Chemopreventive Effect of Tadalafil in Cisplatin-Induced Nephrotoxicity in Rats
Click to view file (PDF)

Keywords

Cisplatin-induced nephrotoxicity
Renal function parameters
Oxidative markers
Histopathology

How to Cite

Chemopreventive Effect of Tadalafil in Cisplatin-Induced Nephrotoxicity in Rats. (2021). Nigerian Journal of Physiological Sciences, 31(1), 001-010. https://ojshostng.com/index.php/njphysiologicalsciences/article/view/1846

Abstract

Summary: Nephrotoxicity remains a common untoward effect of cisplatin therapy with limited effective chemopreventive options available till date. This study aims to evaluate the possible chemopreventive effect and mechanism(s) of action of 2 mgkg-1 and 5 mgkg-1 of Tadalafil in cisplatin-induced nephrotoxic rats. In this study, twenty-five male Wistar rats were randomly divided into five groups (n = 5 rats per group) and daily pretreated with oral doses of distilled water (10 mLkg-1), ascorbic acid (100 mgkg-1), Tadalafil (2 mgkg-1 and 5 mgkg-1) for 7 days before cisplatin (5 mgkg-1, intraperitoneal) was administered. 72 hours post-cisplatin injections, rats were sacrificed humanely and blood samples for serum electrolytes, urea and creatinine and renal tissues for reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malonialdehyde dehydrogenase (MAD) assays and histopathology were collected. Results showed that cisplatin injection caused significant decreases in the serum sodium (Na+), potassium (K+), bicarbonate (HCO3-), calcium (Ca2+), phosphate (PO42-) and concomitant significant increases in the serum urea and creatinine levels. In addition, there were significant decreases in the renal tissue GSH, SOD, CAT and increased MAD and GSH-Px levels which were corroborated by histopathological features of tubulonephritis. However, these histo-biochemical alterations were significantly attenuated by ascorbic acid and Tadalafil pretreatments. Overall, results of this study showed the chemopreventive potential of Tadalafil against cisplatin-induced nephrotoxicity which was possibly mediated via antioxidant and anti-lipoperoxidation mechanisms.

Click to view file (PDF)

References

Aebi, H. (1984) Catalase In vitro In: Colowick, S.P., Kaplane, N.O., editors. Methods in Enzymology 105: 121-126.

Ajiboye, K.I., Oluwole, F.S. (2012). Possible mechanisms for the anti-ulcer protective activity of Tadalafil, a type V phosphodiesterase inhibitor on indomethacin-induced gastric ulceration in rats. European Journal of Scientific Research 89(3): 350-358.

Bishara, B., Abu-Saleh, N., Awad, H., et al. (2012). Phosphodiesterase 5 inhibition protects against increased intra-abdominal pressure-induced renal dysfunction in experimental congestive heart failure. European Journal of Heart Failure 14(10): 1104-1111.

Broderick, G.A., Donatucci, C.F., Hatzichristou, D., et al. (2006). Efficacy of tadalafil in men with erectile dysfunction naïve to phosphodiesterase-5 inhibitor therapy compared with prior responders to sildenafil citrate. Journal of Sexual Medicine 3(4): 668-675.

Buege, J.A., Aust, S.D. (1978). Microsomal lipid peroxidation. Methods in Enzymology 52: 302-310.

Capizzi, R.L. (1999). Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin: laboratory and clinical aspects. Seminars in Oncology 26(2 Suppl 7): 72-81.

Chen-zhe, J., Lihyun, H., Seyoung, C. (2012). Decursin mediated protection on cisplatin-induced nephrotoxicity in SD rats and BDF1 mice. Journal of Northeast Agricultural University 19(1): 50-56.

Chirino, Y.I., Hernández-Pando, R., Pedraza-Chaverrí, J. (2004). Peroxynitrite decomposition catalyst ameliorates renal damage and protein nitration in cisplatin-induced nephrotoxicity in rats. BMC Pharmacology 4: 20.

Cornelison, T.L., Reed, E. (1993). Nephrotoxicity and hydration management for cisplatin, carboplatin, and ormaplatin. Gynecologic Oncology 50(2): 147-158.

Deng, J., Kohda, Y., Chiao, H., et al. (2001). Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney International 60(6): 2118-2128.

Eardley, I., Gentile, V., Austoni, E., et al. (2004). Efficacy and safety of tadalafil in a Western European population of men with erectile dysfunction. British Journal of Urology International 94(6): 871-877.

Egerdie, R.B., Auerbach, S., Roehrborn, C.G., et al. (2012). Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study. J Sex Med 9(1): 271-281.

