Metamizole modulates the concentrations of cytokines and hematopoietic growth factors in an experimental model of depression

Year 2025, Volume: 16 Issue: 55, 100 - 108, 18.08.2025

Erkan Maytalman , Olcay Kıroğlu , Fatih Berktaş , Dilara Nemutlu Samur , Fazilet Aksu

https://doi.org/10.17944/interdiscip.1687684

Abstract

Objective: In recent years, evidence of antidepressant-like activity of non-steroidal anti-inflammatory drugs has been presented. Furthermore, associations between cytokines, which are important components of the immune system, as well as hematopoietic growth factors and depression have also been demonstrated. In this study, it was aimed to analyze the effect of metamizole on the expression of cytokines and hematopoietic growth factors in mice exposed to unpredictable stress models.
Method: In order to develop chronic depression behaviors, an unpredictable chronic mild stress model was applied to mice. The depression group was not given any drug and other groups were given 100 and 200 mg/kg metamizole. Forced swimming test was performed to evaluate the effect of metamizole against depression. Relative concentrations of interleukin-1 alpha (IL-1α), IL-1 beta (IL-1-ß), IL-2, IL-4, IL-6, IL-10, IL-12, IL-17, Interferon gamma (IFN-γ)-, tumor necrosis factor-alpha (TNF-α), Granulocyte-colony-stimulating factor (G-CSF), and Granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed in serum samples of animals with semi-quantitative ELISA.
Results: In the forced swimming test, the immobility time of the depression group significantly increased compared to the control group. The immobility time of groups treated with metamizole significantly decreased compared to the depression group and approached the control. Significant decreases were observed in the relative concentration levels of cytokines and hematopoietic growth factors in the groups treated with 100 and/or 200 mg/kg metamizole compared to the depression group except for IL-1α, IL-4, and IL-10.
Conclusion: Evidence showing the contribution of COX enzymes to the pathophysiology of depression is increasing. In this context, the results indicate that metamizole, which can inhibit both isoforms of COX, may cause changes in cytokine levels and hematopoietic growth factors in a depression model. However, more controlled clinical studies are needed.

Keywords

Metamizole , depression , non-steroidal anti-inflammatory drugs , cytokines , hematopoietic growth factors

