X-Message-Number: 24324 Date: Sat, 3 Jul 2004 21:00:03 -0700 (PDT) From: Doug Skrecky <> Subject: could resveratrol/catechin reverse Alzheimer's disease? Drugs Exp Clin Res. 2003;29(5-6):243-55. Effect of resveratrol and catechin on PC12 tyrosine kinase activities and their synergistic protection from beta-amyloid toxicity. beta-Amyloid peptide (beta-AP) is the main component of amyloid deposits around the cerebral vessel and in the brain parenchyma in Alzheimer's disease and Down's syndrome. In vitro studies in neuronal cells or in PC12 and Hela cell lines have shown that the aggregate form of beta-AP is toxic. Many genetic and environmental factors including metal ions, proteoglycans, plasma proteins and antioxidants modify beta-AP toxicity. We investigated the effect of two plant polyphenols--resveratrol and catechin--on soluble and particulate tyrosine kinase activity from PC12 cells and the protective action of these compounds against beta-AP (1-41) toxicity. beta-AP (1-41) decreased PC12 viability with an IC50 value of 1.1 +/- 0.14 x 10(-8) M. Resveratrol and catechin protected PC12 cells from beta-AP (1-41) toxicity. With 25 microM resveratrol the IC50 value increased to 2.2 +/- 0.19 x 10(-7) M. In the presence of beta-AP (1-41) resveratrol showed a concentration-dependent biphasic effect, and at a concentration of up to 40 microM it protected PC12 cells from beta-AP (1-41) toxicity. At concentrations higher than 40 microM, an inhibitory activity on cell proliferation appeared. This antiproliferative effect was also seen in the absence of beta-AP (1-41). With 100 microM catechin the IC50 value increased from 1.1 +/- 0.14 x 10(-8) M to 3.2 +/- 0.25 x 10(-7) M beta-AP (1-41). The protective effect was concentration dependent. Resveratrol and catechin had a synergistic protective action. In the presence of 40 microM catechin and 10 microM resveratrol or 20 microM resveratrol and 10 microM catechin, the toxicity determined by 10(-7) M beta-AP (1-41) was almost completely removed. Resveratrol and catechin had different effects on PC12 tyrosine kinase activity. With peptide 1-17 of gastrin as substrate, resveratrol inhibited particulate tyrosine kinases while it had no effect on soluble activity. With the same substrate, catechin increased the activity of soluble fraction while it inhibited particulate activity. When peptide 6-20 of cell division kinase p34cdc2 was utilized, catechin showed an opposite effect, inhibiting soluble tyrosine kinase activity and increasing particulate activity. With peptide 6-20, resveratrol inhibited both soluble and particulate activities. These results demonstrate that resveratrol and catechin have different activities on the signal transduction pathway involving protein phosphorylation. These differences may contribute not only to the different effects of these compounds on PC12 growth but also to the synergistic effect against beta-AP (1-41) toxicity. The different activity of resveratrol and catechin on signal transduction pathways, as well as the differences in metal chelation, partition coefficient between water and lipids, hydrogen donation redox potential and enzyme inhibition may be at least in part based on synergistic protection against beta-AP (1-41) toxicity. Ann N Y Acad Sci. 2003 Dec;1010:365-73. Pro-oxidant activity of low doses of resveratrol inhibits hydrogen peroxide-induced apoptosis. We have recently shown that efficient apoptotic signaling is a function of a permissive intracellular milieu created by a decrease in the ratio of superoxide to hydrogen peroxide and cytosolic acidification. Resveratrol, a phytoalexin found in grapes and wines, triggers apoptosis in some systems and inhibits the death signal in others. In this regard, the reported inhibitory effect on hydrogen peroxide-induced apoptosis has been attributed to its antioxidant property. Here, we provide evidence that exposure of human leukemia cells to low concentrations of resveratrol (4-8 micro M) inhibits caspase activation and DNA fragmentation induced by incubation with hydrogen peroxide or upon triggering apoptosis with a novel compound that kills via intracellular hydrogen peroxide production. At these concentrations, resveratrol elicits pro-oxidant properties as evidenced by an increase in intracellular superoxide concentration. This pro-oxidant effect is further supported by our observations that the drop in intracellular superoxide and cytosolic acidification induced by hydrogen peroxide is completely blocked in cells preincubated with resveratrol. Thus, the inhibitory effect of resveratrol on hydrogen peroxide-induced apoptosis is not due to its antioxidant activity, but contrarily via a pro-oxidant effect that creates an intracellular environment nonconducive for apoptotic execution. Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=24324