Flavonoids, a large group of polyphenolic compounds found in fruits and vegetables, have attracted much attention because of their broad pharmacological, particularly antioxidative, activities.1,2) Flavonoids may exert beneficial effects on a number of disease states including cancer, cardiovascular disease, inflammation and neurodegenerative disorders.
1,2)The pathology of neurodegenerative disorders including Alzheimer's disease and aging is associated with oxidative stress caused by reactive oxygen species and reactive nitrogen species.2,3) If oxidative stress is suppressed by compounds in foods, such as flavonoids, this may act as a preventive measure to reduce damage and/or disfunction of cells. Quercetin (3,3Ј,4Ј,5,, which possesses a wide spectrum of pharmacological and biological properties, 2,4) is found in many kinds of food. The daily Western diet contains on average about 25 mg of various flavonoids, of which quercetin is a major ingredient (16 mg/d).5) Quercetin can scavenge free radicals directly and inhibit the oxidation of various molecules resulting in the activation of antioxidant defense pathways in vivo and in vitro. However, the actions of flavonoids are complex and paradoxical in some cases. Several studies have shown that quercetin is a pro-oxidant and cytotoxic in leukemic cells. 7,8) Flavonoids including quercetin caused apoptosis in carcinoma/cancer cells 2,9) and showed cytotoxicity in normal cells including human umbilical vein endothelial cells.10) The neuronal density of the hippocampus in gerbils subjected to infusion of quercetin to the ventricle was significantly lower than that in control.11) Thus, the effects of quercetin on cell death and/or apoptosis in cells including neuronal cells have not been well confirmed.The PC12 cell line, a rat adrenal medullary pheochromocytoma, is a useful model for studying the survival of neuronal cells. Native PC12 cells divide and resemble precursors of adrenal chromaffin cells and sympathetic neurons when grown in the presence of serum, and gradually attain the phenotypic properties of sympathetic neurons on the addition of nerve growth factor (NGF). Previously, we reported that the treatment of native and undifferentiated PC12 cells with an inhibitor of thioredoxin reductase and dopaminergic neurotoxins such as 1-methyl-4-phenylpyridinium ion (MPP ϩ ) caused apoptosis via a caspase-mediated pathway. 12,13) Quercetin has been shown to inhibit cell death and/or apoptosis induced by various stimuli including oxidative stress and MPP ϩ in differentiated PC12 cells. [14][15][16] In undifferentiated PC12 cells, however, antioxidants including quercetin did not have a protective effect against cell death induced by oxidative stress including MPP ϩ . 15,16) The effect of quercetin on cell survival and death in undifferentiated PC12 cells has not been well established. In the present study, we investigated whether quercetin causes cell death in undifferentiated PC12 cells or not. The effect of genistein, a soy isoflavone that has the pro-apoptotic ac...