPS/IFN gamma. The NO generated at the initia l stage of NO synthesis (about 12 h) following exposure to LPS/IFN gamma wa s found to be critical for LPS/IFN gamma -induced neurotoxicity. Furthermor e, the rate of NO production at the initial stage of NO synthesis was corre lated linearly with the extent of neuronal cell death. These findings sugge st that the maximal rate of NO synthesis, instead of the accumulated NO2- l evel, is a sensitive index for predicting endotoxin-induced cytotoxicity. ( C) 2000 Elsevier Science B.V. All rights reserved.