Zeliha Türkyılmaz, Ahmet Hatipoğlu, Mahmut Yüksel, Nurettin Aydoğdu, Gülara Hüseyinova

Comparison of effects of melatonin, pentoxifylline and dimethyl sulfoxide in experimental liver ischemia-reperfusion injury by three different methods

Objectives: Liver transplantation is increasingly being used in the treatment of end-stage liver disease.Ischemia-reperfusion injury is one of the major problems encountered in transplantation. In this study, weaimed to compare the effects of melatonin, pentoxifylline, and dimethyl sulfoxide (DMSO), in hepatic ischemiareperfusion injury with different methods such as biochemical/ultrastructural changes and hepatobiliaryscintigraphy.Methods: Thirty rabbits were used in the Laboratory of Experimental Animals of Trakya University underappropriate conditions. Sham laparotomy and only ischemia reperfusion group were planned. They were usedmelatonin, pentoxifylline, and DMSO after I-R in the other three groups. 6 rabbits were randomly selected foreach group. Rabbits in all groups were subjected to liver scintigraphy. Following scintigraphy, 2 cm2 of livertissue was removed to examining for liver antioxidant enzyme levels (superoxide dismutase [SOD] andglutathione peroxidase [GPx]) and for liver electron microscopy.Results: Pentoxifylline and melatonin protected significantly uptake and excretion functions in liverscintigraphy. When the effects of all three substances were examined by electron microscopy, it was found thatthe three substances protected the liver from the effects of ischemia-reperfusion damage at varying rates. Allthree agents were found to protect SOD and GPx from falling in various amounts.Conclusions: Studies to prevent ischemia-reperfusion injury, which may develop as a result of the Pringlemaneuver applied to liver transplantations as well as to liver resections or liver injuries, still maintain theirpopularity. In our study, the effects of agents were identified in three different ways. Ischemia-reperfusioninjury-reducing effect of pentoxifylline gave parallel results with three methods.

