Chronic mild Hyperhomocysteinemia impairs energy metabolism, promotes DNA damage and induces a Nrf2 response to oxidative stress in rats brain

  • Tiago Marcon dos Santos
  • Cassiana Siebert
  • Micaela Federizzi de Oliveira
  • Vanusa Manfredini
  • Angela T. S. WyseEmail author
Original Research


Homocysteine (HCY) has been linked to oxidative stress and varied metabolic changes that are dependent on its concentration and affected tissues. In the present study we evaluate parameters of energy metabolism [succinate dehydrogenase (SDH), complex II and IV (cytochrome c oxidase), and ATP levels] and oxidative stress [DCFH oxidation, nitrite levels, antioxidant enzymes and lipid, protein and DNA damages, as well as nuclear factor erythroid 2-related (Nrf2) protein abundance] in amygdala and prefrontal cortex of HCY-treated rats. Wistar male rats were treated with a subcutaneous injection of HCY (0.03 µmol/g of body weight) from the 30th to 60th post-natal day, twice a day, to induce mild hyperhomocysteinemia (HHCY). The rats were euthanatized without anesthesia at 12 h after the last injection, and amygdala and prefrontal cortex were dissected for biochemical analyses. In the amygdala, mild HHCY increased activities of SDH and complex II and decreased complex IV and ATP level, as well as increased antioxidant enzymes activities (glutathione peroxidase and superoxide dismutase), nitrite levels, DNA damage, and Nrf 2 protein abundance. In the prefrontal cortex, mild HHCY did not alter energy metabolism, but increased glutathione peroxidase, catalase and DNA damage. Other analyzed parameters were not altered by HCY-treatment. Our findings suggested that chronic mild HHCY changes each brain structure, particularly and specifically. These changes may be associated with the mechanisms by which chronic mild HHCY has been linked to the risk factor of fear, mood disorders and depression, as well as in neurodegenerative diseases.


Homocysteine Mild hyperhomocysteinemia Nrf2 gene Antioxidant enzymes response Energy metabolism DNA damage 



Adenosine triphosphate



Complex II

Succinate dehydrogenase enzyme complexe

Complex IV

Cytochrome c oxidase enzyme






Deoxyribonucleic acid


Glutathione peroxidase


Glutathione reductase


Reduced glutathione


Oxidized glutathione










Nicotinamide adenine dinucleotide phosphate


Nitric oxide


Nuclear factor erythroid 2-related


Reactive nitrogen species


Reactive oxygen species


Succinate dehydrogenase enzyme


Superoxide dismutase


Thiobarbituric acid reactive substances



This study was supported by Edital Universal/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), INCT (EN 465671/2014-4)/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) – Brazil, and PRONEX(16/2551-0000465-0)/Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS) – Brazil.

Authors Contribution

T.M.S., C.S., and A.T S.W. were responsible for most of the experiments developed and the writing of the scientific article. The co-authors M.F.O. and V.M. contributed to the accomplishment of the comet experiment to evaluate DNA damage.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

The experimental protocol was approved by the Ethics Committee of Universidade Federal do Rio Grande do Sul, in Porto Alegre (CEUA/UFRGS #33301). Every effort was made to minimize the number of animals and the distress caused throughout the experiment.


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Authors and Affiliations

  • Tiago Marcon dos Santos
    • 1
  • Cassiana Siebert
    • 1
  • Micaela Federizzi de Oliveira
    • 2
  • Vanusa Manfredini
    • 2
  • Angela T. S. Wyse
    • 1
    Email author
  1. 1.Laboratório de Neuroproteção e Doenças Neurometabólicas, Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Laboratório de Hematologia e Citologia ClínicaUniversidade Federal do PampaUruguaianaBrazil

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