Protective Effect of Silymarin Against Gentamicin-Induced Oxidative Stress in Mice

Öz

This study was conducted to evaluate the protective effects of silymarin against gentamicin-induced oxidative stress and renal damage in mice at both biochemical and histopathological levels. Gentamicin administration significantly weakened the renal antioxidant defense system by markedly reducing GSH levels (P<0.05) and significantly increasing MDA levels, an indicator of oxidative stress (P<0.0001). In contrast, silymarin treatment significantly increased GSH levels compared with the gentamicin group (P<0.05) and markedly decreased MDA levels, thereby reducing oxidative stress (P<0.001). Gentamicin administration also substantially decreased renal PON-1 activity (P<0.0001), whereas silymarin treatment significantly enhanced PON-1 activity, strengthening the antioxidant defense system (P<0.05). Histopathological evaluations revealed glomerular atrophy, necrosis of tubular epithelial cells, and focal hyperemia in the gentamicin group. Although similar lesions were observed in the silymarin + gentamicin group, their severity was notably reduced. No pathological findings were detected in the silymarin-only and control groups, and the kidney tissue preserved its normal histological structure. These results demonstrate that silymarin may effectively ameliorate gentamicin-induced nephrotoxicity by reducing oxidative stress, enhancing antioxidant defense, and alleviating structural damage in renal tissue.

Anahtar Kelimeler

• Gentamicin
• oxidative stress
• pon-1
• silymarin

Farelerde Gentamisin Kaynaklı Oksidatif Strese Karşı Sliymarin'in Koruyucu Etkisi

Öz

Bu çalışma, sıçanlarda gentamisin kaynaklı oksidatif stres ve böbrek hasarına karşı silymarinin koruyucu etkilerini biyokimyasal ve histopatolojik düzeyde değerlendirmek amacıyla gerçekleştirilmiştir. Gentamisin uygulaması böbrek dokusunda antioksidan savunmayı önemli ölçüde zayıflatarak GSH düzeylerini belirgin şekilde azaltmış (p<0.05) ve oksidatif stres göstergesi olan MDA düzeylerini anlamlı olarak artırmıştır (p<0.0001). Buna karşılık, silymarin tedavisi GSH düzeylerini gentamisin grubuna kıyasla anlamlı biçimde yükseltmiş (p<0.05) ve MDA düzeylerini belirgin şekilde düşürerek oksidatif stresi hafifletmiştir (p<0.001). Gentamisin uygulaması ayrıca böbrek PON-1 aktivitesini ciddi biçimde azaltmış (p<0.0001); silymarin tedavisi ise PON-1 aktivitesini anlamlı derecede artırarak antioksidan savunmayı güçlendirmiştir (p<0.05). Histopatolojik değerlendirmelerde gentamisin grubunda glomerüler atrofi, tubulus epitel hücrelerinde nekroz ve fokal hiperemi belirlenmiştir. Silymarin ile gentamisin uygulanan grupta benzer lezyonlar izlenmekle birlikte bu bulguların şiddetinin belirgin şekilde azaldığı görülmüştür. Silymarin tek başına uygulanan grup ve kontrol grubunda ise herhangi bir patolojik bulguya rastlanmamış, böbrek dokusu normal histolojik yapısını korumuştur. Bu sonuçlar, silymarinin gentamisin kaynaklı nefrotoksisiteyi oksidatif stresi azaltarak, antioksidan savunmayı güçlendirerek ve böbrek dokusundaki yapısal bozulmayı hafifleterek etkili bir şekilde iyileştirebileceğini göstermektedir.

