Creatine protects against the convulsive behavior and lactate production elicited by the intrastriatal injection of 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 the accumulating metabolite, L-methylmalonic acid (MMA), inhibits succinate dehydrogenase leading to ATP depletion in vitro, and that the intrastriatal injection of MMA induces convulsions through secondary NMDA receptor stimulation. In this study we investigated the effect of creatine (1.2, 3.6 and 12.0 mg/kg, (i.p.), [DOSAGE ERROR CORRECTED] succinate (1.5 micromol/striatum) and MK-801 (3 nmol/striatum) on the convulsions and on the striatal lactate increase induced by MMA (4.5 micromol/striatum) in rats. The effect of creatine on the striatal phosphocreatine content and on MMA-induced phosphocreatine depletion was also evaluated. Creatine, succinate and MK-801 pretreatment decreased the number and duration of convulsive episodes and the lactate increase elicited by MMA. Creatine, but not succinate, prevented the convulsions and the lactate increase induced by the direct stimulation of NMDA receptors. Acute creatine administration increased the total striatal phosphocreatine content and prevented MMA-induced phosphocreatine depletion. Our results suggest that MMA increases lactate production through secondary NMDA receptor activation, and it is proposed that the anticonvulsant effect of creatine against MMA-induced convulsions may be due to an increase in the phosphocreatine content available for metabolic purposes.
Royes
L F F
LF
Department of Chemistry, Federal University of Santa Maria, 97105-900 Santa Maria, RS, Brazil.
Fighera
M R
MR
Furian
A F
AF
Oliveira
M Schneider
MS
da Silva
L G Martins
LG
Malfatti
C R M
CR
Schneider
P H
PH
Braga
A L
AL
Wajner
M
M
Mello
C F
CF
D000818:Animals; D001522:Behavior, Animal; D003342:Corpus Striatum / Q000187:drug effects / Q000293:injuries; D003401:Creatine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D008764:Methylmalonic Acid / Q000633:toxicity*; D016202:N-Methylaspartate / Q000633:toxicity; D010725:Phosphocreatine / Q000378:metabolism; D011837:Radiation-Protective Agents; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D019802:Succinic Acid / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011837:Radiation-Protective Agents; D010725:Phosphocreatine; D019344:Lactic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D008764:Methylmalonic Acid; D019802:Succinic Acid; D003401:Creatine