Inhibition of PP2A by hesperetin may contribute to Akt and ERK1/2 activation status in cortical neurons
Section snippets
Background
Accumulating evidence suggests that diet and lifestyle can play an important role in delaying the onset or halting the progression of age-related neurodegenerative diseases. A growing number of dietary intervention studies in humans and animals, in particular those using flavonoid-rich diets have been proposed to exert a multiplicity of neuroprotective actions within the brain, including a preservation of cognitive performance with ageing [[1], [2], [3]], a delay in the onset of Alzheimer's
Reagents
Reagents were from Sigma Chemicals Co. (Poole, Dorset, UK) unless otherwise stated. Hesperetin was obtained from Extrasynthese (Genay, France). Antibodies used were: anti-ACTIVE MAPK (ERK1/2), anti-pAkt (Ser-473), ERK1/2, Akt were from New England Biolabs (Hitchin, Hertfordshire, UK). PP2A and PTEN antibodies were from Insight Biotechnology Ltd (Wembley, UK). Horseradish peroxidase-conjugated goat anti-rabbit secondary antibody (Sigma, Poole, UK), ECL reagent and Hyperfilm-ECL were purchased
Hesperetin stimulates Akt and ERK phosphorylation in cortical neurons
To investigate the phosphorylation state of ERK1/2 and Akt/PKB, phospho-specific antibodies were employed that recognise the dually phosphorylated motif pTEpY within activated ERK1/2, and the phosphorylated Ser473 of Akt/PKB respectively. Exposure of cortical neurons to hesperetin (0.3 μM; 30 min) resulted in a significant increase in Akt phosphorylation at Ser473 [F (2, 3) = 15.45; P = 0.0364], an event known to be essential for full activation of the kinase (Fig. 1A). No significant changes
Discussion
Flavonoids have been proposed to exert beneficial effects in a multitude of diseases, including cancer, cardiovascular disease and neurodegenerative disorders [[52], [53], [54]]. Increasingly they have been observed to exert their cellular effects via the modulation of cell signaling pathways, such as the mitogen activated protein kinase (MAPK) and the PI3K pathways, two essential signaling cascades that regulate multiple processes in the central nervous system including proliferation,
Author contributions
DV and JPES conceived and designed the experiments. DV performed the neuronal culture, phosphatase assays and the immunoblotting. SC and MM contributed to the molecular docking. DV and JPES wrote the paper. All authors gave final approval of the version to be published. All authors read and approved the final manuscript.
Conflicts of interest
The authors have no conflict of interest to declare.
Acknowledgments
This research was supported the Medical Research Council (grant ref. G0400278/N102) and is greatly appreciated.
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