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[1] Pringle JG. Notes on the arrest of hepatic hemorrhage due to trauma. Ann Surg 1908;48:541-9.
[2] Park SW, Lee SM. Antioksidant and prooksidant properties of ascorbic acid on hepatic dysfunction induced by cold ischemia-reperfusion, Eur J Pharmacol 2008;580:401-6.
[3] Grossine E, Pollesello P, Bellofatto K, Siguado L, Farruggio S, Origlia V, et al. Protective effects elicited by levosimendan against liver ischemia/reperfusion injury in anesthetized rats. Liver Transpl 2014;20:361-75.
[4] Lee SM, Park MJ, Cho TS, Clemens MG. Hepatic injury and lipid peroxidation during ischemia and reperfusion. Shock 2000;13:279-84.
[5] Reiter RJ, Tan DX, Galano A. Melatonin: exceeding expectations. Physiology 2014;29:325-33.
[6] Hatipoglu AR, Temiz E, Yuksel M, Hoscoskun Z, Coskun I, Huseyinova G. The comparison of electron microscopy and scintigraphy in determining the protective effect of DMSO on ischemiae/reperfusion injury in rats. Hepatogastroenterology 2001;48:798-802.
[7] El-Ghoneimi A. Inhibition of tumor necrosis factor alpha gene transcription by pentoxifylline reduces normothermic liver ischemia-reperfusion injury in rats. Tranplant Proc 2007;39:1761- 4.
[8] Wang WY, Taki Y, Monimoto T, Nishihira T, Yokoo N, Jikko A. Effects of partial ischemia and reflow on mitochondrial metabolism in rat liver. Eur Surg Res 1988;20:181-9.
[9] Halliwell B. Oxidative stress, nutrition health, exprimental strategies for optimization of nutritional antioxidant intake in humans. Free Radic Res 1996;25:57-74.
[10] Valko M, Jomova K, Rhodes CJ, Kuca K, Musilek K. Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol 2016;90:1- 37.
[11] Barber DA, Harris SR. Oxygen free radicals and antioxidants: a review. Am Pharm 1994;34:26-35.
[12] Romani F, Vertamati M, Frangi M, Aseni P, Monti R, Codeghini A, et al. Effects of superoksid dismutase on liver ischemia reperfusion injury in the rat: a biochemical monitoring. Eur Surg Res1988:20:335-40.
[13] Jaeschke H. Molecular mechanisms of hepatic ischemiareperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003;284:15-21.
[14] McCord JM, Edeas MA. SOD, oxidative stress and human pathologies: a brief history and a future vision. Biomed Pharmacother 2005;59:139-42.
[15] Hatipoglu A, Turkyılmaz Z, Mert S. The effects of melatonin on postoperative intraabdominal adhesion formation. Yonsei Med J 2007;48:659-64.
[16] Tan DX, Chen LD, Poeggeler B, Manchrter LC, Reiter RJ. Melatonin: a potent, endogenous hidroxyl radical scavenger. Endocr J 1993;1:57-60.
[17] Reiter RJ. Melatonin: lowering the high price of free radicals. News Physiol Sci 2000;15:246-50.
[18] Baykara B, Tekmen I, Pekcetin C, Ulukus C, Tuncel P, Sagol O, et al. The protective effects of carnosine and melatonin in ischemia-reperfusion injury in the rat liver. Acta Histochem 2009;111:42-51.
[19] Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR. Significance of melatonin in the antioxidativedefence system: reactions and products. Biol Signals Recept 2000;9:137- 59.
[20] Sewerynek E, Reiter RJ, Melchiorri D, Ortiz GG, Lewinski A. Oxidative damage in the liver induced by ischemiareperfusion: protection by melatonin. Hepatogastroenterology 1996;43:898-905.
[21] Kim SH, Lee SM. Cytoprotective effects of melatonin against necrosis and apoptosis induced by ischemia/reperfusion injury in rat liver. J Pineal Res 2008;44:165-71.
[22] Aktoz T, Aydoğdu N, Alagol B, Yalçın O, Hüseyinova G, Atakan IH. The protective effects of melatonin and vitamin E against renal ischemia-reperfusion injury in rats. Ren Fail 2007;29:535-42.
[23] Adams GA, Dhar A, Shukla SD, Silver D. Effects of pentoxifylline on tissue injury and platelet activating factor production during ischemia-reperfusion injury. J Vasc Surg 1995;21:742-8.
[24] Genoves P, Garcia D, Cejalvo D, Martin A, Zaragoza C,Toledo AH, et al. Pentoxifylline in liver ischemia and reperfusion. J Invest Surg 2014;27:114-24.
[25] Dinckan A, Sahin E, Oguz M, Emek K, Gumuslu S. The effect of pentoxifylline on oxidative stress in CO2 pneumoperitoneum.Surg Endosc 2009;23:534-8.
[26] Hammerman C, Goldschimidt D, Caplan MS, Eidelman AY, Branki D, Hochman A. Amelioration of ischemia-reperfusion injury in rat intestine by pentoxifylline-mediated inhibition of xanthine oxidase. J Pediatr Gastroenterol Nutr 1999;29:69-74.
[27] Inal M, Kanbak G, Adali M. Prevention of ischemiareperfusion-induced oxidative injury in liver by allopurinol and pentoxifylline. Transplantationsmedizin 2006;18:29-32.
[28] Petrowsky H, Breitenstein S, Slankamenac K, Vetter D, Lehmann K, Heinrich S, et al. Effects of Pentoxifylline on liver regeneration: A double-blinded, randomized; controlled trial in 101 patients undergoing major liver resection. Ann Surg 2010;252:813-22.
[29] Akyurek N, Kafali EM, Muhtaroglu S. The effects of dimethylsulfoxide on experimental hepatic ischemia. Swiss Surg 2000;6:23-7.
[30] Nishihara G, Sakemi T, Ikeda Y. Multiple organ failure associated with dimethyl sulfoxide and hiroxyethylstrach in autologous blood stem cell transplantation. Nephron 1996;72:356-7.
[31] Sahin M, Avsar FM, Ozel H, Topalaoglu S, Yilmaz B, Pasaoglu H, et al. The effects of dimethyl sulfoxide on liver damage caused by ischemia-reperfusion. Tranplant Proc 2004;36:2590-2.
[32] Loken MK, Ascher NL, Boudreau RJ, Najarian JS. Scintigraphic evaluation of liver transplant function. J Nucl Med 1986;27:451-9.
[33] Graaf W, Bennink R, Vetelainen R, Guulik T. Nuclear imaging techniques for the assessment of hepatic function in liver surgery and transplantation. J Nucl Med 2010;51:742-52.
[34] Ekman M, Fjalling M, Holmberg S, Person H. IODIDA clearance rate: a method for measuring hepatocyte uptake function. Tranplant Proc1992;24:387-8.
[35] Vetelainen RL, Bennink RJ, De Bruin K, Van Vliet A, Van Gulik TM. Hepatobiliary function assessed by 99mTcmebrofenin cholescintigraphy in the evaluation of severity of steatosis in a rat model. Eur J Nucl Med Mol Imaging 2006;33:1107-14.
[36] Kurzawinski TR, Selves L, Farouk M, Dooley J, Hilson A, Buscombe JR, et al. Prospective study of hepatobiliaryscintigraphy and endoscopic cholangiography for the detection of early biliary complications after orthotopic liver transplantation. Br J Surg 1997;84:620-3.
[37] Brunot B, Petras S, Germain P, Vinee P, Constantinesco A. Biopsy and quantitative hepatobiliaryscintigraphy in the evaluation of liver transplantation. J Nucl Med 1994;35:1321-7.
[38] Kim JS, Moon DH, Lee SG, Lee YJ, Park KM, Hwang S, et al. The usefulness of hepatobiliaryscintigraphy in the diagnosis of complications after adult-to-adult living donor liver transplantation. Eur J Nucl Med Mol Imaging 2002;29:473-9.
[39] Tagge EP, Champbell D Jr, Reichie R. Quantitative hepatic scintigrapy to evaluate ischemic-reperfusion injury in porcine liver transplantation. Tranplant Proc 1987;1:1095-7.
[40] Kuni CC, Engeler CM, Nakhieh RE, Du Cret RP, Boudreau RJ. Correlation of technetium-99m-DISIDA hepatobiliary studies with biopsies in liver transplant patients. J Nucl Med 1991;32:1545-7.