NMDA RECEPTOR ANTAGONISTS PREVENT ACUTE AMMONIA TOXICITY IN MICE

We proposed that acute ammonia toxicity is mediated by activation of N MDA receptors. To confirm this hypothesis we have tested whether diffe rent NMDA receptor antagonists, acting on different sites of NMDA rece ptors, prevent death of mice induced by injection of 14 mmol/Kg of amm onium acetate, a dose that induces death of 95% of mice. MK-801, phenc yclidine and ketamine, which block the ion channel of NMDA receptors, prevent death of at least 75% of mice. CPP, AP-5, CGS 19755, and CGP 4 0116, competitive antagonists acting on the binding site for NMDA, als o prevent death of at least 75% of mice. Butanol, ethanol and methanol which block NMDA receptors, also prevent death of mice. There is an e xcellent correlation between the EC,, for preventing ammonia-induced d eath and the IC50 for inhibiting NMDA-induced currents. Acute ammonia toxicity is not prevented by antagonists of kainate/AMPA receptors, of muscarinic or nicotinic acetylcholine receptors or of GABA receptors. Inhibitors of nitric oxide synthase afford partial protection against ammonia toxicity while inhibitors of calcineurin, of glutamine synthe tase or antioxidants did not prevent ammonia-induced death of mice. Th ese results strongly support the idea that acute ammonia toxicity is m ediated by activation of NMDA receptors.