References

• Khalil NA, Ahmed EM, Tharwat T, Mahmoud Z. NSAIDs between past and present; a long journey towards an ideal COX-2 inhibitor lead. RSC Adv. 2024;14(42):30647-61. https://doi.org/10.1039/d4ra04686b
• Eleutério OHP, Veronezi RN, Martinez-Sobalvarro JV, Marrafon DAFO, Eleutério LP, Rascado RR, et al. Safety of metamizole (dipyrone) for the treatment of mild to moderate pain-an overview of systematic reviews. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(11):8515-25. https://doi.org/10.1007/s00210-024-03240-2
• Tomidis Chatzimanouil MK, Goppelt I, Zeissig Y, Sachs UJ, Laass MW. Metamizole-induced agranulocytosis (MIA): a mini review. Mol Cell Pediatr. 2023;10(1):6. https://doi.org/10.1186/s40348-023-00160-8
• Kassab AE, Gedawy EM. Recent Advancements in Refashioning of NSAIDs and their Derivatives as Anticancer Candidates. Curr Pharm Des. 2024;30(16):1217-39. https://doi.org/10.2174/0113816128304230240327044201
• Maytalman E, Nemutlu Samur D. Neuroendocrine modulation by metamizole and indomethacin: investigating the impact on neuronal markers and GnRH release. Endocrine. 2024;85(3):1327-36. https://doi.org/10.1007/s12020-024-03822-3
• Alberfkani N, Naser A. The antidepressant efficacy of flurbiprofen in mice: Behavioural assessment. J Adv VetBio Sci Tech. 2024;9(1):59-64. https://doi.org/10.31797/vetbio.1383152
• Mesripour A, Shahnoosh G. Antidepressant Effects of NSAIDs in Rodent Models of Depression-A Systematic Review. Front Pharmacol. 2022;13:909981. https://doi.org/10.3389/fphar.2022.909981
• Topuz RD, Gündüz Ö, Dökmeci D, Karadağ ÇH, Ulugöl A. Does dipyrone produce anxiolytic-like effects in mice? Cukurova Med J 2019;44(3):866-74. https://doi.org/10.17826/cumj.488406
• Nadi Sakhvidi M, Salami Z, Mosadegh M, Bidaki R, Fallahzadeh H, Salehabadi R, et al. The efficacy and safety of adding celecoxib to escitalopram for improving symptoms of major depressive disorder. Int J Psychiatry Med. 2024;59(5):511-20. https://doi.org/10.1177/00912174231210567
• Du Y, Dou Y, Wang M, Wang Y, Yan Y, Fan H, et al. Efficacy and acceptability of anti-inflammatory agents in major depressive disorder: a systematic review and meta-analysis. Front Psychiatry. 2024;15:1407529. https://doi.org/10.3389/fpsyt.2024.1407529
• Bai S, Guo W, Feng Y, Deng H, Li G, Nie H, et al. Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020;91(1):21-32. https://doi.org/10.1136/jnnp-2019-320912
• Zaroon, Aslam S, Hafsa, Mustafa U, Fatima S, Bashir H. Interleukin in Immune-Mediated Diseases: An Updated Review. Mol Biotechnol. 2024. https://doi.org/10.1007/s12033-024-01347-8
• Avitsur R, Yirmiya R. Cytokines inhibit sexual behavior in female rats: I. Synergistic effects of tumor necrosis factor alpha and interleukin-1. Brain Behav Immun. 1999;13(1):14-32. https://doi.org/10.1006/brbi.1999.0555
• Asnis GM, De La Garza R 2nd, Kohn SR, Reinus JF, Henderson M, Shah J. IFN-induced depression: a role for NSAIDs. Psychopharmacol Bull. 2003;37(3):29-50.
• Swiergiel AH, Dunn AJ. Distinct roles for cyclooxygenases 1 and 2 in interleukin-1-induced behavioral changes. J Pharmacol Exp Ther. 2002;302(3):1031-6. https://doi.org/10.1124/jpet.102.036640
• Gałecki P, Mossakowska-Wójcik J, Talarowska M. The anti-inflammatory mechanism of antidepressants - SSRIs, SNRIs. Prog Neuropsychopharmacol Biol Psychiatry. 2018;80(Pt C):291-4. https://doi.org/10.1016/j.pnpbp.2017.03.016
• Vojvodic J, Mihajlovic G, Vojvodic P, Radomirovic D, Vojvodic A, Vlaskovic-Jovicevic T, et al. The Impact of Immunological Factors on Depression Treatment - Relation Between Antidepressants and Immunomodulation Agents. Open Access Maced J Med Sci. 2019;7(18):3064-9. https://doi.org/10.3889/oamjms.2019.779 Malhi GS, Mann JJ. Depression. Lancet. 2018;392(10161):2299-2312. https://doi.org/10.1016/S0140-6736(18)31948-2
• Willner P, Towell A, Sampson D, Sophokleous S, Muscat R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl). 1987;93(3):358-64. https://doi.org/10.1007/BF00187257
• Kopp C, Vogel E, Rettori MC, Delagrange P, Misslin R. The effects of melatonin on the behavioural disturbances induced by chronic mild stress in C3H/He mice. Behav Pharmacol. 1999;10(1):73-83. https://doi.org/10.1097/00008877-199902000-00007
• Gülmez Mİ, Aydin C. Association of cognitive status, anxiety and depression with hearing loss in the elderly. Interdiscip Med J. 2024;15(52):86-91. doi.org/10.17944/interdiscip.1496779
• Hoffbrand AV, Chowdary P, Collins G, Loke J. Chapter 1: Haemopoiesis. In Hoffbrand’s Essential Haematology. 9th ed.; Wiley Blackwell: West Sussex, UK, 2024. p. 2-10
• Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977;266(5604):730-2. https://doi.org/10.1038/266730a0
