Neurochemical evidence that the metabolites accumulating in 3-methylcrotonyl-CoA carboxylase deficiency induce oxidative damage in cerebral cortex of young rats.
Isolated 3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is an autosomal recessive disorder of leucine metabolism biochemically characterized by accumulation of 3-methylcrotonylglycine (3MCG), 3-methylcrotonic acid (3MCA) and 3-hydroxyisovaleric acid. A considerable number of affected individuals present neurological symptoms with or without precedent crises of metabolic decompensation and brain abnormalities whose pathogenesis is poorly known. We investigated the in vitro effects of 3MCG and 3MCA on important parameters of oxidative stress in cerebral cortex of young rats. 3MCG and 3MCA significantly increased TBA-RS and carbonyl formation, indicating that these compounds provoke lipid and protein oxidation, respectively. In contrast, nitric oxide production was not affected by 3MCG and 3MCA. Furthermore, 3MCG- and 3MCA-induced elevation of TBA-RS values was fully prevented by melatonin, trolox and reduced glutathione, but not by the nitric oxide inhibitor N(ω)-nitro-L-arginine methyl ester or the combination of catalase plus superoxide dismutase, indicating that reactive oxygen species were involved in the oxidative damage caused by these compounds. We also found that the activity of the antioxidant enzymes glutathione peroxidase, catalase, superoxide dismutase and glutathione reductase were not altered in vitro by 3MCG and 3MCA. It is therefore presumed that alterations of the cellular redox homeostasis caused by the major metabolites accumulating in 3MCCD may potentially be involved in the pathophysiology of the neurological dysfunction and structural brain alterations found in patients affected by this disorder.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos No 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
Ângela
Â
Zanatta
Alana Pimentel
AP
Moura
Anelise Miotti
AM
Tonin
Lisiane Aurélio
LA
Knebel
Mateus
M
Grings
Vannessa Araújo
VA
Lobato
César Augusto João
CA
Ribeiro
Carlos Severo
CS
Dutra-Filho
Guilhian
G
Leipnitz
Moacir
M
Wajner
D000367:Age Factors; D000818:Animals; D001923:Brain Chemistry / Q000502:physiology*; D019735:Carbon-Carbon Ligases / Q000172:deficiency*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D056806:Urea Cycle Disorders, Inborn / Q000201:enzymology / Q000503:physiopathology
D017392:Thiobarbituric Acid Reactive Substances; D019735:Carbon-Carbon Ligases; C021573:methylcrotonoyl-CoA carboxylase