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, 3-60mg/kg, i.p.) altered the convulsions, protein oxidative damage, NO(x) (NO(2) plus NO(3)) production and Na(+),K(+)-ATPase activity inhibition induced by MMA. 7-NI decreased striatal NO(x) content, but increased seizures and protein carbonylation induced by MMA (6mumol/striatum). The intrastriatal injection of l-arginine (50nmol/0.5mul), but not of d-arginine (50nmol/0.5mul), increased striatal NO(x) content and protected against MMA-induced electroencephalographic seizures, striatal protein carbonylation and Na(+),K(+)-ATPase inhibition. Furthermore, l-arginine (50nmol/0.5mul) and MMA had no additive effect on NO(x) 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.
Royes
Luiz Fernando Freire
LF
Centro de Educação Física e Desportos, Departamento de Métodos e Técnicas Desportivas, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil. nandoroyes@yahoo.com.br
Fighera
Michele Rechia
MR
Furian
Ana Flávia
AF
Oliveira
Mauro Schneider
MS
Fiorenza
Natália Gindri
NG
Petry
João Carlos
JC
Coelho
Rafael Correa
RC
Mello
Carlos Fernando
CF
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001120:Arginine / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008764:Methylmalonic Acid / Q000008:administration & dosage / Q000009:adverse effects*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects*; D011292:Premedication; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects
D000927:Anticonvulsants; D007191:Indazoles; D009569:Nitric Oxide; D008764:Methylmalonic Acid; D001120:Arginine; D019001:Nitric Oxide Synthase; D000254:Sodium-Potassium-Exchanging ATPase; C080122:7-nitroindazole