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

Hagen Schroeter, Parmvir Bahia, Jeremy P E Spencer, Olivia Sheppard, Marcus Rattray, Enrique Cadenas, Catherine Rice-Evans, Robert J Williams

Research output: Contribution to journalArticle

  • 104 Citations

Abstract

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 μmol/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.
LanguageEnglish
Pages1596-1606
Number of pages11
JournalJournal of Neurochemistry
Volume101
Issue number6
DOIs
StatusPublished - Jun 2007

Fingerprint

Catechin
Extracellular Signal-Regulated MAP Kinases
Response Elements
Cyclic AMP
Neurons
Up-Regulation
Cyclic AMP Response Element-Binding Protein
Phosphorylation
Neuronal Plasticity
Metabolites
Gene expression
Plasticity
Gene Expression
Glutamate Receptors
Luciferases
Phosphatidylinositol 3-Kinases
Flavonoids
Synaptic Transmission
Protein Kinases
Transcription Factors

Cite this

(-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons. / Schroeter, Hagen; Bahia, Parmvir; Spencer, Jeremy P E; Sheppard, Olivia; Rattray, Marcus; Cadenas, Enrique; Rice-Evans, Catherine; Williams, Robert J.

In: Journal of Neurochemistry, Vol. 101, No. 6, 06.2007, p. 1596-1606.

Research output: Contribution to journalArticle

Schroeter, H, Bahia, P, Spencer, JPE, Sheppard, O, Rattray, M, Cadenas, E, Rice-Evans, C & Williams, RJ 2007, '(-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons' Journal of Neurochemistry, vol. 101, no. 6, pp. 1596-1606. DOI: 10.1111/j.1471-4159.2006.04434.x
Schroeter H, Bahia P, Spencer JPE, Sheppard O, Rattray M, Cadenas E et al. (-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons. Journal of Neurochemistry. 2007 Jun;101(6):1596-1606. Available from, DOI: 10.1111/j.1471-4159.2006.04434.x
Schroeter, Hagen ; Bahia, Parmvir ; Spencer, Jeremy P E ; Sheppard, Olivia ; Rattray, Marcus ; Cadenas, Enrique ; Rice-Evans, Catherine ; Williams, Robert J. / (-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons. In: Journal of Neurochemistry. 2007 ; Vol. 101, No. 6. pp. 1596-1606
@article{3a1fb250ca6e4c4682834bb26d69ec47,
title = "(-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons",
abstract = "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 μmol/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.",
author = "Hagen Schroeter and Parmvir Bahia and Spencer, {Jeremy P E} and Olivia Sheppard and Marcus Rattray and Enrique Cadenas and Catherine Rice-Evans and Williams, {Robert J}",
year = "2007",
month = "6",
doi = "10.1111/j.1471-4159.2006.04434.x",
language = "English",
volume = "101",
pages = "1596--1606",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - (-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons

AU - Schroeter,Hagen

AU - Bahia,Parmvir

AU - Spencer,Jeremy P E

AU - Sheppard,Olivia

AU - Rattray,Marcus

AU - Cadenas,Enrique

AU - Rice-Evans,Catherine

AU - Williams,Robert J

PY - 2007/6

Y1 - 2007/6

N2 - 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 μmol/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.

AB - 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 μmol/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.

UR - http://dx.doi.org/10.1111/j.1471-4159.2006.04434.x

U2 - 10.1111/j.1471-4159.2006.04434.x

DO - 10.1111/j.1471-4159.2006.04434.x

M3 - Article

VL - 101

SP - 1596

EP - 1606

JO - Journal of Neurochemistry

T2 - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 6

ER -