FARELERDE OLUŞTURULAN DENEYSEL DEPRESYON MODELİNDE EPİGALLOKATEŞİN-GALLAT’IN ETKİLERİNİN İNCELENMESİ

Öz

Depresyon, yaygın bir hastalıktır. Depresyonun patofizyolojisinde monoamin eksikliği, kortizol düzeylerinde artış, Beyin Kaynaklı Nörotrofik Faktör (BDNF) eksikliği, glutamat artışı ve inflamasyonun rol oynadığı bildirilmektedir. Epigallocatechin gallate (EGCG), yeşil çayda doğal olarak bulunan, antienflamatuvar, antioksidan ve anksiyolitik etkileri bulunan bir flavonoid türevidir. Bu çalışma, EGCG'nin anti inflamatuvar mekanizmalar yoluyla potansiyel antidepresan etkisini araştırmak amacıyla gerçekleştirilmiştir. Bu amaçla, fareler yedi gruba (n=10) ayrılmış ve EGCG'nin klasik antidepresan ilaçlar (paroksetin, venlafaksin, moklobemid) ile etkilerini karşılaştırmak için “Porsolt'un zorlu yüzme testi” uygulanmıştır. Ayrıca, etkili EGCG dozu (100 mg/kg) ile tedaviden önce ve sonra farelerde kortizol ve IL-6 düzeyleri ölçülmüştür. Geleneksel antidepresanlarla gözlenen etkilerin aksine, 25 mg/kg ve 50 mg/kg EGCG dozları önemli bir etki göstermezken, 100 mg/kg dozunda önemli bir antidepresan etki gözlenmiştir. Kontrol ve EGCG 100 mg/kg grupları arasında kortikosteron düzeylerinin karşılaştırılması (sırasıyla 9387,7 pg/ml ve 6147,0 pg/ml) EGCG 100 grubunda kortikosteron düzeylerinde önemli (p<0,05) bir azalma olduğunu ortaya koymuştur. Benzer şekilde, kontrol ve EGCG 100 grupları arasındaki IL-6 düzeylerinin karşılaştırılması (sırasıyla 159,0 pg/ml ve 128,3 pg/ml) EGCG 100 mg/kg grubunda IL-6 düzeylerinde önemli (p<0,05) bir azalma olduğunu ortaya koymuştur. Sonuç olarak, EGCG'nin Porsolt'un zorla yüzme testinde kortikosteron ve IL-6 düzeyleri üzerindeki inhibe edici etkisi, antidepresan etki olarak yorumlanabilir. Potansiyel antidepresan etki, antienflamatuvar mekanizmalar aracılığıyla ortaya çıkabilir. Bu alanda daha fazla çalışma yapılması gerekmektedir.

Anahtar Kelimeler

• Kortikosteron
• Depresyon
• Epigallokateşin gallat (EGKG)
• Zorunlu Yüzme Testi
• IL-6

EXAMINATION OF THE EFFECTS OF EPIGALLOCATECHIN GALLATE IN EXPERIMENTAL DEPRESSION MODEL OF MICE

Öz

Depression has a prevalence of approximately 5%. The pathophysiology of depression is reported to involve monoamine deficiency, elevated cortisol levels, Brain-Derived Neurotrophic Factor (BDNF) deficiency, increased glutamate, and inflammation. To date, no effective treatment protocol has been developed for cortisol elevation and inflammatory factors, which are proposed to play a role in the pathophysiology of depression. Epigallocatechin gallate (EGCG) is a flavonoid derivative that occurs naturally in green tea. Numerous studies have shown that the substance possesses both antiinflammatory and antioxidant properties. It has also been demonstrated to possess anxiolytic properties. The present study was conducted to investigate the potential antidepressant effect of EGCG through anti-inflammatory mechanisms. To this end, the mice were divided into seven groups (n=10) and the "Porsolt's forced swimming test" was administered to compare the effects of EGCG with those of classic antidepressant drugs (paroxetine, venlafaxine, moclobemide). Furthermore, cortisol and IL-6 levels were measured in mice before and after treatment with the effective EGCG dose (100 mg kg⁻¹). In contrast to the effects observed with conventional antidepressants, EGCG doses of 25 mg kg⁻¹ and 50 mg kg⁻¹ did not demonstrate a significant impact, while the 100 mg/kg dose exhibited a substantial antidepressant effect. A subsequent comparison of corticosterone levels between the control and EGCG 100 mg/kg groups (9387.7 pg mL⁻¹ and 6147.0 pg mL⁻¹ respectively) revealed a significant (p<0.05) decrease in corticosterone levels in the EGCG 100 mg kg⁻¹group. In a similar manner, a comparison of IL-6 levels between the control and EGCG 100 mg kg⁻¹ groups (159.0 pg mL⁻¹ and 128.3 pg mL⁻¹, respectively) revealed a significant (p<0.05) reduction in IL-6 levels in the EGCG 100 mg kg⁻¹ group. In conclusion, the inhibitory effect of EGCG on corticosterone and IL-6 levels in Porsolt's forced swimming test can be interpreted as an antidepressant effect. The potential antidepressant effect may be mediated by anti-inflammatory mechanisms. Further studies in this area are required.

