Effects of Valproate and Citrulline on Ammonium-Induced Encephalopathy

Summary: 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 (CD₅₀) from 6.1 to 3.6 mmol/kg, and (b) significant increases in blood ammonia concentrations in NH₄,+ 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 NH₄,+treated animals from 6.1 to 8.6 mmolikg, (b) a statistically significant decrease in ammonia concentration at all doses examined, (c) complete protection from encephalopathic effects of NH, + at citrulline concentrations threeto tenfold greater than basal levels; and (d) a 24% increase in the CD, value and a statistically significant decrease in ammonia concentration of VPA/NH₄,+ 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.