Inhibition of PP2A by hesperetin may contribute to Akt and ERK1/2 activation status in cortical neurons

Abstract

Flavonoids and their metabolites are well reported to modulate the activation/phosphorylation of various cellular kinases, such as ERK1/2 and JNK, although the mechanism by which they do so is unclear. In this study, we investigated the impact of flavanones on the activation of PI3K/Akt and ERK1/2 and determine whether this is mediated, in part, by the inhibition of phosphatases. Primary cortical neurons were exposed to physiological concentrations of hesperetin and the phosphorylation status of the kinases PI3K/Akt and ERK1/2 and the phosphatases PP2A and PTEN were assessed by immunoblotting after 30 min. Exposure to 100-300 nM hesperetin led to significant increases in the phosphorylation of ERK1/2 and Akt and significant decreases in PP2A levels and enzyme activity. Using in silico docking, hesperetin was found to fit into the active site of PP2A interacting within the hydrophobic cage of the catalytic unit. These data suggest a potential mechanism by which flavanones may lead to increased activation of ERK1/2 and Akt, commonly observed in cell models. Their interaction with and inhibition of cellular phosphatases counteract normal physiological regulation of signaling pathway activation thus facilitating and/or maintaining the activation status of ERK1/2 and Akt, important regulators of brain functions.

Polyphenols by Generating H2O2, Affect Cell Redox Signaling, Inhibit PTPs and Activate Nrf2 Axis for Adaptation and Cell Surviving: In Vitro, In Vivo and Human Health

“…Vauzour et al [10] found that hesperetin in very low concentration activates PI3K/Akt and ERK1/2 in neurons via inhibition of the phosphatase PP2A (protein phosphatase 2A). The authors suggest that the inhibition was most probably by interactions with the active site of the enzyme.…”

“…There are several studies on bioavailability of polyphenols in brain tissues founding some transfer, but further work is necessary to confirm that polyphenols can diffuse in the brain and directly modulate brain function [120]. Hesperitin was found to affect Akt and ERK1/2 activation status in cortical neurons [10]. In mice, hesperidin was found to attenuate learning and memory deficiency in APP/PSI mice (β-amyloid precursor protein/presenilin1) through activation of Akt/Nrf2 signaling and inhibition through receptors of advanced glycation end-product (RAGE), which activates the NOX1/H 2 O 2 /NF-kB pathway [121].…”

“…There are several studies on bioavailability of polyphenols in brain tissues founding some transfer, but further work is necessary to confirm that polyphenols can diffuse in the brain and directly modulate brain function [120]. Hesperitin was found to affect Akt and ERK1/2 activation status in cortical neurons [10]. In mice, hesperidin was found to attenuate learning and A variety of cell surface receptors induce protein phosphorylation.…”

“…(1) Polyphenols are inhibitors of NADPH oxidases (NOXs) [6] ("active" only after auto-oxidation to quinones [7,8]). (2) Polyphenols inhibit enzymes and affect receptors by interaction with the protein molecule [9,10].…”

Phenolic Compounds Characteristic of the Mediterranean Diet in Mitigating Microglia-Mediated Neuroinflammation

“…Research on the protective effect of food polyphenols toward the prevention of neurodegenerative disorders has been extensive in recent years ( Singh et al, 2008 ; Joseph et al, 2009 ; Dixon and Pasinetti, 2010 ; Spencer, 2010 ; Jones et al, 2012 ; Vauzour et al, 2018 ). Virgin olive oil (VOO) and wine are two characteristic polyphenol-rich food items of the MD.…”