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

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-b-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.

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

“…One example of this is the flavonol quercetin and some of its in vivo metabolites which were shown to inhibit prosurvival Akt/PKB signaling pathways by inhibiting PI3-kinase activity, 83 whereas flavanones, such as hesperetin, have been shown to activate Akt/PKB signaling to confer prosurvival properties in cortical neurons. 108 Furthermore, it has been shown that EGCG stimulates extracellular signal-regulated kinase (ERK)-and PI3K-dependent increase in CREB phosphorylation and upregulates GluR2 levels in cortical neurons and can therefore act as a modulator in neurotransmission, plasticity, and synaptogenesis. 107 Supplementing the diet of aged animals with blueberry for 12 weeks, has been shown to induce the phosphorylation of hippocampal Akt, the activation downstream of mTOR, and the increased expression of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1).…”

A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone

“…Flavonoids may improve cognitive performance by protecting vulnerable neurons, enhancing existing neuronal function, and stimulating neuronal regeneration (10). Flavonoids exert effects on long-term potentiation underlying learning and memory, on and consequently memory and cognitive performance, through their interactions with the signaling pathways including PI3K/Akt (11) and MAPK (12).…”

Polyphenols and brain health

“…Instead, recent findings have suggested that in lower amounts, typical of those attained in the diet, polyphenols may exert pharmacological activity within the cells with mechanisms that go beyond the classic antioxidant scavenging mechanisms (Williams et al, 2004;Vauzour et al, 2010). In particular, polyphenols are capable of modulating intracellular signalling cascades Vauzour et al, 2010;Kuo et al, 2015), gene expression and interactions with mitochondria (Schroeter et al, 2001;Schroeter et al, 2007;Vauzour et al, 2007b;Mandel et al, 2008). By affecting such pathways, they have the potential to induce new protein synthesis in neurons and thus an ability to induce morphological changes, which have a direct influence on memory acquisition, consolidation and storage.…”

“…There is much evidence to support the actions of polyphenols on the ERK pathway (Schroeter et al, 2007;Vauzour et al, 2007b), which often leads to the activation of CREB (Corona et al, 2013), a transcription factor considered to be critical in the induction of long-lasting changes in synaptic plasticity and memory (Bourtchuladze et al, 1994;Impey et al, 1998). Indeed, CREB activation regulates the expression of a number of important genes, including the brain derived neurotrophic factor (BDNF), thus playing a pivotal role in controlling neuronal survival, and synaptic function in the adult central nervous system (Finkbeiner, 2000;Tully et al, 2003).…”