Ekborn, A., Lindberg, A., Laurell, G., et al. (2003). Ototoxicity, nephrotoxicity and pharmacokinetics of cisplatin and its monohydrated complex in the guinea pig. Cancer Chemotherapy and Pharmacology 51(1): 36-42.

Ellman, G.L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics 17: 214-226.

El-Sayed E-S. M., Abd-Ellah M.F., Attia, S.M. (2008). Protective effect of captopril against cisplatin-induced nephrotoxicity in rats. Pakistani Journal of Pharmaceutical Sciences 21(3): 255-261.

El-Sherbeeny, N.A., Attia, G.M. (2016). The protective effect of trimetazidine against cisplatin-induced nephrotoxicity in rats. Canadian Journal of Physiology and Pharmacology 94(7): 745-751

Gaetani, G.F., Galiano, S., Canepa, L., et al. (1989). Catalase and glutathione peroxidase are equally effective in detoxification of hydrogen peroxide in human erythrocytes. Blood 73: 334-339.

Go, R.S., Adjei, A.A. (1999). Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. Journal of Clinical Oncology 17: 409-422.

Gowda, S., Desai, P.B., Kulkarni, S.S., et al. (2010). Markers of renal function tests. North American Journal of Medical Sciences 2: 170-173.

Greggi-Antunes, L.M., Darin, J.D.C., Bianchi, M.D.P. (2000). Protective effects of vitamin C against cisplatin-induced nephrotoxicity and lipid peroxidation in adult rats: A dose-dependent study. Pharmacological Research 41(4): 405-411.

Hakim, R.M., Lazarus, J.M. (1988). Biochemical parameters in chronic renal failure. American Journal of Kidney Disease 11(3): 238-247.

Hekmat, S., Ardekani, M.S., Ebrahimi, S.E.S., et al. (2013). Tadalafil and gastrointestinal relaxivity effects. Pharmacologia 4(1): 60-64.

Hoitsma, A.J., Wetzels, J.F., Koene, R.A. (1991). Drug-induced nephrotoxicity: Aetiology, clinical features and management. Drug Safety 6(2): 131-147.

Humbert, M., Sitbon, O., Simonneau, G. (2004). Treatment of pulmonary arterial hypertension. New England Journal of Medicine 351: 1425-1436.

Kadikoylu, G., Bolaman, Z., Demir, S., et al. (2004). The effects of desferrioxamine on cisplatin-induced lipid peroxidation and the activities of antioxidant enzymes in rat kidneys. Human and Experimental Toxicology 23: 29-34.

Karimi, G., Ramezani, M., Tahoonian, Z. (2005). Cisplatin nephrotoxicity and protection by milk thistle extract in rats. Evidence Based Complementary and Alternative Medicine 2(3): 383-386.

Kawai, Y., Nakao, T., Kunimura, N., et al. (2006). Relationship of intracellular calcium and oxygen radicals to cisplatin-related renal cell injury. Journal of Pharmacological Sciences 100(1): 65-72.

Kilic, U., Kilic, E., Tuzcu, Z., et al. (2013). Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway. Nutrition & Metabolism 10: 7.

Kintzel, P.E. (2001). Anticancer drug-induced kidney disorders. Drug Safety 24(1): 19-38.

Kodama, A., Watanabe, H., Tanaka, R., et al. (2014) Albumin fusion renders thioredoxin an effective anti-oxidative and anti-inflammatory agent for preventing cisplatin-induced nephrotoxicity. Biochimica et Biophysica Acta 1840: 1152-1162

Kohda, Y., Kawai, Y., Iwamoto, M., et al. (2005). Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation. Biochemical Pharmacology 70(9): 1408-1416.

Koka, S., Das, A., Zhu, S.G., et al. (2010). Long acting phosphodiesterase-5 inhibitor tadalafil attenuates doxorubicin-induced cardiomyopathy without interfering with chemotherapeutic effect. Journal of Pharmacology and Experimental Therapeutics 334(3): 1023-1030.

La Vignera, S., Condorelli, R.A., Vicari, E., et al. (2012). Endothelial antioxidant compound prolonged the endothelial anti-apoptotic effects registered after tadalafil treatment in patients with arterial erectile dysfunction. Journal of Andrology 33(2): 170-175.

La Vignera, S., Condorelli, R.A., Vicari, E., et al. (2011). Endothelial apoptosis decrease following tadalafil administration in patients with arterial ED does not last after its discontinuation. International Journal of Impotence Research 23(5): 200-205.

Laties, A.M. (2009). Vision disorders and phosphodiesterase type 5 inhibitors: A review of the evidence to date. Drug Safety 32: 1-18.

Lawrence, R.A., Burk, R.F. (1976). Glutathione peroxidase activity in selenium-deficient rat liver. Biochemical and Biophysical Research Communication 71: 952-958.

