Sıçanlarda Valproik Asite Bağlı Testis Hasarına Rutin Etkisinin Araştırılması

Öz

Valproik asit (VALP), epilepsi gibi birçok psikiyatrik hastalık için kullanılan bir ilaçtır. Ancak VALP kullanımının testisler de dahil olmak üzere çeşitli dokularda potansiyel yan etkileri vardır. Rutin (RUT), oksidatif stres kaynaklı hastalıklara ve lipid peroksidasyonuna karşı koruyucu etkileri olan bir flavonoiddir. Bu çalışmada VALP'in neden olduğu testis hasarına karşı RUT'un koruyucu etkisi araştırıldı. Bu amaçla çalışmada ağırlıkları 220-250 g olan 35 adet erkek Sprague-Dawley cinsi rat kullanıldı. Ratlar kontrol (serum fizyolojik), RUT (100 mg/kg/va), VALP, (500mg/kg/va), VALP+RUT 50 (500 mg/kg/va VALP+50 mg/kg/va RUT) ve VALP +RUT 100 (500 mg/kg/v VALP+100 mg/kg/va RUT) olarak 5 gruba ayrıldı. Uygulamalarının sonunda ratlar sakrifiye edilerek testis dokuları biyokimyasal ve spermatolojik analizlerde kullanılmak üzere alındı. Sunulan çalışmanın sonuçlarına göre VALP grubunun testis dokularındaki MDA düzeyi diğer deney gruplarına göre istatistiksel olarak yüksek bulundu (p<0,05). Testis dokusu GSH ve Nrf-2 düzeyi VALP grubunda en düşüktü. Testis dokusunda TNF-α, IL-1β ve MAPK14 seviyeleri VALP grubunda en yüksek iken, RUT tedavi gruplarında azaldı. Benzer şekilde en yüksek Bax, Caspase-3 ve MMP-9 seviyeleri VALP grubunda gözlenirken, RUT tedavisi bu değeri azaltmıştır. Spermatolojik analizler incelendiğinde total motilite değerinin VALP grubunda anlamlı olarak düştüğü, ancak RUT tedavi grubunda total motilite değerinin arttığı görüldü (p<0,05). VALP grubunda ölü ve anormal sperm oranında önemli bir artış bulundu, ancak bu parametreler RUT tedavi grubunda düzeldi. Sonuç olarak RUT, sıçanlarda VALP'nin neden olduğu testis hasarına karşı koruyucu etkilere sahiptir.

Anahtar Kelimeler

• Oksidatif stres
• rat
• rutin
• sperma
• valproik asit.

Investigation of the Effects of Rutin on Valproic Acid Induced Testicular Damage in Rats

Abstract

Valproic acid (VALP) is a drug used for many psychiatric diseases such as epilepsy. However, the use of VALP has potential side effects on various tissues, including the testicles. Rutin (RUT) is a flavonoid with protective effects against oxidative stress-induced diseases and lipid peroxidation. In this study, the protective effects of RUT against testicular damage caused by VALP were investigated. For this purpose, 35 male Spraque-Dawley rats weighing 220-250 g were used in the study. The rats were randomly divided into 5 groups as Control (physiological saline), RUT (100 mg/kg/bw), VALP, (500mg/kg/bw), VALP+RUT 50 (500 mg/kg/bw VALP+50 mg/kg/bw RUT), and VALP +RUT 100 (500 mg/kg/bw VALP+100 mg/kg/bw RUT). At the end of the RUT and VALP administrations, the rats were sacrificed and testicular tissues were taken to be used for biochemical and spermatological analyzes. According to the results of this study, the MDA level in the testicular tissues of the VALP group was found to be statistically higher than the other experimental groups (p<0.05). Testicular tissue GSH and Nrf-2 level was the lowest in the VALP group. TNF-α, IL-1Β and MAPK14 levels in testicular tissue were highest in the VALP group, while it was decreased in the RUT treatment groups. Similarly, the highest levels of Bax, Caspase-3 and MMP-9 were observed in the VALP group, while RUT treatment decreased this value. When the spermatological analyzes were examined, it was observed that the total motility value decreased significantly in the VALP group, but the total motility value increased in the RUT treatment group (p<0.05). A significant increase in the rate of dead and abnormal sperm was found in the VALP group, but these parameters improved in the RUT treatment group. As a result, RUT has protective effects against VALP-induced testicular damage in rats.

Keywords

• Oxidative stress
• rat
• rutin
• semen
• valproic acid.

