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Renoprotective effects of montelukast, a cysteinyl leukotriene receptor antagonist, against methotrexate-induced kidney damage in rats

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Abstract

Methotrexate (MTX) is a cytotoxic chemotherapeutic agent used for treatment of several cancers. Nephrotoxicity, an adverse side effect of high-dose MTX, is attributed to abnormal production of reactive oxygen species (ROS), inflammatory mediators, and neutrophil infiltration. Montelukast (MON) is a cysteinyl leukotriene receptor antagonist. Recently, it has gained a considerable interest as a ROS scavenger and inflammatory modulator. In this study, we investigated the effect of MON against MTX-induced nephrotoxicity. Rats were divided into four groups: control group, MON group (10 mg/kg, orally), MTX group (20 mg/kg, i.p., single injection), and MON + MTX group (MON was administered 5 days before and 5 days after MTX administration). At the end of the experiment, serum was collected for analysis of blood urea nitrogen (BUN) and creatinine. Glutathione (GSH), lipid peroxides (malondialdehyde), tumor necrosis factor alpha (TNF-α) levels, superoxide dismutase, myeloperoxidase activities, and nuclear factor kappa beta (NF-κB) protein expression were determined in renal tissues. In addition, kidney tissues were examined histopathologically and immunohistochemically for NF-κB. MTX administration produced acute renal damage as indicated from severe elevation in BUN and serum creatinine. The role of oxidative stress and inflammatory mechanisms in MTX-induced nephrotoxicity was evidenced from the unbalance in tissue oxidative parameters, increased TNF-α levels, and NF-κB expression in renal tissues. On the other hand, MON significantly reduced the toxic effects of MTX as indicted from normalization of kidney-specific parameters, oxidative stress, and inflammatory mediators. This data was further supported by histopathological studies. Thus, co-administration of MON may be promising in alleviating the systemic side effects of MTX.

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References

  • Abraham P, Kolli VK, Rabi S (2010) Melatonin attenuates methotrexate-induced oxidative stress and renal damage in rats. Cell Biochem Funct 28:426–433

    Article  PubMed  CAS  Google Scholar 

  • Alam MK, Sutradhar SR, Pandit H, Ahmed S, Bhattacharjee M, Miah AH et al (2012) Comparative study on methotrexate and hydroxychloroquine in the treatment of rheumatoid arthritis. Mymensingh Med J 21:391–398

    PubMed  CAS  Google Scholar 

  • Asvadi I, Hajipour B, Asvadi A, Asl NA, Roshangar L, Khodadadi A (2011) Protective effect of pentoxyfilline in renal toxicity after methotrexate administration. Eur Rev Med Pharmacol Sci 15:1003–1009

    PubMed  CAS  Google Scholar 

  • Babiak RM, Campello AP, Carnieri EG, Oliveira MB (1998) Methotrexate: pentose cycle and oxidative stress. Cell Biochem Funct 16:283–293

    Article  PubMed  CAS  Google Scholar 

  • Banerjee D, Ercikan-Abali E, Waltham M, Schnieders B, Hochhauser D, Li WW et al (1995) Molecular mechanisms of resistance to antifolates, a review. Acta Biochim Pol 42:457–464

    PubMed  CAS  Google Scholar 

  • Beytur A, Ciftci O, Oguz F, Oguzturk H, Yilmaz F (2012a) Montelukast attenuates side effects of cisplatin including testicular, spermatological, and hormonal damage in male rats. Cancer Chemother Pharmacol 69:207–213

    Article  PubMed  CAS  Google Scholar 

  • Beytur A, Köse E, Sarihan ME, Sapmaz HI, Dogan Z, Cetin A et al (2012b) Beneficial effects of montelukast against cisplatin-induced acute renal damage in rats. Ren Fail 34:343–349

    Article  PubMed  CAS  Google Scholar 

  • Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78:206–209

    Article  PubMed  CAS  Google Scholar 

  • Caetano NN, Campello AP, Carnieri EG, Kluppel ML, Oliveira MB (1997) Effect of methotrexate (MTX) on NAD(P)+ dehydrogenases of HeLa cells: malic enzyme, 2-oxoglutarate and isocitrate dehydrogenases. Cell Biochem Funct 15:259–264

