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The transcription factor NF‐κB is expressed in neurons wherein it is activated in response to a variety of stress‐ and injury‐related stimuli including exposure to cytokines such as tumor necrosis factor‐α (TNFα), and excitotoxic and oxidative insults. NF‐κB may play a role in the anti‐death actions of TNFα in cultured hippocampal neurons exposed to metabolic and oxidative insults. We now report that pretreatment of hippocampal cell cultures with agents that activate NF‐κB (TNFα and C2‐ceramide) confers resistance of neurons to apoptosis induced by the oxidative insults FeSO₄ and amyloid β‐peptide (Aβ25–35). The neuroprotective actions of TNFα and ceramide were abolished in cultures cotreated with κB decoy DNA demonstrating a requirement for NF‐κB activation for prevention of cell death. Levels of manganese superoxide dismutase (Mn‐SOD) in neurons were increased following exposure of cultures to …