References

1. Abarikwu, S., Iserhienrhien, B., & Badejo, T. (2013). Rutin-and selenium-attenuated cadmium-induced testicular pathophysiology in rats. Human & experimental toxicology, 32(4), 395-406.
2. Abarikwu, S. O., Mgbudom-Okah, C. J., & Onuah, C. L. (2022). The protective effect of rutin against busulfan-induced testicular damage in adult rats. Drug and Chemical Toxicology, 45(3), 1035-1043.
3. Abdelkader, N. F., Elyamany, M., Gad, A. M., Assaf, N., Fawzy, H. M., & Elesawy, W. H. (2020). Ellagic acid attenuates liver toxicity induced by valproic acid in rats. Journal of Pharmacological Sciences, 143(1), 23-29.
4. Adewole, K. E., Attah, A. F., & Osawe, S. O. (2021). Exploring phytotherapeutic approach in the management of valproic acid-induced toxicity. Advances in Traditional Medicine, 1-21.
5. Akaras, N., Abuc, O. O., Koc, K., Bal, T., Geyikoglu, F., Atilay, H., Erol, H. S., Yigit, S., & Gul, M. (2020). (1→ 3)‐β‐d‐glucan enhances the toxicity induced by Bortezomib in rat testis. Journal of food biochemistry, 44(3), e13155.
6. Akaras, N., Bal, T., Atilay, H., Selli, J., & Halici, M. (2017). Protective effects of agomelatine on testicular damage caused by bortezomib. Biotechnic & Histochemistry, 92(8), 552-559.
7. Akaras, N., Gur, C., Kucukler, S., & Kandemir, F. M. (2023). Zingerone reduces sodium arsenite-induced nephrotoxicity by regulating oxidative stress, inflammation, apoptosis and histopathological changes. Chemico-Biological Interactions, 374, 110410.
8. Akaras, N., Ileriturk, M., Gur, C., Kucukler, S., Oz, M., & Kandemir, F. M. (2023). The protective effects of chrysin on cadmium-induced pulmonary toxicity; a multi-biomarker approach. Environmental Science and Pollution Research, 1-16.