Anahtar Kelimeler

• Corticosterone
• Depression
• Epigallocathecin-gallate (EGCG)
• Forced Swimming Test
• IL-6

Kaynakça

1. Abdelmeguid, N. E., Hammad, T. M., Abdel-Moneim, A. M., & Salam, S. A. (2022). Effect of epigallocatechin-3-gallate on stress-induced depression in a mouse model: Role of interleukin-1β and brain-derived neurotrophic factor. Neurochemical research, 47(11), 3464- 3475. https://doi.org/10.1007/s11064-022- 03707-9.
2. Ahmed, S., Marotte, H., Kwan, K., Ruth, J. H., Campbell, P. L., Rabquer, B. J., ... & Koch, A. E. (2008). Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production. Proceedings of the National Academy of Sciences, 105(38), 14692-14697. https://doi.org/10.1073/pnas.0802675105
3. Assad, M., Ashaolu, T. J., Khalifa, I., Baky, M. H., & Farag, M. A. (2023). Dissecting the role of microorganisms in tea production of different fermentation levels: a multifaceted review of their action mechanisms, quality attributes and future perspectives. World Journal of Microbiology and Biotechnology, 39(10), 265. https://doi.org/10.1007/s11274-023-03701-5
4. Balogh, R., Gadeyne, S., Jonsson, J., Sarkar, S., Van Aerden, K., Warhurst, C., & Vanroelen, C. (2023). Employment trajectories and mental healthrelated disability in Belgium. International Archives of Occupational and Environmental Health, 96(2), 285-302. https://doi.org/10.1007/s00420-022-01923-y
5. Berk, M., Köhler‐Forsberg, O., Turner, M., Penninx, B. W., Wrobel, A., Firth, J., ... & Marx, W. (2023). Comorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology, mechanisms and management. World Psychiatry, 22(3), 366-387. https://doi.org/10.1002/wps.21110
6. Bhattacharya, T. K., Pence, B. D., Ossyra, J. M., Gibbons, T. E., Perez, S., McCusker, R. H., Kelley, K. W., Johnson, R. W., Woods, J. A., & Rhodes, J. S. (2015). Exercise but not (-)-epigallocatechin-3- gallate or beta-alanine enhances physical fitness, brain plasticity, and behavioral performance in mice. Physiology & Behavior, 145, 29–37. https://doi.org/10.1016/j.physbeh.2015.03.02 3
7. Can, A., Dao, D. T., Arad, M., Terrillion, C. E., Piantadosi, S. C., & Gould, T. D. (2012). The mouse forced swim test. Journal of Visualized Experiments, (59), e3638. DOI: 10.3791/3638
8. Connor, T. J., & Leonard, B. E. (1998). Depression, stress and immunological activation: the role of cytokines in depressive disorders. Life sciences, 62(7),583-606. https://doi.org/10.1016/S00243205(97)0099 0-9

