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(-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons

Schroeter, H., Bahia, P., Spencer, J.P.E., Sheppard, O., Rattray, M., Cadenas, E., Rice-Evans, C. and Williams, R.J. (2007) (-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons. Journal of Neurochemistry, 101 (6). pp. 1596-1606. ISSN 0022-3042

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To link to this article DOI: 10.1111/j.1471-4159.2006.04434.x

Abstract/Summary

Emerging evidence suggests that the cellular actions of flavonoids relate not simply to their antioxidant potential but also to the modulation of protein kinase signalling pathways. We investigated in primary cortical neurons, the ability of the flavan-3-ol, (-)epicatechin, and its human metabolites at physiologically relevant concentrations, to stimulate phosphorylation of the transcription factor cAMP-response element binding protein (CREB), a regulator of neuronal viability and synaptic plasticity. (-)Epicatechin at 100-300 nmol/L stimulated a rapid, extracellular signal-regulated kinase (ERK)- and PI3K-dependent, increase in CREB phosphorylation. At micromolar concentrations, stimulation was no longer apparent and at the highest concentration tested (30 mu mol/L) (-)epicatechin was inhibitory. (-)Epicatechin also stimulated ERK and Akt phosphorylation with similar bell-shaped concentration-response characteristics. The human metabolite 3 '-O-methyl-(-)epicatechin was as effective as (-)epicatechin at stimulating ERK phosphorylation, but (-)epicatechin glucuronide was inactive. (-)Epicatechin and 3 '-O-methyl-(-)epicatechin treatments (100 nmol/L) increased CRE-luciferase activity in cortical neurons in a partially ERK-dependent manner, suggesting the potential to increase CREB-mediated gene expression. mRNA levels of the glutamate receptor subunit GluR2 increased by 60%, measured 18 h after a 15 min exposure to (-)epicatechin and this translated into an increase in GluR2 protein. Thus, (-)epicatechin has the potential to increase CREB-regulated gene expression and increase GluR2 levels and thus modulate neurotransmission, plasticity and synaptogenesis.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > Department of Food and Nutritional Sciences
ID Code:13001
Uncontrolled Keywords:Akt, antioxidants, cyclic AMP-response element, binding protein, flavonoids, mitogen-activated protein kinase, neurodegeneration , TEA POLYPHENOL (-)-EPIGALLOCATECHIN-3-GALLATE, FAMILY TRANSCRIPTION FACTOR, AMYLOID PRECURSOR PROTEIN, LOW-DENSITY-LIPOPROTEIN, GENOME-WIDE ANALYSIS, HYDROGEN-PEROXIDE, BINDING PROTEIN, NEURODEGENERATIVE DISEASES, SYNAPTIC PLASTICITY, ARACHIDONIC-ACID

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