There is mounting evidence implicating the accumulation of intracellular
reactive oxygen species (ROS) and
reactive nitrogen species (RNS) in the pathogenesis of
neurodegenerative disorders, including
Alzheimer's disease. Recently, considerable attention has been focused on identifying naturally occurring
antioxidants that are able to reduce excess ROS and RNS, thereby protecting against oxidative stress and neuron death. The present study investigated the possible protective effects of
piceatannol (trans-3,4,3',5'-tetrahydroxystilbene), which is present in grapes and other foods, on
hydrogen-peroxide- and
peroxynitrite-induced oxidative cell death. PC12 rat
pheochromocytoma (PC12) cells treated with
hydrogen peroxide or SIN-1 (a
peroxynitrite-generating compound) exhibited apoptotic death, as determined by nucleus condensation and cleavage of
poly(ADP-ribose)polymerase (PARP).
Piceatannol treatment attenuated
hydrogen-peroxide- and
peroxynitrite-induced cytotoxicity, apoptotic features, PARP cleavage and intracellular ROS and RNS accumulation. Treatment of PC12 cells with
hydrogen peroxide or SIN-1 led to down-regulation of Bcl-X(L) and activation of
caspase-3 and -8, which were also inhibited by
piceatannol treatment.
Hydrogen peroxide or SIN-1 treatment induced phosphorylation of the
c-Jun-N-terminal kinase (JNK), which was inhibited by
piceatannol treatment. Moreover,
SP600125 (a JNK inhibitor) significantly inhibited
hydrogen-peroxide- and
peroxynitrite-induced PC12 cell death, revealing inactivation of the JNK pathway as a possible molecular mechanism for the protective effects of
piceatannol against
hydrogen-peroxide- and
peroxynitrite-induced apoptosis of PC12 cells. Collectively, these findings suggest that the protective effect of
piceatannol against
hydrogen-peroxide- and
peroxynitrite-induced apoptosis of PC12 cells is associated with blocking the activation of JNK and the down-regulation of Bcl-XL.