Methylmalonate-induced seizures are attenuated in inducible nitric oxide synthase knockout mice

Leandro Rodrigo Ribeiro, Michele Rechia Fighera, Mauro Schneider Oliveira, Ana Flávia Furian, Leonardo Magno Rambo, Ana Paula de Oliveira Ferreira, André Luiz Lopes Saraiva, Mauren Assis Souza, Frederico Diniz Lima, Danieli Valnes Magni, Renata Dezengrini, Eduardo Furtado Flores, D. Allan Butterfield, Juliano Ferreira, Adair Roberto Soares dos Santos, Carlos Fernando Mello, Luiz Fernando Freire Royes

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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 μmol/2 μL; 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 (NO2 plus NO3 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.

Original languageEnglish
Pages (from-to)157-163
Number of pages7
JournalInternational Journal of Developmental Neuroscience
Issue number2
StatePublished - Apr 2009

Bibliographical note

Funding Information:
Work supported by CNPq (grants: 301552/2007-0, 505527/2004-9 and 472300/2004-0), and CAPES. M.S. Oliveira is the recipient of a CAPES fellowship. A.F. Furian, J. Ferreira, A.R. Santos and C.F. Mello are the recipients of CNPq fellowships.


  • 3-Nitrotyrosine
  • INOS
  • Methylmalonic acid
  • Nitric oxide
  • Seizure

ASJC Scopus subject areas

  • Developmental Neuroscience
  • Developmental Biology


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