CERAMIDE PROTECTS HIPPOCAMPAL-NEURONS AGAINST EXCITOTOXIC AND OXIDATIVE INSULTS, AND AMYLOID BETA-PEPTIDE TOXICITY

The transcription factor NF kappa B is activated by various signals as sociated with brain injury, including tumor necrosis factor (TNF), oxi dative insults, and amyloid beta-peptide (A beta). We recently reporte d that TNFs activate NF kappa B in neurons and protect them against ex citotoxic and oxidative insults, including A beta toxicity. We now rep ort that C2-ceramide (C2), a membrane-permeant activator of NF kappa B , protects cultured rat hippocampal neurons against death induced by g lutamate, FeSO4, and A beta. Protection was concentration dependent, s pecific (a ceramide analogue known not to activate NF kappa B was inef fective), 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 in duces antioxidant pathways in neurons and suggest novel approaches for reducing neuronal injury in both acute and chronic neurodegenerative conditions.