Exploring the Potential of IL-1β Inhibitor Diacerein and its Combination
with 5-aminosalicylic Acid for the Possible Ameliorating Effect in TNBSinduced
Experimental Colitis in Wistar Rats

Supriya      Roy; Suneela      Dhaneshwar; Tarique      Mahmood

doi:10.2174/1574885517666220328142715

Abstract

Background: Pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin (IL), and oxidative stress are crucial players in the pathophysiology of inflammatory bowel disease (IBD) that contribute to perpetuating intestinal inflammation. Targeting them presents a novel approach to disease management. In the present study, the potential of an antiosteoarthritic ILinhibitor drug, diacerein (DIA), was investigated in 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)- instigated ulcerative colitis (UC) in Wistar rats. A comparative study was also undertaken to investigate the potential of combination therapy of DIA with the standard drug 5-aminosalicylic acid (5-ASA) versus monotherapy.

Methods: Colitis was developed by single intra-colonic administration of TNBS (100mg/kg); whereas drugs 5-ASA (25.5 mg/kg), DIA (100 mg/kg), and DIA+5-ASA (100 + 25.5 mg/kg) were administered orally for five days post-induction to various groups of rats. Parameters like disease activity score, colon/ body weight ratio, colon length, diameter, and gut pH were assessed, and histopathological analysis was carried out. Biochemical markers of colonic inflammation such as IL-1β, TNF-α, reduced glutathione (GSH), and malondialdehyde (MDA) were also estimated.

Results: Combination of DIA and 5-ASA demonstrated the most significant reduction of the colon to body weight ratio and disease activity score. It prominently restored the colon length, diameter, and gut pH to normal. It attenuated the biochemical alterations induced by TNBS, indicating a highly significant defensive outcome against colonic inflammation. The histopathological report demonstrated the renovating effect of the combination of disrupted colonic histology with minimally distressing liver, stomach, or pancreas compared to individual drugs.

Conclusion: The combination remarkably downregulated the level of inflammation by suppressing both provocative cytokines and reactive oxygen species production. It can be evaluated further used in a clinical setup as a novel and promising drug therapy for UC.

Keywords: Inflammatory bowel disease, ulcerative colitis, anthraquinone derivatives, diacetylrhein, cytokines, oxidative stress.

« Previous Next »

