Astaksantin'in Sıçanlarda 5-Florourasil ile İndüklenen Over Hasarı Üzerindeki Terapötik Etkisi

Abstract

Astaksantin (ASX) üzerinde en çok çalışılan antioksidan moleküllerden biri olmasına rağmen, 5-florourasil (5-FU)'in neden olduğu yumurtalık hasarına karşı iyileştirici etkisi bugüne kadar gösterilmemiştir. Bu nedenle bu çalışmada ASX'in 5-FU ile indüklenen ovotoksisiteye karşı terapötik olup olmadığının araştırılması amaçlandı. Sıçanlar önce 5-FU'ya (100 mg/kg) maruz bırakıldı ve ardından üç gün boyunca ASX (250 μg/kg) tedavisi gördü. Oksidatif stres (OS), inflamasyon ve apoptoz belirteçleri spektrofotometrik yöntemlerle belirlendi. Ayrıca yumurtalık dokuları histolojik olarak da değerlendirildi. OS, inflamasyon ve apoptoz biyobelirteçlerinin seviyeleri 5-FU uygulamasıyla arttı (p<0.05). ASX ile tedavi bu belirteçleri önemli ölçüde iyileştirdi (p<0.05). Bu bulgular, ASX'in yumurtalık dokusunda pro-inflamatuar mediatörleri azaltarak ve antioksidan durumu güçlendirerek yumurtalık koruyucu bir etki gösterebileceğini ortaya koymaktadır.

Keywords

• 5-florourasil
• Astaksantin
• İnflamasyon
• Oksidatif stres
• Yumurtalık dokusu hasarı

Therapeutic Effect of Astaxanthin on 5-Fluorouracil-Induced Ovarian Damage in Rats

Abstract

Although astaxanthin (ASX) is one of the most studied antioxidant molecules, its curative effect against ovarian damage caused by 5-fluorouracil (5-FU) has not been demonstrated to date. It was therefore aimed to investigate whether ASX is therapeutic against 5-FU-induced ovotoxicity in this study. Rats were first exposed to 5-FU (100 mg/kg) and then treated ASX (250 μg/kg) for three days. Oxidative stress (OS), inflammation and apoptosis markers were determined using spectrophotometric methods. Ovarian tissues were also evaluated histologically. The levels of OS, inflammation and apoptosis biomarkers increased by 5-FU administration (p<0.05). Treatment with ASX significantly alleviated these markers (p<0.05). These findings reveal that ASX may exert an ovoprotective effect by reducing pro-inflammatory mediators and enhancing antioxidant status in ovarian tissue.

Keywords

• 5-fluorouracil
• Astaxanthin
• Inflammation
• Ovarian damage
• Oxidative stress

References

1. Findik, H., Tumkaya, L., Yilmaz, A., Aslan M.G., Okutucu, M., Akyildiz, K., & Mercantepe, T. (2019). The protective effects of astaxanthin against cisplatin-induced retinal toxicity. Cutaneous and Ocular Toxicology, 38(1), 59-65.
2. Demir, S., Demir, E.A, & Aliyazicioglu, Y. (2020). Selective cytotoxic effect of astaxanthin on human lung and colon cancer cells. KSU Journal of Agriculture and Nature, 23(6), 1489-1494.
3. Yilmaz, Y., Tumkaya, L., Mercantepe, T., & Akyildiz, K. (2022). Protective effect of astaxanthin against cisplatin-induced gastrointestinal toxicity in rats. European Surgery, 54, 32-38.
4. Sorrentino, M.F., Kim, J., Foderaro, A.E., & Truesdell, A.G. (2012). 5-fluorouracil induced cardiotoxicity: Review of the literature. Cardiology Journal, 19(5), 453-458.
5. Mentese, A., Demir, S., Alemdar, N.T., Aliyazicioglu, Y., & Deger, O. (2022). The effect of chlorogenic acid on 5-fluorouracil-induced oxidative damage in rat ovarian tissue. Farabi Medical Journal, 1(1), 1-7.
6. Rashid, S., Ali, N., Nafees, S., Hasan, S.K., & Sultana, S. (2014). Mitigation of 5-fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in Wistar rats. Food and Chemical Toxicology, 66, 185-193.
7. Wang, Y., Tian, X., Liang, L., Wang, Y., Wang, R., Cheng, X., Yan, Z., Chen, Y., & Qi, P. (2014). Mechanistic study on triptorelin action in protecting from 5-FU-induced ovarian damage in rats. Oncology Research, 22(5-6), 283-292.
8. Zhang, X., Hou, Y., Li, J., & Wang, J. (2021). The role of astaxanthin on chronic diseases. Crystals, 11, 505.

