Novel dimeric bis(7)-tacrine proton-dependently inhibits NMDA-activated currents

Jialie Luo, Wenming Li, Yuwei Liu, Wei Zhang, Hongjun Fu, Nelson T.K. Lee, Hua Yu, Yuanping Pang, Pingbo Huang, Jun Xia, Zhi Wang Li, Chaoying Li, Yifan Han

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Bis(7)-tacrine has been shown to prevent glutamate-induced neuronal apoptosis by blocking NMDA receptors. However, the characteristics of the inhibition have not been fully elucidated. In this study, we further characterize the features of bis(7)-tacrine inhibition of NMDA-activated current in cultured rat hippocampal neurons. The results show that with the increase of extracellular pH, the inhibitory effect decreases dramatically. At pH 8.0, the concentration-response curve of bis(7)-tacrine is shifted rightwards with the IC50 value increased from 0.19 ± 0.03 μM to 0.41 ± 0.04 μM. In addition, bis(7)-tacrine shifts the proton inhibition curve rightwards. Furthermore, the inhibitory effect of bis(7)-tacrine is not altered by the presence of the NMDA receptor proton sensor shield spermidine. These results indicate that bis(7)-tacrine inhibits NMDA-activated current in a pH-dependent manner by sensitizing NMDA receptors to proton inhibition, rendering it potentially beneficial therapeutic effects under acidic conditions associated with stroke and ischemia.

Original languageEnglish (US)
Pages (from-to)505-509
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume361
Issue number2
DOIs
StatePublished - Sep 21 2007

Keywords

  • Bis(7)-tacrine
  • Hippocampus
  • Inhibition
  • NMDA
  • Proton
  • Rat

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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