Graphical Abstract

[1] 
Steinecker-Frohnwieser B, Kaltenegger H, Weigl L, et al. Pharmacological treatment with diacerein combined with mechanical stimulation affects the expression of growth factors in human chondrocytes. Biochem Biophys Rep  2017; 11: 154-60.
[http://dx.doi.org/10.1016/j.bbrep.2017.06.006] [PMID:  28955780] 
[2] 
Abd-Ellatif RN, Hegab II, Atef MM, Sadek MT, Hafez YM. Diacerein protects against glycerol-induced acute kidney injury: Modulating oxidative stress, inflammation, apoptosis and necroptosis. Chem Biol Interact  2019; 306: 47-53.
[http://dx.doi.org/10.1016/j.cbi.2019.04.008] [PMID:  30974099] 
[3] 
Chueakula N, Jaikumkao K, Arjinajarn P, et al. Diacerein alleviates kidney injury through attenuating inflammation and oxidative stress in obese insulin-resistant rats. Free Radic Biol Med  2018; 115: 146-55.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.11.021] [PMID:  29195834] 
[4] 
Bharti R, Dey G, Banerjee I, et al. Somatostatin receptor targeted liposomes with Diacerein inhibit IL-6 for breast cancer therapy. Cancer Lett  2017; 388: 292-302.
[http://dx.doi.org/10.1016/j.canlet.2016.12.021] [PMID:  28025102] 
[5] 
Torina AG, Reichert K, Lima F, et al. Diacerein improves left ventricular remodeling and cardiac function by reducing the inflammatory response after myocardial infarction. PLoS One  2015; 10(3): e0121842.
[http://dx.doi.org/10.1371/journal.pone.0121842] [PMID:  25816098] 
[6] 
Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology  2011; 140(6): 1785-94.
[http://dx.doi.org/10.1053/j.gastro.2011.01.055] [PMID:  21530745] 
[7] 
Panaccione R. Mechanisms of inflammatory bowel disease. Gastroenterol Hepatol (N Y)  2013; 9(8): 529-32.
[PMID: 24719603] 
[8] 
Ponder A, Long MD. A clinical review of recent findings in the epidemiology of inflammatory bowel disease. Clin Epidemiol  2013; 5(1): 237-47.
[http://dx.doi.org/10.2147/CLEP.S33961] [PMID:  23922506] 
[9] 
Ray K. IBD: The IBD genome-new study findings contribute to an ever-growing gene catalogue. Nat Rev Gastroenterol Hepatol  2012; 9(12): 685.
[http://dx.doi.org/10.1038/nrgastro.2012.215] [PMID:  23147660] 
[10] 
Wang L, Plump A, Ringel M. Racing to define pharmaceutical R&D external innovation models. Drug Discov Today  2015; 20(3): 361-70.
[http://dx.doi.org/10.1016/j.drudis.2014.10.008] [PMID:  25448753] 
[11] 
Wheat CL, Ko CW, Clark-Snustad K, Grembowski D, Thornton TA, Devine B. Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: A systematic review and network meta-analysis. BMC Gastroenterol  2017; 17(1): 52.
[http://dx.doi.org/10.1186/s12876-017-0602-0] [PMID:  28407755] 
[12] 
Bevivino G, Monteleone G. Advances in understanding the role of cytokines in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol  2018; 12(9): 907-15.
[http://dx.doi.org/10.1080/17474124.2018.1503053] [PMID:  30024302] 
[13] 
Billmeier U, Dieterich W, Neurath MF, Atreya R. Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J Gastroenterol  2016; 22(42): 9300-13.
[http://dx.doi.org/10.3748/wjg.v22.i42.9300] [PMID:  27895418] 
[14] 
Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol  2014; 14(5): 329-42.
[http://dx.doi.org/10.1038/nri3661] [PMID:  24751956] 
[15] 
Dodda D, Chhajed R, Mishra J, Padhy M. Targeting oxidative stress attenuates trinitrobenzene sulphonic acid induced inflammatory bowel disease like symptoms in rats: Role of quercetin. Indian J Pharmacol  2014; 46(3): 286-91.
[http://dx.doi.org/10.4103/0253-7613.132160] [PMID:  24987175] 
[16] 
Cottone M, Renna S, Modesto I, Orlando A. Is 5-ASA still the treatment of choice for ulcerative colitis? Curr Drug Targets  2011; 12(10): 1396-405.
