The interactions of flavonoids within neuronal signalling pathways

Abstract

Emerging evidence suggests that dietary phytochemicals, in particular flavonoids, may exert beneficial effects in the central nervous system by protecting neurons against stress-induced injury, by suppressing neuroinflammation and by promoting neurocognitive performance, through changes in synaptic plasticity. It is likely that flavonoids exert such effects in neurons, through selective actions on different components within a number of protein kinase and lipid kinase signalling cascades, such as phosphatidylinositol-3 kinase (PI3K)/Akt, protein kinase C and mitogen-activated protein kinase. This review details the potential inhibitory or stimulatory actions of flavonoids within these pathways, and describes how such interactions are likely to affect cellular function through changes in the activation state of target molecules and/or by modulating gene expression. Although, precise sites of action are presently unknown, their abilities to: (1) bind to ATP binding sites on enzymes and receptors; (2) modulate the activity of kinases directly; (3) affect the function of important phosphatases; (4) preserve neuronal Ca(2+) homeostasis; and (5) modulate signalling cascades lying downstream of kinases, are explored. Future research directions are outlined in relation to their precise site(s) of action within the signalling pathways and the sequence of events that allow them to regulate neuronal function in the central nervous system.

Fig. 1

The structures of the five main classes of flavonoids. The major differences between the individual groups reside in the hydroxylation pattern of the ring-structure, the degree of saturation of the C-ring and the substitution of the 3-position

Fig. 2

Overview of MAP kinase and Akt/PKB signalling cascades in neurons. Flavonoid-induced activation of ERK1/2 or PI3K/Akt pathways acts to stimulate neuronal survival and/or enhance synaptic plasticity and long-term potentiation relevant to the laying down of memory. In addition, inhibitory actions within JNK and p38 pathways are likely to be neuroprotective in the presence of stress

Fig. 3

Potential points of action of flavonoids within ERK pathway. ERK1/2 are activated by upstream MAPKK, such as MEK1/2, and MAPKKK, such as c-Raf. MEK1/2 induce ERK1/2 activation via dual phosphorylation on threonine 202 and tyrosine 204 residues within the tripeptide motif TEY. Phosphorylation of ERK leads to the activation of a number of transcription factors, important in controlling differentiation, neuronal survival and various forms of cellular plasticity. For example, ERK activates pro-survival transcription factor CREB, by activating both p90RSK and MSK1/2. Other important targets include, ATF-1, Elk-1 and stat1/3, all of which are implicated in the regulation of various forms of cellular stress, including genotoxic agents, inflammatory cytokines and UV irradiation

Fig. 4

Potential points of action of flavonoids within JNK pathway. JNK is regulated by a variety of MAPKKK’s, including MEKK1/4 and apoptosis-stimulating kinase (ASK1), which is further regulated by GTPases and Rac1. Unlike the ERK pathway, the JNK cascade is strongly activated by stress signals such as UV and γ-radiation, oxidative stress and inflammatory cytokines. The MAPKK, MKK4/7, dually phosphorylates JNK within the Thr¹³⁸-Pro-Tyr-¹⁸⁵ motif (pTPpY) in the catalytic core of active JNK. Active JNK has been strongly linked to transcription-dependent apoptotic signalling, mainly through the activation of c-Jun and other AP-1 proteins including JunB, JunD and ATF-2

Fig. 5

Potential points of action of flavonoids within p38 pathway. p38 is activated by a variety of cellular stresses including osmotic shock, pro-inflammatory inflammatory cytokines, lipopolysacharides, UV light and growth factors. The activity of p38 is regulated by the MKK’s, MKK3 and MKK6, which in turn, are regulated by the upstream MAPKKK, MEK1/4 and ASK. Active p38 regulates the phosphorylation of the transcription factors ATF-2, Max and MEF2, which are implicated in cellular response to a variety of cellular stress, including genotoxic agents and inflammatory cytokines

Fig. 6

The structure of MEK inhibitor PD98059 and the PI3K inhibitors, LY294002, have close structural homology to that of flavonoids. LY294002 and quercetin both fit into the ATP binding pocket of the PI3K, inhibiting its activity. It appears that the number and substitution of hydroxyl groups on the flavonoid B-ring and the degree of un-saturation of the C2–C3 bond are important determinants of their activity. Such inhibitory actions have been proposed as potential mechanisms by which flavonoids act to modulate neuronal function

Fig. 7

Potential points of action of flavonoids within PI3K/Akt signalling pathway. Active PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP₃) which activates phosphoinositide-dependent protein kinase 1 (PDK1). PDK1 plays a central role in many signal transduction pathways, activating Akt and the PKC isoenzymes p70 S6 kinase and RSK. Through its effects on these kinases, PI3K is involved in the regulation of a wide variety of processes, including cell growth, cell proliferation, differentiation, cell cycle entry, cell migration and apoptosis. Flavonoids have been proposed to act on this pathway via direct modulation of PI3K activity via binding to its ATP binding pocket, in a similar manner to that of LY294002. Alternatively, they may act to modulate the activity of the tumour suppressor, PTEN