Resveratrol is a natural polyphenol having a wide range of biological and pharmacological activities. Here we have investigated the effect of resveratrol on neurodegeneration in cultured cerebellar granule cells from slow Wallerian degeneration (Wld(S)) mice, characteristic of substantial delay of degeneration in the distal stump of transected axons. Resveratrol diminished resistance of Wld(S) neurons to axonal degeneration induced by colchicine, a microtubule depolymerizing drug. Resveratrol also decreased the level of tubulin acetylation in Wld(S) neurons and their homogenates. This promoting effect on tubulin deacetylation was mimicked by NAD, suggesting the involvement of SIRT2, an NAD-dependent tubulin deacetylase. Indeed, resveratrol promoted tubulin deacetylation in the presence of GFP-SIRT2 but not GFP-SIRT2 N168A, a catalytically inactive mutant. Moreover, SIRT2 silencing restored the resistance to axonal degeneration in resveratrol-treated Wld(S) neurons. These results suggest that resveratrol abolishes the resistance of Wld(S) mice to axonal degeneration by enharcing SIRT2-mediated tubulin deacetylation. (c) 2007 Elsevier Inc. All rights reserved.