THE EFFECT OF PRETREATMENT WITH TOLL-LIKE RECEPTOR 4 ANTAGONIST RESATORVID ON METHOTREXATE-INDUCED LIVER INJURY IN RATS: HISTOPATHOLOGICAL STUDY

Bassim I Mohammad; Bassim S Ahmed; Alaa F Hassan; Samer F Hassan

doi:10.22159/ajpcr.2018.v11i12.29939

Authors

Bassim I Mohammad Depatment of Pharmacology, College of Pharmacy, University of Al-Qadisiyah, Qadisiyah, Iraq. http://orcid.org/0000-0002-0732-7079
Bassim S Ahmed Depatment of Pathology and Forensic Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq. http://orcid.org/0000-0001-6732-5940
Alaa F Hassan Depatment of Pharmacy, Al-Mahmoudiya General Hospital, Baghdad, Iraq. http://orcid.org/0000-0001-5801-266X
Samer F Hassan Depatment of Surgery, College of Medicine, Wassit University, Wassit, Iraq. http://orcid.org/0000-0003-0764-8849

DOI:

https://doi.org/10.22159/ajpcr.2018.v11i12.29939

Keywords:

Liver steatosis, Methotrexate sodium, Resatorvid, TLR4 receptor

Abstract

Objective: This research aims to evaluate the histopathological changes after pretreatment with resatorvid against methotrexate induced-liver injury.

Methods: 28 male albino-wistar rats divided into random 4 groups (7 rats in each). Control group: Rats left untreated. Vehicle pre-treated group: Rats were administered dimethyl sulfoxide (DMSO) followed by methotrexate (MTX). Methotrexate treated group: Rats left untreated then administered MTX. Resatorvid pre-treated group: Rats were administered resatorvid followed by MTX. 24 h after the end of treatment, the animals were sacrificed. Liver tissue samples dissected out immediately and fixed in 10% formalin. The traditional procedures (paraffin-embedded method) was used to prepare liver tissue for microscopic evaluation by none alcoholic fatty liver disease (NAFLD) Activity Score Components.

Results: Liver tissue sections of MTX-treated group show moderate-to-severe steatosis of hepatic cells and micro- and macro- hepatocellular fatty degeneration and giant fatty cysts with chronic inflammatory cells infiltration. While liver tissue sections of the resatorvid pre-treated group show moderate hepatic cellular fatty degeneration, with a decreased number of fatty cysts chains and the inflammation disappeared.

Conclusion: Resatorvid hepatoprotective effect against MTX-induced injury was promising throughout resolving the accompanying inflammation and partial restoring histopathological fatty alterations.

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Author Biographies

Bassim I Mohammad, Depatment of Pharmacology, College of Pharmacy, University of Al-Qadisiyah, Qadisiyah, Iraq.

Resident Pharmacist, with MSc.Pharmacology

currently at Al-Mahmoudiya General Hospital, Department of pharmacy/ Drug information center

Bassim S Ahmed, Depatment of Pathology and Forensic Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq.

PhD. Pharmacology Department of Pharmacology, College of Pharmacy, University of Alâ€‘Qadisiyah, Qadisiyah,Iraq

Alaa F Hassan, Depatment of Pharmacy, Al-Mahmoudiya General Hospital, Baghdad, Iraq.

FICMS. Histopathology Department of Pathology and Forensic Medicine, College of Medicine, Alâ€‘Mustansiriyah University, Baghdad, Iraq

Samer F Hassan, Depatment of Surgery, College of Medicine, Wassit University, Wassit, Iraq.

CABMS-Rad. Rediology Department of Surgery, College of Medicine, Wassit University

References

Zhang Y, Peng W, Ao X, Dai H, Yuan L, Huang X, et al. TAK-242, a toll-like receptor 4 antagonist, protects against aldosterone-induced cardiac and renal injury. PLoS One 2015;10:e0142456.

GÃ¡rate I, GarcÃa-Bueno B, Madrigal JL, Caso JR, Alou L, GÃ³mez-Lus ML, et al. Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. J Neuroinflammation 2014;11:8.

Hussey SE, Liang H, Costford SR, Klip A, DeFronzo RA, Sanchez-Avila A, et al. TAK-242, a small-molecule inhibitor of toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide-and lipid-induced inflammation and insulin resistance in muscle cells. Biosci Rep 2012;33:37-47.

Takashima K, Matsunaga N, Yoshimatsu M, Hazeki K, Kaisho T, Uekata M, et al. Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br J Pharmacol 2009;157:1250-62.

