Abstract
Background
In search of safer treatments for inflammatory bowel disease in subjects not responding to, or showing adverse effects to TNF-α antagonists, we tested three novel indoline carbamates in the 2,4-dinitrobenzene sulfonic acid (DNBS) model of colitis in rats. The compounds have anti-inflammatory activity in other disease models in mice.
Methods
AN827 (3-(2-(methoxy carbonyl) ethyl) indolin-4-ylethyl methyl) carbamate (0.1 or 1 mg/kg), AN680 (3-(2-(methoxy carbonyl) ethyl) indolin-6-ylethyl methyl) carbamate (1.25 or 2.5 mg/kg) and AN917 (3-(3-amino propyl) indolin-4-ylethyl methyl) carbamate (1 or 2 mg/kg), 5-aminosalycilic acid (5-ASA) (1 or 100 mg/kg) or saline (1 ml/kg) were administered rectally 1 h after intracolonic administration of DNBS, (35 mg/kg in 30% alcohol). Disease severity was assessed four days after DNBS administration by change in body weight, colon weight, area of ulceration, myeloid peroxidase (MPO) activity, colonic TNF-α, IL-6 and IL-1β levels. Histopathological scoring was performed after staining colon sections with hematoxylin and eosin and with antibodies to CD68 and CD11b.
Results
AN827 (0.1 and 1 mg/kg), AN680 (2.5 mg/kg) and AN917 (2.0 mg/kg) significantly reduced all macroscopic and microscopic parameters of colitis, colonic pro-inflammatory cytokines, TNF-α, IL-1β and IL-6 and MPO activity by about 80%.
Conclusions
The indoline derivatives largely prevented the symptoms of colitis and were 500–50 times more potent and more effective than 5-ASA. It may be worth evaluating them in models of established colitis. Since AN827 is strongly bound by plasma proteins no adverse effects are expected if compound is absorbed into the circulation after rectal administration.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Desreumaux P, Brandt E, Gambiez L, Emilie D, Geboes K, Klein O, et al. Distinct cytokine patterns in early and chronic ileal lesions of Crohn’s disease. Gastroenterology 1997;113(1):118–26.
Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389(6652):737–42.
Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361(21):2066–78.
Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76(2):301–14.
Picarella D, Hurlbut P, Rottman J, Shi X, Butcher E, Ringler DJ. Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells. J Immunol 1997;158(5):2099–106.
Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease Crohn’s disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 1996;157(3):1261–70.
Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 2005;129(2):550–64.
Peyrin-Biroulet L. Anti-TNF therapy in inflammatory bowel diseases: a huge review. Minerva Gastroenterol Dietol 2010;56(2):233–43.
Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut 1997;40(4):443–8.
Ben-Horin S, Chowers Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nat Rev Gastroenterol Hepatol 2014;11(4):243–55.
Allez M, Karmiris K, Louis E, Van Assche G, Ben-Horin S, Klein A, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects. J Crohn’s Colitis 2010;4(4):355–66.
Gisbert JP, Marin AC, McNicholl AG, Chaparro M. Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed. Aliment Pharmacol Ther 2015;41(7):613–23.
Hiroz P, Vavricka SR, Fournier N, Safroneeva E, Pittet V, Rogler G, et al. Analysis of TNF-antagonist switch over time and associated risk factors in the Swiss Inflammatory Bowel Disease Cohort. Scand J Gastroenterol 2014;49(10):1207–18.
Furman S, Nissim-Bardugo E, Zeeli S, Weitman M, Nudelman A, Finkin-Groner E, et al. Synthesis and in vitro evaluation of anti-inflammatory activity of ester and amine derivatives of indoline in RAW 264.7 and peritoneal macrophages. Bioorg Med Chem Lett 2014;24(10):2283–7.
Finkin-Groner E, Moradov D, Shifrin H, Bejar C, Nudelman A, Weinstock M. Indoline-3-propionate and 3-aminopropyl carbamates reduce lung injury and pro-inflammatory cytokines induced in mice by LPS. Br J Pharmacol 2015;172(4):1101–13.
Cuzzocrea S, Ianaro A, Wayman NS, Mazzon E, Pisano B, Dugo L, et al. The cyclopentenone prostaglandin 15-deoxy-delta(12,14)- PGJ2 attenuates the development of colon injury caused by dinitrobenzene sulphonic acid in the rat. Br J Pharmacol 2003;138(4):678–88.
Jamontt JM, Molleman A, Pertwee RG, Parsons ME. The effects of Delta-tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis. Br J Pharmacol 2010;160(3):712–23.
Shifrin H, Nadler-Milbauer M, Shoham S, Weinstock M. Rivastigmine alleviates experimentally induced colitis in mice and rats by acting at central and peripheral sites to modulate immune responses. PLoS One 2013;8(2):e57668.
