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Combination of electroconvulsive stimulation with ketamine or escitalopram protects the brain against inflammation and oxidative stress induced by maternal deprivation and is critical for associated behaviors in male and female rats

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Abstract 

This study aimed at evaluating the treatment effects with ketamine, electroconvulsive stimulation (ECS), escitalopram, alone or in combination in adult rats of both sexes, subjected to the animal model of maternal deprivation (MD). All groups were subjected to the forced swimming test (FST), splash and open field tests. The prefrontal cortex (PFC), hippocampus and serum were collected to analyze oxidative stress and inflammatory parameters. MD induced depressive-like behavior in the FST test in males and reduced grooming time in male and female rats. The treatments alone or combined reversed depressive and anhedonic behavior in females. In males, all treatments increased grooming time, except for ECS + escitalopram + ketamine. MD increased lipid peroxidation and protein carbonylation, nitrite/nitrate concentration and myeloperoxidase activity in the PFC and hippocampus of males and females. However, the treatment’s response was sex dependent. Catalase activity decreased in the PFC of males and the PFC and hippocampus of females, and most treatments were not able to reverse it. MD increased the inflammation biomarkers levels in the PFC and hippocampus of males and females, and most treatments were able to reverse this increase. In all groups, a reduction in the interleukin-10 levels in the PFC and hippocampus of female and male rats was observed. Our study shows different responses between the sexes in the patterns evaluated and reinforces the use of the gender variable as a biological factor in MDD related to early stress and in the response of the therapeutic strategies used.

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Acknowledgements

The Translational Psychiatry Program (USA) is funded by a grant from the National Institute of Health/National Institute of Mental Health (1R21MH117636-01A1, to JQ). The Center of Excellence on Mood Disorders (USA) is funded by the Pat Rutherford Jr. Chair in Psychiatry, John S. Dunn Foundation and Anne and Don Fizer Foundation Endowment for Depression Research. The Translational Psychiatry Laboratory (Brazil) is funded by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (GZR and JQ), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (JQ and GZR), Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC) (GZR and JQ), and Instituto Cérebro e Mente (JQ and GZR). JQ is a 1A and GZR is a 2 CNPq Research Fellow.

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Authors and Affiliations

  1. Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, 88806-000, Brazil

    Helena M. Abelaira, Thayse Rosa, Airam B. de Moura, Natalia M. Andrade, Nicoly S. Martinello, Larissa R. Maciel, Maria Eduarda M. Botelho, Laura A. Borba, Beatriz C. Chede, Camila O. Arent, Talita Tuon, João Quevedo & Gislaine Z. Réus

  2. Laboratory of Clinical and Experimental Pathophysiology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNISUL), Tubarão, SC, Brazil

    Larissa Joaquim, Sandra Bonfante, Lucinéia G. Danielski & Fabricia Petronilho

  3. Center of Excellence On Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    João Quevedo

  4. Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    João Quevedo

  5. Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    João Quevedo

Authors
  1. Helena M. Abelaira
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  2. Thayse Rosa
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  3. Airam B. de Moura
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  4. Natalia M. Andrade
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  5. Nicoly S. Martinello
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  6. Larissa R. Maciel
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  7. Maria Eduarda M. Botelho
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  8. Laura A. Borba
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  9. Beatriz C. Chede
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  10. Camila O. Arent
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  11. Larissa Joaquim
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  13. Lucinéia G. Danielski
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  14. Talita Tuon
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  15. Fabricia Petronilho
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  16. João Quevedo
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  17. Gislaine Z. Réus
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Contributions

All authors participated in the design and interpretation of the studies, analyzed the data and reviewed the manuscript; NSM conducted the maternal deprivation protocol. TR, MEMB, ABM, NMA, NSM, LRM, LAB and BCC performed drugs and ECT application, behavioral tests and sample collection. LGD, LJ, SB and FP performed the oxidative stress analysis. GZR and COA performed the statistical analysis. HMA, ABM and GZR wrote the manuscript. JQ and TT reviewed the manuscript. GZR and TR were in charge of designing the experiment and reviewed the manuscript.

Corresponding author

Correspondence to Gislaine Z. Réus.

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This study complies with ethical concerns and was approved by the UNESC's Ethics Committee under protocol number: 133–2019.

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Abelaira, H.M., Rosa, T., de Moura, A.B. et al. Combination of electroconvulsive stimulation with ketamine or escitalopram protects the brain against inflammation and oxidative stress induced by maternal deprivation and is critical for associated behaviors in male and female rats. Mol Neurobiol 59, 1452–1475 (2022). https://doi.org/10.1007/s12035-021-02718-x

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