Intracerebroventricular administration of N-acetylaspartic acid impairs antioxidant defenses and promotes protein oxidation in cerebral cortex of rats

Abstract

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.

Rare Copy Number Deletions Predict Individual Variation in Human Brain Metabolite Concentrations in Individuals with Alcohol Use Disorders

“…Individuals with large numbers of rare deletions who are prone to oxidative damage may adaptively downregulate energy utilization in the brain, perhaps directly through ROS signaling (e.g., [71, 72]). It is noteworthy that the two neurometabolic signals most highly associated with rare deletions in this study, NAA and glutamate (as part of Glx), have both been found to increase production of ROS [73, 74]. Future research may investigate these and other possible mechanisms whereby rare deletions come to covary with neurometabolites.…”

Identification of Cisplatin-Regulated Metabolic Pathways in Pluripotent Stem Cells

“…1A). Furthermore, we detected increased levels of the metabolite N-acetyl-aspartyl-glutamic acid (NAAG), a common neuropeptide and its precursor N-acetyl-L-aspartate (NAA) [24] (Fig. 1A).…”

Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease

“…Several potential mechanisms have been proposed over the last several decades, but the more recent data still does not strongly favor one mechanism over the other. The range of possible NAA-related mechanisms involved in the extensive brain vacuolization in Canavan disease, which are not mutually exclusive, include: (1) NAA has detrimental pro-oxidant (Pederzolli et al, 2007, 2009, 2010) or osmotic effects in neurons or oligodendrocytes (Baslow, 1999, 2002, 2017); (2) energy metabolism is compromised in neurons and/or oligodendrocytes due to impaired NAA catabolism (Francis et al, 2012, 2014, 2016); (3) a lack of NAA catabolism results in altered acetyl-coenzyme A metabolism or availability for lipid synthesis and protein acetylation (D’Adamo et al, 1968; Burri et al, 1991; Madhavarao et al, 2005; Moffett et al, 2007, 2013; Ariyannur et al, 2010b); and (4) NAA has important but as yet unknown functions that are disrupted by a lack of catabolism in oligodendrocytes.…”

“…Investigations into the effects of very high concentrations of NAA on cerebral cortex homogenates from 14 day old rats showed that incubation with 40 mM or 80 mM NAA resulted in small but significant reductions in glutathione levels and total antioxidant reactivity (Pederzolli et al, 2007), and reduced catalase activity (Pederzolli et al, 2010). Injection of 8 micromoles of NAA into the cerebral ventricle of 30 day old rats resulted in significantly reduced total radical-trapping potential, catalase and glucose 6-phosphate dehydrogenase activities, as well as increased protein carbonyl content and superoxide dismutase activity (Pederzolli et al, 2009). The authors concluded that high levels of NAA can lead to oxidative damage in the brain.…”