Involvement of the IL-6 Signaling Pathway in the Anti-Anhedonic Effect of the Antidepressant Agomelatine in the Chronic Mild Stress Model of Depression
Neuroinflammation has emerged as an important factor in the molecular underpinnings of major depressive disorder (MDD) pathophysiology and in the mechanism of action of antidepressants. Among the inflammatory mediators dysregulated in depressed patients, interleukin (IL)-6 has recently been proposed...
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2022-10-01
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| author | Andrea C. Rossetti Maria Serena Paladini Cesar Augusto Brüning Vittoria Spero Maria Grazia Cattaneo Giorgio Racagni Mariusz Papp Marco A. Riva Raffaella Molteni |
| author_facet | Andrea C. Rossetti Maria Serena Paladini Cesar Augusto Brüning Vittoria Spero Maria Grazia Cattaneo Giorgio Racagni Mariusz Papp Marco A. Riva Raffaella Molteni |
| author_sort | Andrea C. Rossetti |
| collection | DOAJ |
| description | Neuroinflammation has emerged as an important factor in the molecular underpinnings of major depressive disorder (MDD) pathophysiology and in the mechanism of action of antidepressants. Among the inflammatory mediators dysregulated in depressed patients, interleukin (IL)-6 has recently been proposed to play a crucial role. IL-6 activates a signaling pathway comprising the JAK/STAT proteins and characterized by a specific negative feedback loop exerted by the cytoplasmic protein suppressor of cytokine signalling-3 (SOCS3). On these bases, here, we explored the potential involvement of IL-6 signaling in the ability of the antidepressant drug agomelatine to normalize the anhedonic-like phenotype induced in the rat by chronic stress exposure. To this aim, adult male Wistar rats were subjected to the chronic mild stress (CMS) paradigm and chronically treated with vehicle or agomelatine. The behavioral evaluation was assessed by the sucrose consumption test, whereas molecular analyses were performed in the prefrontal cortex. We found that CMS was able to stimulate IL-6 production and signaling, including SOCS3 gene and protein expression, but the SOCS3-mediated feedback-loop inhibition failed to suppress the IL-6 cascade in stressed animals. Conversely, agomelatine treatment normalized the stress-induced decrease in sucrose consumption and restored the negative modulation of the IL-6 signaling via SOCS3 expression and activity. Our results provide additional information about the pleiotropic mechanisms that contribute to agomelatine’s therapeutic effects. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T20:06:22Z |
| publishDate | 2022-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-fe69fe7334004ca68fdf979eccea3d202023-11-24T00:31:47ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123201245310.3390/ijms232012453Involvement of the IL-6 Signaling Pathway in the Anti-Anhedonic Effect of the Antidepressant Agomelatine in the Chronic Mild Stress Model of DepressionAndrea C. Rossetti0Maria Serena Paladini1Cesar Augusto Brüning2Vittoria Spero3Maria Grazia Cattaneo4Giorgio Racagni5Mariusz Papp6Marco A. Riva7Raffaella Molteni8Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, ItalyCenter for Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas, Pelotas 96010-900, RS, BrazilDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, ItalyDepartment of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, ItalyMaj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, PolandDepartment of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, ItalyNeuroinflammation has emerged as an important factor in the molecular underpinnings of major depressive disorder (MDD) pathophysiology and in the mechanism of action of antidepressants. Among the inflammatory mediators dysregulated in depressed patients, interleukin (IL)-6 has recently been proposed to play a crucial role. IL-6 activates a signaling pathway comprising the JAK/STAT proteins and characterized by a specific negative feedback loop exerted by the cytoplasmic protein suppressor of cytokine signalling-3 (SOCS3). On these bases, here, we explored the potential involvement of IL-6 signaling in the ability of the antidepressant drug agomelatine to normalize the anhedonic-like phenotype induced in the rat by chronic stress exposure. To this aim, adult male Wistar rats were subjected to the chronic mild stress (CMS) paradigm and chronically treated with vehicle or agomelatine. The behavioral evaluation was assessed by the sucrose consumption test, whereas molecular analyses were performed in the prefrontal cortex. We found that CMS was able to stimulate IL-6 production and signaling, including SOCS3 gene and protein expression, but the SOCS3-mediated feedback-loop inhibition failed to suppress the IL-6 cascade in stressed animals. Conversely, agomelatine treatment normalized the stress-induced decrease in sucrose consumption and restored the negative modulation of the IL-6 signaling via SOCS3 expression and activity. Our results provide additional information about the pleiotropic mechanisms that contribute to agomelatine’s therapeutic effects.https://www.mdpi.com/1422-0067/23/20/12453stressmajor depressive disorderprefrontal cortexneuroinflammationSOCS3 |
| spellingShingle | Andrea C. Rossetti Maria Serena Paladini Cesar Augusto Brüning Vittoria Spero Maria Grazia Cattaneo Giorgio Racagni Mariusz Papp Marco A. Riva Raffaella Molteni Involvement of the IL-6 Signaling Pathway in the Anti-Anhedonic Effect of the Antidepressant Agomelatine in the Chronic Mild Stress Model of Depression International Journal of Molecular Sciences stress major depressive disorder prefrontal cortex neuroinflammation SOCS3 |
| title | Involvement of the IL-6 Signaling Pathway in the Anti-Anhedonic Effect of the Antidepressant Agomelatine in the Chronic Mild Stress Model of Depression |
| title_full | Involvement of the IL-6 Signaling Pathway in the Anti-Anhedonic Effect of the Antidepressant Agomelatine in the Chronic Mild Stress Model of Depression |
| title_fullStr | Involvement of the IL-6 Signaling Pathway in the Anti-Anhedonic Effect of the Antidepressant Agomelatine in the Chronic Mild Stress Model of Depression |
| title_full_unstemmed | Involvement of the IL-6 Signaling Pathway in the Anti-Anhedonic Effect of the Antidepressant Agomelatine in the Chronic Mild Stress Model of Depression |
| title_short | Involvement of the IL-6 Signaling Pathway in the Anti-Anhedonic Effect of the Antidepressant Agomelatine in the Chronic Mild Stress Model of Depression |
| title_sort | involvement of the il 6 signaling pathway in the anti anhedonic effect of the antidepressant agomelatine in the chronic mild stress model of depression |
| topic | stress major depressive disorder prefrontal cortex neuroinflammation SOCS3 |
| url | https://www.mdpi.com/1422-0067/23/20/12453 |
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