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.