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

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 α_2A-ARs and α_2C-AR catalytic pockets, comparing EA behaviour with that of known agonists and antagonists. Structurally, the hydrophobic residues surrounding the α_2A-AR pocket confer specificity on the intermolecular interactions and hence lead to favourable binding of EA in the α_2A-AR, with respect to α_2C-AR. Moreover, EA seems to better accommodate within α_2A-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.

SUBMITTER: Romeo I

PROVIDER: S-EPMC8614955 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Three new large hexanuclear metalla-prisms 9-11 incorporating 1,3, 5-tris(pyridin-4-ylethynyl)benzene (tpeb) 4 and one of the dinuclear arene ruthenium clips [Ru2(p-iPrC6H4Me)2(OO∩OO)][CF3SO3]2 (OO∩OO =2,5-dioxydo-1,4-benzoquinonato [dobq] 1, 5,8-dihydroxy-1,4-naphthaquinonato (donq) 2, and 6,11-dihydroxy-5,12-naphthacenedionato [dotq] 3), which encapsulate the guest molecule ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione, 5) were prepared. All complexes were isolated as triflate salts in good yields and were fully characterized by (1)H NMR spectroscopy and electrospray ionization mass spectrometry. The photophysical properties of these metalla-prisms were also investigated. Compounds 9 and 10 showed potent antioxidant activity, but 10 had the superior ORACPE value (1.30 ± 0.020). Ellagic acid (5) and compound 11 showed weaker activity than that of Trolox. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the metalla-prism compounds exhibit anticancer properties in vitro. Compound 10 inhibited the growth of all cancer cell lines at micromolar concentrations, with the highest cytotoxicity observed against A549 human lung cancer cells (IC50 =25.9 μM). However, these compounds had a lower anti-cancer activity than that of doxorubicin. In a tumoricidal assay, ellagic acid (5) and compound 10 induced cytotoxicity in tumor cells, while doxorubicin did not. While free ellagic acid had no effect on the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein, the encapsulated metalla-prism 10 stimulated granulocyte-colony stimulating factor and reduced regulated on activation normal T cell expressed and secreted protein expression in the RAW264.7 macrophage line. Our results show that ellagic acid encapsulated in metalla-prisms inhibited cancer cells via the modulation of mRNA induction and protein expression levels of the granulocyte-colony stimulating factor and regulated on activation normal T cell expressed and secreted protein in macrophages.

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

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