Resveratrol and its metabolites elicit neuroprotection via high‐affinity binding to the laminin receptor at low nanomolar concentrations

Resveratrol prevents various neurodegenerative diseases in animal models despite reaching only low nanomolar concentrations in the brain after oral administration. In this study, based on the quenching of intrinsic tryptophan fluorescence and molecular docking, we found that trans‐resveratrol, its conjugates (glucuronide and sulfate), and dihydro‐resveratrol (intestinal microbial metabolite) bind with high affinities (Kd, 0.2–2 nm) to the peptide G palindromic sequence (near glycosaminoglycan‐binding motif) of the 67‐kDa laminin receptor (67LR). Preconditioning with low concentrations (0.01–10 nm) of these polyphenols, especially resveratrol‐glucuronide, protected neuronal cells from death induced by serum withdrawal via activation of cAMP‐mediated signaling pathways. This protection was prevented by a 67LR‐blocking antibody, suggesting a role for this cell‐surface receptor in neuroprotection by resveratrol metabolites. Using ligand binding and molecular docking, we found that trans‐resveratrol, its glucuronide and sulfate conjugates, and dihydro‐resveratrol bind with high affinities to polyphenol‐ and glycosaminoglycan‐binding motifs, which are present within the peptide G region of the 67‐kDa laminin receptor (67LR). Neuronal cells were protected from death via 67LR/cAMP‐mediated signaling pathways by preconditioning with low nanomolar concentrations of resveratrol‐glucuronide.