The physiological benefits of dietary flavonoids have been attributed to their antioxidant and signaling properties. Our previous study revealed that hesperetin exhibits neuroprotection in PC12 cells by diverse mechanisms. Biological activities of flavonoids might be determined by their chemical structures. Here, we further studied the effects of hesperetin and its structural counterparts, isorhamnetin and isosakuranetin, on kinases related to survival signaling as well as other cytoprotective actions. Pretreatment with flavonoids (0.8 or 50 microM) increased cell viability and catalase activity (CA) and decreased membrane damage, reactive oxygen species (ROS) generation, intracellular calcium level ([Ca2+]i), and caspase-3 activity in H2O2-treated PC12 cells. Increased CA, [Ca2+]i, and ROS levels, but lower caspase-3 activities, were obtained upon treatment with 50 microM isorhamnetin or isosakuranetin. Based on their structural differences and the concentrations used, these flavonoids differentially activated pro-survival signaling molecules, including Akt/protein kinase B, p38 mitogen-activated protein kinase, and inhibited the activation of c-jun N-terminal kinase, which triggers apoptosis. Our results demonstrate that signaling actions of thses flavonoids are involved in their neuroprotection against oxidative stress and that they act more as signaling molecules than antioxidants.