Effects of valproate and citrulline on ammonium-induced encephalopathy

Hyperammonemia is a recognized side effect of treatment with the antiepileptic drug (AED) valproate (VPA). Encephalopathic complications have also been observed in some patients receiving VPA therapy. The relation between VPA-induced hyperammonemia and encephalopathy is not clear, however. A model of ammonium (NH4+)-induced coma was used to investigate the contribution of VPA and to assess the efficacy of citrulline (a urea cycle intermediate) on hyperammonemia and encephalopathy. In groups of 6-12 rats, administration of VPA (2.5 mmol/kg) was associated with (a) a decrease in the dose of NH4+ that produces coma in 50% of the animals (CD5) from 6.1 to 3.6 mmol/kg, and (b) significant increases in blood ammonia concentrations in NH(4+)-treated animals. In addition, clear evidence also showed that in the presence of VPA, a lesser concentration of ammonia produced coma. Citrulline treatment (5.0 mmol/kg) was associated with (a) an increase in the CD50 value of NH(4+)-treated animals from 6.1 to 8.6 mmol/kg, (b) a statistically significant decrease in ammonia concentration at all doses examined, (c) complete protection from encephalopathic effects of NH4+ at citrulline concentrations three- to tenfold greater than basal levels; and (d) a 24% increase in the CD50 value and a statistically significant decrease in ammonia concentration of VPA/NH(4+)-treated animals. These findings indicate that VPA has a dual effect on encephalopathy and that citrulline should benefit those patients treated with VPA who experience adverse encephalopathic effects.