Matsunaga N, Tsuchimori N, Matsumoto T, Ii M. TAK-242 (resatorvid), a small-molecule inhibitor of toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol 2011;79:34-41.

Kiziltas S. Toll-like receptors in pathophysiology of liver diseases. World J Hepatol 2016;8:1354-69.

Guo J, Friedman SL. Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. Fibrogenesis Tissue Repair 2010;3:21.

Broering R, Lu M, Schlaak JF. Role of toll-like receptors in liver health and disease. Clin Sci (Lond) 2011;121:415-26.

Mahmoud AM, Hussein OE, Hozayen WG, Abd El-Twab SM. Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARÎ³ and nrf2: Protective effect of 18Î²-glycyrrhetinic acid. Chem Biol Interact 2017;270:59-72.

Pandit A, Sachdeva T, Bafna P. Drug-induced hepatotoxicity: A review. J Appl Pharm Sci 2012;2:233-4.

Khafaga AF, El-Sayed YS. Spirulina ameliorates methotrexate hepatotoxicity via antioxidant, immune stimulation, and proinflammatory cytokines and apoptotic proteins modulation. Life Sci 2018;196:9-17.

Pierce RH, Campbell JS, Stephenson AB, Franklin CC, Chaisson M, Poot M, et al. Disruption of redox homeostasis in tumor necrosis factor-induced apoptosis in a murine hepatocyte cell line. Am J Pathol 2000;157:221-36.

Hadi N, Jabber H. Potential activity of GIT27 against renal ischemia reperfusion injury: An experimental study in male rats. Pathophysiol Cell Inj J 2016;5:87-99.

Olayinka ET, Ore A, Adeyemo OA, Ola OS. Ameliorative effect of gallic acid on methotrexate-induced hepatotoxicity in rat. J Xenobiotics 2016;6:6092.

Yucel Y, Oguz E, Kocarslan S, Tatli F, Gozeneli O, Seker A, et al. The effects of lycopene on methotrexate-induced liver injury in rats. Bratisl Lek Listy 2017;118:212-6.

Zhao Y, Xin Y, Gao J, Teng RY, Chu HC. Analgesic effect of TAK-242 on neuropathic pain in rats. Int J Clin Exp Med 2015;8:11202-7.

Yousif NG, Mohammad BI, Al-Khalidy SA. Effect of N-acetyl cysteine and TAK-242 on sepsis induced myocardial injury: Down regulation of MMP-2 pathway in mice. Pathophysiol Cell Inj J 2016;5:111-25.

Hawk CT, Leary ST, Morris TH. Formulary for Laboratory Animals. 3rd ed. IA, USA: Blackwell Publishing; 2005.

Institutional Animal Care and Use Committee (IACUC). IACUC Guidelines: Anesthesia. USA: University of IOWA; 2017.

Demiryilmaz I, Sener E, Cetin N, Altuner D, Suleyman B, Albayrak F, et al. Biochemically and histopathologically comparative review of thiamineâ€™s and thiamine pyrophosphateâ€™s oxidative stress effects generated with methotrexate in rat liver. Med Sci Monit 2012;18:BR475 81.

Dalaklioglu S, Genc GE, Aksoy NH, Akcit F, Gumuslu S. Resveratrol ameliorates methotrexate-induced hepatotoxicity in rats via inhibition of lipid peroxidation. Hum Exp Toxicol 2013;32:662-71.

Suvarna SK, Layton C, Bancroft JD. Bancroftâ€™s Theory and Practice of Histological Techniques. 7th ed. Oxford: Churchill Livingstone Elsevier; 2013.

Armagan I, Bayram D, Candan IA, Yigit A, Celik E, Armagan HH, et al. Effects of pentoxifylline and alpha lipoic acid on methotrexate-induced damage in liver and kidney of rats. Environ Toxicol Pharmacol 2015;39:1122-31.

Akbulut S, Elbe H, Eris C, Dogan Z, Toprak G, Otan E, et al. Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats. World J Gastroenterol 2014;20:10158-65.

Tunali-Akbay T, Sehirli O, Ercan F, Sener G. Resveratrol protects against methotrexate-induced hepatic injury in rats. J Pharm Pharm Sci 2010;13:303-10.

Oya S, Yokoyama Y, Kokuryo T, Uno M, Yamauchi K, Nagino M, et al. Inhibition of toll-like receptor 4 suppresses liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide injection. Am J Physiol Gastrointest Liver Physiol 2014;306:G244-52.

Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313 21.

