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Free Radic Biol Med. 2019 Mar 18;135:261-273. doi: 10.1016/j.freeradbiomed.2019.03.019. [Epub ahead of print]

The antioxidant resveratrol acts as a non-selective adenosine receptor agonist.

Author information

1
Departamento de Química Inorgánica, Orgánica y Bioquímica, CRIB, Universidad de Castilla-La Mancha, Avenida Camilo José Cela 10, 13071, Ciudad Real, Spain; Facultad de Ciencias y Tecnologías Químicas, Avenida Camilo José Cela 10, 13071, Ciudad Real, Spain.
2
Departamento de Química Inorgánica, Orgánica y Bioquímica, CRIB, Universidad de Castilla-La Mancha, Avenida Camilo José Cela 10, 13071, Ciudad Real, Spain; Facultad de Ciencias y Tecnologías Químicas, Avenida Camilo José Cela 10, 13071, Ciudad Real, Spain; Facultad de Medicina de Ciudad Real, Camino Moledores s/n, 13071, Ciudad Real, Spain. Electronic address: jose.albasanz@uclm.es.
3
Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, 08193, Bellaterra, Spain.
4
Section for Biomolecular Sciences, Biology Department, Biocenter, University of Copenhagen, DK-2200, Copenhagen, Denmark.
5
Research Programme on Biomedical Informatics, Hospital del Mar Medical Research Institute (IMIM) & Department of Experimental and Health Sciences, Pompeu Fabra University, Dr. Aiguader 88, 08003, Barcelona, Spain.
6
Departamento de Química Inorgánica, Orgánica y Bioquímica, CRIB, Universidad de Castilla-La Mancha, Avenida Camilo José Cela 10, 13071, Ciudad Real, Spain; Facultad de Ciencias y Tecnologías Químicas, Avenida Camilo José Cela 10, 13071, Ciudad Real, Spain; Facultad de Medicina de Ciudad Real, Camino Moledores s/n, 13071, Ciudad Real, Spain.

Abstract

Resveratrol (RSV) is a natural polyphenolic antioxidant with a proven protective role in several human diseases involving oxidative stress, although the molecular mechanism underlying this effect remains unclear. The present work tried to elucidate the molecular mechanism of RSV's role on signal transduction modulation. Our biochemical analysis, including radioligand binding, real time PCR, western blotting and adenylyl cyclase activity, and computational studies provide insights into the RSV binding pathway, kinetics and the most favored binding pose involving adenosine receptors, mainly A2A subtype. In this study, we show that RSV target adenosine receptors (AdoRs), affecting gene expression, receptor levels, and the downstream adenylyl cyclase (AC)/PKA pathway. Our data demonstrate that RSV activates AdoRs. Moreover, RSV activate A2A receptors by directly binding to the classical orthosteric binding site. Intriguingly, RSV-induced receptor activation can stimulate or inhibit AC activity depending on concentration and exposure time. Such subtle and multifaceted regulation of the AdoRs/AC/PKA pathway might contribute to the protective role of RSV. Our findings suggest that RSV molecular action is mediated, at least in part, by activation of adenosine receptors and create the opportunity to interrogate the therapeutic use of RSV in pathological conditions involving AdoRs, such as Alzheimer.

KEYWORDS:

Adenosine receptors; C6 glioma cells; GPCR modulation; Resveratrol

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