N‐Acetylaspartic acid promotes oxidative stress in cerebral cortex of rats

Abstract

N-acetylaspartic acid accumulates in Canavan Disease, a severe leukodystrophy characterized by swelling and spongy degeneration of the white matter of the brain. This inherited metabolic disease, caused by deficiency of the enzyme aspartoacylase, is clinically characterized by severe mental retardation, hypotonia and macrocephaly, and also generalized tonic and clonic type seizures in about half of the patients. Considering that the mechanisms of brain damage in this disease remain not fully understood, in the present study we investigated whether oxidative stress is elicited by N-acetylaspartic acid. The in vitro effect of N-acetylaspartic acid (10-80 mM) was studied on oxidative stress parameters: total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR), chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), reduced glutathione content, sufhydryl content and carbonyl content in the cerebral cortex of 14-day-old rats. The effect of the acute administration of N-acetylaspartic acid (0.1-0.6 mmol/g body weight) was studied on TRAP, TAR, carbonyl content, chemiluminescence and TBA-RS. TRAP, TAR, reduced glutathione content and sulfhydryl content were significantly reduced, while chemiluminescence, TBA-RS and carbonyl content were significantly enhanced by N-acetylaspartic acid in vitro. The enhancement in TBA-RS promoted by N-acetylaspartic acid was completely prevented by ascorbic acid plus Trolox, and partially prevented by glutathione and dithiothreitol. The acute administration of N-acetylaspartic acid also significantly reduced TRAP and TAR, and significantly enhanced carbonyl content, chemiluminescence and TBA-RS. Our results indicate that N-acetylaspartic acid promotes oxidative stress by stimulating lipid peroxidation, protein oxidation and by decreasing non-enzymatic antioxidant defenses in rat brain. This could be another pathophysiological mechanism involved in Canavan Disease.

An in vitro approach to assess the neurotoxicity of valproic acid-induced oxidative stress in cerebellum and cerebral cortex of young rats

“…Cerebellum and cerebral cortex are important regions of the brain and play a prominent role in the coordination of motor movements as well as basic facets of memory and learning (Pederzolli et al, 2007). There are several investigators who have reported that these parts of the brain are highly vulnerable to oxidative stress because cerebellum and cerebral cortex have low capacity of antioxidants as compared with other tissues.…”

Making the White Matter Matters: Progress in Understanding Canavan’s Disease and Therapeutic Interventions Through Eight Decades

“…NAA inhibited the functions of catalase and GPX enzymes indicating impaired detoxification of hydrogen peroxide, but it had no effect on SOD. Acute administration of NAA also enhanced levels of hydrogen peroxide in vitro which could possibly be involved in the progression of the characteristic neurodegeneration in CD (Pederzolli et al 2007). Though these results could not be extrapolated to humans, they do reveal probable mechanisms since the oxidative stress parameters occurred with concentrations of NAA (~4fold higher) observed in the plasma and cerebrospinal fluid of patients affected by CD (Tsai and Coyle 1995).…”

“…Though these results could not be extrapolated to humans, they do reveal probable mechanisms since the oxidative stress parameters occurred with concentrations of NAA (~4fold higher) observed in the plasma and cerebrospinal fluid of patients affected by CD (Tsai and Coyle 1995). Based on the supposition that NAA may promote oxidative stress in vitro and in vivo both by enhancing reactive species and diminishing antioxidant defenses, administration of antioxidants, especially vitamins E and C, could be considered as a potential adjuvant therapy for patients affected by CD (Pederzolli et al 2007).…”

“…In recent years, intraperitoneal injections of lipoic acid [which can cross the blood brain barrier (Samuel et al 2005)] have also been tried in preclinical studies using tremor rats, the naturally occurring animal model for CD (Pederzolli et al 2007) based on the fact that NAA induces oxidative stress in the CNS. The encouraging results suggest that this might be a good therapeutic approach for symptomatic treatment.…”

Non-genetic therapeutic approaches to Canavan disease

“…Due to evidence that CNS NAA accumulation may be damaging through its initiation of oxidative stress (Pederzolli et al, 2007;Surendran and Bhatnagar, 2011), antioxidants have been considered as a potential treatment for CD. Lipoic acid, being known to cross the BBB and to have a high potency, was tested in its ability to reduce signs of NAA-induced oxidative stress in 14-day-old Wistar rats (Pederzolli et al, 2010): when given before acute NAA-administration (40 mg/kg of body weight, intraperitoneally, 2-days prior to NAA), all signs of oxidative stress induced by NAA were prevented.…”