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Silent Information Regulator 1 (SIRT1), an NAD+-dependent deacetylase, is involved in the regulation of gene transcription, energy metabolism, and cell aging.Recent studies have showed that SIRT1 possesses a neuroprotective role, however, it is unknown whether it protects neurons from NMDA-mediated neurotoxicity.In the study Resveratrol (RSV) as the activator and Sirtinol as the inhibitor of SIRT1 were used to observe the role of SIRT1 in NMDA (100 μmol/L, 2 h) induced excitotoxicity of cultured cortical cell, and further define the role of its downstream signaling molecule p53 in this process.The CCK-8 assay, LDH test and Calcein-AM and PI double staining results showed that RSV elicited inhibitory effects on the decrease of NMDA-induced cell viability which can be prevented by Sirtinol.Western Blot results showed that RSV partly inhibited NMDA-induced the increase of Ace-p53 levels which can also be effectively blocked by Sirtinol.These findings indicated that: (1) Activation of SIRT1 played a protective role in NMDA-induced neurotoxicity.(2) Activation of SIRT1 might inhibit NMDAmediated nerve injury by reducing the level of Ace-p53.