9. Li, M.Y., Gao, C.S., Du, X.Y., Zhao, L., Niu, X.T., Wang, G.Q., & Zhang, D.M. (2020). Amelioration of LPS-induced inflammatory response and oxidative stress by astaxanthin in Channa argus lymphocyte via activating glucocorticoid receptor signalling pathways. Aquaculture Research, 51(7), 2687-2697.
10. Zhang, Q.Y., Wang, F.X., Jia, K.K., & Kong, L.D. (2018). Natural product interventions for chemotherapy and radiotherapy-induced side effects. Frontiers in Pharmacology, 9, 1253.
11. Gunyeli, I., Saygin, M., & Ozmen, O. (2021). Methotrexate-induced toxic effects and the ameliorating effects of astaxanthin on genitourinary tissues in a female rat model. Archives of Gynecology and Obstetrics, 304(4), 985-997.
12. Khoei, H.H., Fakhri, S., Parvardeh, S., Mofarahe, Z.S., Baninameh, Z., & Vardiani, M. (2019) Astaxanthin prevents the methotrexate-induced reproductive toxicity by targeting oxidative stress in male mice. Toxin Reviews, 38(3), 248-254.
13. Deng, X., Wang, M., Hu, S., Feng, Y., Shao, Y., Xie, Y., Wu, M., Chen, Y., & Shi, X. (2019). The neuroprotective effect of astaxanthin on pilocarpine-induced status epilepticus in rats. Frontiers in Cellular Neuroscience, 13, 123.
14. Tripathi, D.N., & Jena, G.B. (2009). Intervention of astaxanthin against cyclophosphamide-induced oxidative stress and DNA damage: A study in mice. Chemico-Biological Interactions, 180, 398-406.
15. El-Agamy, S.E., Abdel-Aziz, A.K., Wahdan, S., Esmat, A., & Azab, S.S. (2018). Astaxanthin ameliorates doxorubicin-induced cognitive impairment (chemobrain) in experimental rat model: Impact on oxidative, inflammatory, and apoptotic machineries. Molecular Neurobiology, 55, 5727-5740.
16. Akca, G., Eren, H., Tumkaya, L., Mercantepe, T., Horsanali, M.O., Deveci, E., Dil, E., & Yilmaz, A. (2018). The protective effect of astaxanthin against cisplatin-induced nephrotoxicity in rats. Biomedicine & Pharmacotherapy, 100, 575-582.
17. Roudmajani, E.G., Roodbari, N.H., Goudarzvand, M., & Parivar, K. (2020). Protective effect of astaxanthin on prenatal bacterial lipopolysaccharide exposed behavioral deficits in adult mice. Iranian Red Crescent Medical Journal, 22(2), e97600.
18. Abbaszadeh, F., Jorjani, M., Joghataei, M.T., & Mehrabi, S. (2022). Astaxanthin modulates autophagy, apoptosis, and neuronal oxidative stress in a rat model of compression spinal cord injury. Neurochemical Research, 47(7), 2043-2051.
19. Zhang, S., Liu, Y., Xiang, D., Yang, J., Liu, D., Ren, X., & Zahng, C. (2018). Assessment of dose-response relationship of 5-fluorouracil to murine intestinal injury. Biomedicine & Pharmacotherapy, 106, 910-916.
20. Kamath, B.S., Srikanta, B.M., Dharmesh, S.M., Sarada, R., & Ravishankar, G.A. (2008). Ulcer preventive and antioxidative properties of astaxanthin from Haematococcus pluvialis. European Journal of Pharmacology, 590(1-3), 387-395.
21. Rao, A.R., Sarada, R., Shylaja, M.D., & Ravishankar, G.A. (2015). Evaluation of hepatoprotective and antioxidant activity of astaxanthin and astaxanthin esters from microalga-Haematococcus pluvialis. Journal of Food Science and Technology, 52(10), 6703-6710.
