Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons

Neuroscience. 2001;105(3):663-9. doi: 10.1016/s0306-4522(01)00206-8.


Huperzine A, a nootropic alkaloid isolated from a Chinese herb, has been proposed as one of the most promising agents to treat Alzheimer's disease. Recently, the agent was found to inhibit the N-methyl-D-aspartate (NMDA) receptors in rat cerebral cortex in addition to causing an inhibitory effect on acetylcholinesterase. In the present study, the mechanisms underlying NMDA receptor inhibition were investigated using whole-cell voltage-clamp recording in CA1 pyramidal neurons acutely dissociated from rat hippocampus. Huperzine A reversibly inhibited the NMDA-induced current (IC(50)=126 microM, Hill coefficient=0.92), whereas it had no effect on the current induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate or kainate. The effect was non-competitive, and showed neither 'voltage-dependency', nor 'use-dependency'. The IC(50) values of huperzine A were neither altered by changing the concentrations of glycine (2-0.2 microM) and pH (7.4-6.7) in the external solution, nor by addition of Zn(2+) (5 microM) and dithiothreitol (5 mM) to the external solution. However, addition of spermine (200 microM) to the external solution caused a parallel shift to the right of the huperzine A concentration-response curve. From these we suggest that huperzine A acts as a non-competitive antagonist of the NMDA receptors, via a competitive interaction with one of the polyamine binding sites. The potential relevance of NMDA receptor antagonist activity of huperzine A to the treatment of Alzheimer's disease is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Animals
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Dithiothreitol / pharmacology
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / pharmacology
  • Glycine / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hydrogen-Ion Concentration / drug effects
  • Kainic Acid / pharmacology
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • N-Methylaspartate / pharmacology
  • Neuroprotective Agents / pharmacology*
  • Nootropic Agents / pharmacology*
  • Patch-Clamp Techniques
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Sesquiterpenes / pharmacology*
  • Spermine / pharmacology
  • Zinc / pharmacology
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology


  • Alkaloids
  • Excitatory Amino Acid Agonists
  • Neuroprotective Agents
  • Nootropic Agents
  • Receptors, N-Methyl-D-Aspartate
  • Sesquiterpenes
  • huperzine A
  • Spermine
  • N-Methylaspartate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Zinc
  • Kainic Acid
  • Dithiothreitol
  • Glycine