Heme oxygenase-1 (HO-1) is a redox-sensitive inducible protein that provides efficient cytoprotection against oxidative stress. Curcumin, a polyphenolic natural compound that possesses anti-tumor and anti-inflammatory properties, has been reported recently to induce potently HO-1 expression in vascular endothelial cells (Free Rad Biol Med 28:1303-1312. Here, we extend our previous findings by showing that caffeic acid phenethyl ester (CAPE), another plant-derived phenolic agent, markedly increases heme oxygenase activity and HO-1 protein in astrocytes. The effect seems to be related to the peculiar chemical structures of curcumin and CAPE, because analogous antioxidants containing only portions of these two molecules were totally ineffective. At a final concentration of 30 M, both curcumin and CAPE maximally up-regulated heme oxygenase activity while promoting marked cytotoxicity at higher concentrations (50 -100 M). Similar results were obtained with Curcumin-95, a mixture of curcuminoids commonly used as a dietary supplement. Incubation of astrocytes with curcumin or CAPE at concentrations that promoted maximal heme oxygenase activity resulted in an early increase in reduced glutathione followed by a significant elevation in oxidized glutathione contents. A curcumin-mediated increase in heme oxygenase activity was not affected by the glutathione precursor and thiol donor N-acetyl-L-cysteine. These data suggest that regulation of HO-1 expression by polyphenolic compounds is evoked by a distinctive mechanism which is not necessarily linked to changes in glutathione but might depend on redox signals sustained by specific and targeted sulfydryl groups. This study identifies a novel class of natural substances that could be used for therapeutic purposes as potent inducers of HO-1 in the protection of tissues against inflammatory and neurodegenerative conditions. Heme oxygenase-1 (HO-1) is a ubiquitous and redox-sensitive inducible stress protein (Motterlini et al., 2002). In mammals, the crucial participation of HO-1 gene expression in alleviating organ dysfunction and counteracting metabolic disorders is supported by consistent reports showing a protective role for the products of the enzymatic activity of HO-1. Heme serves as a substrate for HO-1 in the formation of carbon monoxide, free ferrous iron, and biliverdin; the latter is rapidly converted to bilirubin by biliverdin reductase (Choi and Alam, 1996;. A substantial body of evidence demonstrates that increased carbon monoxide and bilirubin effectively contribute to modulate important physiological processes within the cardiovascular, immune, and nervous systems. These include the regulation of vessel tone (Motterlini et al., 1998), inhibition of platelet aggregation (Durante and Schafer, 1998), and prevention of cell death and tissue injury (Clark et al., 2000b). The overall concept emerging from these and other studies is that the induction of HO-1 is an essential step in the cellular adaptation to stress inflicted by pathological events.Apart from ...