DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20182105

Comparative efficacy of melatonin in attenuation of endotoxin/LPS induced hepatotoxicity in BALB/c mice

Ammara Khan, Ayesha Afzal, Abdul Rauf, Akbar Waheed

Abstract


Background: Sepsis is characterized by overwhelming surge of cytokines and oxidative stress to one of many factors, gram negative bacteria commonly implicated. Despite major expansion and elaboration of sepsis pathophysiology and therapeutic approach; death rate remains very high in septic patients due to multiple organ damage including hepatotoxicity. The present study was aimed to ascertain the adequacy of melatonin (10mg/kg i.p), and its comparability with dexamethasone (3mg/kg i.p), delivered separately and collectively in endotoxin induced hepatotoxicity.

Methods: The number of animals in each group was six. Endotoxin/LPS induced hepatotoxicity was reproduced in mice by giving LPS of serotype E. coli intraperitoneally. Preventive role was questioned by giving the experimental agent half an hour prior to LPS injection whereas therapeutic potential of the experimental agent was searched out via post LPS delivering. The extent of liver damage was adjudged via serum alanine aminotransferases (ALT) and aspartate aminotransferase (AST) estimation along with histopathological examination of liver tissue.

Results: Melatonin was prosperous in aversion (Group 3) and curation (Group 4) of LPS invoked hepatotoxicity as evident by lessening of augmented ALT (≤0.01) and AST (≤0.01) along with restoration of pathological changes on liver sections (p≤0.05). Dexamethasone given before (Group5) and after LPS (Group 6) significantly (p≤0.05) attenuated LPS generated liver injury. Combination therapy with dexamethasone in conjunction with melatonin (Group 7) after LPS administration tapered LPS evoked hepatic dysfunction statistically considerably, however the result was comparable to single agent therapy.

Conclusions: Melatonin set up promising results in endotoxin induced hepatotoxicity and can be used therapeutic adjuncts to conventional treatment strategies in sepsis induced liver failure. Combination therapies however generated no synergistic results.


Keywords


Dexamethasone, Endotoxin, Hepatotoxicity, LPS, Melatonin

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References


Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Critical care medicine. 2001 Jul 1;29(7):1303-10.

Kumar G, Kumar N, Taneja A, Kaleekal T, Tarima S, McGinley E, et al. Nationwide trends of severe sepsis in the 21st century (2000-2007). Chest. 2011 Nov 1;140(5):1223-31.

Martin G, Brunkhorst FM, Janes JM, Reinhart K, Sundin DP, Garnett K, et al. The international PROGRESS registry of patients with severe sepsis: drotrecogin alfa (activated) use and patient outcomes. Critical care. 2009 Jun;13(3):R103.

Nesseler N, Launey Y, Aninat C, Morel F, Mallédant Y, Seguin P. Clinical review: The liver in sepsis. Critical care. 2012 Oct;16(5):235.

Arafah BM. Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods. J Clin Endocr Metab. 2006 Oct 1;91(10):3725-45.

Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111-24.

Aytac HO, Iskit AB, Sayek I. Dexamethasone effects on vascular flow and organ injury in septic mice. J Surg Res. 2014;188:496-502.

Batalhao ME, Moreto V, Stabile AM, Antunes-Rodrigues J, Carnio EC. Role of dexamethasone on vasopressin release during endotoxemic shock. Regul Peptides. 2008;147:67-71.

Araz O, Demirci E, Ucar EY, Calik M, Pulur D, Karaman A, et al. Comparison of reducing effect on lung injury of dexamethasone and bosentan in acute lung injury: an experimental study. Multidscip Respir M. 2013;8:74.

Wang ZH, Liang YB, Tang H, Chen ZB, Li ZY, Hu XC, et al. Dexamethasone down-regulates the expression of microRNA-155 in the livers of septic mice. PLoS One. 2013 Nov 11;8(11):e80547.

Patel, GP, Balk, RA. Systemic steroids in severe sepsis and septic shock. Am J Resp Crit Care. 2012;185:133-9.

Marik PE. Glucocorticoids in sepsis: dissecting facts from fiction. Crit Care. 2011;15:158.

Batzofin BM, Sprung CL, Weiss YG. The use of steroids in the treatment of severe sepsis and septic shock. Best Pract Res Cl En. 2011;25:735-43.

Liu F, Ng TB. Effect of pineal indoles on activities of the antioxidant defense enzymes superoxide dismutase, catalase, and glutathione reductase, and levels of reduced and oxidized glutathione in rat tissues. Biochem Cell Biol. 2000;78:447-53.

Sewerynek E, Melchiorri D, Reiter RJ, Ortiz GG, Lewinski A. Lipopolysaccharide-induced hepatotoxicity is inhibited by the antioxidant melatonin. Eur J Pharm-Environ. 1995;293:327-34.

Srinivasan V, Pandi-Perumal SR, Spence, DW, Kato H, Cardinali DP. Melatonin in septic shock: Some recent concepts. J Crit Care. 2010;25(4):656-e1.

Gitto E, Karbownik M, Reiter RJ, Tan DX, Cuzzocrea S, Chiurazzi P, et al. Effects of melatonin treatment in septic newborns. Pediatric research. 2001 Dec;50(6):756.