[http://dx.doi.org/10.2174/138945011796818126] [PMID:  21466493] 
[17] 
He L, Wen S, Zhong Z, et al. The synergistic effects of 5-aminosalicylic acid and vorinostat in the treatment of ulcerative colitis. Front Pharmacol  2021; 12: 625543.
[http://dx.doi.org/10.3389/fphar.2021.625543] [PMID:  34093178] 
[18] 
Dhaneshwar S, Gautam H, Dhaneshwar S. Exploring novel colon-targeting antihistaminic prodrug for colitis. J Bioequivalence Bioavailab  2012; 63(4): 327-37.
[PMID: 23070081] 
[19] 
Motavallian-Naeini A, Andalib S, Rabbani M, Mahzouni P, Afsharipour M, Minaiyan M. Validation and optimization of experimental colitis induction in rats using 2, 4, 6-trinitrobenzene sulfonic acid. Res Pharm Sci  2012; 7(3): 159-69.
[PMID: 23181094] 
[20] 
Tamura T, Shirai T, Kosaka N, Ohmori K, Takafumi N. Pharmacological studies of diacerein in animal models of inflammation, arthritis and bone resorption. Eur J Pharmacol  2002; 448(1): 81-7.
[http://dx.doi.org/10.1016/S0014-2999(02)01898-8] [PMID:  12126975] 
[21] 
Tamura T, Yokoyama T, Ohmori K. Effects of diacerein on indomethacin-induced gastric ulceration. Pharmacology  2001; 63(4): 228-33.
[http://dx.doi.org/10.1159/000056138] [PMID:  11729361] 
[22] 
Asgharzadeh F, Yaghoubi A, Nazari SE, et al. The beneficial effect of combination therapy with sulfasalazine and valsartan in the treatment of ulcerative colitis. EXCLI J  2021; 20: 236-47.
[PMID: 33628160] 
[23] 
Shivashankar P, Purushotham K, Lahkar M. Effect of rosiglitazone alone and in combination with sulfasalazine in experimentally induced inflammatory bowel disease in rats. Indian J Pharm Pharmacol  2016; 3(3): 108-14.
[http://dx.doi.org/10.5958/2393-9087.2016.00025.X] 
[24] 
Prakash A, Medhi B, Avti PK, Saikia UN, Pandhi P, Khanduja KL. Effect of different doses of Manuka honey in experimentally induced inflammatory bowel disease in rats. Phytother Res  2008; 22(11): 1511-9.
[http://dx.doi.org/10.1002/ptr.2523] [PMID:  18688794] 
[25] 
Raithel M, Winterkamp S, Weidenhiller M, Müller S, Hahn EG. Combination therapy using fexofenadine, disodium cromoglycate, and a hypoallergenic amino acid-based formula induced remission in a patient with steroid-dependent, chronically active ulcerative colitis. Int J Colorectal Dis  2007; 22(7): 833-9.
[http://dx.doi.org/10.1007/s00384-006-0120-y] [PMID:  16944185] 
[26] 
Hartmann G, Bidlingmaier C, Siegmund B, et al. Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice. J Pharmacol Exp Ther  2000; 292: 22-30.
[27] 
Barada KA, Mourad FH, Sawah SI, et al. Up-regulation of nerve growth factor and interleukin-10 in inflamed and non-inflamed intestinal segments in rats with experimental colitis. Cytokine  2007; 37(3): 236-45.
[http://dx.doi.org/10.1016/j.cyto.2007.04.005] [PMID:  17517520] 
[28] 
Mi H, Liu F, Li H, Hou J, Li P. Anti-inflammatory effect of chang-An- Shuan on TNBS-induced experimental colitis in rats. BMC Complement Altern Med  2017; 17(1): 315.
[http://dx.doi.org/10.1186/s12906-017-1794-0] 
[29] 
Kandhare AD, Ghosh P, Ghule AE, Zambare GN, Bodhankar SL. Protective effect of phyllanthus amarus by modulation of endogenous biomarkers and DNA damage in acetic acid induced ulcerative colitis: Role of phyllanthin and hypophyllanthin. Apollo Med  2013; 10(1): 87-97.
[http://dx.doi.org/10.1016/j.apme.2013.01.006] 
[30] 
Malik T, Mannon P. Inflammatory bowel diseases: Emerging
therapies and promising molecular targets. Front Biosci Sch 2012. 4 S: 1172-89.
[31] 
Khanna PV, Shih DQ, Haritunians T, McGovern DP, Targan S. Use of animal models in elucidating disease pathogenesis in IBD. Semin Immunopathol  2014; 36(5): 541-51.
