Structure-activity relationships of quercetin in antagonizing hydrogen peroxide-induced calcium dysregulation in PC12 cells

Oxidative stress can induce neurotoxic insults by increasing intracellular calcium (Ca2+), which has been implicated in various neurodegenerative dise ases in aging. Previously, we showed that hydrogen peroxide induced calcium dysregulation in PC12 cells, as evidenced by (i) an increase in calcium ba selines, (ii) a decrease in depolarization-induced calcium influx, and (iii ) a failure to recover the Ca2+ levels. In the present experiments, we inve stigated whether a dietary flavonoid, quercetin, can antagonize the effects of hydrogen peroxide in the same cell model. We also investigated the poss ible structure-activity relationships of quercetin by comparing the results with four other flavonoids, each having a slightly different structure fro m quercetin. Our results indicated that two structural components, includin g (i) 3',4'-hydroxyl (OH) groups in the B ring and (ii) a 2,3-double bond i n conjugation with a Core group in the C ring, along with the polyphenolic structures were crucial for the protection. These structural components are found in quercetin, and this compound was also the most efficacious in red ucing both the H2O2-induced Ca2+ dysregulation in cells and oxidative stres s assessed via the dichlorofluorescein assay. Collectively, these data indi cated that the particular polyphenolic structural components of quercetin p rovided its strong antioxidant property of protecting cells against H2O2-in duced oxidative stress and calcium dysregulation. (C) 1999 Elsevier Science Inc.