PROTECTION AGAINST LETHAL AMMONIA INTOXICATION - SYNERGISM BETWEEN ENDOGENOUS ORNITHINE AND L-CARNITINE

The protective effects of combinations of 5-fluoromethylornithine (5FM Orn), a selective inhibitor of ornithine aminotransferase, and of comp ounds known to antagonize ammonia toxicity, were studied in acute, let hal ammonia intoxication in mice. Two test conditions were used : (a) Mice were pretreated with 5FMOrn at a dose (5 mumol.kg-1) which partia lly protects against 13 mmol.kg-1 ammonium acetate. (b) Mice were pret reated with a maximally protective dose of 5FMOrn (0.1 mmol.kg-1), how ever, 15 mmol.kg-1 ammonium acetate was used for intoxication. Under t hese conditions treatment with 5FMOrn alone protected only marginally. Under condition (a), administration of L-citrulline, L-carnitine, and L-acetylcarnitine improved the protective effect of 5FMOrn significan tly, in an additive manner. N-acetyl-L-glutamate administration was in effective. Under condition (b), ornithine, arginine and citrulline did not improve the protective effect of 5FMOrn, even when these amino ac ids were given at doses, which were effective in preventing ammonia to xicity induced with 13 mmol.kg-1 ammonium acetate. The inability to im prove the effect of 5FMOrn by these compounds is most probably due to the fact that 5FMOrn and these amino acids enhance urea formation by t he same mechanism, namely by increasing the concentration of substrate s of the urea cycle. In contrast, L-carnitine and L-acetylcarnitine, w hich are assumed to stimulate urea production by different mechanisms, or compounds which antagonize ammonia toxicity by a urea cycle-indepe ndent mechanism, such as antagonists of the NMDA-type glutamate recept or (MK-801; MDL 100,453), potentiated the effects of 5FMOrn. The princ iple reason for the observed protective effects of the treatments desc ribed in this work seems to be the prevention of accumulation of letha l concentrations of ammonia in the brain. But other effects may also c ontribute.