We have recently reported that bis(7)-tacrine could prevent glutamate-induced neuronal apoptosis through NMDA receptors. In this study, we demonstrated that in cultured rat cortical neurons, bis(7)tacrine (IC50, 0.02 mu M) prevented glutamate-induced excitotoxicity more substantially than memantine (IC50, 0.7 mu M). In addition, bis(7)-tacrine was more efficient than memantine in buffering the intracellular Ca2+ triggered by glutamate. In cultured rat hippocampal neurons, bis(7)-tacrine inhibited 50 mu M NMDA-activated current in a concentration-dependent manner with an IC50 of 0.68 +/-0.07 mu M, which is five times more potent than that produced by memantine (IC50, 3.41 +/- 0.36 mu M; p < 0.05). By contrast, bis(7)-tacrine, up to 5 mu M did not significantly affect the current activated by 50 mu M AMPA or 50 mu M kainate. These results suggest that bis(7)-tacrine is more potent than memantine against glutamate-induced neurotoxicity by selectively inhibiting NMDA-activated current. (C) 2008 Elsevier Inc. All rights reserved.