L-carnitine increases the affinity of glutamate for quisqualate receptors and prevents glutamate neurotoxicity.
We have shown that acute ammonia toxicity is mediated by activation of the NMDA type of glutamate receptors. Although it is well known that L-carnitine prevents acute ammonia toxicity, the underlying molecular mechanism is not clear. We suspected that L-carnitine would prevent ammonia toxicity by preventing the toxic effects of glutamate. We have tested this hypothesis using primary cultures of neurons. L-carnitine prevented glutamate neurotoxicity in a dose-dependent manner similar to that required to prevent ammonia toxicity in animals. It is also shown that L-carnitine increases selectively the affinity of glutamate for the quisqualate type of glutamate receptors, while the affinity for the kainate and NMDA receptors is slightly decreased. L-carnitine prevents the increase in cytoplasmic Ca2+ induced by addition of glutamate. The Ca2+ levels rose 4.8-fold following addition of 1 mM glutamate, however, when the neurons were incubated previously with 5 mM L-carnitine, the Ca2+ levels increased only by 50%. Also, AP-3, an antagonist of the metabotropic receptor prevents the protective effect of L-carnitine against glutamate neurotoxicity. We suggest, therefore, that the protective effect of L-carnitine against glutamate toxicity is due to the increased affinity of glutamate for the metabotropic receptor. This mechanism could also explain the protection by L-carnitine against acute ammonia toxicity.
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Instituto de Investigaciones Citológicas de la Fundación Valenciana de Investigaciones Biomédicas, Spain.
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Cabedo
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Grisolía
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D000641:Ammonia / Q000633:toxicity; D000818:Animals; D002331:Carnitine / Q000494:pharmacology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D007700:Kinetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism
D000641:Ammonia; D002331:Carnitine; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018698:Glutamic Acid; D009498:Neurotoxins; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate