THE EFFECT OF PROPHYLACTIC INHIBITION OF INDUCIBLE NITRIC OXIDE SYNTHASE BY AMINOGUANIDINEON SERUM LEVELS OF SOME ADIPOCYTOKINES IN PRISTANE-INDUCED ARTHRITISIN RATS
Objective: The aim of the present study was to evaluate the effect of prophylactic inhibition of inducible nitric oxide synthase (iNOS) by aminoguanidine (AG) on serum levels of some adipocytokines in pristane-induced arthritis in rats.
Methods: Forty white Albino rats were divided randomly into four groups; each group was composed of ten rats (five male and five female). Group I (AP) has received AG (100 mg/kg/day) i. p. for seven days, and then at day 8, has received single 150 Âµl pristane dose sc. at the base of rat's tail. Group II (PC) has only received single 150 Âµl pristane sc. at the base of rat's tail, at day 8 from the start of the experiment. Group III (AC) has only received AG (100 mg/kg/day)i. p. for seven days. Group VI (VC) has only received normal saline via i. p. injection for seven days. At the end of the experiment time, rats were sacrificed, and serum samples were obtained and used for the measurement of iNOS, rheumatoid factor (RF), c-reactive protein (CRP), tumor necrosis factor-alpha (TNF-Î±), interleukine-6 (IL-6), leptin and adiponectin levels, using the corresponding rat ELISA kits.
Results: Administration of pristane for the induction of RA has resulted in significant increase in all of the measured parameters in PC group as compared to VC and AC groups, except for iNOS where the increase was significant as compared to AC group only. Serum levels of RF, CRP and IL-6 in AP group have showed to be significantly elevated as compared to VC and AC groups. Administration of AG has resulted in different levels of reduction in all of the measured parameters in AP group as compared to PC group. The reduction was statistically significant with regard to CRP and leptin.
Conclusion: prophylactic administration of the selective iNOS inhibitor AG, has resulted in a reduction in serum levels of the measured adipocytokines which may reflect a reduction in the severity of PIA.
2. Gabriel SE, Crowson CS, O'Fallon WM. The epidemiology of rheumatoid arthritis in Rochester, Minnesota, 1955-1985. Arthritis Rheum 1999;42:415-20.
3. Neovius M, Simard JF, Askling J. Nationwide prevalence of rheumatoid arthritis and penetration of disease-modifying drugs in Sweden. Ann Rheum Dis 2011;70:624-9.
4. Mac Dougald OA, Burant CF. The rapidly expanding family of adipokines. Cell Metab 2007;6:159-61.
5. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005;115:911-9.
6. Bredt DS. Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res 1999;31:577-96.
7. Bryan NS, Bian K, Murad F. Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci 2009;14:1-18.
8. Nagy G, Clark JM, Buzas EI, Gorman CL, Cope AP. Nitric oxide, chronic inflammation and autoimmunity. Immunol Lett 2007;111:1-5.
9. Lotz M, Hashimoto S, Kuhn K. Mechanisms of chondrocyte apoptosis. Osteoarthritis Cartilage 1999;7:389-91.
10. Grabowski PS, England AJ, Dykhuizen R, Copland M, Benjamin N, Reid DM, et al. Elevated nitric oxide production in rheumatoid arthritis. Detection using the fasting urinary nitrate: creatinine ratio. Arthritis Rheum 1996;39:643-7.
11. Ali AM, Habeeb RA, El-Azizi NO, Khattab DA, Abo-Shady RA, Elkabarity RH. Higher nitric oxide levels are associated with disease activity in Egyptian rheumatoid arthritis patients. Rev Bras Reumatol 2014;54:446-51.
12. Stichtenoth DO, Fauler J, Zeidler H, Frolich JC. Urinary nitrate excretion is increased in patients with rheumatoid arthritis and reduced by prednisolone. Ann Rheum Dis 1995;54:820-4.
13. Onur O, Akinci AS, Akbiyik F, Unsal I. Elevated levels of nitrate in rheumatoid arthritis. Rheumatol Int 2001;20:154-8.
14. Cuzzocrea S. Role of nitric oxide and reactive oxygen species in arthritis. Curr Pharm Des 2006;12:3551-70.
15. Vuolteenaho K, Moilanen T, Knowles RG, Moilanen E. The role of nitric oxide in osteoarthritis. Scand J Rheumatol 2007;36:247-58.
16. Weinberg JB, Granger DL, Pisetsky DS, Seldin MF, Misukonis MA, Mason SN, et al. The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine. J Exp Med 1994;179:651-60.
17. Connor JR, Manning PT, Settle SL, Moore WM, Jerome GM, Webber RK, et al. Suppression of adjuvant-induced arthritis by selective inhibition of inducible nitric oxide synthase. Eur J Pharmacol 1995;273:15-24.
18. Corbett JA, McDaniel ML. The use of aminoguanidine, a selective iNOS inhibitor, to evaluate the role of nitric oxide in the development of autoimmune diabetes. Methods 1996;10:21-30.
19. Vingsbo C, Sahlstrand P, Brun JG, Jonsson R, Saxne T, Holmdahl R. Pristane-induced arthritis in rats: a new model for rheumatoid arthritis with a chronic disease course influenced by both major histocompatibility complex and non-major histocompatibility complex genes. Am J Pathol 1996;149:1675-83.
20. Nordquist N, Olofsson P, Vingsbo-Lundberg C, Petterson U, Holmdahl R. Complex genetic control in a rat model for rheumatoid arthritis. J Autoimmun 2000;15:425-32.
21. Parlakpinar H, Ozer MK, Acet A. Effect of aminoguanidine on ischemia-reperfusion-induced myocardial injury in rats. Mol Cell Biochem 2005;277:137-42.
22. Xu J, Li N, Dai DZ, Yu F, Dai Y. The endothelin receptor antagonist CPU0213 is more effective than aminoguanidine to attenuate isoproterenol-induced vascular abnormality by suppressing overexpression of NADPH oxidase [correction of oxidas], ETA, ETB, and MMP9 in the vasculature. J Cardiovasc Pharmacol 2008;52:42-8.
23. Ozturk A, Firat C, Parlakpinar H, Bay-Karabulut A, Kirimlioglu H, Gurlek A. Beneficial effects of aminoguanidine on skin flap survival in diabetic rats. Exp Diabetes Res 2012;8. doi.org/10.1155/2012/721256. [Article in Press]
24. Pautz A, Art J, Hahn S, Nowag S, Voss C, Kleinert H. Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide 2010;23:75-93.
25. Wimalawansa SJ. Nitric oxide and bone. Ann N Y Acad Sci 2010;1192:391-403.
26. Taylor PC, Mehta P, Tull T. Aetiopathology of rheumatoid arthritis. Medicine 2010;38:163-6.
27. Chiou WF, Chen CF, Lin JJ. Mechanisms of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by andrographolide. Br J Pharmacol 2000;129:1553-60.
28. Casper I, Nowag S, Koch K, Hubrich T, Bollmann F, Henke J, et al. Post-transcriptional regulation of the human inducible nitric oxide synthase (iNOS) expression by the cytosolic poly(A)-binding protein (PABP). Nitric Oxide 2013;33:6-17.
29. Zheng H, Yu X, Collin-Osdoby P, Osdoby P. RANKL stimulates inducible nitric-oxide synthase expression and nitric oxide production in developing osteoclasts: An autocrine negative feedback mechanism triggered by RANKL-induced interferon-Î² via NF-ÎºB that restrains osteoclastogenesis and bone resorption. J Biol Chem 2006;281:15809-20.
30. Kahles F, Findeisen HM, Bruemmer D. Osteopontin: a novel regulator at the crossroads of inflammation, obesity and diabetes. Mol Metab 2014;3:384-93.
31. Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108:2460-6.
32. Vuolteenaho K, Koskinen A, Kukkonen M, Nieminen R, Paivarinta U, Moilanen T, et al. Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage--mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. Mediators Inflammation 2009. doi: 10.1155/2009/345838. [Epub 13 Aug 2009]
33. Tsay TB, Yang MC, Chen PH, Lin CT, Hsu CM, Chen LW. TNF-alpha decreases infection-induced lung injury in burn through negative regulation of TLR4/iNOS. J Surg Res 2013;179:106-14.
34. Cai X, Li X, Li L, Huang XZ, Liu YS, Chen L, et al. Adiponectin reduces carotid atherosclerotic plaque formation in ApoE-/-mice: roles of oxidative and nitrosative stress and inducible nitric oxide synthase. Mol Med Rep 2015;11:1715-21.
35. Fischer P, Hilfiker-Kleiner D. Survival pathways in hypertrophy and heart failure: the gp130-STAT3 axis. Basic Res Cardiol 2007;102:279-97.
36. Otero M, Lago R, Lago F, Reino JJ, Gualillo O. Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: synergistic effect of leptin with interleukin-1. Arthritis Res Ther 2005;7: R581-91.
37. Otero M, Lago R, Gomez R, Lago F, Gomez-Reino JJ, Gualillo O. Phosphatidylinositol 3-kinase, MEK-1 and p38 mediate leptin/interferon-gamma synergistic NOS type II induction in chondrocytes. Life Sci 2007;81:1452-60.
38. Bao JP, Chen WP, Feng J, Hu PF, Shi ZL, Wu LD. Leptin plays a catabolic role on articular cartilage. Mol Biol Rep 2010;37:3265-72.
39. Lago R, Gomez R, Otero M, Lago F, Gallego R, Dieguez C, et al. A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes. Articular Cartilage Osteoarthritis 2008;16:1101-9.
40. Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies. Q J Med 2010;103:139-46.
41. Nell VP, Machold KP, Stamm TA, Eberl G, Heinzl H, Uffmann M, et al. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis 2005;64:1731-6.
42. Jonsson T, Arinbjarnarson S, Thorsteinsson J, Steinsson K, Geirsson AJ, Jonsson H, et al. Raised IgA rheumatoid factor (RF) but not IgM RF or IgG RF is associated with extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol 1995;24:372-5.
43. Jonsson T, Steinsson K, Jonsson H, Geirsson AJ, Thorsteinsson J, Valdimarsson H. Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheumatoid arthritis. Rheumatol Int 1998;18:119-22.
44. Pai S, Pai L, Birkenfeldt R. Correlation of serum IgA rheumatoid factor levels with disease severity in rheumatoid arthritis. Scand J Rheumatol 1998;27:252-6.
45. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.
46. Saxena A, Cronstein BN. 57-Acute phase reactants and the concept of inflammation. In: O'Dell GS, Firestein RC, Budd SE, Gabriel IB, McInnes JR. editor. Kelley's Textbook of Rheumatology (Ninth Edition). Philadelphia, USA: W. B. Saunders; 2013. p. 818-29.
47. Hoffmann MH, Tuncel J, Skriner K, Tohidast-Akrad M, Turk B, Pinol-Roma S, et al. The rheumatoid arthritis-associated autoantigen hnRNP-A2 (RA33) is a major stimulator of autoimmunity in rats with pristane-induced arthritis. J Immunol 2007;179:7568-76.
48. Calabro P, Chang DW, Willerson JT, Yeh ET. Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: linking obesity to vascular inflammation. J Am Coll Cardiol 2005;46:1112-3.
49. Pearle AD, Scanzello CR, George S, Mandl LA, DiCarlo EF, Peterson M, et al. Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis. Osteoarthritis Cartilage 2007;15:516-23.
50. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol 2015;16:448-57.
51. Koerner A, Kratzsch J, Kiess W. Adipocytokines: leptin--the classical, resistin--the controversial, adiponectin--the promising, and more to come. Best Pract Res Clin Endocrinol Metab 2005;19:525-46.
52. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006;6:772-83.
53. Yoshino T, Kusunoki N, Tanaka N, Kaneko K, Kusunoki Y, Endo H, et al. Elevated serum levels of resistin, leptin, and adiponectin are associated with C-reactive protein and also other clinical conditions in rheumatoid arthritis. Intern Med 2011;50:269-75.
54. Allam A, Radwan A. The relationship of serum leptin levels with disease activity in Egyptian patients with rheumatoid arthritis. Egypt Rheumatol 2012;34:185-90.
