NMDA receptor antagonists prevent acute ammonia toxicity in mice.
We proposed that acute ammonia toxicity is mediated by activation of NMDA receptors. To confirm this hypothesis we have tested whether different NMDA receptor antagonists, acting on different sites of NMDA receptors, prevent death of mice induced by injection of 14 mmol/Kg of ammonium acetate, a dose that induces death of 95% of mice. MK-801, phencyclidine 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 40116, competitive antagonists acting on the binding site for NMDA, also prevent death of at least 75% of mice. Butanol, ethanol and methanol which block NMDA receptors, also prevent death of mice. There is an excellent correlation between the EC50 for preventing ammonia-induced death 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 synthetase or antioxidants did not prevent ammonia-induced death of mice. These results strongly support the idea that acute ammonia toxicity is mediated by activation of NMDA receptors.
Hermenegildo
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Instituto de Investigaciones Citológicas de la Fundación Valenciana de Investigaciones Biomédicas, Spain.
Marcaida
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Montoliu
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Grisolía
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Miñana
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Felipo
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D000641:Ammonia / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000819:agonists; D016923:Cell Death / Q000187:drug effects; D004789:Enzyme Activation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005609:Free Radicals; D018698:Glutamic Acid / Q000633:toxicity*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013997:Time Factors
D002148:Calmodulin-Binding Proteins; D018691:Excitatory Amino Acid Antagonists; D005609:Free Radicals; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D000641:Ammonia; D019001:Nitric Oxide Synthase; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases