Intracerebroventricular administration of N-acetylaspartic acid impairs antioxidant defenses and promotes protein oxidation in cerebral cortex of rats
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N-acetylaspartic acid (NAA) is the biochemical hallmark of Canavan Disease, an inherited metabolic disease caused by deficiency of aspartoacylase activity. NAA is an immediate precursor for the enzyme-mediated biosynthesis of N-acetylaspartylglutamic acid (NAAG), whose concentration is also increased in urine and cerebrospinal fluid of patients affected by CD. This neurodegenerative disorder is clinically characterized by severe mental retardation, hypotonia and macrocephaly, and generalized tonic and clonic type seizures. Considering that the mechanisms of brain damage in this disease remain not fully understood, in the present study we investigated whether intracerebroventricular administration of NAA or NAAG elicits oxidative stress in cerebral cortex of 30-day-old rats. NAA significantly reduced total radical-trapping antioxidant potential, catalase and glucose 6-phosphate dehydrogenase activities, whereas protein carbonyl content and superoxide dismutase activity were significantly enhanced. Lipid peroxidation indices and glutathione peroxidase activity were not affected by NAA. In contrast, NAAG did not alter any of the oxidative stress parameters tested. Our results indicate that intracerebroventricular administration of NAA impairs antioxidant defenses and induces oxidative damage to proteins, which could be involved in the neurotoxicity of NAA accumulation in CD patients.
KeywordsN-acetylaspartic acid N-acetylaspartylglutamic acid Aspartoacylase deficiency Canavan Disease Oxidative stress Rat brain
This work was supported by the research grants from Programa de Núcleos de Excelência (PRONEX), CAPES, Brazilian National Research Council (CNPq), PROPESQ/UFRGS, PIC/UFCSPA and FINEP — Rede Instituto Brasileiro de Neurociência (IBN-Net) #01.06.0842-00.
- Beaudet A (2001) Aspartoacylase deficiency (Canavan disease). In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 5799–5805Google Scholar
- Halliwell B, Gutteridge JMC (2007) Cellular responses to oxidative stress: adaptation, damage, repair, senescence and death. In: Halliwell B, Gutteridge JMC (eds) Free radicals in biology and medicine. Oxford University Press Inc., Oxford, pp 187–267Google Scholar
- Kitada K, Akimitsu T, Shigematsu Y, Kondo A, Maihara T, Yokoi N, Kuramoto T, Sasa M, Serikawa T (2000) Accumulation of N-acetylaspartate in the brain of the tremor rat, a mutant exhibiting absence-like seizure and spongiform degeneration in the central nervous system. J Neurochem 74(6):2512–2519PubMedCrossRefGoogle Scholar
- Lissi E, Caceres T, Videla LA (1986) Visible chemiluminescence from rat brain homogenates undergoing autoxidation I. Effect of additives and products accumulation. Free Radic Biol Med 2:63–69Google Scholar
- Marklund SL (1985) Pyrogallol autoxidation. In: Greenwald RA (ed) Handbook of methods for oxygen radical research. CRC, Boca Raton, pp 243–247Google Scholar
- Paxinos G, Watson C (2004) The rat brain in stereotaxic coordinates. Elsevier, New YorkGoogle Scholar
- Thomas AG, Vornov JJ, Olkowski JL, Merion AT, Slusher BS (2000) N-acetylated α-linked acidic dipeptidase converts N-acetylaspartylglutamate from a neuroprotectant to a neurotoxin. JPET 295:16–22Google Scholar