    Article  PubMed  CAS  Google Scholar 

  • Çakır T, Özkan E, Dulundu E, Topaloğlu Ü, Şehirli AÖ, Ercan F et al (2011) Caffeic acid phenethyl ester (CAPE) prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pharm Pharmacol 63:1566–1571

    Article  PubMed  CAS  Google Scholar 

  • Cetinkaya A, Kurutas EB, Bulbuloglu E, Kantarceken B (2007) The effects of N-acetylcysteine on methotrexate-induced oxidative renal damage in rats. Nephrol Dial Transplant 22:284–285

    Article  PubMed  CAS  Google Scholar 

  • Chan AJ, Rajakumar I (2013) High-dose methotrexate in adult oncology patients: a case–control study assessing the risk association between drug interactions and methotrexate toxicity. J Oncol Pharm Prac. doi:10.1177/1078155213482602

    Google Scholar 

  • Chen F, Castranova V, Shi X, Demers LM (1999) New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem 45:7–17

    PubMed  CAS  Google Scholar 

  • Coskun AK, Yigiter M, Oral A, Odabasoglu F, Halici Z, Mentes O et al (2011) 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. Scientific World Journal 11:1341–1356

    Article  PubMed  CAS  Google Scholar 

  • Cuciureanu M, Căruntu ID, Kuchar M, Nechifor M (2008) The influence of leukotriene receptors’ antagonists on experimentally induced ulcer in rats. Rev Med Chir Soc Med Nat Iasi 112:750–756

    PubMed  Google Scholar 

  • Dengiz GO, Odabasoglu F, Halici Z, Cadirci E, Suleyman H (2007) Gastroprotective and antioxidant effects of montelukast on indomethacin-induced gastric ulcer in rats. J Pharmacol Sci 105:94–102

    Article  PubMed  CAS  Google Scholar 

  • Devrim E, Cetin R, Kiliçoğlu B, Ergüder BI, Avci A, Durak I (2005) Methotrexate causes oxidative stress in rat kidney tissues. Ren Fail 27:771–773

    Article  PubMed  CAS  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  PubMed  CAS  Google Scholar 

  • El-Swefy S, Hassanen SI (2009) Improvement of hepatic fibrosis by leukotriene inhibition in cholestatic rats. Ann Hepatol 8:41–49

    PubMed  CAS  Google Scholar 

  • Fawcett JK, Scott JE (1960) A rapid and precise method for the determination of urea. J Clin Pathol 13:156–159

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Granville DJ, Carthy CM, Jiang H, Levy JG, McManus BM, Matroule JY et al (2000) Nuclear factor-kappaB activation by the photochemotherapeutic agent verteporfin. Blood 95:256–262

    PubMed  CAS  Google Scholar 

  • Helmy MM, El-Gowelli HM (2012) Montelukast abrogates rhabdomyolysis-induced acute renal failure via rectifying detrimental changes in antioxidant profile and systemic cytokines and apoptotic factors production. Eur J Pharmacol 683:294–300

    Article  PubMed  CAS  Google Scholar 

  • Hour TC, Chen J, Huang CY, Guan JY, Lu SH, Pu YS (2002) Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21(WAF1/CIP1) and C/EBPbeta expressions and suppressing NF-kappaB activation. Prostate 51:211–218

    Article  PubMed  CAS  Google Scholar 

  • Huang L, Xie JN, Liang JP, Li YH, Zhou Y (2011) Sophoridine inhibits NF-kappaB signaling pathway activation in kidney tissue of endotoxemia mice. Yao Xue Xue Bao 46:1072–1077

    PubMed  CAS  Google Scholar 

  • Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ (2001) Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20:4188–4197

    Article  PubMed  CAS  Google Scholar 

  • Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ (2000) Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res 60:5334–5339

    PubMed  CAS  Google Scholar 

  • Izzedine H, Launay-Vacher V, Karie S, Caramella C, de Person F, Deray G (2005) Is low-dose methotrexate nephrotoxic? Case report and review of the literature. Clin Nephrol 64:315–319

    Article  PubMed  CAS  Google Scholar 

  • Kintzel PE (2001) Anticancer drug-induced kidney disorders. Drug Saf 24:19–38

    Article  PubMed  CAS  Google Scholar 

  • Kolli VK, Abraham P, Isaac B, Selvakumar D (2009) Neutrophil infiltration and oxidative stress may play a critical role in methotrexate-induced renal damage. Chemotherapy 55:83–90

