Deneysel Sisplatin Nefrotoksisitesi Modelinde Sesamolün Etkileri

Öz

Amaç: Sisplatin böbrekte oksidatif hasara neden olmaktadır. Sesamol, susam yağının suda çözünür ve antioksidan bileşenlerinden biridir. Sesamolün, deneysel sisplatin nefrotoksisitesi ve lipid peroksidasyonu üzerindeki etkisini araştırdık. Materyal ve Metot: Yirmi sekiz erkek, Wistar albino rat dört gruba ayrıldı (n=7): konrol, sesamol (8 mg/kg/gün), sisplatin (7 mg/kg i.p., tek doz), ve sisplatin + sesamol. Örnekler biyokimyasal, moleküler ve histopatolojik olarak değerlendirildi. İstatistiksel analiz için SPSS paket program kullanıldı. Bulgular: Üre ve kreatinin düzeyleri sisplatin grubunda kontrol grubuna göre istatistiksel olarak anlamlı yüksek bulunurken, sisplatin+sesamol grubunda ise anlamlı düşüş görüldü (p<0,05). Sisplatin verilen ratlarda malondialdehid (MDA) düzeylerinde anlamlı artış saptandı (p<0,05). Sesamol, MDA düzeylerini anlamlı ölçüde azalttı (p<0,05). Nükleer faktör kappa B (NF-κB) düzeyleri sisplatin grubunda kontrol grubuna göre istatistiksel olarak anlamlı yüksek bulunurken, sisplatin+sesamol grubunda ise anlamlı düşüş görüldü (p<0,05). Nükleer faktör eritroid 2-ilişkili faktör 2 (Nrf2) ve hem oksijenaz-1 (HO-1) düzeyleri sisplatin grubunda kontrol grubuna göre istatistiksel olarak anlamlı düşük (p<0,001) bulunurken, sisplatin+sesamol grubunda ise anlamlı yükselme görüldü (p<0,01). Sisplatinin neden olduğu histopatolojik değişikliklerin, sesamol uygulamasıyla azaldığı görüldü. Sonuç: Sesamolün, sisplatin nedenli nefropatide lipid peroksidasyonu ve NF-κB düzeylerini azalttığını ve antioksidan etki göstererek Nrf2 ve HO-1 düzeylerini artırdığını saptadık.

Anahtar Kelimeler

• sisplatin
• nefrotoksisite
• sesamo
• nükleer faktör kappa B
• nükleer faktör eritroid 2-ilişkili faktör 2
• hem oksijenaz-1

Kaynakça

1. 1. Osanto S, Bukman A, Van Hoek F, Sterk PJ, De Laat JA, Hermans J. Long-term effects of chemotherapy in patients with testicular cancer. J Clin Oncol 1992;10:574-9.
2. 2. Hartmann JT, Fels LM, Knop S, Stolt H, Kanz L, Bokemeyer C.A randomized trial comparing the nephrotoxicity of Cisplatin/ifosfamide-based combination chemotherapy with or without amifostine in patients with solid tumors. Invest New Drugs 2000;18:281-9.
3. 3. Sastry J, Kellie SJ. Severe neurotoxicity, ototoxicity and nephrotoxicity following high-dose cisplatin and amifostine. Pediatr Hematol Oncol 2005;22:441-5.
4. 4. Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci 2007;334:115-24.
5. 5. Ramesh G, Reeves WB. TNFR2-mediated apoptosis and necrosis in Cisplatin-inducedacuterenal failure. Am J Physiol Renal Physiol 2003;285:610-8.
6. 6. Fukuda Y, Osawa T, Namiki M, Ozaki T. Studies on antioxidative substances in sesame seed.Agric Biol Chem 1985;49:301-6.
7. 7. Hsu DZ, Chen KT, Li YH, Chuang YC, Liu MY. Sesamol delays mortality and attenuates hepatic injury after cecal ligation and puncture in rats: role of oxidative stres. Shock 2006;25:528-532.
8. 8. Parihar VK, Prabhakar KR, Veerapur VP, Kumar MS, Reddy YR, Joshi Ret al. Effect of sesamol on radiation-induced cytotoxicity in Swiss albino mice. Mutat Res 2006;611:9-16.

