The CH (2)Cl (2) fraction of the bark of Machilus thunbergii Sieb. et Zucc. (Lauraceae) significantly protected primary cultures of rat cortical cells exposed to the excitotoxic amino acid, L-glutamate. (-)-Isoguaiacin, meso-dihydroguaiaretic acid, machilin A, (+)-galbelgin, licarin A, (-)-sesamin, and (+)-guaiacin were isolated by bioactivity-guided fractionation from the CH (2)Cl (2) fraction and further separated using chromatographic techniques. Isoguaiacin, meso-dihydroguaiaretic acid, licarin A and (+)-guaiacin had significant neuroprotective activities against glutamate-induced neurotoxicity in primary cultures of rat cortical cells at concentrations ranging from 0.1 microM to 10.0 microM.