9. Cui, L., Li, S., Wang, S., Wu, X., Liu, Y., Yu, W., ... & Li, B. (2024). Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal transduction and targeted therapy, 9(1), 30. https://doi.org/10.1038/s41392-024-01738-y
10. Cutler, A. J., Keyloun, K. R., Higa, S., Park, J., Bonafede, M., Gillard, P., & Jain, R. (2022). Annual costs among patients with majör depressive disorder and the impact of key clinical events. Journal of Managed Care & Specialty Pharmacy, 28(12), 1335-1343. https://doi.org/10.18553/jmcp.2022.28.12.13 35
11. Defar, S., Abraham, Y., Reta, Y., Deribe, B., Jisso, M., Yeheyis, T., ... & Ayalew, M. (2023). Health related quality of life among people with mental illness: The role of socio-clinical characteristics and level of functional disability. Frontiers in public health, 11, 1134032. https://doi.org/10.3389/fpubh.2023.1134032
12. Elgellaie, A., Thomas, S. J., Kaelle, J., Bartschi, J., & Larkin, T. (2023). Pro‐inflammatory cytokines IL‐1α, IL‐6 and TNF‐α in major depressive disorder: Sex‐specific associations with psychological symptoms. European Journal of Neuroscience, 57(11), 1913-1928. https://doi.org/10.1111/ejn.15992
13. Ferland, C. L., Hawley, W. R., Puckett, R. E., Wineberg, K., Lubin, F. D., Dohanich, G. P., & Schrader, L. A. (2013). Sirtuin activity in dentate gyrus contributes to chronic stressinduced behavior and extracellular signalregulated protein kinases 1 and 2 cascade changes in the hippocampus. Biological Psychiatry, 74(12), 927–935. https://doi.org/10.1016/j.biopsych.2013.07.02 9
14. Gallagher, P., Watson, S., Smith, M. S., Young, A. H., & Ferrier, I. N. (2007). Plasma cortisoldehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder. Schizophrenia research, 90(1), 258-265. https://doi.org/10.1016/j.schres.2006.11.020
15. García-García, M. L., Tovilla-Zárate, C. A., VillarSoto, M., Juárez-Rojop, I. E., González-Castro, T. B., Genis-Mendoza, A. D., ... & Martinez-Magaña, J. J. (2022). Fluoxetine modulates the proinflammatory process of IL-6, IL-1β and TNF-α levels in individuals with depression: a systematic review and meta-analysis. Psychiatry Research, 307, 114317. https://doi.org/10.1016/j.psychres.2021.1143 17
16. Gold, P. W., & Chrousos, G. P. (1999). The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences. Proceedings of the Association of American Physicians, 111(1), 22- 34. https://doi.org/10.1046/j.1525- 1381.1999.09423.x
17. Greenberg, P., Chitnis, A., Louie, D., Suthoff, E., Chen, S. Y., Maitland, J., ... & Kessler, R. C. (2023). The economic burden of adults with major depressive disorder in the United States (2019). Advances in Therapy, 40(10), 4460-4479. https://doi.org/10.1007/s12325-023-02622-x
18. Harsanyi, S., Kupcova, I., Danisovic, L., & Klein, M. (2022). Selected biomarkers of depression: what are the effects of cytokines and inflammation? International journal of molecular sciences, 24(1), 578. https://doi.org/10.3390/ijms24010578
19. Hwang, S., Kang, S. W., Kim, S. J., Han, K., Kim, B. S., Jung, W., ... & Shin, D. W. (2023). Impact of agerelated macular degeneration and related visual disability on the risk of depression: a nationwide cohort study. Ophthalmology, 130(6), 615-623. https://doi.org/10.1016/j.ophtha.2023.01.014
20. Jia, W., Ma, Q., Xing, R., Yang, X., Liu, D., Zeng, H., ... & Wu, W. (2024). Jianghua Kucha black tea containing theacrine attenuates depression-like behavior in CUMS mice by regulating gut microbiota-brain neurochemicals and cytokines. Food Research International, 198, 115306. https://doi.org/10.1016/j.foodres.2024.11530 6
