Dietary flavonoid (−)epicatechin stimulates phosphatidylinositol 3‐kinase‐dependent anti‐oxidant response element activity and up‐regulates glutathione in cortical astrocytes

Flavonoids are plant‐derived polyphenolic compounds with neuroprotective properties. Recent work suggests that, in addition to acting as hydrogen donors, they activate protective signalling pathways. The anti‐oxidant response element (ARE) promotes the expression of protective proteins including those required for glutathione synthesis (xCT cystine antiporter, gamma‐glutamylcysteine synthetase and glutathione synthase). The use of a luciferase reporter (ARE‐luc) assay showed that the dietary flavan‐3‐ol (−)epicatechin activates this pathway in primary cortical astrocytes but not neurones. We also examined the distribution of NF‐E2‐related factor‐2 (Nrf2), a key transcription factor in ARE‐mediated gene expression. We found, using immunocytochemistry, that Nrf2 accumulated in the nuclei of astrocytes following exposure to tert‐butylhydroquinone (100 μM) and (−)epicatechin (100 nM). (−)Epicatechin signalling via Nrf2 was inhibited by wortmannin implicating a phosphatidylinositol 3‐kinase‐dependent pathway. Finally, (−)epicatechin increased glutathione levels in astrocytes consistent with an up‐regulation of ARE‐mediated gene expression. Together, this suggests that flavonoids may be cytoprotective by increasing anti‐oxidant gene expression.