9. 9. Cho JM, Manandhar S, Lee HR, Park HM, Kwak M. Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer Cisplatin: Implication to cancer cell resistance. Cancer letters 2008;260:96-108.
10. 10. So HS, Kim H, Kim Y, Kim E, Pae HO, Chung HT et al. Evidence that Cisplatin-induced auditory damage is attenuated by downregulation of pro-inflammatory cytokines via Nrf2/ HO-1. J Assoc Res Oto 2008;9:290-306.
11. 11. Winrow VR, Wınyard PG, Morrıs CJ, Blake DR. Free radicals in Inflammation. Secondmessergers and mediators of tissue destruction. British Medical Bulletin 1993:506-22.
12. 12. Kalender S, Kalender Y, Ogutcu A, Uzunhisarcikli M, Durak D, Açikgoz F. Endosulfan-induced cardiotoxicity and free radical metabolizm in rats: the protectiveeffect of vitamin E. Toxicology 2004:202;227-35.
13. 13. Valko M, Leibfritz D, Mancol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. IntJ Biochem&Cell Biology 2007:39;44-84
14. 14. Valko M, Rhodes CJ, Mancol J, Izakovic M, Mazur M. Free radicals,metals andantioxidants in oxidative stres-induced cancer. Chemico-Biological Interactions 2006:160;1-40.
15. 15. Cheeseman KH, Slater TF. An introduction to free radical biochemistry. Br MedBull 1993;49:479-80.
16. 16. Isbir T. Antioksidan Sistemler. Endotel. İzmir Tabib Odası Tıpta Temel Bilimler Kolu Sonbahar Okulu 1994;21:92-8.
17. 17. Abraham NG, Lavrovsky Y, Schwartzman ML, Stoltz RA, Levere RD, Gerritsen ME et al. Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: protective effect against heme and hemoglobin toxicity. ProcNatlAcadSci 1995;92:6798-802.
18. 18. Motterlini R, Foresti R, Intaglietta M, Winslow RM. NO-mediated activation of heme oxygenase: endogenous cytoprotection against oxidative stress to endothelium. Am J Physiol1996;270:107-14.
19. 19. Karatepe M. Simultaneous determination of ascorbic acid and free malondialdehyde in human serum by HPLC/UV. LC-GC North America 2004;22:362-5.
20. 20. Ross MH, Reith EJ. Methods. Ross MH, Reith EJ, Romrell LJ (Eds). Histology-A Text and Atlas. Maryland: Williams and Wilkins, Baltimore, 1989:1-13.
21. 21. Çıtak A, Alpay H, Nayır A. Antineoplastik ilaçlara bağlı böbrek yetersizliği. İstanbul: Tıp Fakültesi Mecmuası 1995;58:116-9.
22. 22. Antunes LM, Darin JD,Bianchi ND. Effects of the antioxidants curcumin or selenium on cisplatin-induced nephrotoxicity and lipid peroxidation in rats. Pharmacol Res 2001;43:145-50.
23. 23. Santos NA, Catão CS, Martins NM, Curti C, Bianchi ML, Santos AC. Cisplatin-induced nephrotoxicity isassociated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Arch Toxicol 2007; 81: 495-504.
24. 24. Kuhad A, Sachdeva AK,Chopra K. Attenuation of renoinflammatory cascade in experimental model of diabetic nephropathy by sesamol. J Agric Food Chem 2009; 57: 6123-8.
25. 25. Gupta A, Sharma S, Kaur I, Chopra K. Renoprotective effects of sesamol in ferricnitrilotriacetate-induced oxidative renal injury in rats. Basic Clin Pharmacol Toxicol 2009;104:316-21.
26. 26. Hsu DZ, Wan CH, Hsu HF, Lin YM, Liu MY. The prophylactic protective effect of sesamol against ferric-nitrilotriacetateinduced acute renal injury in mice. Food Chem Toxicol 2008; 46:2736-41.
27. 27. Chu PY, Srinivasan P, Deng JF, Liu MY. Sesamol attenuates oxidative stress-mediated experimental acute pancreatitis in rats.Hum Exp Toxicol 2012;31:397-404. 28. Kuhad A, Chopra K. Effect of sesamol on diabetes-associated cognitive decline in rats. Exp Brain Res 2008; 185:411–20.
28. 29. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002;2:725-34.
29. 30. Sharma AK, Bharti S, Bhatia J, Nepal S, Malik S, Ray Ret al. Sesamol alleviates diet-induced cardiometabolic syndrome in rats via up-regulating PPARγ, PPARα and e-NOS. J Nutr Biochem 2012;23:1482-9.
30. 31. Chang CC, Lu WJ, Ong ET, Chiang CW, Lin SC, Huang SY, et al. A novel role of sesamol in inhibiting NF-B mediated signaling in platelet activation. Journal of Biomedical Science 2011;18:93.
31. 32. Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008;74:1526-39.
32. 33. Kilic U, Kilic E, Tuzcu Z, Tuzcu M, Ozercan IH, Yilmaz O et al. Melatonin suppresses cisplatin induced nephrotoxicity via activation of Nrf-2/HO- 1 pathway. Nutr Metab 2013;10:7.
33. 33. Parlakpınar H, Sahna E, Ozer MK, Ozugurlu F, Vardi N, Acet A. Physiological and pharmacological concentrations of melatonin protect against Cisplatin-induced acute renal injury. J Pineal Res 2002;33:161-6.
34. 34. Ozyurt H, Yildirim Z, Kotuk M, Yılmaz HR, Yağmurca M, Iraz M, et al. Cisplatin-induced acute renal failure is ameliorated by erdosteine in a dose-dependent manner. J Appl Toxicol 2004;24:269-75
35. 35. Liu Z, Chen Y, QiaoQ, Sun Y, Liu Q, Ren B et al. Sesamol Supplementation Prevents Systemic Inflammation-Induced Memory Impairment and Amyloidogenesis via Inhibition of Nuclear Factor kappaB.Mol Nutr Food Res2017 May;61(5).doi: 10.1002/mnfr.201600734. Epub 2016 Dec 30.
36. 35. Chu PY, Chien SP, Hsu DZ, Liu MY. Protective Effect of Sesamol on the Pulmonary Inflammatory Response and Lung Injury in Endotoxemic Rats. Food Chem Toxicol 2010 Jul;48(7):1821-6. doi: 10.1016/j.fct.2010.04.014. Epub 2010 Apr 14.
37. 36. Chu PY, Hsu DZ,Hsu PY, Liu MY. Sesamol DownRegulates the Lipopolysaccharide-Induced Inflammatory Response by Inhibiting Nuclear Factor-Kappa B Activation. Innate Immun 2010 Oct;16(5):333-9. doi:10.1177/1753425909351880. Epub 2009 Nov 25.