Ameliorative effects of apigenin on a rat model of endometriosis

Year 2023, Volume: 9 Issue: 2, 178 - 185, 04.03.2023

Gulam Hekimoğlu Sümeyye Koç Ali İmran Daştan Kübra Şevgin Muhammetnur Tekayev Eray Metin Güler Neslihan Sayir Halime Tuba Canbaz Fatih Hacımustafaoğlu Halime Hanim Pence Tansel Sapmaz Ebru Kale

https://doi.org/10.18621/eurj.1209679

Abstract

Objectives: Apigenin and parthenolide as natural products have potent antioxidant and anti-inflammatory outcomes that could make them a perfect option for endometriosis therapy. This study aimed to determine the effects of apigenin and parthenolide on created endometrial implants in a rat model of endometriosis.

Methods: Thirty-nine mature, female Sprague-Dawley rats were assigned randomly to six experimental groups four weeks after endometriosis induction. Group 1 (n = 5): Control (CTRL) that opened and closed the abdomen; Group 2 (n = 6): Peritoneal and ovarian endometriosis (POE) + drug-free; Group 3 (n = 7): POE+ Apigenin (APG) (50 mg/kg); Group 4 (n = 7): POE+ Parthenolide (PTL) (10 mg/kg); Group 5 (n = 7): POE+ Apigenin (APG) (50 mg/kg) + Parthenolide (PTL) (10 mg/kg); Group 6 (n = 7): POE+ DMSO. An endometriosis model was created, and histopathological analysis and biochemical evaluation were performed. Serum and peritoneal levels of pro-and-anti-inflammatory cytokine, and oxidative stress of implant tissue were measured.

Results: Serum IL-37 levels decreased significantly in the APG-treated group compared to the drug-free group (p = 0.016). The peritoneum and ovary endometriosis histopathologic scores were significantly lower in APG-treated (p = 0.001) and PTL-treated (p = 0.001) groups in comparison to the drug-free group. The oxidative stress index (OSI) values were increased statistically significantly in ovary endometriosis tissue in the drug-free group, (p = 0.001). However, compared to the drug-free group, OSI values decreased statistically significantly in the APG-treated group (p = 0.003).

Conclusions: The application of apigenin caused a decrease in oxidative stress and an improvement in histopathological grade. Apigenin may be a novel therapeutic agent for the treatment of endometriosis.

Keywords

Apigenin, parthenolide, oxidative stress, endometriosis, IL-6, IL-37

Supporting Institution

This study was supported by the Scientific Research Projects Grants Unit, University of Health Sciences Turkey, Istanbul, Turkey

Project Number

Grant Number: 2020/068

References

• 1. Fauser BC, Diedrich K, Bouchard P, Domínguez F, Matzuk M, Franks S, et al. Contemporary genetic technologies and female reproduction. Hum Reprod Update 2011;17:829-47.
• 2. Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 2014;10:261-75.
• 3. Kupker W, Felberbaum RE, Krapp M, Schill T, Malik E, Diedrich K. Use of GnRH antagonists in the treatment of endometriosis. Reprod Biomed Online 2002;5:12-6.
• 4. Vauzour D, Rodriguez-Mateos A, Corona G, Oruna-Concha MJ, Spencer JP. Polyphenols and human health: prevention of disease and mechanisms of action. Nutrients 2010;2:1106-31.
• 5. Ricci AG, Olivares CN, Bilotas MA, Baston JI, Singla JJ, Meresman GF, et al. Natural therapies assessment for the treatment of endometriosis. Hum Reprod 2013;28:178-88.
• 6. Buwa CC, Mahajan UB, Patil CR, Goyal SN. Apigenin attenuates beta-receptor-stimulated myocardial injury by safeguarding cardiac functions and escalating the antioxidant defense system. Cardiovasc Toxicol 2016;16:286-97.
• 7. Tang D, Chen K, Huang L, Li J. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opin Drug Metab Toxicol 2017;13:323-30.
• 8. Weihuan M, Zhu Z. Parthenolide inhibits hydrogen peroxide-induced osteoblast apoptosis. Mol Med Rep 2018;17:8369-76.
• 9. Ghantous A, Sinjab A, Herceg Z, Darwiche N. Parthenolide: from plant shoots to cancer roots. Drug Discov Today 2013;18:894-905.
• 10. Bulun SE. Endometriosis. N Engl J Med 2009;360:268-79.
• 11. Wu MY, Ho HN. The role of cytokines in endometriosis. Am J Reprod Immunol 2003; 49:285-96.
• 12. Urata Y, Koga K, Hirota Y, Akiyama I, Izumi G, Takamura M, et al. IL-1β increases expression of tryptophan 2,3-dioxygenase and stimulates tryptophan catabolism in endometrioma stromal cells. Am J Reprod Immunol 2014;72:496-503.
• 13. Mosbah A, Nabiel Y, Khashaba E. Interleukin-6, intracellular adhesion molecule-1, and glycodelin A levels in serum and peritoneal fluid as biomarkers for endometriosis. Int J Gynaecol Obstet 2016;134:247-51.
• 14. Jiang J, Jiang Z, Xue M. Serum and peritoneal fluid levels of interleukin-6 and interleukin-37 as biomarkers for endometriosis. Gynecol Endocrinol 2019;35:571-5.
• 15. Gupta S, Agarwal A, Krajcir N, Alvarez JG. Role of oxidative stress in endometriosis. Reprod Biomed Online 2006;13:126-34.
• 16. Bradford M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248-54.
• 17. Cetinkaya N, Attar R, Yildirim G, Ficicioglu C, Ozkan F, Yilmaz B, et al. The effects of different doses of melatonin treatment on endometrial implants in an oophorectomized rat endometriosis model. Arch Gynecol Obstet 2015;291:591-8.
• 18. Iwabuchi T, Yoshimoto C, Shigetomi H, Kobayashi H. Oxidative stress and antioxidant defense in endometriosis and its malignant transformation. Oxid Med Cell Longev 2015;2015:848595.
• 19. Donnez J, Binda MM, Donnez O, Dolmans MM. Oxidative stress in the pelvic cavity and its role in the pathogenesis of endometriosis. Fertil Steril 2016;106:1011-7.
• 20. Harlev A, Gupta S, Agarwal A. Targeting oxidative stress to treat endometriosis. Expert Opin Ther Targets 2015;19:1447-64.
• 21. Park S, Lim W, Bazer FW, Song G. Apigenin induces ROS-dependent apoptosis and ER stress in human endometriosis cells. J Cell Physiol 2018;233:3055-65.
• 22. Takai E, Taniguchi F, Nakamura K, Uegaki T, Iwabe T, Harada T. Parthenolide reduces cell proliferation and prostaglandin estradiol synthesis in human endometriotic stromal cells and inhibits the development of endometriosis in the murine model. Fertil Steril 2013;100:1170-8.
• 23. Kowalski J, Samojedny A, Paul M, Pietsz G, Wilczok T. Effect of apigenin, kaempferol and resveratrol on the expression of interleukin-1beta and tumor necrosis factor-alpha genes in J774. 2 macrophages. Pharmacol Rep 2005;57:390-4.
• 24. Zhang M, Liu RT, Zhang P, Zhang N, Yang CL, Yue LT, et al. Parthenolide inhibits the initiation of experimental autoimmune neuritis. J Neuroimmunol 2017;305:154-61.
• 25. Zhou WJ, Yang HL, Shao J, Mei J, Chang KK, Zhu R, et al. Anti-inflammatory cytokines in endometriosis. Cell Mol Life Sci 2019;76: 2111-32.