• Krishnadas R, Cavanagh J. Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry. 2012;83(5):495-502. https://doi.org/10.1136/jnnp-2011-301779
• Han QQ, Yu J. Inflammation: a mechanism of depression? Neurosci Bull. 2014;30(3):515-23. https://doi.org/10.1007/s12264-013-1439-3
• Gałecki P, Talarowska M. Inflammatory theory of depression. Psychiatr Pol. 2018;52(3):437-47. English, Polish. https://doi.org/10.12740/PP/76863
• Zunszain PA, Hepgul N, Pariante CM. Inflammation and depression. Curr Top Behav Neurosci. 2013;14:135-51. https://doi.org/10.1007/7854_2012_211
• Chen Q, Luo Y, Kuang S, Yang Y, Tian X, Ma J, et al. Cyclooxygenase-2 Signalling Pathway in the Cortex is Involved in the Pathophysiological Mechanisms in the Rat Model of Depression. Sci Rep. 2017;7(1):488. https://doi.org/10.1038/s41598-017-00609-7
• de Paiva VN, Lima SN, Fernandes MM, Soncini R, Andrade CA, Giusti-Paiva A. Prostaglandins mediate depressive-like behaviour induced by endotoxin in mice. Behav Brain Res. 2010;215(1):146-51. https://doi.org/10.1016/j.bbr.2010.07.015
• Mesripour A, Shahnooshi S, Hajhashemi V. Celecoxib, ibuprofen, and indomethacin alleviate depression-like behavior induced by interferon-alfa in mice. J Complement Integr Med. 2019;17(1):/j/jcim.2019.17.issue-1/jcim-2019-0016/jcim-2019-0016.xml. https://doi.org/10.1515/jcim-2019-0016
• Norden DM, McCarthy DO, Bicer S, Devine RD, Reiser PJ, Godbout JP, et al. Ibuprofen ameliorates fatigue- and depressive-like behavior in tumor-bearing mice. Life Sci. 2015;143:65-70. https://doi.org/10.1016/j.lfs.2015.10.020 Keenan EL, Granstein RD. Proinflammatory cytokines and neuropeptides in psoriasis, depression, and anxiety. Acta Physiol (Oxf). 2025;241(3):e70019. https://doi.org/10.1111/apha.70019
• Allison DJ, Sharma B, Timmons BW. The efficacy of anti-inflammatory treatment interventions on depression in individuals with major depressive disorder and high levels of inflammation: A systematic review of randomized clinical trials. Physiol Behav. 2019;207:104-12. https://doi.org/10.1016/j.physbeh.2019.05.006
• Jha MK. Anti-Inflammatory Treatments for Major Depressive Disorder: What's on the Horizon? J Clin Psychiatry. 2019;80(6):18ac12630. https://doi.org/10.4088/JCP.18ac12630
• Kopschina Feltes P, Doorduin J, Klein HC, Juárez-Orozco LE, Dierckx RA, Moriguchi-Jeckel CM, et al. Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy. J Psychopharmacol. 2017;31(9):1149-65. https://doi.org/10.1177/0269881117711708
• Huss B, Bogosyan S, Müller E, Götz E. Treatment of drug-induced agranulocytosis with granulocyte colony stimulating factor (G-CSF) in a surgical intensive care unit. Anasthesiol Intensivmed Notfallmed Schmerzther. 1996;31(8):529-30. https://doi.org/10.1055/s-2007-995979
• Winkler A, Kietz S, Bahlmann H, Jafarzade G, Lode HN, Heckmann M. GM-CSF as successful salvage therapy of metamizole (dipyrone)-induced agranulocytosis with Fournier's gangrene and severe septic shock in an adolescent. Clin Case Rep. 2016;4(8):816-9. https://doi.org/10.1002/ccr3.616
• Kawano Y, Fukui C, Shinohara M, Wakahashi K, Ishii S, Suzuki T, et al. G-CSF-induced sympathetic tone provokes fever and primes antimobilizing functions of neutrophils via PGE2. Blood. 2017;129(5):587-97. https://doi.org/10.1182/blood-2016-07-725754
• Sugimoto Y, Fukada Y, Mori D, Tanaka S, Yamane H, Okuno Y, et al. Prostaglandin E2 stimulates granulocyte colony-stimulating factor production via the prostanoid EP2 receptor in mouse peritoneal neutrophils. J Immunol. 2005;175(4):2606-12. https://doi.org/10.4049/jimmunol.175.4.2606
• Becerril-Villanueva E, Pérez-Sánchez G, Alvarez-Herrera S, Girón-Pérez MI, Arreola R, Cruz-Fuentes C, et al. Alterations in the Levels of Growth Factors in Adolescents with Major Depressive Disorder: A Longitudinal Study during the Treatment with Fluoxetine. Mediators Inflamm. 2019;2019:9130868. https://doi.org/10.1155/2019/9130868
• Hofer M, Pospíšil M, Hoferová Z, Weiterová L, Komůrková D. Stimulatory action of cyclooxygenase inhibitors on hematopoiesis: a review. Molecules. 2012;17(5):5615-25. https://doi.org/10.3390/molecules17055615
• Chitu V, Biundo F, Stanley ER. Colony stimulating factors in the nervous system. Semin Immunol. 2021;54:101511. https://doi.org/10.1016/j.smim.2021.101511
• Alboni S, Poggini S, Garofalo S, Milior G, El Hajj H, Lecours C, et al. Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment. Brain Behav Immun. 2016;58:261-71. https://doi.org/10.1016/j.bbi.2016.07.155
• Sitges M, Gómez CD, Aldana BI. Sertraline reduces IL-1ß and TNF-α mRNA expression and overcomes their rise induced by seizures in the rat hippocampus. PLoS One. 2014;9(11):e111665. https://doi.org/10.1371/journal.pone.0111665