Showing papers by "Vicente Felipo published in 1994"

L-carnitine increases the affinity of glutamate for quisqualate receptors and prevents glutamate neurotoxicity

Abstract: We have shown that acute ammonia toxicity is mediated by activation of the NMDA type of glutamate receptors. Although it is well known thatL-carnitine prevents acute ammonia toxicity, the underlying molecular mechanism is not clear. We suspected thatL-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 thatL-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 mML-carnitine, the Ca2+ levels increased only by 50%. Also, AP-3, an antagonist of the metabotropic receptor prevents the protective effect ofL-carnitine against glutamate neurotoxicity. We suggest, therefore, that the protective effect ofL-carnitine against glutamate toxicity is due to the increased affinity of glutamate for the metabotropic receptor. This mechanism could also explain the protection byL-carnitine against acute ammonia toxicity.

Molecular Mechanism of Acute Ammonia Toxicity and of its Prevention by L-Carnitine

Abstract: One of the more remarkable consequences of liver failure (fulminant hepatic failure, liver cirrhosis, etc) and of deficiencies in the enzymes of the urea cycle is the defective elimination of ammonia and the increase of ammonia levels in blood. Hyperammonemia seems to be one of the main factors contributing to the pathogenesis of hepatic encephalopathy and, probably, to the development of hepatic coma.

High ammonia levels decrease brain acetylcholinesterase activity both in vivo and in vitro

Abstract: We have tested the effect of ammonium injection on the activity of acetylcholinesterase in rat brain. Fifteen minutes after ip injection of 7 mmol/kg of ammonium acetate, the activity of acetylcholinesterase in brain was reduced significantly. The inhibitory effect varied in a wide range, with a maximum decrease of 60%, and was proportional to the concentration of ammonia reached in the brain. It is also shown that ammonium salts added in vitro to the assay mixture inhibit acetylcholinesterase in brain homogenates competitively. The Ki values for inhibition of the enzyme in vitro were 7.2 and 8.5 mM for ammonium acetate and ammonium chloride, respectively, when acetylcholinesterase was assayed in rat brain homogenates, and 7.6 and 8.3 mM when assayed in mice brain homogenates. These results suggest that at least part of the neurologic effects of ammonia could be mediated by an increase of acetylcholine as a consequence of the inhibition of acetylcholinesterase.