Anahtar Kelimeler

• Gentamisin
• oksidatif stres
• pon-1
• silimarin

Kaynakça

1. Ahmadvand, H., Dehnoo, M.G., Dehghani, A., Bagheri, S., & Cheraghi, R.A. (2014). Serum paraoxonase 1 status and its association with atherogenic indexes in gentamicin-induced nephrotoxicity in rats treated with coenzyme Q10. Renal Failure, 36(3), 413–418. https://doi.org/10.3109/0886022x.2013.865154
2. Alharbi, K.S., Ali, T., Singh, Y., Ali Al-Ghamdi, A.S., Kazmi, L. & Gupta, G. (2022). Biochemical interaction of pyrvinium in gentamicin-induced acute kidney injury by modulating calcium dyshomeostasis and mitochondrial dysfunction. Chemico-Biological Interactions, 363, 110020. https://doi.org/10.1016/j.cbi.2022.110020
3. Atsamo, A.D., Lontsie Songmene, A., Metchi Donfack, M.F., Ngouateu, O.B., Nguelefack, T.B., & Dimo, T. (2021). Aqueous extract from Cinnamomum zeylanicum (Lauraceae) stem bark ameliorates gentamicin-induced nephrotoxicity in rats by modulating oxidative stress and inflammatory markers. Evidence- Based Complementary and Alternative Medicine, 5543889. https://doi.org/10.1155/2021/5543889
4. Balakumar, P., Rohilla, A., & Thangathirupathi, A. (2010). Gentamicin- induced nephrotoxicity: Do we have a promising therapeutic approach to blunt it? Pharmacological Research, 62(3), 179–186. https://doi.org/10.1016/j.phrs.2010.04.004
5. Beutler, E., Duron, O & Kelly, BM. (1963). Improved method for the determination of blood glutathione. Journal of Laboratory and Clinical Medicine, 61:882-8.
6. Eckerson, H.W., Wyte, C.M., & La Du, B.N. (1983). The human serum paraoxonase/arylesterase polymorphism. American Journal of Human Genetics, 35(6), 1126.
7. Güven, A., Deveci, H.A., Allahverdi, T.D., Allahverdi, E., & Çolak, M.Y. (2025). Investigation of antioxidant/oxidant potential of some natural biomaterials. Sinop Üniversitesi Fen Bilimleri Dergisi, 10(1), 234–243. https://doi.org/10.33484/sinopfbd.1554557
8. Georgiev, T., Nikolova, G., Dyakova, V., Karamalakova, Y., Georgieva, E., ... & Hadzhibozheva, P. (2023). Vitamin E and silymarin reduce oxidative tissue damage during gentamycin- induced nephrotoxicity. Pharmaceuticals, 16(10), 1365. https://doi.org/10.3390/ph16101365

