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

被引:64
作者
Bahia, Parmvir K. [1 ]
Rattray, Marcus [2 ]
Williams, Robert J. [1 ]
机构
[1] Kings Coll London, Wolfson Ctr Age Related Dis, Wolfson Wing, London SE1 1UL, England
[2] Univ Reading, Reading Sch Pharm, Reading, Berks, England
基金
英国生物技术与生命科学研究理事会;
关键词
Alzheimer's disease; flavonoids; neuroprotection; nuclear factor erythroid-2-related factor; oxidative stress; phosphatidylinositol; 3-kinase;
D O I
10.1111/j.1471-4159.2008.05542.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu M) 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.
引用
收藏
页码:2194 / 2204
页数:11
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