Ammonia potentiates methylmalonic acid-induced convulsions and TBARS production.
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.
Marisco
Patricia da Costa
Pda C
Department of Chemistry, Center of Natural and Exact Sciences, Federal University of Santa Maria, 97105-900, Santa Maria, RS, Brazil.
Ribeiro
Marinei Cristina Pereira
MC
Bonini
Juliana Sartori
JS
Lima
Telmo Tiburcio Fortes
TT
Mann
Keli Cristina
KC
Brenner
Guilherme Marasciulo
GM
Dutra-Filho
Carlos Severo
CS
Mello
Carlos Fernando
CF
D000085:Acetates / Q000494:pharmacology; D000641:Ammonia / Q000494:pharmacology*; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity; D008297:Male; D008764:Methylmalonic Acid / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism*
D000085:Acetates; D004791:Enzyme Inhibitors; D017392:Thiobarbituric Acid Reactive Substances; D000643:Ammonium Chloride; D000641:Ammonia; D008764:Methylmalonic Acid; D013385:Succinate Dehydrogenase; C018824:ammonium acetate