De Filippis D, Iuvone T, Esposito G, Steardo L, Herman Arnold G, Pelckmans Paul A, et al. Melatonin reverses lipopolysaccharide‐induced gastro‐intestinal motility disturbances through the inhibition of oxidative stress. J of Pin Reser. 2008 Jan 1;44(1):45-51.

Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intens Care Med. 2013 Feb 1;39(2):165-228.

Bernard AM, Bernard GR. The immune response: targets for the treatment of severe sepsis. International journal of inflammation. 2012;2012.

Wei SD, Li JZ, Liu ZJ, Chen Q, Chen Y, Chen M, et al. Dexamethasone attenuates lipopolysaccharide‐induced liver injury by down regulating glucocorticoid‐induced tumor necrosis factor receptor ligand in Kupffer cells. Hepatol Res. 2011;41(10):989-99.

Wang X, Nelin LD, Kuhlman JR, Meng X, Welty SE, Liu Y. The role of MAP kinase phosphatase-1 in the protective mechanism of dexamethasone against endotoxemia. Life sciences. 2008 Nov 7;83(19-20):671-80.

Rishi P, Bharrhan S, Bhalla MP, Koul A, Chopra K. Inhibition of endotoxin-induced hepatotoxicity by melatonin in rats. International journal of biomedical science: Int J Biomed Sci. 2008 Jun;4(2):103.

Irie K, Fujii E, Ishida H, Wada K, Suganuma T, Nishikori T, et al. Inhibitory effects of cyclic AMP elevating agents on lipopolysaccharide (LPS)‐induced microvascular permeability change in mouse skin. Brit J Pharmacol. 2001 May 1;133(2):237-42.

González-Renovato ED, Alatorre-Jiménez M, Bitzer-Quintero OK, Sánchez-Luna S, Flores-Alvarado LJ, Romero-Dávalos R, et al. Effect of Nutrisim© on endotoxic shock induced by lipopolysaccharide from Escherichia coli: 0111: b4 in rats: structural study of liver, kidney and lung. J Clin Exp Pathol. 2013;4(1):1-5.

Brunt EM. Grading and staging the histopathological lesions of chronic hepatitis: the Knodell histology activity index and beyond. Hepatology. 2000 Jan 1;31(1):241-6.

Schmöcker C, Weylandt KH, Kahlke L, Wang J, Lobeck H, Tiegs G, et al. Omega‐3 fatty acids alleviate chemically induced acute hepatitis by suppression of cytokines. Hepatology. 2007 Apr 1;45(4):864-9.

Anwer S, Zafar MH, Awan HM, Shamim Mumtaz NA, Hayat A, Memon BA, et al. Study on the prevalence of enterobacteriacae in hospital acquired and community acquired infections. Pak J Med Res. 2002 Jan;41(1):39-40.

Fink MP. Animal models of sepsis. Virulence. 2014 Jan 1;5(1):143-53.

Buness A, Roth A, Herrmann A, Schmitz O, Kamp H, Busch K, et al. Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity. PloS one. 2014 May 16;9(5):e97249.

Klopfleisch R. Multiparametric and semiquantitative scoring systems for the evaluation of mouse model histopathology-a systematic review. BMC Vet Res. 2013;9(1):123.

Nemzek JA, Hugunin K, Opp MR. Modeling sepsis in the laboratory: merging sound science with animal well-being. Comparative medicine. 2008 Apr 16;58(2):120-8.

Lowes DA, Webster NR, Murphy MP, Galley HF. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Brit J Anaesth. 2013 Mar 1;110(3):472-80.

Wang H, Xu DX, Lv JW, Ning H, Wei W. Melatonin attenuates lipopolysaccharide (LPS)-induced apoptotic liver damage in D-galactosamine-sensitized mice. Toxicology. 2007 Jul 31;237(1-3):49-57.

Crespo E, MacÍas M, Pozo D, Escames G, MartÍn M, Vives F, et al. Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats. The FASEB J. 1999 Sep 1;13(12):1537-46.

Carrillo‐Vico A, Lardone PJ, Naji L, Fernández‐Santos JM, Martín‐Lacave I, Guerrero JM, et al. Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro‐/anti‐inflammatory cytokine network, protection against oxidative damage and anti‐apoptotic effects. J Pineal Res. 2005;39:400-8.

Wu JY, Tsou MY, Chen TH, Chen SJ, Tsao CM, Wu CC. Therapeutic effects of melatonin on peritonitis‐induced septic shock with multiple organ dysfunction syndrome in rats. J Pineal Res. 2008;45(1):106-16.

Li YX, Wang YZ, Wang JL, Xie JM, Kang HB, Liu YP. The Therapeutic Effect of Dexamethasone on Liver Injury Rat induced By Lps/D-Galn. J of Inner Mongolia Agricultural University (Natural Science Edition). 2012;3:029.

Campolo M, Ahmad A, Crupi R, Impellizzeri D, Morabito R, Esposito E, et al. Combination therapy with melatonin and dexamethasone in a mouse model of traumatic brain injury. J Endocrinol. 2013;217:291-301.

Li ZQ, Liang GB, Xue YX, Liu YH. Effects of combination treatment of dexamethasone and melatonin on brain injury in intracerebral hemorrhage model in rats. Brain Res. 2009;1264:98-103.