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. 2021 Nov 4;10(11):1759.
doi: 10.3390/antiox10111759.

Presynaptic Release-Regulating Alpha2 Autoreceptors: Potential Molecular Target for Ellagic Acid Nutraceutical Properties

Isabella Romeo  1   2   3 , Giulia Vallarino  4 , Federica Turrini  4 , Alessandra Roggeri  4 , Guendalina Olivero  4 , Raffaella Boggia  4 , Stefano Alcaro  1   2   3 , Giosuè Costa  1   2   3 , Anna Pittaluga  4   5
Affiliations

Presynaptic Release-Regulating Alpha2 Autoreceptors: Potential Molecular Target for Ellagic Acid Nutraceutical Properties

Isabella Romeo et al. Antioxidants (Basel). .

Abstract

Polyphenol ellagic acid (EA) possesses antioxidant, anti-inflammatory, anti-carcinogenic, anti-diabetic and cardio protection activities, making it an interesting multi-targeting profile. EA also controls the central nervous system (CNS), since it was proven to reduce the immobility time of mice in both the forced swimming and the tail-suspension tests, with an efficiency comparable to that of classic antidepressants. Interestingly, the anti-depressant-like effect was almost nulled by the concomitant administration of selective antagonists of the noradrenergic receptors, suggesting the involvement of these cellular targets in the central effects elicited by EA and its derivatives. By in silico and in vitro studies, we discuss how EA engages with human α2A-ARs and α2C-AR catalytic pockets, comparing EA behaviour with that of known agonists and antagonists. Structurally, the hydrophobic residues surrounding the α2A-AR pocket confer specificity on the intermolecular interactions and hence lead to favourable binding of EA in the α2A-AR, with respect to α2C-AR. Moreover, EA seems to better accommodate within α2A-ARs into the TM5 area, close to S200 and S204, which play a crucial role for activation of aminergic GPCRs such as the α2-AR, highlighting its promising role as a partial agonist. Consistently, EA mimics clonidine in inhibiting noradrenaline exocytosis from hippocampal nerve endings in a yohimbine-sensitive fashion that confirms the engagement of naïve α2-ARs in the EA-mediated effect.

