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.

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