We studied the potential neuroprotective action of nicergoline in immortalized hypothalamic GT1-7 cells exposed to agents which deplete levels of reduced glutathione, thus causing oxidative stress and cell death. Treatment with diethylmaleate (1 mM), buthionine sulfoximine (500 microM) or menadione (10-50 microM) caused diffuse GT1-7 cell degeneration, as assessed by using either the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay or the fluorescent dyes fluorescein diacetate and propidium iodide. Pre- and/or co-exposure of the cells to nicergoline significantly prevented diethylmaleate- or buthionine sulfoximine-induced neuronal death, whereas nicergoline was ineffective against menadione-induced toxicity. This effect was concentration-dependent and was mimicked by the classical antioxidants idebenone and vitamin E, and did not depend on interference with protein kinase C. Interestingly, the antineurodegenerative activity of nicergoline and vitamin E or idebenone was not additive, suggesting that these compounds share some intracellular mechanism(s) responsible for their protective effects. In conclusion, the present data indicate that nicergoline has neuroprotective activity, possibly mediated by the antioxidant activity of the molecule, and give support to the potential use of nicergoline in the prevention and therapy of neurodegenerative diseases.