Li, G., Sha, S.H., Zotova, E., et al. (2002). Salicylate protects hearing and kidney function from cisplatin toxicity without compromising its oncolytic action. Laboratory Investigation 82(5): 585-596.

Li, J., Xu, Z., Jiang, L., et al. (2014) Rictor/mTORC2 protects against cisplatin-induced tubular cell death and acute kidney injury. Kidney International 86: 86-102.

Li, J., Gui, Y., Ren, J., et al. (2016). Metformin protects against cisplatin-induced tubular cell apoptosis and acute kidney injury via AMPKα-regulated autophagy induction. Scientific Reports 6: Article number 23975

Lieberthal, W., Triaca, V., Levine, J. (1996). Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis. American Journal of Physiology 270: F700-708.

Lynch, E.D., Gu, R., Pierce, C., et al. (2005). Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen. Hearing Research 201(1-2): 81-89.

Miller RP, Tadagavadi RK, Ramesh G, et al. (2010). Mechanisms of cisplatin nephrotoxicity. Toxins 2: 2490-2518.

Modesti, P.A., Burberi, F., Moroni, F. (2003). Drug-induced nephropathy. Annali Italiani di Medicina Interna 18(3): 126-135.

Mora, L.O., Greggi-Antunes, L.M., Francescato, H.D., et al. (2003). The effects of oral glutamine on cisplatin-induced nephrotoxicity in rats. Pharmacological Research 47(6): 517-522.

Morgan, K.P., Buie, L.W., Savage, S.W. (2012). The role of mannitol as nephroprotectant in patients receiving cisplatin therapy. The Annals of Pharmacotherapy 46(2): 276-281.

Nagothu, K.K., Bhatt, R., Kaushal, G.P., et al. (2005). Fibrate prevents cisplatin-induced proximal tubule cell death. Kidney International 68(6): 2680-2693.

National Institutes for Health (1985). Guide for the Care and Use of Laboratory Animals. NIH Publication no. 85-23, United States National Institutes for Health, Bethesda, U.S.A.

Naughton, C.A. (2008). Drug-induced nephrotoxicity. American Family Physician 78(6): 743-750.

Nisar, S., Feinfeld, D.A. (2002). N-acetylcysteine as salvage therapy in cisplatin nephrotoxicity. Renal Failure 24: 529-533.

Oudot, A., Behr-Roussel, D., Le Coz, O, et al. (2009). How does chronic sildenafil prevent vascular oxidative stress in insulin-resistant rats? Journal of Sexual Medicine 7(1 Pt1): 79-88.

Ozkok, A., Edelstein, C.L. (2014). Pathophysiology of cisplatin-induced acute kidney injury. BioMed Research International Article ID 967826, 17 pages.

Padma-Nathan, J. (2003). Efficacy and tolerability of tadalafil, a novel phosphodiesterase-5 inhibitor, in treatment of erectile dysfunction. American Journal of Cardiology 92(9A): 19M-25M.

Paller, M.S. (1990). Drug-induced nephropathies. Medical Clinics of North America 74(4): 909-917.

Perk, H., Armagan, A., Naziroğlu, M., et al. (2008) Sildenafil citrate as phosphodiesterase inhibitor has an antioxidant effect in the blood of men. Journal of Clinical Pharmacology and Therapeutics 33(6): 635-640.

Pisansky, T.M., Pugh, S.L., Greenberg, R.E., et al. (2014). Tadalafil for prevention of erectile dysfunction after radiotherapy for prostate cancer: The Radiation Therapy Oncology Group [0831] Randomized Clinical Trial. JAMA 311(13): 1300-1307.

Porst, H., Giuliano, F., Glina, S., et al. (2006). Evaluation of the efficacy and safety of once-a-day dosing of tadalafil 5 mg and 10 mg in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled trial. European Urology 50(2):351-359.

Prabhu, V.V., Kannan, N., Guruvayoorappan, C. (2013). 1,2-diazole prevents cisplatin-induced nephrotoxicity in experimental rats. Pharmacological Report 65(4): 980-990.

Perazella, M.A. (2003). Drug-induced renal failure: update on new medications and unique mechanisms of nephropathy. American Journal of Medical Sciences 325(6): 349-362.

Sadzuka, Y., Shoji, T., Takino, Y. (1992a) Effect of cisplatin on the activities of enzymes which protect against lipid peroxidation. Biochemical Pharmacology 43: 1872-1875.

Sadzuka, Y., Shoji, T., Takino, Y. (1992b). Mechanism of the increase in lipid peroxide induced by cisplatin in the kidneys of rats. Toxicology Letters 62: 293-300.

Sadzuka, Y., Shimizu, Y., Takino, Y. (1994) Role of glutathione S-transferase isoenzymes in cisplatin-induced nephrotoxicity in the rat. Toxicology Letters 70: 211-222.

