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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antioxidants / metabolism
-
Antioxidants / pharmacology
-
Astrocytes / drug effects*
-
Astrocytes / metabolism
-
COS Cells
-
Catechin / metabolism
-
Catechin / pharmacology*
-
Cells, Cultured
-
Cerebral Cortex / drug effects
-
Cerebral Cortex / metabolism
-
Chlorocebus aethiops
-
Enzyme Inhibitors / pharmacology
-
Flavonoids / metabolism
-
Flavonoids / pharmacology
-
Food, Formulated
-
Gene Expression Regulation / drug effects
-
Gene Expression Regulation / physiology
-
Glutathione / metabolism*
-
Hydroquinones / pharmacology
-
Mice
-
NF-E2-Related Factor 2 / drug effects
-
NF-E2-Related Factor 2 / metabolism
-
Neuroprotective Agents / metabolism
-
Neuroprotective Agents / pharmacology
-
Oxidative Stress / drug effects*
-
Oxidative Stress / physiology
-
Phosphatidylinositol 3-Kinases / drug effects*
-
Phosphatidylinositol 3-Kinases / genetics
-
Phosphatidylinositol 3-Kinases / metabolism
-
Response Elements / drug effects*
-
Response Elements / genetics
-
Signal Transduction / drug effects
-
Signal Transduction / physiology
-
Up-Regulation / drug effects
-
Up-Regulation / physiology
Substances
-
Antioxidants
-
Enzyme Inhibitors
-
Flavonoids
-
Hydroquinones
-
NF-E2-Related Factor 2
-
Neuroprotective Agents
-
Nfe2l2 protein, mouse
-
Catechin
-
2-tert-butylhydroquinone
-
Glutathione