Aim: To investigate whether sodium ferulate (SF) can protect cortical neurons from glutamate-induced neurotoxicity and the mechanisms responsible for this protection. Methods: Cultured cortical neurons were incubated with 50 μmol/L glutamate for either 30 min or 24 h, with or without pre-incubation with SF (100, 200, and 500 μmol/L, respectively). LY294002, wortmannin, PD98059, and U0126 were added respectively to the cells 1 h prior to SF treatment. After incubation with glutamate for 24 h, neuronal apoptosis was quantified by scoring the per- centage of ceils with apoptotic nuclear morphology after Hoechst 33258 staining. After incubation with glutamate for either 30 min or 24 h, cellular extracts were prepared for Weste blotting of active caspase-3, poly (ADP-ribose) polymerase (PARP), μ-calpain, Bcl-2, phospho-Akt, phosphorylated ribosomal protein S6 pro- tein kinase (p70S6K), phospho-mitogen-activated protein kinase kinase (MEK1/2) and phosphorylated extracellular signal-regulated kinase (ERK) 1/2. Results: SF reduced glutamate-evoked apoptotic morphology, active caspase-3 protein expression, and PARP cleavage and inhibited the glutamate-induced upregulation of the μ-calpain protein level. The inhibition of the phosphatidylinositol 3-kinase (PI3K) and the MEK/ERK1/2 pathways partly abrogated the protective effect ot SF against glutamate-induced neuronal apoptosis. SF prevented the glutamate-induced decrease in the activity of the PI3K/Akt/p70S6K and the MEK/ERK1/2 pathways. Moreover, incubation of cortical neurons with SF for 30 min inhibited the reduction of the Bcl-2 expression induced by glutamate. Conclusion: The results indicate that PI3K/Akt/p70S6K and the MEK/ERK signaling pathways play important roles in the protective effect of SF against glutamate toxicity in cortical neurons.