OLİVETOL, ANTİOKSİDAN SAVUNMAYI ARTIRARAK OVER İSKEMİ/REPERFÜZYON KAYNAKLI OKSİDATİF VE İNFLAMATUVAR HASARI AZALTIR

Öz

Over torsiyonu, iskemiye ve bunu takiben gelişen reperfüzyon (İ/R) hasarına yol açarak oksidatif stres, inflamasyon ve doku hasarı oluşturur; bu durum over fonksiyonlarını olumsuz etkileyebilir. Antioksidan ve anti-inflamatuvar özellikleri bilinen doğal bir resorsinol türevi olan Olivetol’ün, over İ/R hasarına karşı koruyucu potansiyeli daha önce değerlendirilmemiştir. Bu deneysel çalışmada, sıçanlar sekiz gruba ayrılmıştır: Sham, Sham + Olivetol (100 mg/kg), İskemi, İskemi + Olivetol (50 mg/kg), İskemi + Olivetol (100 mg/kg), İskemi/Reperfüzyon (İ/R), İ/R + Olivetol (50 mg/kg) ve İ/R + Olivetol (100 mg/kg). İskemi, over pedikülünün 3 saatlik bir süreyle klemplenmesiyle oluşturulmuş, ardından ilgili gruplarda reperfüzyon uygulanmıştır. Olivetol, iskemi veya reperfüzyon indüksiyonu öncesinde oral yoldan verilmiştir. Oksidatif ve inflamatuvar değişiklikleri değerlendirmek amacıyla over dokularında süperoksit dismutaz (SOD), glutatyon (GSH), miyeloperoksidaz (MPO) ve malondialdehit (MDA) düzeyleri analiz edilmiştir. Sham grubuna kıyasla iskemi ve İ/R gruplarında SOD aktivitesi ve GSH düzeyleri anlamlı şekilde azalmış, Olivetol uygulaması ise bu antioksidan parametreleri doza bağlı olarak artırmıştır. Buna karşın, MPO ve MDA düzeyleri iskemi ve reperfüzyon sonrası belirgin şekilde yükselmiş, bu da artmış oksidatif stres ve inflamasyonu göstermiştir; Olivetol tedavisi özellikle 100 mg/kg dozda (p<0.001) bu parametreleri anlamlı düzeyde azaltmıştır. Yüksek doz Olivetol’ün sağlıklı sıçanlarda herhangi bir toksik etkisi gözlenmemiştir. Olivetol, antioksidan savunmayı güçlendirerek ve oksidatif ile inflamatuvar hasarı azaltarak over iskemi/reperfüzyon hasarına karşı anlamlı koruyucu etki göstermiştir. Bu bulgular, Olivetol’ün reperfüzyon kaynaklı over hasarının önlenmesinde ve over fonksiyonlarının korunmasında umut verici bir terapötik aday olabileceğini göstermektedir.

Anahtar Kelimeler

• Antioksidan
• İnflamasyon
• Oksidatif stres
• Olivetol
• Over iskemi/reperfüzyonu

OLIVETOL MITIGATES OVARIAN ISCHEMIA/REPERFUSION-INDUCED OXIDATIVE AND INFLAMMATORY DAMAGE VIA ENHANCEMENT OF ANTIOXIDANT DEFENSE

Öz

Ovarian torsion leads to ischemia and subsequent reperfusion (I/R) injury, resulting in oxidative stress, inflammation, and tissue damage that may impair ovarian function. Olivetol, a natural resorcinol derivative with known antioxidant and anti-inflammatory properties, has not been previously evaluated for its protective potential in ovarian I/R injury. In this experimental study, rats were divided into eight groups: Sham, Sham + Olivetol (100 mg/kg), Ischemia, Ischemia + Olivetol (50 mg/kg), Ischemia + Olivetol (100 mg/kg), Ischemia/Reperfusion (I/R), I/R + Olivetol (50 mg/kg), and I/R + Olivetol (100 mg/kg). Ischemia was induced by clamping the ovarian pedicle for 3 hours’ period, followed by reperfusion in relevant groups. Olivetol was administered orally before ischemia or reperfusion induction. Superoxide dismutase (SOD), glutathione (GSH), myeloperoxidase (MPO), and malondialdehyde (MDA) levels were analyzed in ovarian tissues to assess oxidative and inflammatory changes. SOD activity and GSH levels were significantly decreased in ischemia and I/R groups compared to the Sham group, whereas Olivetol administration dose-dependently restored these antioxidant parameters. In contrast, MPO and MDA levels were markedly elevated following ischemia and reperfusion, indicating increased oxidative stress and inflammation; these parameters were significantly reduced by Olivetol treatment, particularly at the 100 mg/kg dose (p<0.001). High-dose Olivetol showed no toxic effects in healthy rats. Olivetol exerted significant protective effects against ovarian ischemia/reperfusion injury by enhancing antioxidant defenses and reducing oxidative and inflammatory damage. These findings suggest that Olivetol may represent a promising therapeutic candidate for preventing reperfusion-induced ovarian injury and preserving ovarian function.