55. Del Prete A, Salvi V, Sozzani S. Adipokines as potential biomarkers in rheumatoid arthritis. Mediators Inflammation 2014;2014:11.
56. Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 2009;5:667-76.
57. Chu CQ, Field M, Feldmann M, Maini RN. Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum 1991;34:1125-32.
58. Matsuno H, Yudoh K, Katayama R, Nakazawa F, Uzuki M, Sawai T, et al. The role of TNF-alpha in the pathogenesis of inflammation and joint destruction in rheumatoid arthritis (RA): a study using a human RA/SCID mouse chimera. Rheumatology (Oxford) 2002;41:329-37.
59. Schulz M, Dotzlaw H, Neeck G. Ankylosing spondylitis and rheumatoid arthritis: serum levels of TNF-alpha and Its soluble receptors during the course of therapy with etanercept and infliximab. BioMed Res Int 2014. doi.org/10.1155/2014/675108. [Article in Press]
60. Osta B, Roux JP, Lavocat F, Pierre M, Ndongo-Thiam N, Boivin G, et al. Differential effects of IL-17A and TNF-alpha on osteoblastic differentiation of isolated synoviocytes and on bone explants from arthritis patients. Front Immunol 2015;6:151.
61. Ranganathan P. Rheumatoid arthritis: biomarkers of response to TNF inhibition in RA. Nat Rev Rheumatol 2015;11:446-8.
62. Nishimoto N, Ito A, Ono M, Tagoh H, Matsumoto T, Tomita T, et al. IL-6 inhibits the proliferation of synovial fibroblastic cells from rheumatoid arthritis patients in the presence of soluble IL-6 receptor. Int Immunol 2000;12:187-93.
63. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344:907-16.
64. Hashizume M, Hayakawa N, Mihara M. IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatol (Oxford) 2008;47:1635-40.
65. Gan L, Guo K, Cremona ML, McGraw TE, Leibel RL, Zhang Y. TNF-alpha up-regulates protein level and cell surface expression of the leptin receptor by stimulating its export via a PKC-dependent mechanism. Endocrinology 2012;153:5821-33.
66. Agrawal S, Gollapudi S, Su H, Gupta S. Leptin activates human B cells to secrete TNF-alpha, IL-6, and IL-10 via JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathway. J Clin Immunol 2011;31:472-8.
67. Kopec-Medrek M, Kotulska A, Widuchowska M, Adamczak M, Wiecek A, Kucharz EJ. Plasma leptin and neuropeptide Y concentrations in patients with rheumatoid arthritis treated with infliximab, a TNF-alpha antagonist. Rheumatol Int 2012;32:3383-9.
68. Lee SM, Choi HJ, Oh CH, Oh JW, Han JS. Leptin increases TNF-alpha expression and production through phospholipase D1 in Raw 264.7 cells. PloS one 2014;9:e102373. doi: 10.1371/journal.pone.0102373. [Article in Press]
69. Madhok R, Crilly A, Watson J, Capell HA. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 1993;52:232-4.
70. Sack U, Kinne RW, Marx T, Heppt P, Bender S, Emmrich F. Interleukin-6 in synovial fluid is closely associated with chronic synovitis in rheumatoid arthritis. Rheumatol Int 1993;13:45-51.
71. Marnell L, Mold C, Du Clos TW. C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 2005;117:104-11.
72. Jequier E. Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci 2002;967:379-88.
73. Gualillo O, Eiras S, Lago F, Dieguez C, Casanueva FF. Elevated serum leptin concentrations induced by experimental acute inflammation. Life Sci 2000;67:2433-41.
74. Lee SW, Park MC, Park YB, Lee SK. Measurement of the serum leptin level could assist disease activity monitoring in rheumatoid arthritis. Rheumatol Int 2007;27:537-40.
75. Targonska-Stepniak B, Majdan M, Dryglewska M. Leptin serum levels in rheumatoid arthritis patients: relation to disease duration and activity. Rheumatol Int 2008;28:585-91.
76. Olama SM, Senna MK, Elarman M. Synovial/serum leptin ratio in rheumatoid arthritis: the association with activity and erosion. Rheumatol Int 2012;32:683-90.
77. Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol 2007;4:1-13.
78. Anders HJ, Rihl M, Heufelder A, Loch O, Schattenkirchner M. Leptin serum levels are not correlated with disease activity in patients with rheumatoid arthritis. Metabolism 1999;48:745-8.
79. Hizmetli S, Kisa M, Gokalp N, Bakici MZ. Are plasma and synovial fluid leptin levels correlated with disease activity in rheumatoid arthritis? Rheumatol Int 2007;27:335-8.
80. Popa C, Netea MG, Radstake TR, van Riel PL, Barrera P, van der Meer JW. Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis. Ann Rheum Dis 2005;64:1195-8.
81. Neumann E FK, Muller-Ladner U. 58-Acute-phase responses and adipocytokines. In: Watts RA CP, Denton C, Foster H, Isaacs J, Muller-Ladner U. editor. Oxford Textbook of Rheumatology (Fourth Edition). Oxford, UK: Oxford University Press; 2013. p. 424-30.
82. Shapiro L, Scherer PE. The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol 1998;8:335-8.
83. Oh DK, Ciaraldi T, Henry RR. Adiponectin in health and disease. Diabetes Obes Metab 2007;9:282-9.
84. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001;86:1930-5.
85. Beauloye V, Zech F, Tran HT, Clapuyt P, Maes M, Brichard SM. Determinants of early atherosclerosis in obese children and adolescents. J Clin Endocrinol Metab 2007;92:3025-32.
86. Ouchi N, Walsh K. Adiponectin as an anti-inflammatory factor. Clin Chim Acta 2007;380:24-30.
87. Rovin BH, Song H, Hebert LA, Nadasdy T, Nadasdy G, Birmingham DJ, et al. Plasma, urine, and renal expression of adiponectin in human systemic lupus erythematosus. Kidney Int 2005;68:1825-33.
88. Rho YH, Solus J, Sokka T, Oeser A, Chung CP, Gebretsadik T, et al. Adipocytokines are associated with radiographic joint damage in rheumatoid arthritis. Arthritis Rheum 2009;60:1906-14.
89. Choi HM, Lee YA, Lee SH, Hong SJ, Hahm DH, Choi SY, et al. Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators. Arthritis Res Ther 2009;11: R161.
90. Ehling A, Schaffler A, Herfarth H, Tarner IH, Anders S, Distler O, et al. The potential of adiponectin in driving arthritis. J Immunol 2006;176:4468-78.
91. Tan W, Wang F, Zhang M, Guo D, Zhang Q, He S. High adiponectin and adiponectin receptor 1 expression in synovial fluids and synovial tissues of patients with rheumatoid arthritis. Semin Arthritis Rheum 2009;38:420-7.
92. Schaffler A, Ehling A, Neumann E, Herfarth H, Tarner I, Scholmerich J, et al. Adipocytokines in synovial fluid. JAMA 2003;290:1709-10.
93. Senolt L, Pavelka K, Housa D, Haluzik M. Increased adiponectin is negatively linked to the local inflammatory process in patients with rheumatoid arthritis. Cytokine 2006;35:247-52.
94. Giles JT, Allison M, Bingham CO. 3rd. Scott WM Jr, Bathon JM. Adiponectin is a mediator of the inverse association of adiposity with radiographic damage in rheumatoid arthritis. Arthritis Rheum 2009;61:1248-56.
95. Ebina K, Fukuhara A, Ando W, Hirao M, Koga T, Oshima K, et al. Serum adiponectin concentrations correlate with severity of rheumatoid arthritis evaluated by the extent of joint destruction. Clin Rheumatol 2009;28:445-51.
96. Laurberg TB, Frystyk J, Ellingsen T, Hansen IT, Jorgensen A, Tarp U, et al. Plasma adiponectin in patients with active, early, and chronic rheumatoid arthritis who are steroid and disease-modifying antirheumatic drug-naive compared with patients with osteoarthritis and controls. J Rheumatol 2009;36:1885-91.
97. Targonska-Stepniak B, Dryglewska M, Majdan M. Adiponectin and leptin serum concentrations in patients with rheumatoid arthritis. Rheumatol Int 2010;30:731-7.