title: Dietary flavonoid (-)epicatechin stimulates phosphatidylinositol 3-kinase-dependent anti-oxidant response element activity and up-regulates glutathione in cortical astrocytes.
abstract: 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 microM) 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.
authors.affiliation: The Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
authors.forename: Parmvir K
authors.initials: PK
authors.lastname: Bahia
authors.forename: Marcus
authors.initials: M
authors.lastname: Rattray
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Williams
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D019556:COS Cells; D002392:Catechin / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology; D005526:Food, Formulated; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000378:metabolism*; D006873:Hydroquinones / Q000494:pharmacology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D000975:Antioxidants; D002392:Catechin; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005978:Glutathione; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; C495636:Nfe2l2 protein, mouse; C018855:2-tert-butylhydroquinone