Sıçanlarda Lipopolisakkarit ile Uyarılan Ovaryum Hasarında Timol’ün Hormonal, Antiinflamatuvar ve Antioksidan Yollarla Koruyucu Etkileri

Öz

Bu çalışmada LPS ile uyarılan ovaryum hasarında timolün koruyucu etkileri araştırıldı. Bu amaçla Wistar albino dişi sıçanlar beş gruba ayrıldı (n=35, grup=7): kontrol, çözücü, lps, timol, lps+timol. Çalışma sonunda hayvanlardan alınan numunelerde hormon (E2 ve AMH), oksidatif stres (MDA, GSH, GSH-Px ve katalaz), yangısal sitokin (TNF-α ve IL-6) analizleri gerçekleştirildi. Ayrıca ovaryum ve canlı ağırlıklarda da ölçüldü. Lipopolisakkarit uygulaması, E2 AMH, GSH, GSH-Px ve katalaz seviyelerinde azalmalara neden olurken MDA, TNF-α ve IL-6 düzeylerinde artışlara neden oldu. Lps+timol grubunda ise timol uygulaması E2, AMH, GSH, GSH-Px ve katalaz da artışlara, MDA, TNF-α ve IL-6 seviyelerinde ise azalmalara neden olduğu görüldü. Sonuç olarak timol uygulaması antioksidan ve anti-inflamatuvar mekanizmalar üzerinden Lps kaynaklı hormonal, oksidatif stres, yangısal değişiklikleri olumlu olarak etkilediği ancak timolün uzun süreli etkilerinin özellikle daha ileri moleküler mekanizmalarla ortaya konmasına ihtiyaç olduğu düşünülmektedir.

Anahtar Kelimeler

• LPS
• timol
• ovaryum rezerv
• yangı
• oksidan-antioksidan durum

Protective Effects of Thymol with Hormonal, Antiinflammatory and Antioxidant Pathways in Lipopolysaccharide-Induced Ovarian Damage in Rats

Abstract

This study investigated the protective effects of thymol on LPS-induced ovarian damage. Female Wistar albino rats were divided into five groups (n=35, group=7): control, solvent, LPS, thymol, and LPS+thymol. At the end of the study, hormone (E2 and AMH), oxidative stress (MDA, GSH, GSH-Px and catalase), and inflammatory cytokine (TNF-α and IL-6) analyses were performed in the samples taken from the animals. Ovary and body weights were also measured. Lipopolysaccharide treatment caused decreases in E2 AMH, GSH, GSH-Px and catalase levels but increased MDA, TNF-α and IL-6 levels. In the Lps+thymol group, thymol administration caused increases in E2, AMH, GSH, GSH-Px and catalase levels and decreased MDA, TNF-α and IL-6 levels. In conclusion, thymol administration positively affected Lps-induced hormonal, oxidative stress and inflammatory changes via antioxidant and anti-inflammatory mechanisms. However, it is thought that the long-term effects of thymol need to be demonstrated, especially by further molecular mechanisms.

Keywords

• LPS
• thymol
• ovarian reserve
• inflammation
• oxidant-antioxidant status

Kaynakça

1. 1.Li H, Zang Y, Wang C, et al. The Interaction between microorganisms, metabolites, and immune system in the female genital tract microenvironment. Front Cell Infect Microbiol. 2020;10:609488.
2. 2.Turner ML, Healey GD, Sheldon IM. Immunity and inflammation in the uterus. Reprod Domest Anim. 2012;47(4):402-409.
3. 3.Rosales E, Ametaj B. Reproductive tract infections in dairy cows: can probiotics curb down the incidence rate? Dairy. 2021;2(1):40-64.
4. 4.Deb K, Chaturvedi MM, Jaiswal YK. Gram-negative bacterial LPS induced poor uterine receptivity and implantation failure in mouse: alterations in IL-1beta expression in the preimplantation embryo and uterine horns. Infect Dis Obstet Gynecol. 2005;13(3):125-133.
5. 5.Lee AJ, Kandiah N, Karimi K, Clark DA, Ashkar AA. Interleukin-15 is required for maximal lipopolysaccharide-induced abortion. J Leukoc Biol. 2013;93(6):905-912.
6. 6.Bromfield JJ, Sheldon IM. Lipopolysaccharide reduces the primordial follicle pool in the bovine ovarian cortex ex vivo and in the murine ovary in vivo. Biol Reprod. 2013;88(4):98.
7. 7.Heidari M, Kafi M, Mirzaei A, Asaadi A, Mokhtari A. Effects of follicular fluid of preovulatory follicles of repeat breeder dairy cows with subclinical endometritis on oocyte developmental competence. Anim Reprod Sci. 2019;205:62-69.
8. 8.Pal S, Haldar C, Verma R. Melatonin attenuates LPS-induced ovarian toxicity via modulation of SIRT-1, PI3K/pAkt, pErk1/2 and NFĸB/COX-2 expressions. Toxicol Appl Pharmacol. 2022;451:116173.

