Ethyl ferulate, a lipophilic polyphenol, induces HO-1 and protects rat neurons against oxidative stress

In the CNS, the heme oxygenase (HO) system has been reported to be active and to operate as a fundamental
defensive mechanism for neurons exposed to an oxidant challenge. We have recently shown that both curcumin
and caffeic acid phenethyl ester, two phenolic natural compounds, potently induce HO-1 expression
and activity in rat astrocytes. We have extended our previous findings examining the effects of two other
plant-derived phenolic compounds, with analogous chemical structures, in rat astrocytes and neurons. Ethyl
ferulate (ethyl 4-hydroxy-3-methoxycinnamate) (EFE), the naturally occurring ester of ferulic acid, was able
to induce HO-1 protein expression. Maximal expression of HO-1 mRNA and protein and a significant increase
in HO activity were detected after 6 h of incubation with 15 μM EFE in astrocytes and 5 μM EFE in neurons.
Higher concentrations of EFE (50 μM) caused a substantial cytotoxic effect with no change in HO-1 protein
expression and activity. Exposure of astrocytes to resveratrol, a phytoalexin derived from grapes, resulted in
an increase of HO-1 mRNA, but it was not able to induce HO-1 protein expression and activity. Interestingly,
preincubation (12 h) of neurons with EFE resulted in an enhanced cellular resistence to glucose oxidasemediated
oxidative damage; this cytoprotective effect was considerably attenuated by zinc protoporphyrin
IX, an inhibitor of HO activity. This study identifies a novel natural compound that could be used for therapeutic
purposes as a potent inducer of HO-1 for the protection of brain cells against oxidative and neurodegenerative
conditions.