9. Ghaznavi, H., Mehrzadi, S., Dormanesh, B., Tabatabaei, S.M.T.H., Vahedi, H., ...& Rashidian, A. (2016). Comparison of the protective effects of melatonin and silymarin against gentamicin- induced nephrotoxicity in rats. Journal of Evidence-Based Complementary and Alternative Medicine, 21(4), 49–55. https://doi.org/10.1177/2156587215621672
10. Gülcü, F., & Gürsu M.F. (2003). The standardization of paraoxonase and arylesterase activity measurements (Paraoksonaz ve aril esteraz aktivite ölçümlerinin standardizasyonu). Turkish Journal of Biochemistry, 28(2), 45–49.
11. Hilmi, S.R., Dewan, Z.F., Kabir, A.N., Islam, M.M., Yusuf, M.A., ... & Akter, M. (2023). Effect of silymarin on gentamicin induced nephrotoxicity in rats. Bangladesh Journal of Infectious Diseases, 10(2), 71–76. https://doi.org/0.3329/bjid.v10i2.70636
12. Jakubowski, H. (2024). The molecular bases of anti-oxidative and anti- inflammatory properties of paraoxonase 1. Antioxidants, 13(11), 1292. https://doi.org/10.3390/antiox13111292
13. Kovacic, P., & Somanathan, R. (2013). Unifying mechanism for eye toxicity: Electron transfer, reactive oxygen species, antioxidant benefits. Cell Membranes and Free Radical Research, 1(2), 56–69.
14. Kükürt, A., & Gelen, V. (2023). Paraoxonase 1 in Cattle Health and Disease. Intechopen. https://doi.org/10.5772/ıntechopen.110844
15. Léonard, D.F., Basile, T., Oumarou Bibi Farouck, A., Emmanuel, O.P., Albert, S., ... & Théophile, D. (2025). Aqueous extract of Cucurbita pepo L. Fruits exhibits nephroprotective activity in a mouse model of gentamicin-induced nephrotoxicity using In Vivo and In Silico approaches. Pharmacological Research - Natural Products, 7, 100261. https://doi.org/10.1016/j.prenap.2025.100261Merhan, O., &
16. Bozukluhan, K. (2022). Acute phase response and some acute phase proteins in animals. Current Multidisciplinary Studies in Veterinary Medicine I. Ankara: Iksad Publishing House, 3-33.
17. Morales, A.I., Detaille, D., Prieto, M., Puente, A., Briones, E., ...& El-Mir, M.Y. (2010). Metformin prevents experimental gentamicin-induced nephropathyby a mitochondria-dependent pathway. Kidney International, 77(10), 861–869. https://doi.org/0.1038/ki.2010.11
18. Nabavi, S.F., Nabavi, S.M., Moghaddam, A. H., Naqinezhad, A., Bigdellou, R., & Mohammadzadeh, S. (2012). Protective effects of Allium paradoxum against gentamicin-induced nephrotoxicity in mice. Food & Function, 3(1), 28–29. https://doi.org/10.1039/c1fo10173k
19. Oliyarnyk, O., Malinska, H., Markova, I., Trnovska, J., Skop, V., ... & Pravenec, M. (2016). Comparative effect of silymarin and silybin treatment on inflammation and oxidative stress in transgenic spontaneously hypertensive rats overexpressing human C-reactive protein. Atherosclerosis, 252, e220. https://doi.org/10.1016/j.atherosclerosis.2016.07.182
20. Samouilidou, E.C., Liaouri, A., Kostopoulos, V., Nikas, D., & Grapsa, E. (2024). The importance of paraoxonase 1 activity in chronic kidney disease. Renal Failure, 46(2), 2376930. https://doi.org/0.1080/0886022X.2024.2376930
21. Sozmen, M., Erginsoy, S.D., Cenesis, S., & Devrim, A.K. (2005). The Protective Effect of Kefir and Vitamin C on Azoxymethane Induced Toxicity and Induction of Metallothionein in Mice. Scandinavian Journal of Laboratory Animal Science, 32(4), 211–220. https://doi.org/10.23675/sjlas.v32i4.90
22. Steflik, H.J., Askenazi, D., & Selewski, D.T. (2023). Acute Kidney Injury. Avery’s Diseases of the Newborn, 1125-1138.e4. https://doi.org/10.1016/B978-0-323-82823-9.00077-5
23. Ustuner, M.A., Kaman, D., & Colakoglu, N. (2017). Effects of benfotiamine and coenzyme Q10 on kidney damage induced gentamicin. Tissue and Cell, 49(6), 691–696. https://doi.org/10.1016/j.tice.2017.10.001
24. Wadhwa, K., Pahwa, R., Kumar, M., Kumar, S., Sharma, P.C., ... & Jeandet, P. (2022). Mechanistic insights into the pharmacological significance of silymarin. Molecules, 27(16), 5327. https://doi.org/10.3390/molecules27165327
25. Yoshioka, T., Kawada, K., Shimada, T., & Mori, M. (1979). Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood. American Journal of Obstetrics and Gynecology. 135(3), 372–376. https://doi.org/10.1016/0002-9378(79)90708-7
26. Zaulet, M., Kevorkian, S.E.M., Dinescu, S., Cotoraci, C., Suciu, M., ... & Hermenean, A. (2017). Protective effects of silymarin against bisphenol A-induced hepatotoxicity in mouse liver. Experimental and Therapeutic Medicine, 13(3), 821. https://doi.org/10.3892/etm.2017.4066
27. Zhao, Y., Zhou, Y., Gong, T., Liu, Z., Yang, W., ...& Lu, W. (2024). The clinical anti-inflammatory effects mechanisms of silymarin. IScience. https://doi.org/10.1016/j.isci.2024.111109