The transcription factor NF kappa B is activated by various signals associated with brain injury, including tumor necrosis factor (TNF), oxidative insults, and amyloid beta-peptide (A beta). We recently reported that TNFs activate NF kappa B in neurons and protect them against excitotoxic and oxidative insults, including A beta toxicity. We now report that C2-ceramide (C2), a membrane-permeant activator of NF kappa B, protects cultured rat hippocampal neurons against death induced by glutamate, FeSO4, and A beta. Protection was concentration dependent, specific (a ceramide analogue known not to activate NF kappa B was ineffective), required pretreatment, and was blocked by inhibitors of RNA and protein synthesis. Lipid peroxidation and accumulation of cellular peroxides induced by glutamate, FeSO4, and A beta were significantly attenuated in neurons pretreated with C2. The data indicate that C2 induces antioxidant pathways in neurons and suggest novel approaches for reducing neuronal injury in both acute and chronic neurodegenerative conditions.