Alternative medicines such as herbal products are increasingly being used for preventive and therapeutic purposes. Ginseng is the best known and most popular herbal medicine used worldwide. In spite of some beneficial effects of ginseng on the CNS, little scientific evidence shows at the cellular level. In the present study, we have examined the direct modulation of ginseng on the activation of glutamate, especially NMDA. receptors in cultured hippocampal neurons. Using fura-2-based digital imaging techniques, we found ginseng total saponins inhibited NMDA-induced but less effectively glutamate-induced increase in [Ca2+](i). Ginseng total saponins also modulated Ca2+ transients evoked by depolarization with 50 mM KCl along with its own effects on [Ca2+](i). Furthermore, we demonstrated that ginsenoside Rg(3) is an active component for ginseng actions on NMDA receptors. The data obtained suggest that the inhibition of NMDA receptors by ginseng, in particular by ginsenoside Rg(3), could be one of the mechanisms for ginseng-mediated neuroprotective actions. (C) 2002 Elsevier Science (USA). All rights reserved.