Methylmalonate-induced seizures are attenuated in inducible nitric oxide synthase knockout mice.
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.
Ribeiro
Leandro Rodrigo
LR
Centro de Ciências da Saúde, Departamento de Fisiologia e Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
Fighera
Michele Rechia
MR
Oliveira
Mauro Schneider
MS
Furian
Ana Flávia
AF
Rambo
Leonardo Magno
LM
Ferreira
Ana Paula de Oliveira
AP
Saraiva
André Luiz Lopes
AL
Souza
Mauren Assis
MA
Lima
Frederico Diniz
FD
Magni
Danieli Valnes
DV
Dezengrini
Renata
R
Flores
Eduardo Furtado
EF
Butterfield
D Allan
DA
Ferreira
Juliano
J
dos Santos
Adair Roberto Soares
AR
Mello
Carlos Fernando
CF
Royes
Luiz Fernando Freire
LF
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
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