A novel glycine site-specific N-methyl-D-aspartate receptor antagonist prevents activation of the NMDA/NO/CGMP pathway by ammonia

Brain Res. 2004 Jul 23;1015(1-2):186-8. doi: 10.1016/j.brainres.2004.05.014.

Abstract

Intrastriatal administration of ammonium ions ("ammonia") via a microdialysis probe overactivates N-methyl-D-aspartate (NMDA) receptors, which results in cGMP accumulation in the microdialysates. Co-administration of a potent glycine site-specific NMDA receptor antagonist CGP 78608 ([(1S)-1-[[(7-bromo-1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl]amino]ethyl]phosphonate) significantly reduced (at 20 nM) or abolished (at 100 nM) ammonia-dependent cGMP synthesis. Since NMDA receptor activation is an important causative factor in ammonia neurotoxicity, the present results suggest the glycine site of the receptor to be a potential valuable target for protective intervention.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Ammonia / toxicity*
  • Animals
  • Binding Sites
  • Corpus Striatum / cytology
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Cyclic GMP / metabolism*
  • Glycine / metabolism*
  • Male
  • Microdialysis
  • Microinjections
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurotoxins / toxicity
  • Nitric Oxide / metabolism
  • Organophosphonates / pharmacology*
  • Quinoxalines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / classification
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • ((1S)-1-(((7-bromo-1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl)amino)ethyl)phosphonate
  • Neurotoxins
  • Organophosphonates
  • Quinoxalines
  • Receptors, N-Methyl-D-Aspartate
  • Nitric Oxide
  • Ammonia
  • Cyclic GMP
  • Glycine