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

A. Sánchez-Melgar, J. L. Albasanz, R. Guixà-González, N. Saleh, J. Selent, M. Martín

Research output: Contribution to journalArticleResearch

20 Citations (Scopus)


© 2019 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 A 2A 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 A 2A 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.
Original languageEnglish
Pages (from-to)261-273
JournalFree Radical Biology and Medicine
Publication statusPublished - 1 May 2019


  • Adenosine receptors
  • C6 glioma cells
  • GPCR modulation
  • Resveratrol


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