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

  • Biochem Biophys Res Commun. 2007 Sep 21;361(2):505-9. doi: 10.1016/j.bbrc.2007.07.043.
Jialie Luo  1 ,  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
Affiliations
  • 1. Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China.
PMID: 17655827 DOI: 10.1016/j.bbrc.2007.07.043
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 IC(50) value increased from 0.19+/-0.03 microM to 0.41+/-0.04 microM. 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.

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