9. 9.Valluru L, Dasari S, Wudayagiri R. Role of free radicals and antioxidants in gynecological cancers: current status and future prospects. Oxid Antioxid Med Sci, 2014;3(1):15-26.
10. 10.Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10:49.
11. 11.Gao H, Yang T, Chen X, Song Y. Changes of Lipopolysaccharide-induced acute kidney and liver injuries in rats based on metabolomics analysis. J Inflamm Res. 2021;14:1807-1825.
12. 12.Boots CE, Jungheim ES. Inflammation and human ovarian follicular dynamics. Semin Reprod Med. 2015;33(4):270-275.
13. 13.Kong QQ, Wang J, Xiao B, et al. Cumulus cell-released tumor necrosis factor (TNF)-α promotes post-ovulatory aging of mouse oocytes. Aging. 2018;10(7):1745-1757.
14. 14.Khan KN, Kitajima M, Hiraki K, et al. Toll-like receptors in innate immunity: role of bacterial endotoxin and toll-like receptor 4 in endometrium and endometriosis. Gynecol Obstet Invest. 2009;68(1):40-52.
15. 15.Marchese A, Orhan IE, Daglia M, et al. Antibacterial and antifungal activities of thymol: A brief review of the literature. Food Chem. 2016;210:402-414.
16. 16.Güvenç M, Cellat M, Gökçek İ, Yavaş İ, Yurdagül Özsoy Ş. Effects of thymol and carvacrol on sperm quality and oxidant/antioxidant balance in rats. Arch Physiol Biochem. 2019;125(5):396-403.
17. 17.Mahran YF, Badr AM, Aldosari A, Bin-Zaid R, Alotaibi HN. Carvacrol and thymol modulate the cross-talk between TNF-α and IGF-1 signaling in radiotherapy-induced ovarian failure. Oxid Med Cell Longev. 2019;2019:3173745. 18.Sun H, Lin Y, Lin D, et al. Mediterranean diet improves embryo yield in IVF: a prospective cohort study. Reprod Biol Endocrinol. 2019;17(1):73.
18. 19.Frye BM, Register TC, Appt SE, et al. Differential effects of western versus mediterranean diets and psychosocial stress on ovarian function in female monkeys (Macaca fascicularis). Psychoneuroendocrinology. 2023;153:106107.
19. 20.Ghorbani Ranjbary A, Mehrzad J, Talebkhan Garoussi M, Zohdi J. Long term oral administration of oregano essence effectively relieves polycystic ovarian rats through endocrine and inflammatory balance. Evid Based Complement Alternat Med. 2022;2022:5303583.
20. 21.Lin GJ, Sytwu HK, Yu JC, et al. Dimethyl sulfoxide inhibits spontaneous diabetes and autoimmune recurrence in non-obese diabetic mice by inducing differentiation of regulatory T cells. Toxicol Appl Pharmacol. 2015;282(2):207-214.
21. 22.Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem. 1966;16(2):359-364.
22. 23.Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968;25(1):192-205.
23. 24.Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun. 1976;71(4):952-958.
24. 25.Aebi H. Catalase in vitro. Methods in Enzymology. 1984;105:121-126.
25. 26.Imai A, Ichigo S, Matsunami K, Takagi H, Kawabata I. Ovarian function following targeted anti-angiogenic therapy with bevacizumab. Mol Clin Oncol. 2017;6(6):807-810.
26. 27.Han SS, Kim YH, Lee SH, et al. Underuse of ovarian transposition in reproductive-aged cancer patients treated by primary or adjuvant pelvic irradiation. J Obstet Gynaecol Res. 2011;37(7):825-829.
27. 28.Lliberos C, Liew SH, Zareie P, La Gruta NL, Mansell A, Hutt K. Evaluation of inflammation and follicle depletion during ovarian ageing in mice. Sci Rep. 2021;11(1):278.
