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Aims Flax Lignan ( FLL), a chemical widespread within the plant and animal kingdoms, has antioxidant, antiinfectious, and antitumor activities. However, little is known about the effects of FLL on the central nervous system ( CNS). Methods The neuroprotective actions of FLL against N-methyl-d-aspartate ( NMDA) are investigated in primary cultured cortical neurons by MTT assay. The expression levels of proteins related to apoptosis and GluN2-containing receptor were detected by Western blot analysis. Intracellular Ca2+ was measured under a confocal laser scanning microscope. Results After challenged with 100 μM NMDA for 30 min, loss of cell viability and excessive apoptotic cell death were observed in cultured cortical neurons. FLL protected the neurons against the NMDA-induced cell loss in a concentration-dependent manner. FLL also significantly inhibited the neuronal apoptosis induced by NMDA exposure through reversing intracellular concentration of Ca2+ overload and balancing of Bcl-2 and Bax expression. Furthermore, FLL significantly reversed the upregulation of GluN2B-containing NMDA receptors by exposure to NMDA, but did not affect the expression of GluN2A-containing NMDA receptor. Conclusions These findings suggest that FLL protects cortical neurons by inhibiting the expression of GluN2B-containing NMDA receptor and regulating the Bcl-2 family. [ABSTRACT FROM AUTHOR]