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

Abstract

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.

• Authors: Luiz Fernando Freire Royes, Michele Rechia Fighera, Ana Flávia Furian, Mauro Schneider Oliveira, Natália Gindri Fiorenza, João Carlos Petry, Rafael Correa Coelho, Carlos Fernando Mello
• Journal: Epilepsy research (Epilepsy Res) Vol. 73 Issue 3 Pg. 228-37 (Mar 2007) ISSN: 0920-1211 [Print] Netherlands
• PMID: 17137751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Indazoles
• Nitric Oxide
• Methylmalonic Acid
• Arginine
• Nitric Oxide Synthase
• Sodium-Potassium-Exchanging ATPase
• 7-nitroindazole

Topics

• Animals
• Anticonvulsants (pharmacology, therapeutic use)
• Arginine (pharmacology)
• Corpus Striatum (metabolism)
• Dose-Response Relationship, Drug
• Electroencephalography (drug effects)
• Indazoles (pharmacology, therapeutic use)
• Male
• Methylmalonic Acid (administration & dosage, adverse effects)
• Nitric Oxide (physiology)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Oxidative Stress (drug effects)
• Premedication
• Rats
• Rats, Wistar
• Seizures (chemically induced, drug therapy, physiopathology)
• Sodium-Potassium-Exchanging ATPase (drug effects)