Methylene blue prevents methylmalonate-induced seizures and oxidative damage in rat striatum

Abstract

Methylene blue (MB) is a thiazine dye with cationic and lipophilic properties that acts as an electron transfer mediator in the mitochondria. Due to this metabolic improving activity and free radicals scavenging effects, MB has been used in the treatment of methemoglobinemia and ifosfamide-induced encephalopathy. Considering that methylmalonic acidemia consists of a group of inherited metabolic disorders biochemically characterized by impaired mitochondrial oxidative metabolism and reactive species production, we decided to investigate whether MB, protects against the behavioral and neurochemical alterations elicited by the intrastriatal injection of methylmalonate (MMA). In the present study we showed that intrastriatal injection of MB (0.015–1.5 nmol/0.5 μl) protected against seizures (evidenced by electrographic recording), protein carbonylation and Na +,K +-ATPase inhibition ex vivo induced by MMA (4.5 μmol/1.5 μl). Furthermore, we investigated whether convulsions elicited by intrastriatal MMA administration are accompanied by striatal protein carbonyl content increase and changes in Na +,K +-ATPase activity in rat striatum. The effect of MB (0.015–1.5 nmol/0.5 μl) and MMA (4.5 μmol/0.5 μl) on striatal NO x (NO 2 plus NO 3) content was also evaluated. Statistical analysis revealed that the MMA-induced NO x content increase was attenuated by intrastriatal injection of MB and the duration of convulsive episodes correlated with Na +,K +-ATPase inhibition, but not with MMA-induced total protein carbonylation. In view of that MB decreases MMA-induced neurotoxicity assessed by behavioral and neurochemical parameters, the authors suggest that MB may be of value to attenuate neurological deficits of methylmalonic acidemic patients.