Keywords: antidepressant activity; antioxidant; ellagic acid; food chemistry; molecular dynamic simulations; molecular modelling; natural compounds; pomegranate tannins; α2-ARs; α2-adrenoreceptors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The polypharmacological effects regulated by ellagic acid contained within the pomegranate.
Figure 2
Figure 2
The superfusion apparatus (see text) [54,55].
Figure 3
Figure 3
(a) Top view: Ribbon representation of overlaid binding orientation of co-crystallized ligands into the binding site of α2A-AR6KUY (orange), α2A-AR6KUX (green) and α2C-AR6KUW (magenta) structures; (b) Front view of the superposed α2A-C-ARSs. Three-dimensional superimposition between the re-docked pose (blue carbon ball and sticks) and the conformation of the native ligand; (c) Indole derivative into the binding site of 6KUY; (d) Naphthyridine derivative into both 6KUX (green) and (e) 6KUW (magenta) X-ray structures.
Figure 4
Figure 4
Key contacting elements inside (a–c) the α2A-AR6KUX/clonidine, (d–f) the α2A-AR6KUX/EA, and (g–i) the α2A-AR6KUX/yohimbine best docked pose. Panels (b,e,h) show all side chains involved in H-bonds (violet), π-π interactions (cyan) and π-cation interactions (red) in stick representation. Panels (a,d,g) show the surface area of α2A-AR6KUX complexed to clonidine, EA and yohimbine, respectively. The surface area of the receptor is shown in solid orange solid. 2D representation of the key interactions of (c) clonidine, (f) EA and (i) yohimbine into the α2A-AR6KUY structure.
Figure 5
Figure 5
Key contacting elements inside (a–c) the α2A-AR6KUY/clonidine, (d–f) the α2A-AR6KUY/EA, and (g–i) the α2A-AR6KUY/yohimbine best docked pose. Panels (b,e,h) show all side chains involved in H-bonds (violet), π-π interactions (cyan) and π-cation interactions (red) in stick representation. Panels (a,d,g) show the surface area of α2A-AR6KUY complexed to clonidine, EA and yohimbine, respectively. The surface area of the receptor is shown in solid green. 2D representation of the key interactions of (c) clonidine, (f) EA and (i) yohimbine into the α2A-AR6KUY structure.
Figure 6
Figure 6
Key contacting elements inside (a–c) the α2A-AR6KUW/clonidine, (d–f) the α2A-AR6KUW/EA, and (g–i) the α2A-AR6KUW/yohimbine best docked pose. Panels (b,e,h) show all side chains involved in H-bonds (violet), π-π interactions (cyan) and π-cation interactions (red) in stick representation. Panels (a,d,g) show the surface area of α2A-AR6KUW complexed to clonidine, EA and yohimbine, respectively. The surface area of the receptor is shown in solid magenta. 2D representation of the key interactions of (c) clonidine, (f) EA and (i) yohimbine into α2A-AR6KUY structure.
Figure 7
Figure 7
Plots of the distances between the centroid atom of EA, clonidine and yohimbine and (a) D113 (orange), S200 (green) and S204 (blue) into the α2A-AR structure; (b) D131 (orange), S214 (green), and S218 (blue) into the α2C-AR structure, throughout 50 ns of MDs. Right-hand images show zoomed-in context of the pivotal residues, depicted in orange and magenta carbon ball and sticks, involved in the α2A-AR and α2C-AR binding pockets, respectively.
Figure 8
Figure 8
Plots of MM/GBSA trend for EA, clonidine and yohimbine in complex to (a) α2A-AR6KUX, (b) α2A-AR6KUY, and (c) α2C-AR6KUW, during 50 ns of MDs.
Figure 9
Figure 9
Mouse hippocampal lysates are endowed with (A) the α2A-AR and (B) the α2C-AR proteins. The images are representative of three analyses run on different preparations. Protein weights are expressed in kDa.
Figure 10
Figure 10
Ellagic acid mimics clonidine in inhibiting the 3[H]noradrenaline (3[H]NA) exocytosis from mouse hippocampal synaptosomes, and its effect is reversed by yohimbine. (a) Effects of ellagic acid (1 and 10 nM) and clonidine (100 nM) on the 12 mM KCl-evoked 3[H]NA release from mouse hippocampal synaptosomes. (b) Effect of ellagic acid (10 nM), alone or concomitantly added with yohimbine (1–100 nM), on the 12 mM KCl-evoked 3[H]NA release from mouse hippocampal synaptosomes. Results are expressed as percentage of residual of the 12 mM KCl-evoked tritium release. Data represent the means ± SEM of four to five experiments run in triplicate. * p < 0.05 versus 12 mM KCl-induced tritium overflow; ^ p < 0.05 versus 12 mM KCl/10 nM ellagic acid-induced tritium overflow.
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References

    1. Barbieri M., Heard C.M. Isolation of punicalagin from Punica granatum rind extract using mass-directed semi-preparative ESI-AP single quadrupole LC-MS. J. Pharm. Biomed. Anal. 2019;166:90–94. doi: 10.1016/j.jpba.2018.12.033. - DOI - PubMed
    1. Turrini F., Malaspina P., Giordani P., Catena S., Zunin P., Boggia R. Traditional decoction and PUAE aqueous extracts of pomegranate peels as potential anti-tyrosinase ingredients. Appl. Sci. 2020;10:2795. doi: 10.3390/app10082795. - DOI
    1. Global Pomegranate Market Industry Trends, Sales, Supply, Demand, Analysis & Forecast. 2017. [(accessed on 17 November 2020)]. Available online: https://www.researchmoz.us/global-pomegranate-market-2017-industry-trend....
    1. Shahkoomahally S., Khadivi A., Brecht J.K., Sarkhosh A. Chemical and physical attributes of fruit juice and peel of pomegranate genotypes grown in Florida USA. Food Chem. 2020;342:128302. doi: 10.1016/j.foodchem.2020.128302. - DOI - PubMed
    1. Ifeanyichukwu U.L., Fayemi O.E., Ateba C.N. Green Synthesis of Zinc Oxide Nanoparticles from Pomegranate (Punica granatum) Extracts and Characterization of Their Antibacterial Activity. Molecules. 2020;25:4521. doi: 10.3390/molecules25194521. - DOI - PMC - PubMed