Ammonia potentiates methylmalonic acid-induced convulsions and TBARS production.

Abstract

Hyperammonemia is a common finding in children with methylmalonic acidemia, an inherited metabolic disease characterized by mental retardation, convulsions, and accumulation of methylmalonic acid (MMA). Although it has been suggested that MMA induces convulsions through succinate dehydrogenase (SDH) inhibition, very little is known about the contribution of hyperammonemia to the development of convulsions in these patients. In the present study we investigated the effects of ammonium ions on the convulsant action of MMA, MMA-induced inhibition of striatal succinate dehydrogenase, and the striatal content of thiobarbituric acid-reactive substances (TBARS). Adult rats were injected with ammonium acetate (1.5 mmol/kg, sc) or sodium acetate (1.5 mmol/kg, sc), followed 5 min later by buffered MMA (3 micromol/microl) or NaCl (4.5 micromol/microl) injected into the striatum. The animals were observed in an open field for the appearance of convulsive episodes. After 30 min of behavioral evaluation, the animals were sacrificed and had their striatal TBARS content measured. Ammonium acetate pretreatment caused no behavioral effects per se, but potentiated MMA-induced convulsions and increased basal TBARS content and MMA-induced TBARS production in the striatum. Ammonium chloride had no effect on basal succinate dehydrogenase activity and did not alter MMA-induced inhibition of SDH in vitro. These results suggest that ammonia potentiates MMA-induced behavioral effects through a mechanism that does not involve further succinate dehydrogenase inhibition, but may involve facilitation of MMA-induced oxidative damage and provide evidence that ammonia and MMA may have mutually additive toxicity.

• Authors: Patricia da Costa Marisco, Marinei Cristina Pereira Ribeiro, Juliana Sartori Bonini, Telmo Tiburcio Fortes Lima, Keli Cristina Mann, Guilherme Marasciulo Brenner, Carlos Severo Dutra-Filho, Carlos Fernando Mello
• Journal: Experimental neurology (Exp Neurol) Vol. 182 Issue 2 Pg. 455-60 (Aug 2003) ISSN: 0014-4886 [Print] United States
• PMID: 12895456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• Enzyme Inhibitors
• Thiobarbituric Acid Reactive Substances
• Ammonium Chloride
• Ammonia
• Methylmalonic Acid
• Succinate Dehydrogenase
• ammonium acetate

Topics

• Acetates (pharmacology)
• Ammonia (pharmacology)
• Ammonium Chloride (pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Corpus Striatum (chemistry, drug effects, metabolism)
• Drug Synergism
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (toxicity)
• Male
• Methylmalonic Acid (toxicity)
• Rats
• Rats, Wistar
• Seizures (chemically induced, physiopathology)
• Succinate Dehydrogenase (antagonists & inhibitors, metabolism)
• Thiobarbituric Acid Reactive Substances (metabolism)