Silibinin Improves the Anti-arthritic Activity of Methotrexate in Zymosan-Induced Arthritis in Rats

Ahmed Hashem Mortada¹ and Saad Abdulrahman Hussain^2,

¹Department of Pharmacology, College of Pharmacy, University of Kufa, Iraq

²Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq

Cite this paper:
Ahmed Hashem Mortada and Saad Abdulrahman Hussain. Silibinin Improves the Anti-arthritic Activity of Methotrexate in Zymosan-Induced Arthritis in Rats. American Journal of Pharmacological Sciences. 2014; 2(3):47-51. doi: 10.12691/ajps-2-3-1

Abstract

Because of low toxic effects of plant-derived drugs, it has become a research focus in disease prevention and treatment, especially those chronic diseases requiring long-term treatment. The present study was designed to evaluate the effects of silibinin (SIL) when administered with methotrexate (MTX) in animal model of zymosan-induced arthritis in rats. Male Wistar rats are used for induction and arthritic inflammation in the knee joint and hind paw using zymosan. The animals are treated with MTX alone (10 mg/kg), SIL (10mg/kg) or their combination. The effect was followed through edema formation, tissue cytokines release (IL-1β, IL-8, TNF-α) and infiltration of leukocytes in synovial fluid. The results showed that SIL has weak antiarthritic activity when used alone, and improves the antiarthitic activity of MTX when both are concomitantly administered before challenge with zymosan. In conclusion, although SIL has a relatively weak anti-arthritic activity, it strongly augments the effect of MTX in animal model of zymosan-induced arthritis.

Keywords:
silibinin zymosan arthritis methotrexate rats

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References:

