The present study is designed to investigate the effect of some natural prenyloxyphenylpropanoids as neuroprotective agents against NMDA-induced toxicity in mixed cortical cell cultures containing both neurons and astrocytes. Excitotoxicity was induced by exposure of cultures to NMDA (100microM) at room temperature in a HEPES-buffered salt solution followed by incubation at 37 degrees C for the following 24h in MEM-Eagle's supplemented with 15.8mM NaHCO(3) and 25mM glucose. Tested compounds were mixed with NMDA. Neuronal injury was measured in all experiments by examination of cultures with phase-contrast microscopy at 20x, 18-20h after the insult while neuronal damage was quantitatively assessed by counting dead neurons stained with trypan blue and by measuring lactate dehydrogenase (LDH) released in the medium. Results showed that only natural prenyloxyphenylpropanoids containing a coumarin nucleus, namely 7-isopentenyloxycoumarin and auraptene, both found in nature from plants belonging to the genus Citrus and other of the family of Rutaceae, including edible ones, exerted a good dose-dependent manner protective effect against NMDA-induced neurotoxicity in particular at concentrations ranging from 1 to 10microM.