Showing papers by "Vicente Felipo published in 1996"

NMDA receptor antagonists prevent acute ammonia toxicity in mice.

Abstract: 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.

Carnitine and choline derivatives containing a trimethylamine group prevent ammonia toxicity in mice and glutamate toxicity in primary cultures of neurons.

Abstract: Carnitine prevents acute ammonia toxicity in animals. We propose that acute ammonia toxicity is mediated by activation of N-methyl-D-aspartate receptors and have shown that carnitine prevents glutamate neurotoxicity. The aim of this work was to assess whether other compounds containing a trimethylamine group are able to prevent ammonia toxicity in mice and/or glutamate toxicity in primary neuronal cultures. It is shown that betaine, trimethylamine-N-oxide, choline, acetylcholine, carbachol and acetylcarnitine prevent ammonia toxicity in mice. They also prevent glutamate but not N-methyl-D-aspartate neurotoxicity. Choline, acetylcholine and acetylcarnitine afford partial (approximately 50%) protection at nanomolar concentrations and nearly complete protection at micromolar concentrations. Trimethylamine-N-oxide, carbachol and betaine afford nearly complete protection at approximately 0.2 mM. The protective effect against glutamate neurotoxicity is prevented by 2-amino-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 toxicity in mice and against glutamate toxicity in cultured neurons. These results support the idea that acute ammonia toxicity is mediated by activation of N-methyl-D-aspartate receptors and that glutamate neurotoxicity could be prevented by activating metabotropic glutamate receptors and/or muscarinic receptors.

Effects of Hyperammonemia on Brain Protein Kinase C Substrates

Abstract: Ammonia is a product of the degradation of proteins and of other compounds ; however, when it is in excess, ammonia is a toxic compound . A fiveto ten-fold increase in blood ammonia levels leads to alterations in the function of the central nervous system, and can lead to coma and death . To prevent these toxic effects, ureotelic animals have developed the urea cycle, which is mainly located in liver, and eliminates ammonia by incorporating it into urea, which is eliminated in urine . This maintains safe levels of ammonia in blood and tissues. However, when this process fails due to a congenital defect in the urea cycle enzymes or by impairment of liver function, the levels of ammonia in blood rise and can lead to altered brain function. This syndrome, known as hepatic encephalopathy, can lead to coma and death. Ammonia interferes with neurotransmission and with electrophysiological processes (Fan et al., 1990; Szerb and Butterworth, 1992 ; Raabe and Lin, 1984 ; Raabe, 1992 and 1994, Butterworth, 1994) . There are a number of human illnesses that are associated with increased levels of ammonia in blood, including liver cirrhosis, fulminant hepatic failure and congenital defects of urea cycle enzymes . Independently of its origin, in these situations the levels of ammonia in blood increase 5 to 10-fold, leading to hepatic encephalopathy, and high mortality . In fact, hepatic encephalopathy is one of the main causes of death in occidental countries . In Spain 12,000 people die every year for this reason, which represents about