[http://dx.doi.org/10.1007/s00281-014-0444-6] [PMID:  25212688] 
[32] 
Antoniou E, Margonis GA, Angelou A, et al. The TNBS-induced colitis animal model: An overview. Ann Med Surg (Lond)  2016; 11: 9-15.
[http://dx.doi.org/10.1016/j.amsu.2016.07.019] [PMID:  27656280] 
[33] 
Papadakis KA, Targan SR. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med  2000; 51(1): 289-98.
[http://dx.doi.org/10.1146/annurev.med.51.1.289] [PMID:  10774465] 
[34] 
Műzes G, Molnár B, Tulassay Z, Sipos F. Changes of the cytokine profile in inflammatory bowel diseases. World J Gastroenterol  2012; 18(41): 5848-61.
[http://dx.doi.org/10.3748/wjg.v18.i41.5848] [PMID:  23139600] 
[35] 
Kremer B, Mariman R, van Erk M, Lagerweij T, Nagelkerken L. Temporal colonic gene expression profiling in the recurrent colitis model identifies early and chronic inflammatory processes. PLoS One  2012; 7(11): e50388.
[http://dx.doi.org/10.1371/journal.pone.0050388] [PMID:  23226271] 
[36] 
Engel MA, Neurath MF. New pathophysiological insights and modern treatment of IBD. J Gastroenterol  2010; 45(6): 571-83.
[http://dx.doi.org/10.1007/s00535-010-0219-3] [PMID:  20213337] 
[37] 
Jin BR, Chung KS, Cheon SY, et al. Rosmarinic acid suppresses colonic inflammation in dextran sulphate sodium (DSS)-induced mice via dual inhibition of NF-KB and STAT3 activation. Sci Rep  2017; 7: 46252.
[38] 
Lied GA, Milde AM, Nylund K, et al. Increased wall thickness using ultrasonography is associated with inflammation in an animal model of experimental colitis. Clin Exp Gastroenterol  2012; 5: 195-201.
[http://dx.doi.org/10.2147/CEG.S31150] [PMID:  23055765] 
[39] 
Nugent SG, Kumar D, Rampton DS, Evans DF. Intestinal luminal pH in inflammatory bowel disease: Possible determinants and implications for therapy with aminosalicylates and other drugs. Gut  2001; 48(4): 571-7.
[http://dx.doi.org/10.1136/gut.48.4.571] [PMID:  11247905] 
[40] 
Leppkes M, Neurath MF. Cytokines in inflammatory bowel diseases - Update 2020. Pharmacol Res  2020; 158: 104835.
[http://dx.doi.org/10.1016/j.phrs.2020.104835] [PMID:  32416212] 
[41] 
Friedrich M, Pohin M, Powrie F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity  2019; 50(4): 992-1006.
[http://dx.doi.org/10.1016/j.immuni.2019.03.017] [PMID:  30995511] 
[42] 
Paiotti APR, Miszputen SJ, Oshima CTF, Artigiani Neto R, Ribeiro DA, Franco M. Etanercept attenuates TNBS-induced experimental colitis: Role of TNF-α expression. J Mol Histol  2011; 42(5): 443-50.
[http://dx.doi.org/10.1007/s10735-011-9349-z] [PMID:  21863329] 
[43] 
Polat FR, Karaboga I, Polat MS, Erboga Z, Yilmaz A, Güzel S. Effect of hesperetin on inflammatory and oxidative status in trinitrobenzene sulfonic acid-induced experimental colitis model. Cell Mol Biol  2018; 64(11): 58-65.
[http://dx.doi.org/10.14715/cmb/2018.64.11.11] [PMID:  30213290] 
[44] 
Almezgagi M, Zhang Y, Hezam K, et al. Diacerein: Recent insight into pharmacological activities and molecular pathways. Biomed Pharmacother  2020; 131: 110594.
[http://dx.doi.org/10.1016/j.biopha.2020.110594] [PMID:  32858499] 
[45] 
Pasin JSM, Ferreira APO, Saraiva ALL, et al. Diacerein decreases TNF-α and IL-1β levels in peritoneal fluid and prevents Baker’s yeast-induced fever in young rats. Inflamm Res  2010; 59(3): 189-96.
[http://dx.doi.org/10.1007/s00011-009-0085-8] [PMID:  19730987] 
[46] 
Paulino DSM, Mendes MCS, Camargo JA, et al. Diacerein treatment prevents colitis-associated cancer in mice. World J Clin Oncol  2020; 11(9): 732-46.
[http://dx.doi.org/10.5306/wjco.v11.i9.732] [PMID:  33033695] 
[47] 
Li YH, Zhang M, Xiao HT, et al. Addition of Berberine to 5-Aminosalicylic Acid for treatment of Dextran Sulfate Sodium-induced Chronic Colitis in C57BL/6 mice. PLoS One  2015; 10(12): e0144101.
