The Effect of Montelukast on Liver Damage in an Experimental Obstructive Jaundice Model

Serdar Kuru, Kemal Kismet, Aziz M Barlas, Salih Tuncal, Pinar Celepli, Hatice Surer, Elmas Ogus, Ertugrul Ertas, Serdar Kuru, Kemal Kismet, Aziz M Barlas, Salih Tuncal, Pinar Celepli, Hatice Surer, Elmas Ogus, Ertugrul Ertas

Abstract

Background: Montelukast is a cysteinyl-leukotriene type 1 (CysLT1) selective receptor antagonist. In recent years, investigations have shown that montelukast possesses secondary anti-inflammatory activities and also antioxidant effects. For this reason, we aimed to determine the possible effects of montelukast on liver damage in experimental obstructive jaundice.

Methods: 30 Wistar-Albino male rats were randomized and divided into three groups of 10 animals each: group I, sham-operated; group II, ligation and division of the common bile duct (BDL) followed by daily intraperitoneal injection of 1 ml of saline; group III, BDL followed by daily intraperitoneal injection of 10 mg/kg montelukast dissolved in saline. The animals were killed on postoperative day 7 by high-dose diethyl ether inhalation. Blood and liver samples were taken for examination.

Results: In this study, liver malondialdehyde (MDA) (p = 0.001), myeloperoxidase (p = 0.003), and total sulfhydryl (SH) (p = 0.009) were found to be significantly different between the BDL + montelukast and the BDL groups. Plasma total SH (p = 0.002) and MDA (p = 0.027) values were also statistically different between these groups. Statistical analyses of histological activity index scores showed that the histopathological damage in the BDL + montelukast group was significantly less than the damage in the control group (p < 0.05 for all pathological parameters).

Conclusion: According to the results of this study, montelukast showed a significant hepatoprotective effect in this experimental obstructive jaundice model, which might be due to its antioxidant and anti-inflammatory activities.

Keywords: Hepatobiliary diseases; Histopathology; Montelukast; Obstructive jaundice; Oxidative stress.

Figures

Fig. 1
Fig. 1
Group I: Terminal branch of the portal vein (pv), terminal branch of the hepatic artery (a), bile duct (marked with arrow). a, b Portal area: Bile ducts and branches of the hepatic artery located at the periphery of the portal vein. c Hepatocytes with one or two polygonal nuclei (H & E, ×400).
Fig. 2
Fig. 2
Group II: Histopathological changes in the portal areas (a-d). Significant bile duct proliferation in the portal areas, swelling of hepatocytes, and sinusoidal dilatation (H & E, ×100, ×100, ×200, ×200).
Fig. 3
Fig. 3
Group III: Histopathological changes in the portal areas (a-c). Bile duct proliferation in the portal areas, swelling of hepatocytes, and congestion of portal veins (H & E, ×100, ×200, ×400).

