Using [3H]resveratrol (3,5,4'-trihydroxy-trans-stilbene) as radioligand, we investigated the possible existence of specific polyphenol binding sites at the level of the cellular plasma membrane in rat brain. Specific [3H]resveratrol binding sites were found to be enriched in the plasma membrane pellet with lower levels in the nuclear and cell debris fraction. Specific [3H]resveratrol binding to the plasma membrane fraction was sensitive to trypsin digestion and protein denaturation but not to DNase and RNase treatment. Saturation binding experiments revealed that specific [3H]resveratrol recognized a single class of sites with an apparent affinity (KD) of 220+/-45 nM and a maximal capacity (Bmax) of 1060+/-120 fmol/mg protein. Various polyphenols and resveratrol derivatives competed against specific [3H]resveratrol binding in rat brain plasma membrane homogenates with the tea catechin gallates (epigallocatechin gallate and epicatechin gallate) displaying the highest affinities (Ki=25-45 nM) followed by resveratrol (Ki=102 nM). Quantitative autoradiographic studies revealed that specific [3H]resveratrol binding sites are broadly distributed in the rat brain, with highest levels of labeling seen in the choroid plexus and subfornical organ. Finally, the potency of various polyphenols and resveratrol analogs in protecting hippocampal cells against beta-amyloid-induced toxicity correlated well (r=0.74) with their apparent affinity in the [3H]resveratrol binding assay. Taken together, these results suggest that the neuroprotective action of various polyphenols and resveratrol analogs could be mediated by the activation of common "receptor" binding sites particularly enriched at the level of the cellular plasma membrane in the rat brain.