title: Effect of resveratrol and catechin on PC12 tyrosine kinase activities and their synergistic protection from beta-amyloid toxicity.
abstract: 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.
authors.affiliation: Department of Agricultural Science, University of Modena e Reggio Emilia, Reggio Emilia, Italy. conte@unimo.it
authors.forename: A
authors.initials: A
authors.lastname: Conte
authors.forename: S
authors.initials: S
authors.lastname: Pellegrini
authors.forename: D
authors.initials: D
authors.lastname: Tagliazucchi
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005434:Flow Cytometry; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D010446:Peptide Fragments; D013267:Stilbenes; C497285:amyloid beta-protein (1-41); D002392:Catechin; D011505:Protein-Tyrosine Kinases; D000077185:Resveratrol