Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons

David Vauzour, Katerina Vafeiadou, Catherine Rice-Evans, Robert J Williams, Jeremy P E Spencer

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Abstract

There is growing interest in the potential beneficial effects of flavonoids in the aging and diseased brain. We have investigated the potential of the flavanone hesperetin and two of its metabolites, hesperetin-7-O-beta-d-glucuronide and 5-nitro-hesperetin, to inhibit oxidative stress-induced neuronal apoptosis. Exposure of cortical neurons to hydrogen peroxide led to the activation of apoptosis signal-regulating kinase 1 via its de-phosphorylation at Ser963, the phosphorylation of c-jun N-terminal kinase and c-Jun (Ser73) and the activation of caspase 3 and caspase 9. Whilst hesperetin glucuronide failed to exert protection, both hesperetin and 5-nitro-hesperetin were effective at preventing neuronal apoptosis via a mechanism involving the activation/phosphorylation of both Akt/protein kinase B and extracellular signal-regulated kinase 1 and 2 (ERK1/2). Protection against oxidative injury and the activation of Akt and ERK1/2 followed a bell-shaped response and was most apparent at 100 nmol/L concentrations. The activation of ERK1/2 and Akt by flavanones led to the inhibition of the pro-apoptotic proteins, apoptosis signal-regulating kinase 1, by phosphorylation at Ser83 and Bad, by phosphorylation at both Ser136 and Ser112 and to the inhibition of peroxide-induced caspase 9 and caspase 3 activation. Thus, flavanones may protect neurons against oxidative insults via the modulation of neuronal apoptotic machinery.
Original languageEnglish
Pages (from-to)1355-67
Number of pages13
JournalJournal of Neurochemistry
Volume103
Issue number4
DOIs
Publication statusPublished - 2007

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Flavanones
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Phosphorylation
Neurons
Chemical activation
MAP Kinase Kinase Kinase 5
Caspase 9
Glucuronides
Caspase 3
Apoptosis
Proto-Oncogene Proteins c-akt
Apoptosis Regulatory Proteins
Oxidative stress
JNK Mitogen-Activated Protein Kinases
Peroxides
Brain Diseases
Metabolites
Flavonoids
Hydrogen Peroxide

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Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. / Vauzour, David; Vafeiadou, Katerina; Rice-Evans, Catherine; Williams, Robert J; Spencer, Jeremy P E.

In: Journal of Neurochemistry, Vol. 103, No. 4, 2007, p. 1355-67.

Research output: Contribution to journalArticle

Vauzour, David ; Vafeiadou, Katerina ; Rice-Evans, Catherine ; Williams, Robert J ; Spencer, Jeremy P E. / Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. In: Journal of Neurochemistry. 2007 ; Vol. 103, No. 4. pp. 1355-67.
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