Tetrahydroaminoacridine selectively attenuates NMDA receptor-mediated neurotoxicity

Eur J Pharmacol. 1988 Sep 1;154(1):73-8. doi: 10.1016/0014-2999(88)90365-2.


Addition of the acetylcholinesterase inhibitor 1,2,3,4-tetra-9-hydroaminoacridine (THA) at 1-3 mM markedly reduced the neuronal cell loss that otherwise followed brief exposure of murine cortical cell cultures to 500 microM N-methyl-D-aspartate (NMDA). This novel antagonism was selective for NMDA receptor-mediated toxicity, as it extended to glutamate toxicity but not to quisqualate toxicity, and was THA concentration-dependent between 100 microM and 3 mM, with IC50 approximately 500 microM. The antagonism was probably not due to enhancement of endogenous cholinergic action, as it was not mimicked by acetylcholine, carbachol, or bethanechol; rather, it likely reflected a recently described interaction of THA with the phencyclidine receptor. Exploration of structural specificity revealed some partial neuron-protection with high concentrations of other cholinesterase inhibitors--physostigmine, neostigmine, and edrophonium, but not the structurally related potassium channel blocker, 4-aminopyridine. Further examination of correlations between THA-like structure, and neuron-protective activity, may provide useful insights in the development of new antagonists of NMDA receptor-mediated neurotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminoacridines / pharmacology*
  • Animals
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / toxicity
  • Cells, Cultured
  • Cholinesterase Inhibitors / pharmacology
  • Glutamates / toxicity
  • Glutamic Acid
  • Mice
  • N-Methylaspartate
  • Neurons / drug effects*
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter / drug effects*
  • Receptors, Neurotransmitter / physiology
  • Tacrine / pharmacology*


  • Aminoacridines
  • Cholinesterase Inhibitors
  • Glutamates
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter
  • Aspartic Acid
  • Glutamic Acid
  • Tacrine
  • N-Methylaspartate