[1]	Firestein GS. Evolving concepts of rheumatoid arthritis. Nature, 423: 356-361. 2003.
[2]	Hootman J, Helmick C. Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum., 54: 226-229. 2006.
[3]	Cooles FA, Isaacs JD. Pathophysiology of rheumatoid arthritis. Curr. Opin. Rheumatol., 23: 233-240. 2011.
[4]	Szekanecz Z, Koch AE. Update on synovitis. Curr. Rheumatol. Rep., 3: 53-63. 2001.
[5]	Smolen JS, Landewe R, Breedveld FC, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying anti-rheumatic drugs. Annals. Rheum. Dis., 69: 964-975. 2010.
[6]	Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N. Engl. J. Med., 344: 907-916. 2001.
[7]	Gibbons LJ, Hyrich KL. Biologic therapy for rheumatoid arthritis: clinical efficacy and predictors of response. Bio. Drugs Clin. Immunother. Biopharm. Gene Ther., 23: 111-124. 2009.
[8]	Mease PJ, Cohen S,Gaylis NB, Chubick A, et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. J. Rheumatol., 37: 917-927. 2010.
[9]	Kren V, Walterov D. Silybin and Silymarin- New effects and applications. Biomed. Papers, 149 (1): 29-41. 2005.
[10]	Fraschini F, Dermartini G, Esposti D. Pharmacology of silymarin. Clin. Drug Invest., 22: 51-65. 2002.
[11]	Vereckei AS, Besch HR, Zipes DP. Combined amiodarone and silymarin treatment, but not amiodarone alone, prevents sustained atrial flutter in dogs. J. Cardiovasc. Electrophysiol., 14: 861-867. 2003.
[12]	Singh RP, Mallikarjuna GU, Sharma G, Dhanalakshmi S, et al. Oral silibinin inhibits lung tumor growth in athymic nude mice and forms a novel chemocombination with doxorubicin targeting nuclear factor κB-mediated inducible chemoresistance. Clin. Cancer Res., 10: 8641-8647. 2014.
[13]	Kang JS, Park SK, Yang KH, Kim HM. Silymarin inhibits TNF-α-induced expression of adhesion molecules in human umbilical vein endothelial cells. FEBS Lett., 550: 89-93. 2002.
[14]	Jacobs BP, Dennehy C, Ramirez G, Sapp J, Lawrence VA.Milk thistle for the treatment of liver disease: A systematic review and meta-analysis.Am. J. Med., 113: 506-515. 2002.
[15]	Invernizzi R, Bernuzzi S, Ciani D, Ascari E. Silymarin during maintenance therapy of acute promyelocytic leukemia. Haematologica, 78: 340-341. 1993.
[16]	Hussain SA, Jassim NA, Numan IT, Al-Khalifa II, Abdullah TA. Anti-inflammatory activity of silymarin in patients with knee osteoarthritis: A comparative study with piroxicam and meloxicam. Saudi Med. J., 30 (1): 179-184. 2009.
[17]	Juma'a KM, Ahmed ZA, Numan IT, Hussain SA.Dose-dependent anti-inflammatory effect of silymarin in experimental animal model of chronic inflammation. Afr. J. Pharmacy Pharmacol., 3 (5): 242-247. 2009.
[18]	Zimmermann M. Ethical guidelines for investigation of experimental pain in conscious animals. Pain, 16: 109. 1993.
[19]	Rosengren S, Firestein GS, Boyle DL. Measurement of inflammatory biomarkers in synovial tissue extracts by enzyme-linked immunosorbent assay. Clin. Diagn. Lab. Immunol., 10: 1002-1010. 2003.
[20]	Lowry OH, Rosebrough NJ, Farr AL, Randall RJ.Protein measurement with Folin phenol reagent.J. Biol. Chem., 193: 265-275. 1951.
[21]	Kobayashi K, Suda T, Nanya K, Sakaguchi N, et al. Cytokine production profile of splenocytes derived from zymosan-treated SKG mice developing arthritis. Inflamm. Res., 55: 335-341. 2006.
[22]	Yuhki KI, Ushikubi F, Naraba H, Ueno A, et al. Prostaglandin I2 plays a key role in Zymosan A-induced mouse pleurisy. J. Pharmacol. Exp. Ther., 325: 601-609. 2008.
[23]	Kannan K, Ortmann RA, Kimpel D. Animal models of rheumatoid arthritis and their relevance to human disease. Pathophysiology, 12: 167-181. 2005.
[24]	Nagate T, Tamura T, Sato F, Kuroda J, et al. Tranilast suppresses the disease development of the adjuvant- and streptococcal cell wall-induced arthritis in rats. J. Pharmacol. Sci., 105: 48-56. 2007.
[25]	Venkatesha SH, Rajaiah R, Berman BM, Moudgil KD. Immunomodulation of autoimmune arthritis by herbal cam. Evid. Based Complement. Alternat. Med., 11: 797-803. 2011.
[26]	Jung HW, Jung JK, Son KH, Lee DH, et al. Inhibitory effects of the root extract of Dipsacusasperoides on collagen-induced arthritis in mice. J. Ethnopharmacol., 139: 98-103. 2012.
[27]	Gupta OP, Sing S. Anti-inflammatory and antiarthritic activities of silymarin acting through inhibition of 5-lipoxygenase. Phytomedicine, 7 (1): 21-24. 2000.
[28]	Polyak SJ, Morishima C. Inhibition of T-cell inflammatory cytokines, hepatocyte NF-κB signaling and HCV infection by standardized silymarin. Gastroenterology, 132: 1925-1936. 2007.
[29]	Barnes PJ, Karin M. NF-κB a pivotal transcription factor in chronic inflammatory diseases. N. Eng. J. Med., 336: 1066-1071. 1997.
[30]	Monna SK, Mukhopadhya A, Van NT. Silymarin suppresses TNF-induced activation of NF-κB, c-Jun N-terminal kinase and apoptosis. J. Immunol., 163 (12): 6800-6809. 1999.
[31]	Lee JS, Kim SG. Silibinin polarize Th1/Th2 immune responses through the inhibition of immunostimulatory function of dendritic cells. J. Cell Physiol., 210: 385-397. 2007.
[32]	Kraan MC, Haringman JJ, Ahern MJ, Breedveld FC, et al. Quantification of the cell infiltrate in synovial tissue by digital image analysis. Rheumatology, 39: 43-49. 2000.
[33]	Jonsson H, Allen P, Peng SL. Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Nat. Med., 11: 666-671. 2005.
[34]	Asquith DL, Miller AM, McInnes IB, Liew FY.Animal models of rheumatoid arthritis.Eur. J. Immunol., 39: 2040-2044. 2009.
[35]	Frasnelli ME, Tarussio D, Chobaz-Peclat V, Busso N, So A. TLR2 modulates inflammation in zymosan-induced arthritis in mice. Arthritis Res. Ther., 7: 370-379. 2005.
[36]	Jain NK, Ishikawa TO, Spigelman I, Herschman HR. COX-2 expression and function in the hyperalgesic response to paw inflammation in mice. Prostaglandins Leukot. Essent. Fatty Acids, 79: 183-190. 2008.
[37]	Setty AR, Sigal LH. Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side effects. Semin. Arthritis Rheum., 34: 773-784. 2005.