Apigenin and Structurally Related Flavonoids Allosterically Potentiate the Function of Human α7-Nicotinic Acetylcholine Receptors Expressed in SH-EP1 Cells

Bassem Sadek,Murat Oz,Waheed Shabbir,Keun-Hang Susan Yang

doi:10.3390/cells10051110

Bassem Sadek, Murat Oz + Show 2 more

Open Access

https://doi.org/10.3390/cells10051110

Copy DOI

Abstract

Phytochemicals, such as monoterpenes, polyphenols, curcuminoids, and flavonoids, are known to have anti-inflammatory, antioxidant, neuroprotective, and procognitive effects. In this study, the effects of several polyhydroxy flavonoids, as derivatives of differently substituted 5,7-dihydroxy-4H-chromen-4-one including apigenin, genistein, luteolin, kaempferol, quercetin, gossypetin, and phloretin with different lipophilicities (cLogP), as well as topological polar surface area (TPSA), were tested for induction of Ca2+ transients by α7 human nicotinic acetylcholine (α7 nACh) receptors expressed in SH-EP1 cells. Apigenin (10 μM) caused a significant potentiation of ACh (30 μM)-induced Ca2+ transients, but did not affect Ca2+ transients induced by high K+ (60 mM) containing solutions. Co-application of apigenin with ACh was equally effective as apigenin preincubation. However, the effect of apigenin significantly diminished by increasing ACh concentrations. The flavonoids tested also potentiated α7 nACh mediated Ca2+ transients with descending potency (highest to lowest) by genistein, gossypetin, kaempferol, luteolin, phloretin, quercetin, and apigenin. The specific binding of α7 nACh receptor antagonist [125I]-bungarotoxin remained unchanged in the presence of any of the tested polyhydroxy flavonoids, suggesting that these compounds act as positive allosteric modulators of the α7-nACh receptor in SH-EP1 cells. These findings suggest a clinical potential for these phytochemicals in the treatment of various human diseases from pain to inflammation and neural disease.

Highlights

Nicotinic acetylcholine receptors belong to the ligand-gated ion channel family that includes serotonin type-3, glycine, and γ-aminobutyric acid (GABA)-A receptors.The homomeric α7 human nicotinic acetylcholine (α7 nACh) receptor subtype is expressed in both central and peripheral nervous systems, as well as non-neuronal cells, and plays an important role in synaptic plasticity and various disease pathologies [1]
No detectable changes in intracellular Ca2+ levels were observed after 30 s application of apigenin alone in Fluo-4 loaded SHobserved after 30 s application of apigenin alone in Fluo-4 loaded SH-EP1
Ca2+ transients by theofstimulation of human α7 nACh receptors expressed in SH-EP1 cells. (A) The effect of 10 μM apigenin and 10 μM

Summary

Introduction

The homomeric α7 nACh receptor subtype is expressed in both central and peripheral nervous systems, as well as non-neuronal cells, and plays an important role in synaptic plasticity and various disease pathologies [1]. Α7-nACh receptors are recognized targets for drug development in several preclinical experimental models of pain, inflammation, neurodegenerative diseases, and psychosis [1,2]. Chemical entities modulating the function these receptors have clinical significance in treating pain and inflammation, and alleviating several neurodegenerative disorders. Phytochemicals, such as terpenes, polyphenols, curcuminoids, and flavonoids, have been shown extensively to exert antioxidant, anti-inflammatory, anti-hypertensive, neuroprotective, antiepileptic, and procognitive effects [3,4,5,6,7].

Methods

Results

Conclusion