In the present study, we have examined any possible involvement of L-type Ca2+ channels in ginseng-mediated neuroprotective actions. Exposure to a 50 mM KCl (high-K) produced neuronal cell death, which was blocked by a selective L-type Ca2+ channel blocker in cultured cortical neurons. When cultured cells were co-treated with ginseng total saponin (GTS) and high-K, GTS reduced high-K-induced neuronal death. Using Ca2+ imaging techniques, we found that GTS inhibited high-K-mediated acute and long-term [Ca2+](i) changes. These GTS-mediated [Ca2+](i) changes were diminished by nifedipine. Furthermore, GTS-mediated effects were also diminished by a saturating concentration of Bay K (10 mu M). After confirming the protective effect of GTS using a TUNEL assay, we found that ginsenosides Rf and Rg(3) are active components in ginseng-mediated neuroprotection. These results suggest that inhibition of L-type Ca2+ channels by ginseng could be one of the mechanisms for ginseng-mediated neuroprotection in cultured rat cortical neurons. (c) 2007 Published by Elsevier Inc.