Neuroprotection exerted by alpha-tocopherol against oxidative stress was investigated in cultured rat hippocampal neurons. In addition to its direct action as a radical scavenger revealed at concentrations above 10 microM, a transient application of 1 microM alpha-tocopherol phosphate (alpha-TP) to neurons induced a complete delayed long-lasting protection against oxidative insult elicited by exposure to Fe2+ ions, but not against excitotoxicity. A minimal 16-h application of alpha-TP was required to observe the protection against subsequent oxidative stress. This delayed protection could last up to a week after the application of alpha-TP, even when medium was changed after the alpha-TP treatment. Cycloheximide, added either 2 h before or together with alpha-TP, prevented the delayed neuroprotection, but not the acute. However, cycloheximide applied after the 16-h alpha-TP pretreatment did not alter the delayed neuroprotection. Neither Trolox, a cell-permeant analogue of alpha-tocopherol, nor other antioxidants, such as epigallocatechin-gallate and N-acetyl-L-cysteine, elicited a similar long-lasting protection. Only tert-butylhydroquinone could mimic the alpha-TP effect. Depletion of glutathione (GSH) by L-buthionine sulfoximine did not affect the delayed alpha-TP protection. Thus, in addition to its acute anti-radical action, alpha-TP induces a long-lasting protection of neurons against oxidative damage, via a genomic action on antioxidant defenses apparently unrelated to GSH biosynthesis.