Singh R, Kumar S, Rana AC, Sharma N. Different models of hepatotoxicity and related liver disease: A review. Int Res J Pharm 2012;3:86-95.

Cao L, Quan XB, Zeng WJ, Yang XO, Wang MJ. Mechanism of hepatocyte apoptosis. J Cell Death 2016;9:19-29.

Fagone P, Mangano K, Mammana S, Pesce A, Pesce A, Caltabiano R, et al. Identification of novel targets for the diagnosis and treatment of liver fibrosis. Int J Mol Med 2015;36:747-52.

Miele L, Liguori A, Marrone G, Biolato M, Araneo C, Vaccaro FG, et al. Fatty liver and drugs: The two sides of the same coin. Eur Rev Med Pharmacol Sci 2017;21:86-94.

Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol 2009;62:481-92.

Kleiner DE. The histopathological evaluation of drug-induced liver injury. Histopathology 2017;70:81-93.

Uraz S, Tahan V, Aygun C, Eren F, Unluguzel G, Yuksel M, et al. Role of ursodeoxycholic acid in prevention of methotrexate-induced liver toxicity. Dig Dis Sci 2008;53:1071-7.

Coskun M, Steenholdt C, de Boer NK, Nielsen OH. Pharmacology and optimization of thiopurines and methotrexate in inflammatory bowel disease. Clin Pharmacokinet 2016;55:257-74.

Gaies E, Jebali N, Trabelsi S, Salouage I, Charfi R, Lakhal M, et al. Methotrexate side effects review. J Drug Metab Toxicol 2012;3:125.

Dey P, Saha MR, Sen A. An overview on drug-induced hepatotoxicity. Asian J Pharm Clin Res 2013;6:1-4.

Anila R, Sathiya S, Babu CS, Rajkumar J. In vitro and in vivo protective effects of ambrex, a polyherbal formulation against methotrexate induced damages in hepatic cells. Int J Pharm Pharm Sci 2015;7:164 70.

David AV, Satyanarayana N, Parasuraman S, Bharathi S, Arulmoli R. Ameliorative effect of quercetin on methotrexate induced toxicity in Sprague-Dawley rats: A histopathological study. Indian J Pharm Educ Res 2016;50 S 3:S200-8.

Cure E, Kirbas A, Tumkaya L, Cure MC, Kalkan Y, Yilmaz A, et al. Protective effect of infliximab on methotrexate-induced liver injury in rats: Unexpected drug interaction. J Cancer Res Ther 2015;11:164-9.

Vardi N, Parlakpinar H, Cetin A, Erdogan A, Cetin Ozturk I. Protective effect of beta-carotene on methotrexate-induced oxidative liver damage. Toxicol Pathol 2010;38:592-7.

Daniel JA, Das S, Jayan N, Devi SA. Protective activity of Asparagus racemosus in methotrexate-induced liver toxicity in wistar rats. Asian J Pharm Clin Res 2018;11:253-6.

Khokhar A, Qayyum A, Khan MW. Protective effect of melatonin against methotrexate induced hepatotoxicity in mice. Pak Armed Forces Med J 2017;67:126-30.

Abo-Haded HM, Elkablawy MA, Al-Johani Z, Al-Ahmadi O, El-Agamy DS. Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity. PLoS One 2017;12:e0174295.

Salama M, Elgamal M, Abdelaziz A, Ellithy M, Magdy D, Ali L, et al. Toll-like receptor 4 blocker as potential therapy for acetaminophen-induced organ failure in mice. Exp Ther Med 2015;10:241-6.

Wen Z, Ji X, Tang J, Lin G, Xiao L, Liang C, et al. Positive feedback regulation between transglutaminase 2 and toll-like receptor 4 signaling in hepatic stellate cells correlates with liver fibrosis post Schistosoma japonicum infection. Front Immunol 2017;8:1808.

Khan M, Farahvash A, Douda D, Licht JC, Grasemann H, Sweezey N, et al. JNK activation turns on LPS-and gram-negative bacteria-induced NADPHt oxidase-dependent suicidal NETosis. Sci Rep 2017;7:3409.

Yu P, Cheng X, Du Y, Huang L, Dong R. TAK-242 can be the potential agent for preventing invasion and metastasis of hepatocellular carcinoma. Med Hypotheses 2013;81:653-5.

Lin A, Wang G, Zhao H, Zhang Y, Han Q, Zhang C, et al. TLR4 signaling promotes a COX-2/PGE2/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells. Oncoimmunology 2016;5:e1074376.