22. Demir, E.A., Mentese, A., Kucuk, H., Alemdar, N.T., & Demir, S. (2022). p-Coumaric acid alleviates cisplatin-induced ovarian toxicity in rats. Journal of Obstetrics and Gynaecology Research, 48(2), 411-419.
23. Mihara, M., & Uchiyama, M. (1978). Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Analitical Biochemistry, 86(1), 271-278.
24. Kazaz, I.O., Demir, S., Kerimoglu, G., Colak, F., Alemdar, N.T., Dogan, S.Y., Bostan, S., & Mentese, A. (2022). Chlorogenic acid ameliorates torsion/detorsion-induced testicular injury via decreasing endoplasmic reticulum stress. Journal of Pediatric Urology, 18(3), 289.e1-289.e7.
25. Demir, S., Kazaz, I.O., Kerimoglu, G., Demir, E.A., Colak, F., Yilmaz, S., & Mentese, A. (2022). Astaxanthin protects testicular tissue against torsion/detorsion-induced injury via suppressing endoplasmic reticulum stress in rats. Journal of Investigative Surgery, 35(5), 1044-1049.
26. Kaygusuzoglu, E., Caglayan, C., Kandemir, F.M., Yıldırım, S., Kucukler, S., Kilinc, M.A., & Saglam, Y.S. (2018). Zingerone ameliorates cisplatin-induced ovarian and uterine toxicity via suppression of sex hormone imbalances, oxidative stress, inflammation and apoptosis in female wistar rats. Biomedicine & Pharmacotherapy, 102, 517-530.
27. Demir, E.A., Mentese, A., Livaoglu, A., Alemdar, N.T., & Demir, S. (2023). Ameliorative effect of gallic acid on cisplatin-induced ovarian toxicity in rats. Drug and Chemical Toxicology, 46(1), 97-103.
28. Kükürt, A., Karapehlivan, M., & Gelen, V. (2022). The use of astaxanthin as a natural antioxidant on ovarian damage. Animal models and experimental research in medicine. IntechOpen, doi: 10.5772/intechopen.108854.
29. Stringer, J.M., Swindells, E.O.K., Zerafa, N., Liew, S.H., & Hutt, K.J. (2018). Multidose 5-fluorouracil is highly toxic to growing ovarian follicles in mice. Toxicological Sciences, 166(1), 97-107.
30. Lambouras, M., Liew, S.H., Horvay, K., Abud, H.E., Stringer, J.M., & Hutt, K.J. (2018). Examination of the ovotoxicity of 5-fluorouracil in mice. Journal of Assisted Reproduction and Genetics, 35, 1053-1060.
31. Meirow, D., Biederman, H., Anderson, R.A., & Wallace, W.H.B. (2010). Toxicity of chemotherapy and radiation on female reproduction. Clinical Obstetrics and Gynecology, 53(4), 727-739.
32. Naren, G., Guo, J., Bai, Q., Fan, N., & Nashun, B. (2022). Reproductive and developmental toxicities of 5-fluorouracil in model organisms and humans. Expert Reviews in Molecular Medicine, 24, e9.
33. Si, P., & Zhu, C. (2022). Biological and neurological activities of astaxanthin (Review). Molecular Medicine Reports, 26(4), 300.
34. Li, Y., Dong, Z., Liu, S., Gao, F., Zhang, J., Peng, Z., Wang, L., & Pan, X. (2022). Astaxanthin improves the development of the follicles and oocytes through alleviating oxidative stress induced by BPA in cultured follicles. Scientific Reports, 12(1), 7853.
35. 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), 173-178.
