A novel glycine site-specific N-methyl-D-aspartate receptor antagonist prevents activation of the NMDA/NO/CGMP pathway by ammonia.
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.
Hilgier
Wojciech
W
Department of Neurotoxicology, Medical Research Centre, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland.
Oja
Simo S
SS
Saransaari
Pirjo
P
Albrecht
Jan
J
D000494:Allosteric Regulation; D000641:Ammonia / Q000633:toxicity*; D000818:Animals; D001665:Binding Sites; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism
C492387:((1S)-1-(((7-bromo-1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl)amino)ethyl)phosphonate; D009498:Neurotoxins; D063065:Organophosphonates; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D000641:Ammonia; D006152:Cyclic GMP; D005998:Glycine