The role of nitric oxide on the convulsive behavior and oxidative stress induced by methylmalonate: An electroencephalographic and neurochemical study

Methylmalonic acidemias consist of a group of inherited metabolic disorders caused by deficiency of methylmalonyl-CoA mutase activity and biochemically characterized by methylmalonate (MMA) accumulation, impairment mitochondrial oxidative metabolism and reactive species production. Preliminary studies with nitric oxide synthase (NOS) inhibitors have suggested that nitric oxide (NO) plays a role in the convulsant effect of MMA. However, definitive biochemical and electrophysiological evidence of the involvement of NO in the convulsions induced by MMA are lacking. In this study, we investigated whether the inhibition of NOS by 7-nitroindazole (7-NI, 3-60 mg/kg, i.p.) altered the convulsions, protein oxidative damage, NOx (NO2 plus NO3) production and Na+,K+-ATPase activity inhibition induced by MMA. 7-NI decreased striatal NOx content, but increased seizures and protein carbonylation induced by MMA (6 μmol/striatum). The intrastriatal injection of l-arginine (50 nmol/0.5 μl), but not of d-arginine (50 nmol/0.5 μl), increased striatal NOx content and protected against MMA-induced electroencephalographic seizures, striatal protein carbonylation and Na+,K+-ATPase inhibition. Furthermore, l-arginine (50 nmol/0.5 μl) and MMA had no additive effect on NOx increase. These results are experimental evidence that endogenous NO plays a protective role in the convulsions and acute neurochemical alterations induced by this organic acid.