    Article  PubMed  CAS  Google Scholar 

  • Kose E, Beytur A, Dogan Z, Ekincioglu Z, Vardi N, Cinar K et al (2012) The effects of montelukast against amikacin-induced acute renal damage. Eur Rev Med Pharmacol Sci 16:503–511

    PubMed  CAS  Google Scholar 

  • Marklund SL (1985) Superoxide dismutase isoenzymes in tissues and plasma from New Zealand black mice, nude mice and normal BALB/c mice. Mutat Res 148:129–134

    Article  PubMed  CAS  Google Scholar 

  • May J, Carson KR, Butler S, Liu W, Bartlett NL, Wagner-Johnston ND, May J, Carson KR, Butler S, Liu W, Bartlett NL, Wagner-Johnston ND (2013) High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis. Leuk Lymphoma. doi:10.3109/10428194.2013.840780

    PubMed  Google Scholar 

  • Mihara M, Uchiyama M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86:271–278

    Article  PubMed  CAS  Google Scholar 

  • Miyazaki J, Kawai K (2003) Prevention and management of nephrotoxicity from anti-cancer agents. Nihon Rinsho 61:973–977

    PubMed  Google Scholar 

  • Oktem F, Yilmaz HR, Ozguner F, Olgar S, Ayata A, Uzare E et al (2006) Methotrexate-induced renal oxidative stress in rats: the role of a novel antioxidant caffeic acid phenethyl ester. Toxicol Ind Health 22:241–247

    Article  PubMed  CAS  Google Scholar 

  • Otunctemur A, Ozbek E, Cekmen M, Cakir SS, Dursun M, Polat EC et al (2013) Protective effect of montelukast which is cysteinyl-leukotriene receptor antagonist on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney. Ren Fail 35:403–410

    Article  PubMed  CAS  Google Scholar 

  • Ozbakış-Dengiz G, Cadırcı E, Yurdakan G (2013) Histopathologic evaluation of anti-ulcerogenic effect of montelukast in indomethacin-induced experimental ulcer model. Turk J Gastroenterol 24:88–92

    PubMed  Google Scholar 

  • Perez-Verdia A, Angulo F, Hardwicke FL, Nugent KM (2005) Acute cardiac toxicity associated with high-dose intravenous methotrexate therapy: case report and review of the literature. Pharmacotherapy 25:1271–1276

    Article  PubMed  Google Scholar 

  • Peters-Golden M (2003) Do anti-leukotriene agents inhibit asthmatic inflammation. Clin Exp Allergy 33:721–724

    Article  PubMed  CAS  Google Scholar 

  • Ramesh G, Reeves WB (2002) TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 110:835–842

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661

    Article  PubMed  CAS  Google Scholar 

  • Sener G, Sehirli O, Cetinel S, Ercan F, Yüksel M, Gedik N et al (2005) Amelioration of sepsis-induced hepatic and ileal injury in rats by the leukotriene receptor blocker montelukast. Prostaglandins Leukot Essent Fatty Acids 73:453–462

    Article  PubMed  CAS  Google Scholar 

  • Sener G, Sehirli O, Velioğlu-Oğünç A, Cetinel S, Gedik N, Caner M et al (2006a) Montelukast protects against renal ischemia/reperfusion injury in rats. Pharmacol Res 54:65–71

    Article  PubMed  CAS  Google Scholar 

  • Sener G, Ekşioğlu-Demiralp E, Cetiner M, Ercan F, Sirvanci S, Gedik N et al (2006b) L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death. Cell Biol Toxicol 22:47–60

    Article  PubMed  CAS  Google Scholar 

  • Slot C (1965) Plasma creatinine determination. A new and specific Jaffe reaction method. Scand J Clin Lab Invest 17:381–387

    Article  PubMed  CAS  Google Scholar 

  • Stark AN, Jackson G, Carey PJ, Arfeen S, Proctor SJ (1989) Severe renal toxicity due to intermediate-dose methotrexate. Cancer Chemother Pharmacol 24:243–245

    PubMed  CAS  Google Scholar 

  • Suddek GM (2013) Montelukast ameliorates kidney function and urinary bladder sensitivity in experimentally induced renal dysfunction in rats. Fundam Clin Pharmacol 27:186–191

