Reversible inhibition of intracellular calcium influx through NMDA receptors by imidazoline I(2) receptor antagonists

Eur J Pharmacol. 2010 Mar 10;629(1-3):12-9. doi: 10.1016/j.ejphar.2009.11.063. Epub 2009 Dec 1.


Intracellular calcium ([Ca(2+)]i) influx through N-methyl-d-aspartic acid (NMDA) receptors in cortical neurons is central to NMDA receptor-mediated excitotoxicity. Drugs that uncompetitively modulate NMDA receptor-mediated [Ca(2+)]i influx are potential leads for development to treat NMDA receptor-mediated neuronal damage since these drugs spare NMDA receptor normal functions. Ligands to alpha(2)-adrenoceptors and imidazoline I(2) receptors confer neuroprotection possibility through modulating NMDA receptor-mediated [Ca(2+)]i influx. Here, we investigated the characteristics of several ligands to alpha(2)-adrenoceptors and imidazoline I(2) receptor, in inhibiting NMDA receptor-mediated [Ca(2+)]i influx in cultured cortical neurons using a ratiometric calcium imaging technique. In contrast to MK801, which non-reversibly blocks NMDA receptor-mediated [Ca(2+)]i influx, imidazoline I(2) receptor antagonists, Idazoxan, and 2-(2-benzofuranyl)-2-imidazoline (2-BFI)-mediated inhibition of [Ca(2+)]i influx can be rapidly reversed when removed, in a manner similar to that of memantine, an uncompetitive antagonist to NMDA receptors. Interestingly, ligands to alpha(2)-adrenoceptors, including agmatine sulfate and yohimbine, and a ligand to the nicotinic receptor, levamisol, neither inhibited NMDA receptor-mediated [Ca(2+)]i influx, nor provided neuroprotection against glutamate toxicity, suggesting selective inhibition of NMDA receptor activities. The inhibition of NMDA receptor by Idazoxan and 2-BFI also led to the suppression of NMDA receptor-mediated calpain activity as a result of blocking NMDA receptor activity, rather than through direct inhibition of calpain activity. Collectively, these studies demonstrated that imidazoline I(2) receptor antagonists transiently and reversibly block NMDA receptor-mediated [Ca(2+)]i influx. These compounds are leads for further development as uncompetitive antagonists to NMDA receptor-mediated excitotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzofurans / pharmacology
  • Calcium / metabolism*
  • Cerebral Cortex / cytology
  • Glutamic Acid / toxicity
  • Idazoxan / pharmacology
  • Imidazoles / pharmacology
  • Imidazoline Receptors / antagonists & inhibitors*
  • Intracellular Space / drug effects*
  • Intracellular Space / metabolism*
  • Mice
  • Molecular Imaging
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neurotoxins / toxicity
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*


  • Benzofurans
  • Imidazoles
  • Imidazoline Receptors
  • Neuroprotective Agents
  • Neurotoxins
  • Receptors, N-Methyl-D-Aspartate
  • imidazoline receptor 2
  • Glutamic Acid
  • 2-(2-benzofuranyl)-2-imidazoline
  • Calcium
  • Idazoxan