References

    1. Kismet K, Sabuncuoğlu MZ, Kilicoglu SS, et al. Effect of propolis on oxidative stress and histomorphology of liver tissue in experimental obstructive jaundice. Eur Surg Res. 2008;41:231–237.
    1. Guicciardi ME, Gores GJ. Apoptosis: a mechanism of acute and chronic liver injury. Gut. 2005;54:1024–1033.
    1. Scott-Conner CEH, Grogan JB. The pathophysiology of biliary obstruction and its effect on phagocytic and immune function. J Surg Res. 1994;57:316–336.
    1. Kilicoglu B, Gencay C, Kismet K, et al. The ultrastructural research of liver in experimental obstructive jaundice and effect of honey. Am J Surg. 2008;195:249–256.
    1. Tintinger GR, Feldman C, Theron AJ, Anderson R. Montelukast: more than a cysteinyl leukotriene receptor antagonist? Sci World J. 2010;10:2403–2413.
    1. Sener G, Kabasakal L, Cetinel S, Contuk G, Gedik N, Yegen BC. Leukotriene receptor blocker montelukast protects against burn-induced oxidative injury of the skin and remote organs. Burns. 2005;31:587–596.
    1. Tugtepe H, Sener G, Cetinel S, Velioglu-Ogunc A, Yegen BC. Oxidative renal damage in pyelonephritic rats is ameliorated by montelukast, a selective leukotriene CysLT1 receptor antagonist. Eur J Pharmacol. 2007;557:69–75.
    1. Coskun AK, Yigiter M, Oral A, et al. The effects of montelukast on antioxidant enzymes and proinflammatory cytokines on the heart, liver, lungs, and kidneys in a rat model of cecal ligation and puncture-induced sepsis. Sci World J. 2011;11:1341–1356.
    1. Mohamadin AM, Elberry AA, Elkablawy MA, Gawad HS, Al-Abbasi FA. Montelukast, a leukotriene receptor antagonist abrogates lipopolysaccharide-induced toxicity and oxidative stress in rat liver. Pathophysiology. 2011;18:235–242.
    1. Wasowicz W, Neve J, Peretz A. Optimized steps in fluorometric determination of thiobarbituric acid-reactive substance in serum: importance of extraction pH and influence of sample preservation and storage. Clin Chem. 1993;39:2522–2526.
    1. Sedlak J, Lindsay RH. Estimation of total, protein bound, and non-protein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968;25:192–205.
    1. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol. 1982;78:206–209.
    1. Ishak K. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696–699.
    1. Ishak KG. Pathologic features of chronic hepatitis. A review and update. Am J Clin Pathol. 2000;113:40–55.
    1. Koca G, Gültekin SS, Ünsal H, Kuru S, Demirel K, Korkmaz M. The efficacy of montelukast as a protective agent against 131I-induced salivary gland damage in rats: scintigraphic and histopathological findings. Nucl Med Commun. 2013;34:507–517.
    1. Cuciureanu M, Căruntu ID, Păduraru O, et al. The protective effect of montelukast sodium on carbon tetrachloride induced hepatopathy in rat. Prostaglan Other Lipid Mediat. 2009;88:82–88.
    1. Farzaneh-Far R, Moore K. Cysteinyl-leukotrienes and the liver. Prostaglan Other Lipid Mediat. 2003;72:35–50.
    1. Paggiaro P, Bacci E. Montelukast in asthma: a review of its efficacy and place in therapy. Ther Adv Chronic Dis. 2011;2:47–58.
    1. Aller MA, Arias JL, García-Domínguez J, Arias JI, Durán M, Arias J. Experimental obstructive cholestasis: the wound-like inflammatory liver response. Fibrogenesis Tissue Repair. 2008;1:6.
    1. Lechner AJ, Velasquez A, Knudsen KR, et al. Cholestatic liver injury increases circulating TNF-α and IL-6 and mortality after Escherichia coli endotoxemia. Am J Respir Crit Care Med. 1998;157:1550–1558.
    1. Ding JW, Andersson R, Soltesz V, et al. Obstructive jaundice impairs reticuloendothelial function and promotes bacterial translocation in the rat. J Surg Res. 1994;57:238–245.
    1. Padillo FJ, Cruz A, Navarrete C, et al. Melatonin prevents oxidative stress and hepatocyte cell death induced by experimental cholestasis. Free Radic Res. 2004;38:697–704.
    1. Baron V, Muriel P. Role of glutathione, lipid peroxidation and antioxidants on acute bile duct obstruction in the rat. Biochim Biophys Acta. 1999;1472:173–180.
    1. Ljubuncic P, Tanne Z, Bomzon A. Evidence of a systemic phenomenon for oxidative stress in cholestatic liver disease. Gut. 2000;47:710–716.
    1. Pizzimenti S, Ciamporcero E, Daga M, et al. Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Front Physiol. 2013;4:242.
    1. Malle E, Furtmuller PG, Sattler W, Obinger C. Myeloperoxidase: a target for new drug development? Br J Pharmacol. 2007;152:838–854.
    1. Hill BG, Ramana KV, Jian Cai J, Bhatnagar A, Srivastava SK. Measurement and identification of s-glutathiolated proteins. Methods Enzymol. 2010;473:179–197.
    1. Gideroglu K, Yilmaz F, Aksoy F, Bugdayci G, Saglam I, Yilmaz F. Montelukast protects axial pattern rat skin flaps against ischemia/reperfusion injury. J Surg Res. 2009;157:181–186.
    1. Ozkan E, Yardimci S, Dulundu E, Topaloğlu U, Sehirli O, Ercan F, Velioğlu-Oğünç A, Sener G. Protective potential of montelukast against hepatic ischemia/reperfusion injury in rats. J Surg Res. 2010;159:588–594.
    1. Steib CJ, Bilzer M, op den Winkel M, Pfeiler S, Hartmann AC, Hennenberg M, Göke B, Gerbes AL. Treatment with the leukotriene inhibitor montelukast for 10 days attenuates portal hypertension in rat liver cirrhosis. Hepatology. 2010;51:2086–2096.
    1. Alturfan AA, Aytaç E, Emekli-Alturfan E, Yarat A, Sarıbeyoğlu K, Pekmezci S, Seymen O. Serum total sialic acid as a novel complementary candidate marker of hepatic damage in obstructive jaundice. Ann Clin Lab Sci. 2014;44:56–61.
    1. Wang G, Xiu P, Li F, Xin C, Li K. Vitamin A supplementation alleviates extrahepatic cholestasis liver injury through Nrf2 activation. Oxid Med Cell Longev. 2014;2014:273692.
    1. Kosar NM, Tosun M, Polat C, Kahraman A, Arikan Y. Hepatocyte apoptotic index and p53 expression in obstructive jaundice rats. Bratisl Lek Listy. 2014;115:352–356.
    1. Zhou YX, Ni Y, Liu YB, Liu X. Histone preconditioning protects against obstructive jaundice-induced liver injury in rats. Exp Ther Med. 2014;8:15–20.

Source: PubMed

3
Tilaa