Mechanism of bis(7)-tacrine inhibition of GABA-activated current in cultured rat hippocampal neurons

Li Zhou, Yu Wei Liu, Robert W. Peoples, Min Yang, Xiang Tian, Yong Xun Ai, Yuan Ping Pang, Zhi Wang Li, Yi Fan Han, Chao Ying Li

Research output: Contribution to journalArticle

4 Scopus citations

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 GABAA receptors. In the present study we investigated the mechanism of bis(7)-tacrine inhibition of GABAA 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 pA2 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 GABAA 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.

Original languageEnglish (US)
Pages (from-to)33-40
Number of pages8
JournalNeuropharmacology
Volume57
Issue number1
DOIs
StatePublished - Jul 1 2009

Keywords

  • Acetylcholinesterase inhibitor
  • Competitive inhibition
  • GABA receptor
  • Kinetics
  • pA

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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    Zhou, L., Liu, Y. W., Peoples, R. W., Yang, M., Tian, X., Ai, Y. X., Pang, Y. P., Li, Z. W., Han, Y. F., & Li, C. Y. (2009). Mechanism of bis(7)-tacrine inhibition of GABA-activated current in cultured rat hippocampal neurons. Neuropharmacology, 57(1), 33-40. https://doi.org/10.1016/j.neuropharm.2009.04.004