    Article  PubMed  CAS  Google Scholar 

  • Tintinger GR, Feldman C, Theron AJ, Anderson R (2010) Montelukast: more than a cysteinyl leukotriene receptor antagonist. Scientific World Journal 10:2403–2413

    Article  PubMed  CAS  Google Scholar 

  • Tuğtepe H, Sener G, Cetinel S, Velioğlu-Oğünç A, Yeğen BC (2007) Oxidative renal damage in pyelonephritic rats is ameliorated by montelukast, a selective leukotriene CysLT1 receptor antagonist. Eur J Pharmacol 557:69–75

    Article  PubMed  CAS  Google Scholar 

  • Ueda A, Ishigatsubo Y, Okubo T, Yoshimura T (1997) Transcriptional regulation of the human monocyte chemoattractant protein-1 gene. Cooperation of two NF-kappaB sites and NF-kappaB/Rel subunit specificity. J Biol Chem 272:31092–31099

    Article  PubMed  CAS  Google Scholar 

  • Van’t Land B, Blijlevens NM, Marteijn J, Timal S, Donnelly JP, de Witte TJ et al (2004) Role of curcumin and the inhibition of NF-kappaB in the onset of chemotherapy-induced mucosal barrier injury. Leukemia 18:276–284

    Article  CAS  Google Scholar 

  • Vardi N, Parlakpinar H, Ates B, Cetin A, Otlu A (2013) The protective effects of Prunus armeniaca L (apricot) against methotrexate-induced oxidative damage and apoptosis in rat kidney. J Physiol Biochem 69:371–381

    Article  PubMed  CAS  Google Scholar 

  • Wang B, Peng L, Zhu L, Ren P (2007) Protective effect of total flavonoids from Spirodela polyrrhiza (L.) Schleid on human umbilical vein endothelial cell damage induced by hydrogen peroxide. Colloids Surf B Biointerfaces 60:36–40

    Article  PubMed  CAS  Google Scholar 

  • Weinblatt ME (2013) Methotrexate in rheumatoid arthritis: a quarter century of development. Trans Am Clin Climatol Assoc 124:16–25

    PubMed Central  PubMed  Google Scholar 

  • Welch GN, Loscalzo J (1998) Homocysteine and atherothrombosis. N Engl J Med 338:1042–1050

    Article  PubMed  CAS  Google Scholar 

  • Widemann BC, Adamson PC (2006) Understanding and managing methotrexate nephrotoxicity. Oncologist 11:694–703

    Article  PubMed  CAS  Google Scholar 

  • Widemann BC, Balis FM, Kim A, Boron M, Jayaprakash N, Shalabi A et al (2010) Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol 28:3979–3986

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Williams JD, Czop JK, Austen KF (1984) Release of leukotrienes by human monocytes on stimulation of their phagocytic receptor for particulate activators. J Immunol 132:3034–3040

    PubMed  CAS  Google Scholar 

  • Wu Y, Zhou C, Tao J, Li S (2006) Montelukast prevents the decrease of interleukin-10 and inhibits NF-kappaB activation in inflammatory airway of asthmatic guinea pigs. Can J Physiol Pharmacol 84:531–537

    Article  PubMed  CAS  Google Scholar 

  • Zeller JM, Buys CM, Gudewicz PW (1984) Effects of high-dose methotrexate on rat alveolar and inflammatory macrophage populations. Inflammation 8:231–239

    Article  PubMed  CAS  Google Scholar 

  • Zheng L, Sinniah R, Hsu SI (2006) Renal cell apoptosis and proliferation may be linked to nuclear factor-kappaB activation and expression of inducible nitric oxide synthase in patients with lupus nephritis. Hum Pathol 37:637–647

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful to Prof. Dr. Mona Yehia, professor of histochemistry and cell biology, Medical Research Institute, Alexandria University for executing histopathological and immunohistochemical analysis and interpretation of the results.

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  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt

    Ihab T. Abdel-Raheem

  2. Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt

    Naglaa F. Khedr

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  1. Ihab T. Abdel-Raheem
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Correspondence to Ihab T. Abdel-Raheem.

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Abdel-Raheem, I.T., Khedr, N.F. Renoprotective effects of montelukast, a cysteinyl leukotriene receptor antagonist, against methotrexate-induced kidney damage in rats. Naunyn-Schmiedeberg's Arch Pharmacol 387, 341–353 (2014). https://doi.org/10.1007/s00210-013-0949-x

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