Tese
Papel da óxido nítrico sintase induzível no córtex cerebral de modelos experimentais da acidemia metilmalônica
Fecha
2012-12-15Registro en:
RIBEIRO, Leandro Rodrigo. Role of inducible nitric oxide synthase in cerebral cortex of experimental models for methylmalonic acidemia. 2012. 117 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Santa Maria, Santa Maria, 2012.
Autor
Ribeiro, Leandro Rodrigo
Institución
Resumen
Methylmalonic acidemia is an inborn error of metabolism characterized clinically and biochemically by
tissue accumulation of methylmalonic acid (MMA) and neurological dysfunction, including convulsion.
Furthermore, clinical data suggest that infections conditions can precipitate metabolic crisis and cause
neurological changes observed in patients of acidemia. Provided that the MMA cause neurological
complications, and that the inflammation can contribute to the occurrence of convulsions and cognitive deficit in
several animal models, it is possible to suggest that inflammatory mediators, such as inducible nitric oxide
synthase (iNOS), facilitate MMA-induced convulsions. The iNOS is one of three isoforms of nitric oxide
synthase (NOS), which generates nitric oxide (NO), a simple gaseous signaling molecule and free radical. The
iNOS is induced at injury/inflammation sites, but is also constitutively expressed on some cells, such as in
neurons. Studies in experimental models have already demonstrated that NO generated in the central nervous
system (CNS), by endothelial and neuronal isoforms of NOS, is involved in MMA-induced convulsions.
However, until the present moment are scarce the data in the literature evaluating the relationship of iNOS in
experimental models of Methylmalonic Acidemia. The results published in the article has shown that iNOS
knock-out C57BL/6 mice, when injected acutely with MMA (2 μmols/2 μl, intracerebroventricularly), have a
shorter duration of seizures, no significant change in the mean amplitude of electroencephalographic waves
(EEG); not increase the levels of nitrite and nitrate (NOx) compared to animals injected with saline, but have a
partial reduction in the levels of 3-nitrotyrosine (3-NT) compared to wild animals that were also treated with
MMA; similarly, show a partially lower inhibition of Na+,K+-ATPase, but exhibit no difference in succinate
dehydrogenase (SDH) inhibition on cerebral cortex compared to wild mice which also received MMA. The
results submitted in the manuscript has shown that Wistar rats, after being injected chronically with MMA (from
5th to 28th day of life, twice daily, with doses ranging from 0.76 to 1.67 mmol/g depending on the age of the
animal, via subcutaneous) showed a reduced index of recognition in spatial learning/memory test, but show no
anxiety at elevated plus maze test; they have a reduction in neutrophils, but an increase in the number of
mononuclear leukocytes in the blood; and in addition show increased levels of interleukin-1beta (IL-1β), tumor
necrosis factor-alpha (TNF-α), iNOS and 3-NT in the cerebral cortex. Considering the data presented in both
studies, it was concluded that the MMA can cause seizures, nitrosative stress and inhibition of Na+,K+-ATPase
activity in cerebral cortex of mice by mechanisms related to NO production via iNOS; and that the MMA can
also cause neurocognitive deficits, altered immune system in blood and increase of pro-inflammatory cytokines,
leading to increased expression of iNOS and nitrosative stress.