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

• Published in: Brain research Vol. 1015; no. 1; pp. 186 - 188
• Main Authors: Hilgier, Wojciech, Oja, Simo S, Saransaari, Pirjo, Albrecht, Jan
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 23.07.2004; Amsterdam Elsevier; New York, NY
• Subjects: Allosteric Regulation; Ammonia; Ammonia - toxicity; Animals; Binding Sites; Biological and medical sciences; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; cGMP; Corpus Striatum - cytology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Cyclic GMP - metabolism; Fundamental and applied biological sciences. Psychology; Glycine - metabolism; Glycine site; Male; Microdialysis; Microinjections; Neurons - drug effects; Neurons - metabolism; Neurotoxins - toxicity; Nitric Oxide - metabolism; NMDA receptor; 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; Striatum; Vertebrates: nervous system and sense organs; Striatum; Ammonia; cGMP; Microdialysis; NMDA receptor; Glycine site; Rat; Rodentia; Central nervous system; 3',5'-GMP; Glutamate receptor; Corpus striatum; Glycine; Encephalon; Vertebrata; Mammalia; Nitric oxide; NMDA; Antagonist
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2004.05.014

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 ([(1 S)-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.