In the present paper, we report a strong intracellular antioxidant activity of the sesquiterpene lactone parthenolide in the hippocampal HT22 cells. This effect is mediated by an increase of total glutathione at both, low (5 microM) and high (10 microM), concentrations. Parthenolide also increases the activation of the antioxidant/electrophile response element. This effect is the possible mediator of glutathione increase, since the limiting enzyme on its synthesis possesses this response element on its promoter. Finally, we demonstrate that its antioxidant properties do not mediate its antiproliferative effect nor its inhibition of NF-kappaB.