9. Akondi, B. R., Challa, S. R., & Akula, A. (2011). Protective effects of rutin and naringin in testicular ischemia-reperfusion induced oxidative stress in rats. Journal of reproduction & infertility, 12(3), 209.
10. Aksu, E., Kandemir, F., Özkaraca, M., Ömür, A., Küçükler, S., & Çomaklı, S. (2017). Rutin ameliorates cisplatin‐induced reproductive damage via suppression of oxidative stress and apoptosis in adult male rats. Andrologia, 49(1), e12593.
11. Aksu, E. H., Kandemir, F. M., & Küçükler, S. (2021). Ameliorative effect of hesperidin on streptozotocin‐diabetes mellitus‐induced testicular DNA damage and sperm quality degradation in Sprague–Dawley rats. Journal of food biochemistry, 45(10), e13938.
12. Aksu, E. H., Kandemir, F. M., Küçükler, S., & Mahamadu, A. (2018). Improvement in colistin‐induced reproductive damage, apoptosis, and autophagy in testes via reducing oxidative stress by chrysin. Journal of biochemical and molecular toxicology, 32(11), e22201.
13. Aksu, E. H., Kandemir, F. M., Yıldırım, S., Küçükler, S., Dörtbudak, M. B., Çağlayan, C., & Benzer, F. (2019). Palliative effect of curcumin on doxorubicin‐induced testicular damage in male rats. Journal of biochemical and molecular toxicology, 33(10), e22384.
14. Aktaş, M., Kandemir, F. M., Ozkaraca, M., Hanedan, B., & Kirbaş, A. (2017). Protective effects of rutin on acute lung injury induced by oleic acid in rats. Kafkas Üniversitesi Veteriner Fakültesi Dergisi, 23(3).
15. Alsemeh, A. E., Ahmed, M. M., Fawzy, A., Samy, W., Tharwat, M., & Rezq, S. (2022). Vitamin E rescues valproic acid-induced testicular injury in rats: Role of autophagy. Life Sciences, 296, 120434.
16. Ambriz-Pérez, D. L., Leyva-López, N., Gutierrez-Grijalva, E. P., & Heredia, J. B. (2016). Phenolic compounds: Natural alternative in inflammation treatment. A Review. Cogent Food & Agriculture, 2(1), 1131412.
17. Ansar, S., AlGhosoon, H. T., & Hamed, S. (2015). Evaluation of protective effect of rutin on lead acetate-induced testicular toxicity in Wistar rats. Toxin Reviews, 34(4), 195-199.
18. Bairy, L., Paul, V., & Rao, Y. (2010). Reproductive toxicity of sodium valproate in male rats. Indian journal of pharmacology, 42(2), 90.
19. Belhan, S., Özkaraca, M., Kandemir, F. M., Gülyüz, F., Yildirim, S., ÖMÜR, A. D., & Yener, Z. (2017). Effectiveness of hesperidin on methotrexate-induced testicular toxicity in rats. Kafkas Üniversitesi Veteriner Fakültesi Dergisi, 23(5).
20. Bradbury, C. A., Khanim, F., Hayden, R., Bunce, C., White, D., Drayson, M., Craddock, C., & Turner, B. (2005). Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia, 19(10), 1751-1759.
21. Caglayan, C., Kandemir, F. M., Darendelioğlu, E., Yıldırım, S., Kucukler, S., & Dortbudak, M. B. (2019). Rutin ameliorates mercuric chloride-induced hepatotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. Journal of Trace Elements in Medicine and Biology, 56, 60-68.
22. Caglayan, C., Kandemir, F. M., Yildirim, S., Kucukler, S., & Eser, G. (2019). Rutin protects mercuric chloride‐induced nephrotoxicity via targeting of aquaporin 1 level, oxidative stress, apoptosis and inflammation in rats. Journal of Trace Elements in Medicine and Biology, 54, 69-78.
23. Cihan, G., Aydın, G., & Kandemir, Ö. (2022). Ratlarda Deltametrin’in Neden Olduğu Dalak Toksisitesine Karşı Rutin’in Potansiyel Koruyucu Etkilerinin Oksidatif Stres, Apoptoz ve İnflamasyon Belirteçleri Üzerinden Araştırılması. Atatürk Üniversitesi Veteriner Bilimleri Dergisi, 17(1), 6-10.
24. De Souza, A., Gerlach, R., & Line, S. (2000). Inhibition of human gingival gelatinases (MMP-2 and MMP-9) by metal salts. Dental Materials, 16(2), 103-108.
25. Galaly, S. R., Abdella, E. M., & Mohammed, H. M. (2014). Effects of royal jelly on genotoxicity and nephrotoxicity induced by valproic acid in albino mice. Beni-Suef University journal of basic and applied sciences, 3(1), 1-15.
26. Gur, C., Akarsu, S. A., & Kandemir, F. M. (2022). Carvacrol reduces abnormal and dead sperm counts by attenuating sodium arsenite-induced oxidative stress, inflammation, apoptosis and autophagy in testicular tissues of rats.
27. Gur, C., & Kandemir, F. M. (2023). Molecular and biochemical investigation of the protective effects of rutin against liver and kidney toxicity caused by malathion administration in a rat model. Environmental Toxicology, 38(3), 555-565.