Saka, W., Akhigbe, R., Popoola, O., et al. (2012). Changes in serum electrolyte, urea and creatinine in Aloe vera-treated rats. Journal of Young Pharmacists 4(2): 78-81.

Santoso, J.T., Lucci, J.A. III, Coleman, R.L., et al. (2003)Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a randomized trial. Cancer Chemotherapy and Pharmacology 52(1): 13-18.

Schetz, M., Dasta, J., Goldstein, S., et al. (2005). Drug-induced acute kidney injury. Current Opinions in Critical Care 11(6): 555-565.

Sedlak, J., Lindsay, R.H. (1968). Estimation of total, protein-bound, and non-protein sulfhydryl groups in tissue with Ellman's reagent. Analytical Biochemistry 25(1): 192-205.

Serarslan, Y., Yönden, Z., Ozgiray, E., et al. (2010) Protective effects of tadalafil on experimental spinal cord injury in rats. Journal of Clinical Neurosciences 17: 349-352.

Shimeda, Y., Hirotani, Y., Akimoto, Y., et al. (2005). Protective effects of capsaicin against cisplatin-induced nephrotoxicity in rats. Biological & Pharmaceutical Bulletin 28(9): 1635-1638.

Shino, Y., Itoh, Y., Kubota, T., et al. (2003). Role of poly(ADP-ribose-)polymerase in cisplatin-induced injury in LLC-PK1 cells. Free Radicals Biology & Medicine 35(8): 966-977.

Somani, S.M., Husain, K., Withworth, C., et al. (2008). Dose-dependent protection of lipoic acid against cisplatin-induced nephrotoxicity in rats: Antioxidant defense system. Pharmacology & Toxicology 86(5): 234-241.

Sun, M., Zigma, S. (1978). An improved spectrophotometric assay of superoxide dismutase based on ephinephrine antioxidation. Analytical Biochemistry 90: 81-89.

Tanaka, H., Ishikawa, E., Teshima, S., et al. (1986). Histopathological study of human cisplatin nephropathy. Toxicological Pathology 14(2): 247-257.

Tew, K., Colvin, M., Chabner, B.A. (2001). Alkylating agents. In: Chabner, B.A., Longo, D.L., editors. Cancer Chemotherapy and Biotherapy: Principles and Practice. 3rd ed., Lippincott Williams and Witkins, Philadelphia, pp: 373-414.

Tietz, N.W., Pruden, E.L., Siggaard-Anderson, O. (1994). In: Burtis, C.A., Ashwood, E.R., editors. Tietz Textbook of Clinical Chemistry. W.B. Saunders Company, London, pp. 1354-1374.

Usho, I.F., Akpan, E.J., Etim, E.O., et al. (2005). Antioxidant actions of dried flower extracts of Hibiscus sabdariffa L. on sodium arsenite-induced oxidative stress in rats. Pakistani Journal of Nutrition 4(3): 135-141.

Varley, H., Alan, H.G. (1984). Tests in renal disease. In: Practical Clinical Biochemistry. William Heinemann Medical Book Ltd., London, vol. 1123.

Vermeulen, N.P., Baldew, G.S., Los, G., et al. (1993) Reduction of cisplatin nephrotoxicity by sodium selenite. Lack of interaction at the pharmacokinetic level of both compounds. Drug Metabolism and

Disposition 21(1): 30-36.

Viale, M., Vannozzi, M.O., Pastrone, I., et al. (2000). Reduction of cisplatin nephrotoxicity by procainamide: does the formation of a cisplatin-procainamide complex play a role? Journal of Pharmacology and Experimental Therapeutics 293(3): 829-836.

Vickers, A.E., Rose, K., Fisher, R., et al. (2004). Kidney slices of human and rat to characterize cisplatin-induced injury on cellular pathways and morphology. Toxicological Pathology 32(5): 577-590.

Yao, X., Panichpisal, K., Kurtzman, N., et al. (2007). Cisplatin nephrotoxicity: A review. American Journal of Medical Sciences 334(2): 115-124.

Yildirim, Z., Sogut, S., Odaci, E., et al. (2003). Oral erdosteine administration attenuates cisplatin-induced renal tubular damage in rats. Pharmacological Research 47(2): 149-156.

Yilmaz, H.R., Iraz, M., Sogut, S., et al. (2004). The effects of erdosteine on the activities of some metabolic enzymes during cisplatin-induced nephrotoxicity in rats. Pharmacological Research 50(3): 287-290.

Zager, R.A. (1997). Pathogenetic mechanisms in nephrotoxic acute renal failure. Seminars in Nephrology 17(1): 3-14.

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.