Anahtar Kelimeler

• Antioxidant
• Inflammation
• Olivetol
• Ovarian ischemia/reperfusion
• Oxidative stress

Kaynakça

1. Bayir, Y., Cadirci, E., Polat, B., Kilic Baygutalp, N., Albayrak, A., Karakus, E., Un, H., Keles, M. S., Kocak Ozgeris, F. B., & Toktay, E. (2016). Aliskiren–a promising strategy for ovarian ischemia/reperfusion injury protection in rats via RAAS. Gynecological Endocrinology, 32(8), 675-683. https://doi.org/10.3109/09513590.2016.1153055
2. Bircan, B., Tanyeli, A., Eraslan, E., Akdemir, F. N. E., Yazici, Ş., Güzel, D., Polat, E., & Güler, M. C. (2025). Therapeutic potential of cepharanthine in ovarian ischemia-reperfusion injury: insights from a rat ovarian torsion-detorsion model. Journal of Laboratory Animal Science and Practices, 5(2), 110-118. https://doi.org/10.62425/jlasp.1673052
3. Bodur, A., Alver, A., Kahraman, C., Altay, D. U., & İnce, İ. (2016). Investigation of N-acetylcysteine on contralateral testis tissue injury by experimental testicular torsion: long-term effect. The American Journal of Emergency Medicine, 34(6), 1069-1074. https://doi.org/10.1016/j.ajem.2016.03.021
4. Bridwell, R. E., Koyfman, A., & Long, B. (2022). High risk and low prevalence diseases: Ovarian torsion. The American Journal of Emergency Medicine, 56, 145-150. https://doi.org/10.1016/j.ajem.2022.03.046
5. Cascio, M., Bisogno, T., Palazzo, E., Thomas, A., Van der Stelt, M., Brizzi, A., de Novellis, V., Marabese, I., Ross, R., & Van de Doelen, T. (2006). In vitro and in vivo pharmacology of synthetic olivetol‐or resorcinol‐derived cannabinoid receptor ligands. British Journal of Pharmacology, 149(4), 431-440. https://doi.org/10.1038/sj.bjp.0706888
6. Ciortan, L., Macarie, R. D., Barbu, E., Naie, M. L., Mihaila, A. C., Serbanescu, M., & Butoi, E. (2025). Cross-talk between neutrophils and macrophages post-myocardial infarction: from inflammatory drivers to therapeutic targets. International Journal of Molecular Sciences, 26(21). https://doi.org/10.3390/ijms262110575
7. Divya, B., & Narayanan, J. (2022). Evaluation of anti-convulsant activity of olivetol on ptz induced seizure model. NeuroQuantology, 20(16), 372-381. https://doi.org/10.14704/Nq.2022.20.17.Nq88051
8. Kalogeris, T., Baines, C. P., Krenz, M., & Korthuis, R. J. (2016). Ischemia/reperfusion. Comprehensive Physiology, 7(1), 113-170. https://doi.org/10.1002/j.2040-4603.2017.tb00741.x

