Effectiveness of creatine monohydrate on seizures and oxidative damage induced by methylmalonate.
Methylmalonic acidemias are metabolic disorders caused by a severe deficiency of methylmalonyl CoA mutase activity, which are characterized by neurological dysfunction, including convulsions. It has been reported that methylmalonic acid (MMA) accumulation inhibits succinate dehydrogenase (SDH) and beta-hydroxybutyrate dehydrogenase activity and respiratory chain complexes in vitro, leading to decreased CO2 production, O2 consumption and increased lactate production. Acute intrastriatal administration of MMA also induces convulsions and reactive species production. Though creatine has been reported to decrease MMA-induced convulsions and lactate production, it is not known whether it also protects against MMA-induced oxidative damage. In the present study we investigated the effects of creatine (1.2-12 mg/kg, i.p.) and MK-801 (3 nmol/striatum) on the convulsions, striatal content of thiobarbituric acid reactive substances (TBARS) and on protein carbonylation induced by MMA. Moreover, we investigated the effect of creatine (12 mg/kg, i.p.) on the MMA-induced striatal creatine and phosphocreatine depletion. Low doses of creatine (1.2 and 3.6 mg/kg) protected against MMA-induced oxidative damage, but did not protect against MMA-induced convulsions. A high dose of creatine (12 mg/kg, i.p.) and MK-801 (3 nmol/striatum) protected against MMA-induced seizures (evidenced by electrographic recording), protein carbonylation and TBARS production ex vivo. Furthermore, acute creatine administration increased the striatal creatine and phosphocreatine content and protected against MMA-induced creatine and phosphocreatine depletion. Our results suggest that an increase of the striatal high-energy phosphates elicited by creatine protects not only against MMA-induced convulsions, but also against MMA-induced oxidative damage. Therefore, since NMDA antagonists are limited value in the clinics, the present results indicate that creatine may be useful as an adjuvant therapy for methylmalonic acidemic patients.
Departamento de Fisiologia e Farmacologia, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil.
Luiz Fernando Freire
LF
Royes
Michele Rechia
MR
Fighera
Ana Flávia
AF
Furian
Mauro Schneider
MS
Oliveira
Jociane de Carvalho
Jde C
Myskiw
Natália Gindri
NG
Fiorenza
João Carlos
JC
Petry
Rafael Correa
RC
Coelho
Carlos Fernando
CF
Mello
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003401:Creatine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D008297:Male; D008314:Malonates / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008845:Microinjections; D017072:Neostriatum; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D008314:Malonates; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D017392:Thiobarbituric Acid Reactive Substances; D010725:Phosphocreatine; D016291:Dizocilpine Maleate; C005230:methyl malonate; D003401:Creatine