Quercetin versus folic acid: a comparative evaluation of protective effects on methotrexate-induced ovarian damage
Öz
Background: Methotrexate (MTX) is a chemotherapeutic and immunosuppressive agent that acts as a folic acid reductase inhibitor and is widely used in various clinical settings. Despite its therapeutic efficacy, MTX has been shown in some experimental models to induce oxidative stress–mediated damage in ovarian tissue. This study aimed to evaluate and compare the protective effects of quercetin and folic acid against MTX-induced ovarian injury.
Methods: Forty-two female Wistar albino rats were randomly divided into six groups (n=7): Control, QRC (quercetin), FA (folic acid), MTX (methotrexate), MTX+QRC (methotrexate+ folic acid), and MTX+FA (methotrexate+folic acid). Methotrexate was administered intraperitoneally at1mg/kg on days 1, 3, 5, and 7. quercetin(50mg/kg) and folic acid(20mg/kg) were administered orally on days 2, 4, 6, and 8. On day 9, ovarian tissues were collected for histopathological, immunohistochemical and biochemical analyses. Statistical analysis was conducted using one-way ANOVA and Kruskal-Wallis tests with Bonferroni and Dunn’s post hoc corrections (p<0.05).
Results: Methotrexate significantly increased follicular degeneration, inflammation, vascular congestion, hemorrhage, edema, and fibrosis (p<0.001), as well as malondialdehyde (MDA) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) (p<0.001). It also significantly reduced anti-Mullerian hormone (AMH) levels, superoxide dismutase (SOD) and catalase (CAT) activities, and all follicle counts including primordial follicles (p<0.001). Both quercetin and folic acid treatments ameliorated these effects. Quercetin showed greater efficacy in reducing TNF-α and IL-1β levels (p<0.01) and restoring antioxidant enzyme activities(p<0.05), while folic acid was more effective in preserving AMH levels (p<0.01) and increasing primordial and Graafian follicle numbers (p<0.05).
Conclusion: Although methotrexate remains an effective therapeutic agent, its ovarian toxicity poses a potential risk to long-term fertility. The present findings indicate that quercetin and folic acid exert protective effects against MTX-induced ovarian damage through distinct mechanisms: quercetin primarily by attenuating oxidative stress and inflammation, and folic acid by supporting folliculogenesis and preserving ovarian reserve.
Anahtar Kelimeler
Ovarian reserve, reproductive toxicology, methotrexate, quercetin, folic acid.
Destekleyen Kurum
This research received no external funding.
Etik Beyan
The rats were obtained and accommodated at the Experimental and Clinical Research Center of Erciyes University. The study was designed and conducted in compliance with the ARRIVE guidelines for in vivo animal research. Erciyes University Animal Experiments Local Ethics Committee approved our experimental guidelines (decision no: 22/174 date: 08.08.2022).
Kaynakça
- ACOG Practice Bulletin No. 193: Tubal Ectopic Pregnancy. Obstet Gynecol. 2018;131(3):613-615. doi:10.1097/AOG.0000000000002559.
- Orazulike NC, Konje JC. Diagnosis and management of ectopic pregnancy. Womens Health (Lond). 2013;9(4):373–385. doi:10.2217/whe.13.35.
- Stabile G, Romano F, Buonomo F, Zinicola G, Ricci G. Conservative treatment of interstitial ectopic pregnancy with the combination of mifepristone and methotrexate: our experience and review of the literature. Biomed Res Int. 2020;2020:8703496. doi:10.1155/2020/8703496.
- Tonick S, Conageski C. Ectopic pregnancy. Obstet Gynecol Clin North Am. 2022;49(3):537–549. doi:10.1016/j.ogc.2022.02.018.
- Kamel MY, Ahmed SM, Abdelzaher WY, Welson NN, Abdel Aziz AM. Role of IL-6/STAT3 pathway in mediating the protective effect of agomelatine against methotrexate-induced lung and intestinal tissue damage in rats. Immunopharmacol Immunotoxicol. 2022;44(1):35–46. doi:10.1080/08923973.2021.1999973.
- Kiremitli T, Kiremitli S, Akselim B, et al. Protective effect of coenzyme Q10 on oxidative ovarian and uterine damage induced by methotrexate in rats. Hum Exp Toxicol. 2021;40(9):1537-1544. doi:10.1177/09603271211002891.
- Carrillo Martinez EJ, Flores Hernández FY, Salazar Montes AM, Nario Chaidez HF, Hernández Ortega LD. Quercetin, a flavonoid with great pharmacological capacity. Molecules. 2024;29(3):1000. doi:10.3390/molecules29031000.
- Chen Z, Yuan Q, Xu G, et al. Effects of quercetin on proliferation and H2O2-induced apoptosis of intestinal porcine enterocyte cells. Molecules. 2018;23(8):2012. doi:10.3390/molecules23082012.
- Aldemir M, Özgün G, Önen E, Okulu EM, Kayıgil Ö. Quercetin has a protective role on histopathological findings in testicular ischaemia–reperfusion injury in rats. Andrologia. 2012;44(Suppl 1):479–483. doi:10.1111/j.1439-0272.2011.01210.x.
- Wang J, Zhu H, Wang K, Yang Z, Liu Z. Protective effect of quercetin on rat testes against cadmium toxicity by alleviating oxidative stress and autophagy. Environ Sci Pollut Res Int. 2020;27(24):25278–25286. doi:10.1007/s11356-020-09029-4.