Bradley PP, Christensen RD, Rothstein G. Cellular and extracellular myeloperoxidase in pyogenic inflammation. Blood 1982;60(3):618–22.
Cooper HS, Murthy SN, Shah RS, Sedergran DJ. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 1993;69(2):238–49.
Dmitrieva NA, Strang CE, Keyser KT. Expression of alpha 7 nicotinic acetylcholine receptors by bipolar, amacrine, and ganglion cells of the rabbit retina. J Histochem Cytochem 2007;55(5):461–76.
Yang XD, Ai W, Asfaha S, Bhagat G, Friedman RA, Jin G, et al. Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells. Nat Med 2011;17(1):87–95.
Deng X, Tolstanova G, Khomenko T, Chen L, Tarnawski A, Szabo S, et al. Mesalamine restores angiogenic balance in experimental ulcerative colitis by reducing expression of endostatin and angiostatin: novel molecular mechanism for therapeutic action of mesalamine. J Pharmacol Exp Ther 2009;331(3):1071–8.
Goyal N, Rana A, Bijjem KR, Kumar P. Effect of chenodeoxycholic acid and sodium hydrogen sulfide in dinitro benzene sulfonic acid (DNBS)—induced ulcerative colitis in rats. Pharmacol Rep 2015;67(3):616–23.
Song M, Xia B, Li J. Effects of topical treatment of sodium butyrate and 5-aminosalicylic acid on expression of trefoil factor 3, interleukin 1beta, and nuclear factor kappaB in trinitrobenzene sulphonic acid induced colitis in rats. Postgrad Med J 2006;82(964):130–5.
Chin AC, Parkos CA. Neutrophil transepithelial migration and epithelial barrier function in IBD: potential targets for inhibiting neutrophil trafficking. Ann N Y Acad Sci 2006;1072:276–87.
Elson CO, Sartor RB, Tennyson GS, Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology 1995;109(4):1344–67.
Wirtz S, Neurath MF. Animal models of intestinal inflammation: new insights into the molecular pathogenesis and immunotherapy of inflammatory bowel disease. Int J Colorectal Dis 2000;15(3):144–60.
Dharmani P, Leung P, Chadee K. Tumor necrosis factor-alpha and Muc2 mucin play major roles in disease onset and progression in dextran sodium sulphate-induced colitis. PLoS One 2011;6(9):e25058.
Sasaki M, Elrod JW, Jordan P, Itoh M, Joh T, Minagar A, et al. CYP450 dietary inhibitors attenuate TNF-alpha-stimulated endothelial molecule expression and leukocyte adhesion. Am J Physiol Cell Physiol 2004;286(4):C931–9.
Jurjus AR, Khoury NN, Reimund JM. Animal models of inflammatory bowel disease. J Pharmacol Toxicol Methods 2004;50(2):81–92.
Amanzada A, Malik IA, Blaschke M, Khan S, Rahman H, Ramadori G, et al. Identification of CD68(+) neutrophil granulocytes in in vitro model of acute inflammation and inflammatory bowel disease. Int J Clin Exp Pathol 2013;6(4):561–70.
Bain CC, Bravo-Blas A, Scott CL, Gomez Perdiguero E, Geissmann F, Henri S, et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol 2014;15 (10):929–37.
Hudcovic T, Kolinska J, Klepetar J, Stepankova R, Rezanka T, Srutkova D, et al. Protective effect of Clostridium tyrobutyricum in acute dextran sodium sulphate-induced colitis: differential regulation of tumour necrosis factor-alpha and interleukin-18 in BALB/c and severe combined immunodeficiency mice. Clin Exp Immunol 2012;167(2):356–65.
Ishiguro Y. Mucosal proinflammatory cytokine production correlates with endoscopic activity of ulcerative colitis. J Gastroenterol 1999;34(1):66–74.
Pitchumoni CS, Rubin A, Das K. Pancreatitis in inflammatory bowel diseases. J Clin Gastroenterol 2010;44(4):246–53.
Patel H, Barr A, Jeejeebhoy KN. Renal effects of long-term treatment with 5-aminosalicylic acid. Can J Gastroenterol 2009;23(3):170–6.
Finkin-Groner E. Novel Multi-Functional Drugs for the Treatment of Neurodegenerative Diseases. Israel: The Hebrew University of Jerusalem; 2013 Ph.D. thesis.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shifrin, H., Moradov, D., Bejar, C. et al. Novel indoline derivatives prevent inflammation and ulceration in dinitro-benzene sulfonic acid-induced colitis in rats. Pharmacol. Rep 68, 1312–1318 (2016). https://doi.org/10.1016/j.pharep.2016.08.008
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1016/j.pharep.2016.08.008