28. Gur, C., Kandemir, O., & Kandemir, F. M. (2022). Investigation of the effects of hesperidin administration on abamectin‐induced testicular toxicity in rats through oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, autophagy, and JAK2/STAT3 pathways. Environmental Toxicology, 37(3), 401-412.
29. Hamza, A. A., & Amin, A. (2007). Apium graveolens modulates sodium valproate‐induced reproductive toxicity in rats. Journal of Experimental Zoology Part A: Ecological Genetics and Physiology, 307(4), 199-206.
30. Hozayen, W. G. (2012). Effect of hesperidin and rutin on doxorubicin induced testicular toxicity in male rats. Int J Food Nutr Sci, 1(1), 31-42.
31. İleriturk, M., Kandemir, O., Akaras, N., Simsek, H., Genc, A., & Kandemir, F. M. (2023). Hesperidin has a protective effect on paclitaxel-induced testicular toxicity through regulating oxidative stress, apoptosis, inflammation and endoplasmic reticulum stress. Reproductive Toxicology, 118, 108369.
32. Jin, J., Xiong, T., Hou, X., Sun, X., Liao, J., Huang, Z., Huang, M., & Zhao, Z. (2014). Role of Nrf2 activation and NF-κB inhibition in valproic acid induced hepatotoxicity and in diammonium glycyrrhizinate induced protection in mice. Food and chemical toxicology, 73, 95-104.
33. Kamalakkannan, N., & Prince, P. S. M. (2006). Rutin improves the antioxidant status in streptozotocin-induced diabetic rat tissues. Molecular and cellular biochemistry, 293, 211-219.
34. Kandemir, F. M., Caglayan, C., Aksu, E. H., Yildirim, S., Kucukler, S., Gur, C., & Eser, G. (2020). Protective effect of rutin on mercuric chloride‐induced reproductive damage in male rats. Andrologia, 52(3), e13524.
35. Kandemir, F. M., Ileriturk, M., & Gur, C. (2022). Rutin protects rat liver and kidney from sodium valproate-induce damage by attenuating oxidative stress, ER stress, inflammation, apoptosis and autophagy. Molecular Biology Reports, 49(7), 6063-6074.
36. Kandemir, F. M., Kucukler, S., Caglayan, C., Gur, C., Batil, A. A., & Gülçin, İ. (2017). Therapeutic effects of silymarin and naringin on methotrexate‐induced nephrotoxicity in rats: Biochemical evaluation of anti‐inflammatory, antiapoptotic, and antiautophagic properties. Journal of food biochemistry, 41(5), e12398.
37. Kandemir, F. M., Yıldırım, S., Kucukler, S., Caglayan, C., Darendelioğlu, E., & Dortbudak, M. B. (2020). Protective effects of morin against acrylamide-induced hepatotoxicity and nephrotoxicity: A multi-biomarker approach. Food and chemical toxicology, 138, 111190.
38. Kucukler, S., Caglayan, C., Darendelioğlu, E., & Kandemir, F. M. (2020). Morin attenuates acrylamide-induced testicular toxicity in rats by regulating the NF-κB, Bax/Bcl-2 and PI3K/Akt/mTOR signaling pathways. Life Sciences, 261, 118301.
39. Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods, 25(4), 402-408.
40. Ma, Q. (2013). Role of nrf2 in oxidative stress and toxicity. Annual review of pharmacology and toxicology, 53, 401-426.
41. Mandana, S. N., Fatemeh, N., Hossein, N., Azam, M., & Saleh, A. (2013). Protective effect of ghrelin on sodium valproate-induced liver injury in rat. Journal of Stress Physiology & Biochemistry, 9(1), 96-105.
42. Martin, R. H., Ernst, S., Rademaker, A., Barclay, L., Ko, E., & Summers, N. (1999). Analysis of sperm chromosome complements before, during, and after chemotherapy. Cancer genetics and cytogenetics, 108(2), 133-136.
43. Moshahid Khan, M., Raza, S. S., Javed, H., Ahmad, A., Khan, A., Islam, F., Safhi, M. M., & Islam, F. (2012). Rutin protects dopaminergic neurons from oxidative stress in an animal model of Parkinson’s disease. Neurotoxicity research, 22, 1-15.
44. Nalivaeva, N. N., Belyaev, N. D., & Turner, A. J. (2009). Sodium valproate: an old drug with new roles. Trends in pharmacological sciences, 30(10), 509-514.
45. Ola, M. S., Ahmed, M. M., Ahmad, R., Abuohashish, H. M., Al-Rejaie, S. S., & Alhomida, A. S. (2015). Neuroprotective effects of rutin in streptozotocin-induced diabetic rat retina. Journal of Molecular Neuroscience, 56, 440-448.
46. Phillips, A., Bullock, T., & Plant, N. (2003). Sodium valproate induces apoptosis in the rat hepatoma cell line, FaO. Toxicology, 192(2-3), 219-227.
47. Placer, Z. A., Cushman, L. L., & Johnson, B. C. (1966). Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Analytical biochemistry, 16(2), 359-364.
