Effects of Silibin Nanocapsules on Acetic Acid Induced Ulcerative Colitis in Rats

Document Type : Original Article (s)

Authors

1 Professor, Department of Pharmacology, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran

2 Student of Pharmacy, Department of Pharmaceutics, School of Pharmacy AND Novel Drug Delivery Systems Research Center AND Students Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Silibin is the major (70–80%) and the most active biological flavonolignan of silymarin with antioxidant and anti-inflammatory effects. Studies have shown that nanoparticles can effectively be swallowed by macrophages which are associated with inflammation procedure of ulcerative colitis. In addition, further reducing the particle size increases particle uptake into the intestinal cells and the particles could be deposited more effectively on affected areas. In the present study, nanoparticles of silibin were designed to evaluate their effectiveness on ulcerative colitis in rats.Methods: Test nanoparticles consisted of 15 mg of silibin loaded in 15 mg of poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonium ethyl methacrylate) polymer with average particle size of 109 nm which had been coated by 20% w/w of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) polymer in order to deliver nanoparticles to colon specifically. Five separate groups of rats were fasted for 36 hours and then, colitis was induced with 2 ml of acetic acid 4%. Treatments were made for 5 days, once a day, started 2 hours before colitis induction. The designed groups were: nanocapsules containing 75 mg/kg silibin, nanocapsules without silibin, dexamethasone (1 mg/kg), normal saline (2 ml/kg) and normal group. 24 hours after the last administration, colon tissue was removed; macroscopic and histopathologic assessment, also determination of myeloperoxidase (MPO) activity, tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) levels were conducted.Findings: Silibin nanocapsules were effective to diminish inflammation and ulcer severity while it was not able to reduce ulcer area statistically. Weight/length ratio in dexamethason and silibin nanocapsule group was close to that in normal group. Microscopic assessment of silibin nanocapsule group showed a mild to moderate inflammation of mucosa and minimal crypt damage as the values were significantly different from those of control group. Treatment with silibin nanocapsules resulted in decreasing of myeloperoxidase activity and also both levels of IL-6 and TNF-α compared to control group.Conclusion: Poly (ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonium ethyl methacrylate) nanocapsules of silibin could be considered as a suitable alternative for present drugs with anti-colitis property. However, more studies are needed to support this hypothesis for clinical use.