9. Kılıç, A., Uyanıkoğlu, H., & İncebıyık, A. (2016). Protective effect of N-acetylcystein and resveratrol on ischemia-reperfusion injury in rat ovary. Dicle Medical Journal, 43(2), 229-236.
10. Kilkenny, J., & Wilson, M. (2023). Gynecological Emergencies. In Mini-invasive Approach in Acute Care Surgery (pp. 301-317). Springer. https://doi.org/10.1007/978-3-031-39001-2_22
11. Li, C., & Jackson, R. M. (2002). Reactive species mechanisms of cellular hypoxia-reoxygenation injury. American Journal of Physiology-Cell Physiology, 282(2), 227-241. https://doi.org/10.1152/ajpcell.00112.2001
12. Okur, D. T., Aydin, Ş., Okur, S., Bedir, A. G., Orhun, Ö. T., Tohumcu, V., Yıldırım, S., Sağlam, Y., & Elban, Ş. (2025). Prevention of intraabdominal adhesion using rifampicin alone or in combination with oxidized regenerated cellulose following ovariohysterectomy in rats. Journal of Laboratory Animal Science and Practices, 5(1), 21-29. https://doi.org/10.62425/jlasp.1536699
13. Oral, A., Halici, Z., Bayir, Y., Topçu, A., Un, H., Bilgin, A., & Atmaca, H. T. (2017). Effects of oral zinc administration on long‐term ipsilateral and contralateral testes damage after experimental testis ischaemia–reperfusion. Andrologia, 49(6), e12673. https://doi.org/10.1111/and.12673
14. Özkan, G., Demir, D., Taner, İ., Bal, N. B., & Demirel, M. (2025). Deneysel sıçan kolit modelinde alfa lipoik asit tedavisinin SOD ve NLRP3 seviyesi üzerine etkisi. Journal of Laboratory Animal Science and Practices, 5(1), 38-48. https://doi.org/10.62425/jlasp.1565052
15. Öztürk, A. B., Akaras, N., Şimşek, H., & Kandemir, F. M. (2025). Investigation of the effects of chrysin on intestinal ischemia-reperfusion via apoptotic, oxidative stress, inflammation, and autophagy parameters. Journal of Laboratory Animal Science and Practices, 5(1). 49-59, https://doi.org/10.62425/jlasp.1574905
16. Reshma, A., Tamilanban, T., Chitra, V., Subramaniyan, V., Gupta, G., Fuloria, N. K., Sekar, M., Fuloria, S., Sahu, R., & Narayanan, J. (2023). Anti-obesity effects of olivetol in adult zebrafish model induced by short-term high-fat diet. Scientific Reports, 13(1), 18449. https://doi.org/10.1038/s41598-023-44462-3
17. Rizo-Tellez, S. A., Sekheri, M., & Filep, J. G. (2022). Myeloperoxidase: regulation of neutrophil function and target for therapy. Antioxidants (Basel), 11(11). https://doi.org/10.3390/antiox11112302
18. Shanmugasundaram, N., & Jayasankar, N. (2025). In silico profiling and pharmacokinetic modelling of olivetol: evaluating its potential as a therapeutic agent for diabetic wound healing. Current Drug Discovery Technologies, 22(2), E15701638332872. https://doi.org/10.2174/0115701638332872240922184903
19. Tang, S. P., Mao, X. L., Chen, Y. H., Yan, L. L., Ye, L. P., & Li, S. W. (2022). Reactive oxygen species induce fatty liver and ischemia-reperfusion injury by promoting inflammation and cell death. Frontiers in Immunology, 13, 870239. https://doi.org/10.3389/fimmu.2022.870239
20. Taura, F., Tanaka, S., Taguchi, C., Fukamizu, T., Tanaka, H., Shoyama, Y., & Morimoto, S. (2009). Characterization of olivetol synthase, a polyketide synthase putatively involved in cannabinoid biosynthetic pathway. FEBS letters, 583(12), 2061-2066. https://doi.org/10.1016/j.febslet.2009.05.024
21. Toktay, E., Tastan, T. B., Gurbuz, M. A., Erbas, E., Demir, O., Ugan, R. A., & Selli, J. (2022). Potential protective effect of astaxanthin on ovary ischemia-reperfusion injury. Iranian Journal of Basic Medical Sciences, 25(2), 173. https://doi.org/10.22038/IJBMS.2022.61289.13559
22. Un, H., Bayir, Y., Halici, Z., Akpinar, E., Karakus, E., Oral, A., Ziypak, T., & Selli, J. (2015). The effects of RAAS inhibition in rate limiting step by aliskiren on testicular torsion injury in rats. The Journal of Urology, 194(3), 828-833. https://doi.org/10.1016/j.juro.2015.03.117
23. Ün, H., & Ugan, R. A. (2021). Olivetol’ün SHSY-5Y nöroblastoma hücrelerinin proliferasyonu ve invazyonu üzerindeki inhibe edici etkileri. Kafkas Journal of Medical Sciences, 11(1), 57-62. https://doi.org/10.5505/kjms.2021.56688
24. Yilmaz, E. P. T., Un, H., Gundogdu, B., Polat, E., Askin, S., Topdagi, Y. E., & Halici, Z. (2020). Protective effect of lycopene against reperfusion injury in rats with ovarian torsion: a biochemical and histopathological evaluation. Journal of Laboratory Physicians, 12(01), 32-37. https://doi.org/10.1055/s-0040-1715553
25. Zabolotneva, A. A., Popruga, K. E., Makarov, V. V., Yudin, S. M., Gaponov, A. M., Roumiantsev, S. A., & Shestopalov, A. V. (2025). Olivetol’s effects on metabolic state and gut microbiota functionality in mouse models of alimentary obesity, diabetes mellitus type 1 and 2, and hypercholesterolemia. Biomedicines, 13(1), 183. https://doi.org/10.3390/biomedicines13010183