48. Pourahmad, J., Eskandari, M. R., Kaghazi, A., Shaki, F., Shahraki, J., & Fard, J. K. (2012). A new approach on valproic acid induced hepatotoxicity: involvement of lysosomal membrane leakiness and cellular proteolysis. Toxicology in vitro, 26(4), 545-551.
49. Raza, M., Al-Bekairi, A., Ageel, A., & Qureshi, S. (1997). Biochemical basis of sodium valproate hepatotoxicity and renal tubular disorder: time dependence of peroxidative injury. Pharmacological research, 35(2), 153-157.
50. Safdar, A., & Ismail, F. (2022). A Comprehensive Review on Pharmacological Applications and Drug-Induced Toxicity of Valproic Acid. Saudi Pharmaceutical Journal.
51. Saleh, D., Ismail, M. A., & Ibrahim, A. M. (2012). Non alcoholic fatty liver disease, insulin resistance, dyslipidemia and atherogenic ratios in epileptic children and adolescents on long term antiepileptic drug therapy. Pakistan journal of biological sciences: PJBS, 15(2), 68-7.
52. Salem, E., Salem, N., & Hellstrom, W. (2017). Therapeutic effect of ozone and rutin on adriamycin‐induced testicular toxicity in an experimental rat model. Andrologia, 49(1), e12603.
53. Savran, M., Ascı, H., Armagan, İ., Erzurumlu, Y., Azırak, S., Kaya Ozer, M., Bilgic, S., & Korkmaz, D. T. (2020). Thymoquinone could be protective against valproic acid‐induced testicular toxicity by antioxidant and anti‐inflammatory mechanisms. Andrologia, 52(7), e13623.
54. Sedlak, J., & Lindsay, R. H. (1968). Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Analytical biochemistry, 25, 192-205.
55. Şimşek, H., Akaras, N., Cihan, G., Küçükler, S., & Kandemir, F. M. (2023). Beneficial effects of Chrysin on Cadmium‐induced nephrotoxicity in rats: Modulating the levels of Nrf2/HO‐1, RAGE/NLRP3, and Caspase-3/Bax/Bcl-2 signaling pathways. Gene, 147502.
56. Şimşek, H., Küçükler, S., Gür, C., İleritürk, M., Aygörmez, S., & Kandemir, F. M. (2023). Protective effects of zingerone against sodium arsenite-induced lung toxicity: A multi-biomarker approach. Iranian Journal of Basic Medical Sciences, 26(9), 1098-1106. https://doi.org/10.22038/ijbms.2023.71905.15623
57. Temel, Y., Kucukler, S., Yıldırım, S., Caglayan, C., & Kandemir, F. M. (2020). Protective effect of chrysin on cyclophosphamide-induced hepatotoxicity and nephrotoxicity via the inhibition of oxidative stress, inflammation, and apoptosis. Naunyn-Schmiedeberg's archives of pharmacology, 393, 325-337.
58. Tolou-Ghamari, Z., & Palizban, A. A. (2015). Review of sodium valproate clinical and biochemical properties. Zahedan Journal of Research in Medical Sciences, 17(8).
59. Tong, V., Teng, X. W., Chang, T. K., & Abbott, F. S. (2005). Valproic acid I: time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats. Toxicological Sciences, 86(2), 427-435.
60. Tuncer, S. Ç., Akarsu, S. A., Küçükler, S., Gür, C., & Kandemir, F. M. Effects of sinapic acid on lead acetate-induced oxidative stress, apoptosis and inflammation in testicular tissue. Environmental Toxicology.
61. Wang, Y. B., Ge, Z. M., Kang, W. Q., Lian, Z. X., Yao, J., & Zhou, C. Y. (2015). Rutin alleviates diabetic cardiomyopathy in a rat model of type 2 diabetes. Experimental and therapeutic medicine, 9(2), 451-455.
62. Wei, S.-M., Yan, Z.-Z., & Zhou, J. (2011). Protective effect of rutin on testicular ischemia-reperfusion injury. Journal of pediatric surgery, 46(7), 1419-1424.
63. Yardim, A., Kandemir, F. M., Ozdemir, S., Kucukler, S., Comakli, S., Gur, C., & Celik, H. (2020). Quercetin provides protection against the peripheral nerve damage caused by vincristine in rats by suppressing caspase 3, NF-κB, ATF-6 pathways and activating Nrf2, Akt pathways. Neurotoxicology, 81, 137-146.
64. Yıldız, M. O., Çelik, H., Caglayan, C., Genç, A., Doğan, T., & Satıcı, E. (2022). Neuroprotective effects of carvacrol against cadmium-induced neurotoxicity in rats: role of oxidative stress, inflammation and apoptosis. Metabolic brain disease, 37(4), 1259-1269.
65. Youssef, S. S., Ibrahim, N. K., El-Sonbaty, S. M., & El-Din Ezz, M. K. (2022). Rutin Suppresses DMBA Carcinogenesis in the Breast Through Modulating IL-6/NF-κB, SRC1/HSP90 and ER-α. Natural Product Communications, 17(9), 1934578X221118213.
66. Zhou, L., Chen, L., Zeng, X., Liao, J., & Ouyang, D. (2020). Ginsenoside compound K alleviates sodium valproate-induced hepatotoxicity in rats via antioxidant effect, regulation of peroxisome pathway and iron homeostasis. Toxicology and applied pharmacology, 386, 114829.