Quercetin ve folik asit: metotreksat kaynaklı yumurtalık hasarı üzerindeki koruyucu etkilerin karşılaştırmalı değerlendirmesi

Yıl 2026, Cilt: 7 Sayı: 1, 232 - 243, 31.01.2026

Halime Tozak Yıldız , Kübra Tuğçe Kalkan , Özge Göktepe , Ozge Cengiz Mat , Arzu Yay

https://doi.org/10.47482/acmr.1729326

Öz

Giriş: Metotreksat (MTX), folik asit redüktaz inhibitörü olarak görev yapan ve çeşitli klinik durumlarda yaygın olarak kullanılan bir kemoterapötik ve immünsüpresif ajandır. Terapötik etkinliğine rağmen, MTX sitotoksik bir ilaç olup, fertiliteyi olumsuz etkileyebilecek oksidatif stres aracılı over hasarı gibi önemli yan etkilere sahiptir. Bu çalışma, quercetin ve folik asidin MTX kaynaklı over hasarına karşı koruyucu etkilerini değerlendirmeyi ve karşılaştırmayı amaçlamıştır.
Yöntemler: Kırk iki adet dişi Wistar albino sıçan, rastgele olarak altı gruba (n=7) ayrıldı: Kontrol, QRC (quercetin), FA (folik asit), MTX (metotreksat), MTX+QRC (metotreksat + quercetin) ve MTX+FA (metotreksat+folik asit). Metotreksat, 1 mg/kg dozunda intraperitoneal olarak 1., 3., 5. ve 7. günlerde uygulanmıştır. Quercetin (50 mg/kg) ve folik asit (20 mg/kg) ise 2., 4., 6. ve 8. günlerde oral olarak verilmiştir. 9. günde over dokuları histopatolojik, immünohistokimyasal ve biyokimyasal analizler için toplanmıştır. İstatistiksel analizler, tek yönlü ANOVA ve Kruskal-Wallis testleri ile Bonferroni ve Dunn post hoc düzeltmeleri kullanılarak yapılmış olup p<0,05 değeri anlamlı kabul edilmiştir.
Bulgular: Metotreksat, folikül dejenerasyonu, inflamasyon, vasküler konjesyon, hemoraji, ödem ve fibrozisi anlamlı şekilde artırmıştır (p<0,001) ve malondialdehit (MDA) ile pro-inflamatuvar sitokinler (TNF-α, IL-1β, IL-6) düzeylerini yükseltmiştir (p<0,001). Ayrıca anti-Müllerian hormon (AMH) düzeyleri, süperoksit dismutaz (SOD) ve katalaz (CAT) aktiviteleri ile tüm folikül sayıları, özellikle primordial foliküller, anlamlı şekilde azalmıştır (p<0,001). Hem quercetin hem de folik asit tedavileri bu etkileri hafifletmiştir. Quercetin, TNF-α ve IL-1β düzeylerini azaltmada (p<0,01) ve antioksidan enzim aktivitelerini geri kazandırmada (p<0,05) daha etkili olurken, folik asit AMH düzeylerini korumada (p<0,01) ve primordial ile graaf folikül sayısını artırmada (p<0,05) daha etkili olmuştur.
Sonuç: Metotreksat etkili bir terapötik ajan olmaya devam etse de, over toksisitesi uzun vadeli fertilite açısından potansiyel bir risk oluşturmaktadır. Mevcut bulgular, quercetin ve folik asidin MTX kaynaklı over hasarına karşı koruyucu etkiler gösterdiğini ve bunun farklı mekanizmalarla gerçekleştiğini göstermektedir: quercetin esas olarak oksidatif stres ve inflamasyonu azaltarak, folik asit ise folikülogenezi destekleyerek ve over rezervini koruyarak etkili olmaktadır.

Anahtar Kelimeler

Over rezervi , üreme toksikolojisi , metotreksat , kuersetin , folik asit

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.

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).

Destekleyen Kurum

This research received no external funding.

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