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Intranasal administration of interleukin-4 ameliorates depression-like behavior and biochemical alterations in mouse submitted to the chronic unpredictable mild stress: modulation of neuroinflammation and oxidative stress

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Abstract

Physical and psychological stress modulates the hypothalamic pituitary adrenal (HPA) axis, and the redox and inflammatory systems. Impairments in these systems have been extensively reported in major depression (MD) patients. Therefore, our study aimed to investigate the effects of the intranasal administration of interleukin-4 (IL-4) in mice with depressive-like behavior induced by chronic unpredictable mild stress (CUMS) for 28 days. On the 28th day, mice received IL-4 intranasally (1 ng/mouse) or vehicle (sterile saline), and after 30 min, they were submitted to behavioral tests or euthanasia for blood collection and removal of the adrenal glands, axillary lymph nodes, spleen, thymus, prefrontal cortices (PFC), and hippocampi (HC). A single administration of IL-4 reversed CUMS-induced depression-like behavior in the tail suspension test and splash test, without evoking locomotor changes. IL-4 administration reduced the plasma levels of corticosterone and the increased weight of suprarenal glands in stressed mice. Moreover, IL-4 restored the expression of nuclear factor erythroid 2-related factor 2 (NRF2), nuclear factor kappa B (NF-kB), interleukin 1 beta (IL-1β), IL-4, brain derived neurotrophic factor (BDNF), and indoleamine 2,3-dioxygenase (IDO) in the PFC and HC and modulated oxidative stress markers in these brain structures in stressed mice. Our results showed for the first time the antidepressant-like effect of IL-4 through the modulation of neuroinflammation and oxidative stress. The potential effect of IL-4 administered intranasally arises as an innovative strategy for MD treatment.

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Funding

This study was financed by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001.

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Authors and Affiliations

  1. Technology Development Center, Division of Biotechnology, Neurobiotechnology Research Group, Federal University of Pelotas, Pelotas, RS, 96010900, Brazil

    Thiago Ângelo Smaniotto, Angela Maria Casaril, Darling de Andrade Lourenço & Lucielli Savegnago

  2. Technology Development Center, Division of Biotechnology, Cancer Biotechnology Laboratory, Federal University of Pelotas, Pelotas, RS, 96010900, Brazil

    Fernanda S. Sousa, Fabiana K. Seixas & Tiago Collares

  3. Technology Development Center, Division of Biotechnology, Bioinformatics and Proteomics Laboratory, Federal University of Pelotas, Pelotas, RS, 96010900, Brazil

    Rafael Woloski & Luciano da Silva Pinto

  4. Center of Chemical, Pharmaceutical and Food Sciences, Laboratory of Clean Organic Synthesis, Federal University of Pelotas, Pelotas, RS, 96010900, Brazil

    Diego Alves & Lucielli Savegnago

Authors
  1. Thiago Ângelo Smaniotto
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  2. Angela Maria Casaril
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Contributions

TAS developed the design and writing of the project, participated in the experiments, and wrote the manuscript; AMC helped in the design and writing of the project and manuscript, and participated in the experiments; DAL helped with the experiments and writing the manuscript. FSS, FKS, and TC provided help for the biochemical analysis; RW and LSP provided help for the in silico analysis; DA participated in the writing of the manuscript; LS is the project supervisor. All authors provide critical feedback for the manuscript conceptualization.

Corresponding author

Correspondence to Lucielli Savegnago.

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All institutional and national guidelines for the care and use of laboratory animals were followed. All procedures were approved by the Committee on the Care and Use of Experimental Animal Resources at the Federal University of Pelotas, Brazil (38715), and comply with The Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines, items 5 to 13 (Kilkenny et al. 2010).

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Smaniotto, T.Â., Casaril, A.M., de Andrade Lourenço, D. et al. Intranasal administration of interleukin-4 ameliorates depression-like behavior and biochemical alterations in mouse submitted to the chronic unpredictable mild stress: modulation of neuroinflammation and oxidative stress. Psychopharmacology 240, 935–950 (2023). https://doi.org/10.1007/s00213-023-06336-4

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