Free Radical Scavengers Prevent Argininosuccinic Acid-Induced Oxidative Stress in the Brain of Developing Rats: a New Adjuvant Therapy for Argininosuccinate Lyase Deficiency?

  • Bianca Seminotti
  • Janaína Camacho da Silva
  • Rafael Teixeira Ribeiro
  • Guilhian Leipnitz
  • Moacir WajnerEmail author


Tissue accumulation and high urinary excretion of argininosuccinate (ASA) is the biochemical hallmark of argininosuccinate lyase deficiency (ASLD), a urea cycle disorder mainly characterized by neurologic abnormalities, whose pathogenesis is still unknown. Thus, in the present work, we evaluated the in vitro and in vivo effects of ASA on a large spectrum of oxidative stress parameters in brain of adolescent rats in order to test whether disruption of redox homeostasis could be involved in neurodegeneration of this disorder. ASA provoked in vitro lipid and protein oxidation, decreased reduced glutathione (GSH) concentrations, and increased reactive oxygen species generation in cerebral cortex and striatum. Furthermore, these effects were totally prevented or attenuated by the antioxidants melatonin and GSH. Similar results were obtained by intrastriatal administration of ASA, in addition to increased reactive nitrogen species generation and decreased activities of superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. It was also observed that melatonin and N-acetylcysteine prevented most of ASA-induced in vivo pro-oxidant effects in striatum. Taken together, these data indicate that disturbance of redox homeostasis induced at least in part by high brain ASA concentrations per se may potentially represent an important pathomechanism of neurodegeneration in patients with ASLD and that therapeutic trials with appropriate antioxidants may be an adjuvant treatment for these patients.


Argininosuccinate lyase deficiency Argininosuccinate Oxidative stress Antioxidants Brain 


Funding Information

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant number no. 425914/2016-0), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (grant number no. 2266-2551/14-2), Financiadora de Estudos e Projetos/Rede Instituto Brasileiro de Neurociência (grant number no. 01.06.0842-00), and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN) (grant number no. 465671/2014-4).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.


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Authors and Affiliations

  1. 1.Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Serviço de Genética MédicaHospital de Clínicas de Porto AlegrePorto AlegreBrazil

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