Failure of L-Carnitine to Protect Mice against Hyperammonemia Induced by Ammonium Acetate or Urease Injection

Abstract

ABSTRACT. Reports indicate that L-carnitine administration before 100% lethal dose of ammonium acetate suppresses the symptoms of ammonia toxicity and prevents death in mice. However, we have been unable to confirm this observation. The cause of discrepancy between our results and the results of others was investigated with two models of hyperammonemia in mice: I) that induced by intraperitoneal injection of urease and 2) that induced by intraperitoneal injection of ammonium acetate. L-Carnitine administration failed to protect mice against ammonia toxicity induced by intraperitoneal injection of urease. Mortality in mice treated with L-carnitine 30 min before injection of ammonium acetate was similar to that of controls pretreated with saline. Ammonia and urea levels in plasma, liver, and brain were also similar in both groups. However, the values were significantly lower than those in mice denied either pretreatment before the ammonium acetate challenge. These results indicate that pretreatment acts to reduce blood and tissue ammonia simply by diminishing the rate of absorption of the challenge, owing to the dilution of ammonium acetate upon mixing with the contents of the peritoneal cavity. Thus, any protocol that does not compare results of a putative protective agent with those obtained with an equal volume of solvents or saline runs the risk of ascribing protective property to the agent when the protection may, in fact, have been afforded by the solvent. (Pediatr Res 28: [256][257][258][259][260] 1990) Abbreviations Hyperammonemia occurs in several pathologic conditions such as cirrhosis of the liver, inborn errors of the urea cycle, and other hereditary disorders such as organic acidemia and hyperlysinemia. Elevated ammonia is toxic to the brain and leads to convulsions, coma, and death. Several approaches have been recommended to combat hyperamrnonemia. These include limiting nitrogen intake, improving protein quality, supplying dietary metabolites such as arginine, and increasing nitrogen excretion in the form of derived conjugates (1,2). It has been reported that L-carnitine administration to mice prevents the lethal effects of acute hyperammonemia induced by ammonium acetate injection (3, 4). These authors proposed that L-carnitine decreases the ammonia in blood and brain by inducing ureagenesis. Another group of investigators carried out similar studies using an identical protocol and also reported that L-carnitine protected mice against ammonia toxicity (5). However, when we attempted to repeat this work, we were unable to demonstrate the eficacy of L-carnitine in reducing hyperammonemia (6). Hearn et al. (7) recently reported that the protective effect of L-carnitine was short lived and was not consistently reproducible. They observed that in some experiments 100% of rats treated with L-carnitine survived an ammonium acetate challenge, whereas in other experiments more than 60% of the animals died after an identical treatment (7).The first objective of our study was to investigate the cause for ...

Protection of the Brain by Carnitine

“…Hence, am monia may be regarded as an intrinsic neurotoxin as well as an extrinsic toxin. O'Connor and his col leagues first reported that carnitine suppressed the toxicity of ammonia in mice11,12) but contradictory results have also been presented13, 14). Moreover, if the findings of O'Connor et al are correct, the mech anisms of the effects of carnitine in suppressing the toxicity of ammonia are not clear.…”

The nutritional management of urea cycle disorders

“…16 In some studies neurologic symptoms and toxicity have been reduced, [17][18][19] but not in others. 20 Reduced plasma carnitine concentrations in rats and infants with urea cycle disorders have been described. 21,22 However, although the use of carnitine is advocated by some, there are no systematic studies in humans, and its therapeutic value in these disorders is uncertain.…”