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S-Adenosylmethionine Promotes Oxidative Stress and Decreases Na+, K+-ATPase Activity in Cerebral Cortex Supernatants of Adolescent Rats: Implications for the Pathogenesis of S-Adenosylhomocysteine Hydrolase Deficiency

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Abstract

S-Adenosylmethionine (AdoMet) concentrations are highly elevated in tissues and biological fluids of patients affected by S-adenosylhomocysteine hydrolase deficiency, who are clinically characterized by cerebral symptoms whose pathogenesis is still unknown. In the present work, we investigated the effects of AdoMet on redox homeostasis and on the activity of Na+, K+-ATPase in the cerebral cortex of young rats. AdoMet caused lipid peroxidation (increase of malondialdehyde concentrations) and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content). AdoMet also reduced the antioxidant defenses (reduced glutathione, GSH) and Na+, K+-ATPase activity. Furthermore, AdoMet-induced lipid peroxidation was fully prevented by the antioxidants trolox, melatonin, and resveratrol, and the decrease of GSH concentrations was abolished by trolox, suggesting the involvement of reactive oxygen species in these effects. In this context, AdoMet induced reactive oxygen (increase of 2′,7′-dichloroflurescein-DCFH oxidation) but not nitrogen (nitrate and nitrite levels) species generation. Finally, the decrease of Na+, K+-ATPase activity provoked by AdoMet was totally prevented by trolox, implying a possible oxidation of cysteine groups of the enzyme that are critical for its function and highly susceptible to oxidative attack. It is also noted that adenosine and methionine did not alter the parameters evaluated, suggesting selective effects of AdoMet. Our data strongly indicate that disturbance of redox homeostasis caused by a major metabolite (AdoMet) accumulating in S-adenosylhomocysteine hydrolase deficiency may represent a deleterious mechanism of brain damage in this disease. Finally, reduction of Na+, K+-ATPase activity provoked by AdoMet may lead to impaired neurotransmission, but disturbance of this system should be better clarified in future studies.

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Funding

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (#404883/2013-3), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (#2266-2551/14-2), Pró-Reitoria de Pesquisa/Universidade Federal do Rio Grande do Sul (#PIBIC 27613), FIPE/HCPA, and Financiadora de Estudos e Projetos/Rede Instituto Brasileiro de Neurociência (# 01.06.0842-00).

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  1. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Ângela Zanatta, Cristiane Cecatto, Rafael Teixeira Ribeiro, Alexandre Umpierrez Amaral, Angela TS Wyse, Guilhian Leipnitz & Moacir Wajner

  2. Departamento de Ciências Biológicas, Universidade Regional Integrada do Alto Uruguai e das Missões, Erechim, RS, Brazil

    Alexandre Umpierrez Amaral

  3. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil

    Angela TS Wyse, Guilhian Leipnitz & Moacir Wajner

  4. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Moacir Wajner

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  1. Ângela Zanatta
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Correspondence to Moacir Wajner.

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The experimental protocol was approved by the Ethics Committee for animal research of the Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, and followed the “Principles of Laboratory Animal Care” (NIH publication 85-23, revised 1996). All efforts were made to minimize the number of animals used and their suffering.

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The authors declare that they have no potential conflicts of interest.

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Zanatta, Â., Cecatto, C., Ribeiro, R.T. et al. S-Adenosylmethionine Promotes Oxidative Stress and Decreases Na+, K+-ATPase Activity in Cerebral Cortex Supernatants of Adolescent Rats: Implications for the Pathogenesis of S-Adenosylhomocysteine Hydrolase Deficiency. Mol Neurobiol 55, 5868–5878 (2018). https://doi.org/10.1007/s12035-017-0804-z

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