Keywords

References

  1. Maines LW, Fitzpatrick LR, French KJ, Zhuang Y, Xia Z, Keller SN, et al. Suppression of ulcerative colitis in mice by orally available inhibitors of sphingosine kinase. Dig Dis Sci 2008; 53(4): 997-1012.
  2. Xie F, Blackhouse G, Assasi N, Gaebel K, Robertson D, Goeree R. Cost-utility analysis of infliximab and adalimumab for refractory ulcerative colitis. Cost Eff Resour Alloc 2009; 7: 20.
  3. Triantafillidis JK, Merikas E, Georgopoulos F. Current and emerging drugs for the treatment of inflammatory bowel disease. Drug Des Devel Ther 2011; 5: 185-210.
  4. Cuadrado E, Alonso M, de Juan MD, Echaniz P, Arenas JI. Regulatory T cells in patients with inflammatory bowel diseases treated with adacolumn granulocytapheresis. World J Gastroenterol 2008; 14(10): 1521-7.
  5. Mateen S, Tyagi A, Agarwal C, Singh RP, Agarwal R. Silibinin inhibits human nonsmall cell lung cancer cell growth through cell-cycle arrest by modulating expression and function of key cell-cycle regulators. Mol Carcinog 2010; 49(3): 247-58.
  6. Vaid M, Katiyar SK. Molecular mechanisms of inhibition of photocarcinogenesis by silymarin, a phytochemical from milk thistle (Silybum marianum L. Gaertn.) (Review). Int J Oncol 2010; 36(5): 1053-60.
  7. Cui W, Gu F, Hu KQ. Effects and mechanisms of silibinin on human hepatocellular carcinoma xenografts in nude mice. World J Gastroenterol 2009; 15(16): 1943-50.
  8. Jamshidi AH, Ahmadi Ashtiani HR, Oliazadeh N, Jafarzadeh M, Taheri Boroujerdi M, Naderi MM, et al. A key for the thousand lock: comprehensive review of herbal medicine (silymarin) and Introducing of Silybum. Tehran, Iran: Noavar Publications; 2007. [In Persian].
  9. Tabata Y, Inoue Y, Ikada Y. Size effect on systemic and mucosal immune responses induced by oral administration of biodegradable microspheres. Vaccine 1996; 14(17-18): 1677-85.
  10. Pinto-Alphandary H, Balland O, Laurent M, Andremont A, Puisieux F, Couvreur P. Intracellular visualization of ampicillin-loaded nanoparticles in peritoneal macrophages infected in vitro with Salmonella typhimurium. Pharm Res 1994; 11(1): 38-46.
  11. Lamprecht A, Schafer U, Lehr CM. Size-dependent bioadhesion of micro- and nanoparticulate carriers to the inflamed colonic mucosa. Pharm Res 2001; 18(6): 788-93.
  12. Ulbrich W, Lamprecht A. Targeted drug-delivery approaches by nanoparticulate carriers in the therapy of inflammatory diseases. J R Soc Interface 2010; 7(Suppl 1): S55-S66.
  13. Asghar LF, Chure CB, Chandran S. Colon specific delivery of indomethacin: effect of incorporating pH sensitive polymers in xanthan gum matrix bases. AAPS PharmSciTech 2009; 10(2): 418-29.
  14. Mascolo N, Izzo AA, Autore G, Maiello FM, Di CG, Capasso F. Acetic acid-induced colitis in normal and essential fatty acid deficient rats. J Pharmacol Exp Ther 1995; 272(1): 469-75.
  15. Varshosaz J, Ahmadi F, Emami J, Tavakoli N, Minaiyan M, Mahzouni P, et al. Colon delivery of budesonide using solid dispersion in dextran for the treatment and secondary prevention of ulcerative colitis in rat. Int J Prev Med 2010; 1(2): 115-23.
  16. Motavallian-Naeini A, Minaiyan M, Rabbani M, Mahzuni P. Anti-inflammtaory effect of ondansetron through 5-HT3 receptors on TNBS –induced colitis in rat. EXCLI Journal 2012; 11: 30-44.
  17. Minaiyan M, Ghannadi A, Etemad M, Mahzouni P. A study of the effects of Cydonia oblonga Miller (Quince) on TNBS-induced ulcerative colitis in rats. Res Pharm Sci 2012; 7(2): 103-10.
  18. Sadeghi H, Hajhashemi V, Minaiyan M, Movahedian A, Talebi A. A study on the mechanisms involving the anti-inflammatory effect of amitriptyline in carrageenan-induced paw edema in rats. Eur J Pharmacol 2011; 667(1-3): 396-401.
  19. Blalock TD, Varela JC, Gowda S, Tang Y, Chen C, Mast BA, et al. Ischemic skin wound healing models in rats. Wounds 2001; 13(1): 35-44.
  20. Probert CS, Chott A, Turner JR, Saubermann LJ, Stevens AC, Bodinaku K, et al. Persistent clonal expansions of peripheral blood CD4+ lymphocytes in chronic inflammatory bowel disease. J Immunol 1996; 157(7): 3183-91.
  21. Lamprecht A, Ubrich N, Yamamoto H, Schafer U, Takeuchi H, Maincent P, et al. Biodegradable nanoparticles for targeted drug delivery in treatment of inflammatory bowel disease. J Pharmacol Exp Ther 2001; 299(2): 775-81.
  22. Makhlof A, Tozuka Y, Takeuchi H. pH-Sensitive nanospheres for colon-specific drug delivery in experimentally induced colitis rat model. Eur J Pharm Biopharm 2009; 72(1): 1-8.
  23. Minaiyan M, Ghannadi AR, Afsharipour M, Mahzouni P. Effects of extract and essential oil of Rosmarinus officinalis L. on TNBS-induced colitis in rats. Res Pharm Sci 2011; 6(1): 13-21.
  24. Paiva LA, Gurgel LA, De Sousa ET, Silveira ER, Silva RM, Santos FA, et al. Protective effect of Copaifera langsdorffii oleo-resin against acetic acid-induced colitis in rats. J Ethnopharmacol 2004; 93(1): 51-6.
  25. Deep G, Gangar SC, Rajamanickam S, Raina K, Gu M, Agarwal C, et al. Angiopreventive efficacy of pure flavonolignans from milk thistle extract against prostate cancer: targeting VEGF-VEGFR signaling. PLoS One 2012; 7(4): e34630.
  26. Ozyurek M, Bektasoglu B, Guclu K, Apak R. Hydroxyl radical scavenging assay of phenolics and flavonoids with a modified cupric reducing antioxidant capacity (CUPRAC) method using catalase for hydrogen peroxide degradation. Anal Chim Acta 2008; 616(2): 196-206.
  27. Kruidenier L, Verspaget HW. Review article: oxidative stress as a pathogenic factor in inflammatory bowel disease--radicals or ridiculous? Aliment Pharmacol Ther 2002; 16(12): 1997-2015.
  28. Korenaga D, Takesue F, Kido K, Yasuda M, Inutsuka S, Honda M, et al. Impaired antioxidant defense system of colonic tissue and cancer development in dextran sulfate sodium-induced colitis in mice. J Surg Res 2002; 102(2): 144-9.
  29. Simmonds NJ, Rampton DS. Inflammatory bowel disease--a radical view. Gut 1993; 34(7): 865-8.
  30. Hosseini-Tabatabaei A, Esmaily H, Rahimian R, Khorasani R, Baeeri M, Barazesh-Morgani A, et al. Benefits of nicorandil using an immunologic murine model of experimental colitis. Cent Eur J-Biol 2009; 4(1): 74-85.
  31. Rogler G, Andus T. Cytokines in inflammatory bowel disease. World J Surg 1998; 22(4): 382-9.
  32. Grulke S, Franck T, Gangl M, Peters F, Salciccia A, Deby-Dupont G, et al. Myeloperoxidase assay in plasma and peritoneal fluid of horses with gastrointestinal disease. Can J Vet Res 2008; 72(1): 37-42.
  33. Shen C, de HG, Bullens DM, Van AG, Geboes K, Rutgeerts P, et al. Remission-inducing effect of anti-TNF monoclonal antibody in TNBS colitis: mechanisms beyond neutralization? Inflamm Bowel Dis 2007; 13(3): 308-16.
  34. Ebrahimi F, Esmaily H, Baeeri M, Mohammadirad A, Fallah S, Abdollahi M. Molecular evidences on the benefits of N-acetylcysteine in experimental colitis. Cent. Eur J Biol 2008; 3(2): 135-42.
  35. Jurjus AR, Khoury NN, Reimund JM. Animal models of inflammatory bowel disease. J Pharmacol Toxicol Methods 2004; 50(2): 81-92.
Journal of Isfahan Medical School
Volume 31, Issue 236 - Serial Number 236
March and April 2013
Pages 661-674

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History

  • Receive Date: 29 March 2013
  • Revise Date: 05 May 2024
  • Accept Date: 06 April 2022

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