CARNITINE AND CHOLINE DERIVATIVES CONTAINING A TRIMETHYLAMINE GROUP PREVENT AMMONIA TOXICITY IN MICE AND GLUTAMATE TOXICITY IN PRIMARY CULTURES OF NEURONS

Carnitine prevents acute ammonia toxicity in animals. We propose that acute ammonia toxicity is mediated by activation of N-methyl-D-asparta te receptors and have shown that carnitine prevents glutamate neurotox icity. The aim of this work was to assess whether other compounds cont aining a trimethylamine group are able to prevent ammonia toxicity in mice and/or glutamate toxicity in primary neuronal cultures. It is sho wn that betaine, trimethylamine-N-oxide, choline, acetylcholine, carba chol and acetylcarnitine prevent ammonia toxicity in mice. They also p revent glutamate but not N-methyl-D-aspartate neurotoxicity. Choline, acetylcholine and acetylcarnitine afford partial (approximate to 50%) protection at nanomolar concentrations and nearly complete protection at micromolar concentrations. Trimethylamine-N-oxide, carbachol and be taine afford nearly complete protection at approximate to 0.2 mM. The protective effect against glutamate neurotoxicity is prevented by 2-am ino-3-phosphonopropionic acid, an antagonist of metabotropic glutamate receptors. Atropine, an antagonist of muscarinic receptors, prevents the protective effect of most of the above compounds against ammonia t oxicity in mice and against glutamate toxicity in cultured neurons. Th ese results support the idea that acute ammonia toxicity is mediated b y activation of N-methyl-D-aspartate receptors and that glutamate neur otoxicity could be prevented by activating metabotropic glutamate rece ptors and/or muscarinic receptors.