Resveratrol is neuroprotective because it is not a direct activator of Sirt1-A hypothesis.

The plant polyphenol resveratrol (3,5,4'-trihydroxystilbene) has been touted to have multiple health benefits. A commonly cited mechanism of resveratrol action is via the activation of the longevity factor Sir2/Sirt1, whose deacetylase activity on several transcription factors has stress resistance and pro-survival effects. Resveratrol has been shown to be beneficial in various in vitro and in vivo models of central nervous system (CNS) neuron death and degeneration, presumably acting through Sirt1. However, accumulating recent evidence suggests that Sirt1 inhibitors are also neuroprotective. These contradictory results leave us with an apparently irreconcilable paradox. Based on other recent findings that resveratrol also activate AMP-activated protein kinase (AMPK), particularly in neurons, we hypothesize that reseveratrol does not exert its neuroprotective effect via direct Sirt1 activation. In fact, resveratrol is neuroprotective precisely because it does not activate Sirt1 during the acute phase of neuronal cell demise. However, its activation of AMPK may be neuroprotective. Furthermore, resveratrol may indirectly increase Sirt1 activity in recovering or spared cells via AMPK's elevation of NAD levels, which then translates into an overall beneficial outcome. The hypothesis could potentially be tested via selective AMPK silencing in various neuronal death and degeneration models, to see if the neuroprotective effect of resveratrol will be blunted. If proven true, the hypothesis has important ramifications in how reseveratrol, as well as novel Sirt1 activators, may be best used in treatment of CNS injuries and disorders.