title: Methylmalonate-induced seizures are attenuated in inducible nitric oxide synthase knockout mice.
abstract: Methylmalonic acidemias consist of a group of inherited neurometabolic disorders caused by deficiency of methylmalonyl-CoA mutase activity clinically and biochemically characterized by neurological dysfunction, methylmalonic acid (MMA) accumulation, mitochondrial failure and increased reactive species production. Although previous studies have suggested that nitric oxide (NO) plays a role in the neurotoxicity of MMA, the involvement of NO-induced nitrosative damage from inducible nitric oxide synthase (iNOS) in MMA-induced seizures are poorly understood. In the present study, we showed a decrease of time spent convulsing induced by intracerebroventricular administration of MMA (2 micromol/2 microL; i.c.v.) in iNOS knockout (iNOS(-/-)) mice when compared with wild-type (iNOS(+/+)) littermates. Visual analysis of electroencephalographic recordings (EEG) showed that MMA injection induced the appearance of high-voltage synchronic spike activity in the ipsilateral cortex which spreads to the contralateral cortex while quantitative electroencephalographic analysis showed larger wave amplitude during MMA-induced seizures in wild-type mice when compared with iNOS knockout mice. We also report that administration of MMA increases NOx (NO(2) plus NO(3) content) and 3-nitrotyrosine (3-NT) levels in a greater extend in iNOS(+/+) mice than in iNOS(-/-) mice, indicating that NO overproduction and NO-mediated damage to proteins are attenuated in iNOS knockout mice. In addition, the MMA-induced decrease in Na(+), K(+)-ATPase activity, but not in succinate dehydrogenase (SDH) activity, was less pronounced in iNOS(-/-) when compared with iNOS(+/+) mice. These results reinforce the assumption that metabolic collapse contributes for the secondary toxicity elicited by MMA and suggest that oxidative attack by NO derived from iNOS on selected target such as Na(+), K(+)-ATPase enzyme might represent an important role in this excitotoxicity induced by MMA. Therefore, these results may be of value in understating the pathophysiology of the neurological features observed in patients with methylmalonic acidemia and in the development of new strategies for treatment of these patients.
authors.affiliation: Centro de Ciências da Saúde, Departamento de Fisiologia e Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Leandro Rodrigo
authors.initials: LR
authors.lastname: Ribeiro
authors.forename: Michele Rechia
authors.initials: MR
authors.lastname: Fighera
authors.forename: Mauro Schneider
authors.initials: MS
authors.lastname: Oliveira
authors.forename: Ana Flávia
authors.initials: AF
authors.lastname: Furian
authors.forename: Leonardo Magno
authors.initials: LM
authors.lastname: Rambo
authors.forename: Ana Paula de Oliveira
authors.initials: AP
authors.lastname: Ferreira
authors.forename: André Luiz Lopes
authors.initials: AL
authors.lastname: Saraiva
authors.forename: Mauren Assis
authors.initials: MA
authors.lastname: Souza
authors.forename: Frederico Diniz
authors.initials: FD
authors.lastname: Lima
authors.forename: Danieli Valnes
authors.initials: DV
authors.lastname: Magni
authors.forename: Renata
authors.initials: R
authors.lastname: Dezengrini
authors.forename: Eduardo Furtado
authors.initials: EF
authors.lastname: Flores
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
authors.forename: Adair Roberto Soares
authors.initials: AR
authors.lastname: dos Santos
authors.forename: Carlos Fernando
authors.initials: CF
authors.lastname: Mello
authors.forename: Luiz Fernando Freire
authors.initials: LF
authors.lastname: Royes
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D001931:Brain Mapping; D004569:Electroencephalography; D005260:Female; D008297:Male; D008764:Methylmalonic Acid / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D009566:Nitrates; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008764:Methylmalonic Acid; D052247:Nitric Oxide Synthase Type II; D013385:Succinate Dehydrogenase; D000254:Sodium-Potassium-Exchanging ATPase