36. Polk, A., Vistisen, K., Vaage-Nilsen, M., & Nielsen, D.L. (2014). A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity. BMC Pharmacological Toxicology, 15, 47.
37. Angsutararux, P., Luanpitpong, S., & Issaragrisil, S. (2015). Chemotherapy-induced cardiotoxicity: overview of the roles of oxidative stress. Oxidative Medicine and Cellular Longevity, 2015, 795602.
38. Turan, I., Demir, S., Aliyazicioglu, R., Kilinc, K., Yaman, S.O., Cakiroglu, K.A., Kanbolat, S., Demir, E.A., Mentese, A., Aliyazicioglu, Y., & Deger, O. (2019). Dimethyl sulfoxide extract of Dianthus carmelitarum induces S phase arrest and apoptosis in human colon cancer cells. Nutrition and Cancer, 71(7), 1181-1188.
39. Demir, S., Yaman, S.O., Sener, S.O., Demir, E.A., Aliyazicioglu, R., Ozgen, U., Mentese, A., Deger, O., & Aliyazicioglu, Y. (2020). Dorycnium pentaphyllum extract has antiproliferative effect on human cervix and colon cancer cells. Nutrition and Cancer, 72(3), 504-512.
40. Aliyazicioglu, Y., Demir, S., Yaman, S.O., Sener, S.O., Demir, E.A., Aliyazicioglu, R., & Turan, I. (2019). Phytochemical analysis of Dorycnium pentaphyllum and its antiproliferative effect on cervix cancer cells. KSU Journal of Agriculture and Nature, 22(Suppl 2), 365-373.
41. Lee, J., Kim, M.H., & Kim, H. (2022). Anti-oxidant and anti-inflammatory effects of astaxanthin on gastrointestinal diseases. International Journal of Molecular Sciences, 23(24), 15471.
42. Durak, I., Karaayvaz, M., Kavutcu, M., Cimen, M.Y., Kacmaz, M., Buyukkocak, S., & Ozturk, H.S. (2000). Reduced antioxidant defense capacity in myocardial tissue from guinea pigs treated with 5-fluorouracil. Journal of Toxicology and Environmental Health, 59, 585-589.
43. Gelen, V., Şengül, E., Yıldırım, S., Senturk, E., Tekin, S., & Kükürt, A. (2021). The protective effects of hesperidin and curcumin on 5-fluorouracil-induced nephrotoxicity in mice. Environmental Science and Pollution Research, 28(34), 47046-47055.
44. Pereira, C.P.M., Souza, A.C.R., Vasconcelos, A.R., Prado, P.S., & Name, J.J. (2021). Antioxidant and anti-inflammatory mechanisms of action of astaxanthin in cardiovascular diseases (Review). International Journal of Molecular Medicine, 47(1), 37-48.
45. Sudharshan, S.J., & Dyavaiah, M. (2021). Astaxanthin protects oxidative stress mediated DNA damage and enhances longevity in Saccharomyces cerevisiae. Biogerontology, 22(1), 81-100.
46. Chang, M.X., & Xiong, F. (2020). Astaxanthin and its effects in inflammatory responses and inflammation-associated diseases: Recent advances and future directions. Molecules, 25(22), 5342.
47. Kohandel, Z., Farkhondeh, T., Aschner, M., Pourbagher-Shahri, A.M., & Samarghandian, S. (2022). Anti-inflammatory action of astaxanthin and its use in the treatment of various diseases. Biomedicine & Pharmacotherapy, 145, 112179.
48. Zeng, D., Wang, Y., Chen, Y., Li, D., Li, G., Xiao, H., Hou, J., Wang, Z., Hu, L., Wang, L., & Li, J. (2021). Angelica polysaccharide antagonizes 5-FU-induced oxidative stress injury to reduce apoptosis in the liver through Nrf2 pathway. Frontiers in Oncology, 11, 720620.