beta-Amyloid peptide (beta-AP) elicits a toxic effect on neurons in vitro and in vivo. Many environmental factors including antioxidants, metal ions and proteoglycans modify beta-AP toxicity. We have investigated on PC12 cells, the protective effect from beta-AP (1-41) of two plant polyphenols, resveratrol and catechin. PC12 cells treated with 10(-6)M beta-AP (1-41) for 16h decrease the cell viability at 24% of the control with an IC(50) value of 1.1+/-0.14 x 10(-8)M. Twenty-five micromolar resveratrol and 50 microM catechin protect PC12 cells from beta-AP (1-41) toxicity with the IC(50) value increased at 2.2+/-0.19 x 10(-7)M and at 8.9+/-0.7 x 10(-8)M, respectively. While the protective effect is concentration dependent for catechin, resveratrol shows a concentration-dependent biphasic effect. Up to 50 microM concentration, resveratrol protects PC12 cells from beta-AP (1-41) toxicity. At concentration higher than 50 microM, an inhibitory activity on cell proliferation appears. This antiproliferative effect is shown also in the absence of beta-AP (1-41). Resveratrol and catechin have a synergistic protective action. In the presence of 50 microM catechin and 10 microM resveratrol or 25 microM resveratrol and 10 microM catechin, the toxicity determined by 10(-7)M beta-AP (1-41) is almost completely abolished. Catechin is more effective than resveratrol in protecting PC12 cells from the toxicity of hydrogen peroxide. The protection from Oxygen Reactive Species (ROS) toxicity is concentration dependent for both resveratrol and catechin. In this case the protection is merely additive and the synergistic effect is not observed. These results demonstrate that resveratrol and catechin protect PC12 cells from beta-AP (1-41) toxicity and that their protective effect is synergistic. Such a protective effect probably is not due only to their antioxidant activity. The different chemical and biological activity shown by these compounds on several cell types and the complexity of the beta-AP (1-41) toxicity may explain the synergistic protective effect and suggest that the utilization of different compounds with synergistic activity may protect more effectively from complex mechanisms of toxicity.