Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/23787
Title: Mechanism of bis(7)-tacrine inhibition of GABA-activated current in cultured rat hippocampal neurons
Authors: Zhou, L
Liu, YW
Peoples, RW
Yang, M
Tian, X
Ai, YX
Pang, YP
Li, ZW
Han, YF 
Li, CY
Keywords: Acetylcholinesterase inhibitor
Competitive inhibition
GABA A receptor
Kinetics
pA 2
Issue Date: 2009
Publisher: Pergamon-Elsevier Science Ltd
Source: Neuropharmacology, 2009, v. 57, no. 1, p. 33-40 How to cite?
Journal: Neuropharmacology 
Abstract: Bis(7)-tacrine is a novel dimeric acetylcholinesterase inhibitor derived from tacrine that shows promise for the treatment of Alzheimer's disease. We have previously reported that bis(7)-tacrine inhibits GABA A receptors. In the present study we investigated the mechanism of bis(7)-tacrine inhibition of GABA A receptor function using whole-cell patch-clamp recording in cultured rat hippocampal neurons. Bis(7)-tacrine produced a gradual decline of GABA-activated current to a steady-state, but this was not an indication of use-dependence, as the gradually declining component could be eliminated by exposure to bis(7)-tacrine prior to GABA application. In addition, bis(7)-tacrine inhibition did not require the presence of agonist, and GABA-activated current recovered completely from inhibition by bis(7)-tacrine in the absence of agonist. The slow onset of inhibition by bis(7)-tacrine was not apparently due to an action at an intracellular site, as inclusion of 25 μM bis(7)-tacrine in the recording pipette did not alter inhibition by bis(7)-tacrine applied externally. Bis(7)-tacrine shifted the GABA concentration-response curve to the right in a parallel manner and the pA 2 value estimated from a Schild plot was 5.7. Bis(7)-tacrine increased the time constant of activation of GABA-gated ion channels without affecting the time constants of deactivation or desensitization. These results suggest that bis(7)-tacrine is a competitive GABA A receptor antagonist with slow onset and offset kinetics. The competitive inhibition of GABA receptors by bis(7)-tacrine could contribute to its ability to enhance memory.
URI: http://hdl.handle.net/10397/23787
DOI: 10.1016/j.neuropharm.2009.04.004
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