21. Lee, B., Sur, B., Kwon, S., Yeom, M., Shim, I., Lee, H., & Hahm, D. H. (2013). Chronic administration of catechin decreases depression and anxietylike behaviors in a rat model using chronic corticosterone injections. Biomolecules & Therapeutics, 21(4), 312–322. https://doi.org/10.4062/biomolther.2013.004
22. Liu, Y., Jia, G., Gou, L., Sun, L., Fu, X., Lan, N., ... & Yin, X. (2013). Antidepressant-like effects of tea polyphenols on mouse model of chronic unpredictable mild stress. Pharmacology Biochemistry and Behavior, 104, 27-32. https://doi.org/10.1016/j.pbb.2012.12.024
23. Marx, W., Penninx, B. W., Solmi, M., Furukawa, T. A., Firth, J., Carvalho, A. F., & Berk, M. (2023). Major depressive disorder. Nature Reviews Disease Primers, 9(1), 44. Mazzio, E. A., Harris, N., & Soliman, K. F. (1998). Food constituents attenuate monoamine oxidase activity and peroxide levels in C6 astrocyte cells. Planta medica, 64(07), 603-606. https://doi.org/10.1055/s-2006-957530
24. Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and humans. Journal of Basic and Clinical Pharmacy, 7(2), 27–31. DOI: 10.4103/0976-0105.177703
25. Nakadate, K., Kawakami, K., & Yamazaki, N. (2023). Anti-obesity and anti-inflammatory synergistic effects of green tea catechins and citrus βcryptoxanthin ingestion in obese mice. International Journal of Molecular Sciences, 24(8), 7054. https://doi.org/10.3390/ijms24087054
26. Nierenberg, A. A., Agustini, B., Köhler-Forsberg, O., Cusin, C., Katz, D., Sylvia, L. G., ... & Berk, M. (2023). Diagnosis and treatment of bipolar disorder: a review. Jama, 330(14), 1370-1380. doi:10.1001/jama.2023.18588
27. Ogłodek, E. (2022). Changes in the serum levels of cytokines: IL-1β, IL-4, IL-8 and IL-10 in depression with and without posttraumatic stress disorder. Brain Sciences, 12(3), 387. https://doi.org/10.3390/brainsci12030387
28. Ortiz-López, L., Márquez-Valadez, B., GómezSánchez, A., Silva-Lucero, M. D. C., Torres-Pérez, M., Téllez-Ballesteros, R. I., ... & RamírezRodríguez, G. B. (2016). Green tea compound epigallo-catechin-3-gallate (EGCG) increases neuronal survival in adult hippocampal neurogenesis in vivo and in vitro. Neuroscience, 322, 208-220. https://doi.org/10.1016/j.neuroscience.2016.0 2.040
29. Raposo, D., Morgado, C., Pereira-Terra, P., & Tavares, I. (2015). Nociceptive spinal cord neurons of laminae I–III exhibit oxidative stress damage during diabetic neuropathy which is prevented by early antioxidant treatment with epigallocatechin-gallate (EGCG). Brain Research Bulletin, 110, 68–75. https://doi.org/10.1016/j.lfs.2015.06.008
30. Rezaeezade_Roukerd, M., Dogani, M., Motaghi, S., & Abbasnejad, M. (2025). Abscisic Acid Regulates Immune-inflammatory Responses to Induce Neuroprotection in Spinal Cord Injury: Insights from Gene Expression and Network Analysis. Iranian Journal of Allergy, Asthma and Immunology, 1-16. https://ijaai.tums.ac.ir/index.php/ijaai/article/ view/4329
31. Rong, Y., Yan, W., Gao, Z., Yang, Y., Xu, C., & Zhang, C. (2025). NRXN3-NLGN1 complex influences the development of depression induced by maternal separation in rats. Brain Research, 149659. https://doi.org/10.1016/j.brainres.2025.14965 9
32. Sachdeva, A. K., Kuhad, A., & Chopra, K. (2011). Epigallocatechin gallate ameliorates behavioral and biochemical deficits in rat model of loadinduced chronic fatigue syndrome. Brain Research Bulletin, 86(3–4), 165–172. https://doi.org/10.1016/j.brainresbull.2011.06 .007
33. Sharma, R., Sharma, A., Kumari, A., Kulurkar, P. M., Raj, R., Gulati, A., & Padwad, Y. S. (2017). Consumption of green tea epigallocatechin-3- gallate enhances systemic immune response, antioxidative capacity and HPA axis functions in aged male swiss albino mice. Biogerontology, 18(3), 367-382. https://doi.org/10.1007/s10522-017-9696-6