[http://dx.doi.org/10.1371/journal.pone.0144101] [PMID:  26642326] 
[48] 
Horváth K, Varga C, Berkó A, Pósa A, László F, Whittle BJ. The involvement of heme oxygenase-1 activity in the therapeutic actions of 5-aminosalicylic acid in rat colitis. Eur J Pharmacol  2008; 581(3): 315-23.
[http://dx.doi.org/10.1016/j.ejphar.2007.12.004] [PMID:  18215658] 
[49] 
Perrotta C, Pellegrino P, Moroni E, et al. Five-aminosalicylic Acid: An update for the reappraisal of an old drug. Gastroenterol Res Pract  2015; 2015: 456895.
[http://dx.doi.org/10.1155/2015/456895] [PMID:  25685145] 
[50] 
Piechota-Polanczyk A, Fichna J. Review article: The role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases. Naunyn Schmiedebergs Arch Pharmacol  2014; 387(7): 605-20.
[http://dx.doi.org/10.1007/s00210-014-0985-1] [PMID:  24798211] 
[51] 
Abdel-Aziz AM, Ibrahim MA, El-Shiekh AA, Osman NAT, Geddawy A, Abdelrahman A. Prophylactic effect of diacerein against cisplatin-induced nephrotoxicity in rats. Int J Pharmacol  2018; 14(3): 384-90.
[http://dx.doi.org/10.3923/ijp.2018.384.390] 
[52] 
Refaie MMM, Amin EF, El-Tahawy NF, Abdelrahman AM. Possible protective effect of diacerein on doxorubicin-induced nephrotoxicity in rats. J Toxicol  2016; 2016: 9507563.
[http://dx.doi.org/10.1155/2016/9507563] 
[53] 
Al-Rejaie SS, Abuohashish HM, Al-Enazi MM, Al-Assaf AH, Parmar MY, Ahmed MM. Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats. World J Gastroenterol  2013; 19(34): 5633-44.
[http://dx.doi.org/10.3748/wjg.v19.i34.5633] [PMID:  24039355] 
[54] 
Dudzińska E, Gryzinska M, Ognik K, Gil-Kulik P, Kocki J. Oxidative stress and effect of treatment on the oxidation product decomposition processes in IBD. Oxid Med Cell Longev  2018; 2018: 7918261.
[http://dx.doi.org/10.1155/2018/7918261] 
[55] 
Kabil SL. Diacerein ameliorates liver ischemia reperfusion insult in rats. Egypt J Basic Clin Pharmacol  2018; 8: 14.
[http://dx.doi.org/10.11131/2018/101371] 
[56] 
Moura RM, Hartmann RM, Licks F, et al. Antioxidant effect of mesalazine in the experimental colitis model induced by acetic acid. J Coloproctol (Rio J)  2016; 36(3): 139-48.
[http://dx.doi.org/10.1016/j.jcol.2016.03.003] 
[57] 
Isik F, Tunali Akbay T, Yarat A, et al. Protective effects of black cumin (Nigella sativa) oil on TNBS-induced experimental colitis in rats. Dig Dis Sci  2011; 56(3): 721-30.
[http://dx.doi.org/10.1007/s10620-010-1333-z] [PMID:  20658190] 
[58] 
Margonis GA, Christoloukas N, Antoniou E, et al. Effectiveness of sildenafil and U-74389G in a rat model of colitis. J Surg Res  2015; 193(2): 667-74.
[http://dx.doi.org/10.1016/j.jss.2014.08.064] [PMID:  25277360] 
[59] 
La Villa G, Marra F, Laffi G, et al. Effects of rhein on renal arachidonic acid metabolism and renal function in patients with congestive heart failure. Eur J Clin Pharmacol  1989; 37(1): 1-5.
[http://dx.doi.org/10.1007/BF00609415] [PMID:  2512175] 
[60] 
Pomarelli P, Berti M, Gatti MT, Mosconi P. A non steroidal anti-inflammatory drug that stimulates prostaglandin release. Farmaco, Sci  1980; 35(10): 836-42.
[PMID:  7450019] 

Rights & Permissions Print Cite

Article Metrics

16

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1574885517666220328142715	Print ISSN 1574-8855
Publisher Name Bentham Science Publisher	Online ISSN 2212-3903

Current Drug Therapy

Exploring the Potential of IL-1β Inhibitor Diacerein and its Combination with 5-aminosalicylic Acid for the Possible Ameliorating Effect in TNBSinduced Experimental Colitis in Wistar Rats

Abstract Play Pause

Graphical Abstract

Abstract