Bis(7)-tacrine prevents glutamate-induced excitotoxicity more potently than memantine by selectively inhibiting NMDA receptors

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 μM) prevented glutamate-induced excitotoxicity more substantially than memantine (IC50, 0.7 μM). 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 μM NMDA-activated current in a concentration-dependent manner with an IC50 of 0.68 ± 0.07 μM, which is five times more potent than that produced by memantine (IC50, 3.41 ± 0.36 μM; p < 0.05). By contrast, bis(7)-tacrine, up to 5 μM, did not significantly affect the current activated by 50 μM AMPA or 50 μM kainate. These results suggest that bis(7)-tacrine is more potent than memantine against glutamate-induced neurotoxicity by selectively inhibiting NMDA-activated current.