28. 29.Snider AP, Wood JR. Obesity induces ovarian inflammation and reduces oocyte quality. Reproduction. 2019;158(3):79-90.
29. 30.Shen J, Zhao W, Cheng J, et al. Lipopolysaccharide accelerates tryptophan degradation in the ovary and the derivative kynurenine disturbs hormone biosynthesis and reproductive performance. J Hazard Mater. 2023;458:131988.
30. 31.Lv SJ, Hou SH, Gan L, Sun J. Establishment and mechanism study of a primary ovarian insufficiency mouse model using lipopolysaccharide. Anal Cell Pathol. 2021;2021:1781532.
31. 32.Magata F, Toda L, Sato M, et al. Intrauterine LPS inhibited arcuate Kiss1 expression, LH pulses, and ovarian function in rats. Reproduction. 2022;164(5):207-219.
32. 33.Shalom-Paz E, Weill S, Ginzberg Y, et al. IUGR induced by maternal chronic inflammation: long-term effect on offspring's ovaries in rat model-a preliminary report. J Endocrinol Invest. 2017;40(10):1125-1131.
33. 34.Espey LL. Current status of the hypothesis that mammalian ovulation is comparable to an inflammatory reaction. Biol Reprod. 1994;50(2):233-238.
34. 35.Clancy KB, Baerwald AR, Pierson RA. Systemic inflammation is associated with ovarian follicular dynamics during the human menstrual cycle. PLoS One. 2013;8(5):64807.
35. 36.Sarapik A, Velthut A, Haller-Kikkatalo K, et al. Follicular proinflammatory cytokines and chemokines as markers of IVF success. Clin Dev Immunol. 2012;2012:606459.
36. 37.Wang L, Tang J, Wang L, et al. Oxidative stress in oocyte aging and female reproduction. J Cell Physiol. 2021;236(12):7966-7983.
37. 38.Oyawoye O, Abdel Gadir A, Garner A, Constantinovici N, Perrett C, Hardiman P. Antioxidants and reactive oxygen species in follicular fluid of women undergoing IVF: relationship to outcome. Hum Reprod. 2003;18(11):2270-2274.
38. 39.Pekel A, Gönenç A, Turhan NÖ, Kafalı H. Changes of sFas and sFasL, oxidative stress markers in serum and follicular fluid of patients undergoing IVF. J Assist Reprod Genet. 2015;32(2):233-241.
39. 40.Tatone C, Carbone MC, Falone S, et al. Age-dependent changes in the expression of superoxide dismutases and catalase are associated with ultrastructural modifications in human granulosa cells. Mol Hum Reprod. 2006;12(11):655-660.
40. 41.Yan F, Zhao Q, Li Y, et al. The role of oxidative stress in ovarian aging: a review. J Ovarian Res. 2022;15(1):100.
41. 42.Yang L, Chen Y, Liu Y, et al. The role of oxidative stress and natural antioxidants in ovarian aging. Front Pharmacol. 2021;11:617843.
42. 43.Beena, Kumar D, Rawat DS. Synthesis and antioxidant activity of thymol and carvacrol based Schiff bases. Bioorg Med Chem Lett. 2013;23(3):641-645.
43. 44.Jafarisani M, Masoomikarimi M, Kazemi SS, Mirzaeidelaviz S, Naderi Z, Ahmadi R. Effect of thymus vulgaris ethanol extract, on serum total antioxidant in experimental induced poly cystic ovarian syndrome (PCOs) rats. Int J Health Stud. 2016;2(1):30-34.
44. 45.Büscher U, Chen FC, Kentenich H, Schmiady H. Cytokines in the follicular fluid of stimulated and non-stimulated human ovaries; is ovulation a suppressed inflammatory reaction? Hum Reprod. 1999;14(1):162-166.
45. 46. Riella KR, Marinho RR, Santos JS, et al. Anti-inflammatory and cicatrizing activities of thymol, a monoterpene of the essential oil from Lippia gracilis, in rodents. J Ethnopharmacol. 2012;143(2):656-663.