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Title: Inhibition of NMDA-gated ion channels by bis(7)-tacrine : whole-cell and single-channel studies
Authors: Liu, YW
Luo, JL
Ren, H
Peoples, RW
Ai, YX
Liu, LJ
Pang, YP
Li, ZW
Han, YF 
Li, CY
Keywords: Acetylcholinesterase inhibitor
Glutamate receptor
NMDA receptor
Issue Date: 2008
Source: Neuropharmacology, 2008, v. 54, no. 7, p. 1086-1094 How to cite?
Journal: Neuropharmacology 
Abstract: Bis(7)-tacrine is a novel dimeric acetylcholinesterase inhibitor derived from tacrine, and has been proposed as a promising agent to treat Alzheimer's disease. We have recently reported that bis(7)-tacrine prevents glutamate-induced neuronal apoptosis by antagonizing NMDA receptors. The purpose of this study was to characterize bis(7)-tacrine inhibition of NMDA-activated current by using patch-clamp recording techniques. In cultured rat hippocampal neurons, bis(7)-tacrine inhibited NMDA-activated whole-cell current in a concentration-dependent manner with an IC 50 of 0.66 ± 0.07 μM. Bis(7)-tacrine produced a gradual decline of NMDA-activated current to a steady-state, but this was not an indication of use-dependence. Also, the slow onset of inhibition by bis(7)-tacrine was not apparently due to an action at an intracellular site. Bis(7)-tacrine, 0.5 μM, decreased the maximal response to NMDA by 40% without changing its EC 50. Bis(7)-tacrine inhibition of NMDA-activated current was not voltage-dependent, and was independent of glycine concentration. Results of single-channel experiments obtained from cells expressing NR1 and NR2A subunits revealed that bis(7)-tacrine decreased the open probability and frequency of channel opening, but did not significantly alter the mean open time or introduce rapid closures. These results suggest that bis(7)-tacrine can inhibit NMDA receptor function in a manner that is slow in onset and offset and noncompetitive with respect to both NMDA and glycine. The noncompetitive inhibition of NMDA receptors by bis(7)-tacrine could contribute to its protective effect against glutamate-induced neurotoxicity.
ISSN: 0028-3908
DOI: 10.1016/j.neuropharm.2008.02.015
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