34. Sharma, S., Chawla, S., Kumar, P., Ahmad, R., & Verma, P. K. (2024). The chronic unpredictable mild stress (CUMS) paradigm: Bridging the gap in depression research from bench to bedside. Brain Research, 149123. https://doi.org/10.1016/j.brainres.2024.14912 3
35. Shi, J., Yang, G., You, Q., Sun, S., Chen, R., Lin, Z., ... & Lv, H. (2023). Updates on the chemistry, processing characteristics, and utilization of tea flavonoids in last two decades (2001-2021). Critical Reviews in Food Science and Nutrition, 63(20), 4757-4784. https://doi.org/10.1080/10408398.2021.2007 353
36. Sigvardsen, P. E., Fosbøl, E., Jørgensen, A., TorpPedersen, C., Køber, L., & Kofoed, K. F. (2025). Medical conditions and the risk of subsequent major depressive disorder: a nationwide, register-based, retrospective cohort study. The Lancet Public Health, 10(6), e503-e511. DOI: 10.1016/S2468-2667(25)00073-8
37. Skosnik, P. D., Sloshower, J., Safi-Aghdam, H., Pathania, S., Syed, S., Pittman, B., & D’Souza, D. C. (2023). Sub-acute effects of psilocybin on EEG correlates of neural plasticity in major depression: relationship to symptoms. Journal of Psychopharmacology, 37(7), 687-697. https://doi.org/10.1177/02698811231179800 Stoeva,
38. S., Hvarchanova, N., Georgiev, K. D., & Radeva-Ilieva, M. (2025). Green tea: Antioxidant vs. Pro-oxidant activity. Beverages, 11(3), 64. https://doi.org/10.3390/beverages11030064
39. Wang, Y., Li, M., Xu, X., Song, M., Tao, H., & Bai, Y. (2012). Green tea epigallocatechin-3-gallate (EGCG) promotes neural progenitor cell proliferation and sonic hedgehog pathway activation during adult hippocampal neurogenesis. Molecular Nutrition & Food Research, 56, 1292–1303. https://doi.org/10.1002/mnfr.201200035
40. Vanhee, C., Deconinck, E., George, M., Hansen, A., Hackl, A., Wollein, U., … & Miquel, M. (2025). The occurrence of illicit smart drugs or nootropics in Europe and Australia and their associated dangers: Results from a market surveillance study by 12 official medicines control laboratories. Journal of Xenobiotics, 15(3), 88. https://doi.org/10.3390/jox15030088
41. Yang, Z., Liu, T., Kong, X., & Wei, J. (2025). Neuroprotective effect of abscisic acid on MPTP‐induced Parkinson's disease in mice. Molecular Nutrition & Food Research, e70111. https://doi.org/10.1002/mnfr.70111
42. Yankelevitch-Yahav, R., Franko, M., Huly, A., & Doron, R. (2015). The forced swim test as a model of depressive-like behavior. Journal of Visualized Experiments: JoVE, (97). Young, E. A., Haskett, R. F., Murphy-Weinberg, V.,
43. Watson, S. J., & Akil, H. (1991). Loss of glucocorticoid fast feedback in depression. Archives of General Psychiatry, 48(8), 693–699. https://doi.org/10.1001/archpsyc.1991.01810 320017003
44. Zhang, Y., Liu, C., Zhu, Q., Wu, H., Liu, Z., & Zeng, L. (2025). Relationship between depression and epigallocatechin gallate from the perspective of gut microbiota: A systematic review. Nutrients, 17(2), 259. https://doi.org/10.1002/fsn3.3761
45. Zhang, P. F., You, W. Y., Gao, Y. J., & Wu, X. B. (2024). Activation of pyramidal neurons in the infralimbic cortex alleviates LPS-induced depressive-like behavior in mice. Brain Research Bulletin, 214, 111008. https://doi.org/10.1016/j.brainresbull.2024.11 1008
46. Zhou, F., Deng, S., Luo, Y., Liu, Z., & Liu, C. (2025). Research progress on the protective effect of green tea polyphenol (-)-epigallocatechin-3- gallate (EGCG) on the liver. Nutrients, 17(7), 1101. https://doi.org/10.3390/nu17071101
47. Zhu, W. L., Shi, H. S., Wei, Y. M., Wang, S. J., Sun, C. Y., Ding, Z. B., & Lu, L. (2012). Green tea polyphenols produce antidepressant-like effects in adult mice. Pharmacological Research, 65(1), 74–80. https://doi.org/10.1016/j.phrs.2011.09.007