title: Molecular mechanism of acute ammonia toxicity and of its prevention by L-carnitine.
abstract: In summary, we propose that acute ammonia intoxication leads to increased extracellular concentration of glutamate in brain and results in activation of the NMDA receptor. Activation of this receptor mediates ATP depletion and ammonia toxicity since blocking the NMDA receptor with MK-801 prevents both phenomena. Ammonia-induced metabolic alterations (in glycogen, glucose, pyruvate, lactate, glutamine, glutamate, etc) are not prevented by MK-801 and, therefore, it seems that they do not play a direct role in ammonia-induced ATP depletion nor in the molecular mechanism of acute ammonia toxicity. The above results suggest that ammonia-induced ATP depletion is due to activation of Na+/K(+)-ATPase, which, in turn, is a consequence of decreased phosphorylation by protein kinase C. This can be due to decreased activity of PKC or to increased activity of a protein phosphatase. We also show that L-carnitine prevents glutamate toxicity in primary neuronal cultures. The results shown indicate that carnitine increases the affinity of glutamate for the quisqualate type (including metabotropic) of glutamate receptors. Also, blocking the metabotropic receptor with AP-3 prevents the protective effect of L-carnitine, indicating that activation of this receptor mediates the protective effect of carnitine. We suggest that the protective effect of carnitine against acute ammonia toxicity in animals is due to the protection against glutamate neurotoxicity according to the above mechanisms.
authors.affiliation: Instituto de Investigaciones Citológicas, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Felipo
authors.forename: E
authors.initials: E
authors.lastname: Kosenko
authors.forename: M D
authors.initials: MD
authors.lastname: Miñana
authors.forename: G
authors.initials: G
authors.lastname: Marcaida
authors.forename: S
authors.initials: S
authors.lastname: Grisolía
mesh_terms: D000641:Ammonia / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002331:Carnitine / Q000494:pharmacology*; D006801:Humans
chemical_list: D000641:Ammonia; D002331:Carnitine