Abstract
The goal of this investigation was to study the protective effects of thymoquinone (TQ) and methotrexate (MTX) on collagen-induced arthritis (CIA) in rats. On day 0 under ether anesthesia, the experimental groups were immunized with 0.5 mg native chick collagen II (CII) solubilized in 0.1 M acetic acid and emulsified in Freund’s incomplete adjuvant. Control rats were gavaged with vehicle, whereas CII was administered intradermally. In addition, arthritis treated with TQ group received TQ (10 mg kg−1 bw by gavage once a week for 3 weeks starting on day 0); and arthritis treated with MTX group received MTX (MTX was suspended in corn oil and administered by gavage at 1 mg kg −1 bw once a week for 3 weeks starting on day 0). A significant decrease in the incidence and severity of arthritis by clinical and radiographic assessments was found in recipients of therapy, compared with that of controls. The MTX treatment significantly (P<0.01) decreased the elevated serum NO, urea and creatinine in arthritic rats. Likewise, TQ treatment was also able to reduce significantly (P<0.05) serum NO, urea and creatinine levels, but to lesser extent than MTX. The histopathologic abnormalities are consistent with the hydropic epithelial cell degenerations and moderate tubular dilatation in the some proximal and distal tubules. The severity of the degenerative changes in most of the shrunken glomerules and vascular congestion were also observed in arthritic animals. Preventive treatment of TQ and especially MTX significantly inhibited kidney dysfunction and this histopathologic alterations. These studies indicate that TQ can be used similar to MTX as a safe and effective therapy for CIA and may be useful in the treatment of rheumatoid arthritis.
Similar content being viewed by others
References
Aboutabl EA, El-Azzouny AA, Hammerschmidt FJ et al (1986) Aroma volatiles of Nigella sativa L. seeds. In: Brunke EJ, (eds) Progress in essential oil research. Proceedings of the international symposium on essential oils, Berlin de Gruyter, pp 44–55
Al-Ghamdi MS (2001) The anti-inflammatory, analgesic and antipyretic activity of Nigella sativa. J Ethnopharmacol 76:45–48
Al-Gharably M, Badary OA, Nagi MN et al (1997) Protective effect of thymoquinone against carbon tetrachloride-induced hepatotoxicity in mice. Res Commun Pharmacol Toxicol 2:41–50
Al-Shabanah OA, Badary OA, Naagi MN et al (1998) Thymoquinone protects against doxorubicin-induced cardiotoxicity without compromising its antitumor activity. J Exp Clin Cancer Res 17:193–198
Andersen PA, West SG, O’Dell JR et al (1985) Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double blind study. Ann Intern Med 103:489–496
Badary OA (1999) Thymoquinone attenuates ifosfamide-induced Fanconi syndrome in rats and enhances its antitumor activity in mice. J Ethnopharmacol 67:135–142
Badary OA, Nagi MN, Al-Shabanah OA et al (1997) Thymoquinone ameliorates the nephrotoxicity induced by cisplatin in rodents and potentiates its antitumor activity. Can J Physiol Pharmacol 75:1356–1361
Barba L, Pawlowski I, Brentjens JR et al (1983) Diagnostic immunopathology of the kidney biopsy in rheumatic diseases. Hum Pathol 14: 290–304
Blantz RC, Munger K (2002) Role of nitric oxide in inflammatory conditions. Nephron 90:373–378
Boers M, Croonen AM, Dijmans et al (1987) Renal findings in rheumatoid arthritis: clinical aspects of 132 necropsies. Ann Rheum Dis 46:658–663
Boers M, Dijkmans BA, Breedveld FC et al (1990) Subclinical renal dysfunction in rheumatoid arthritis. Arthritis Rheum 33:95–101
Brahn E, Peacock DJ, Banquerigo ML et al (1991) Suppression of collagen-induced arthritis by combination cyclosporin A and methotrexate therapy. Arthritis Rheum 34:1282–8
Brahn E, Peacock DJ, Banquerigo ML et al (1992) Effects of tumor necrosis factor alpha (TNF-alpha) on collagen arthritis. Lymphokine Cytokine Res 11:253–256
Burry HC (1972) Reduced glomerular function in rheumatoid arthritis. Ann Rheum Dis 31:65–68
Burtis M, Bucar F (2000) Antioxidant activity of Nigella sativa essential oil. Phytother Res 14:323–328
Cannon GW, Openshaw SJ, Hibbs Jr et al (1996) Nitric oxide production during adjuvant-induced and collagen-induced arthritis. Arthritis Rheum 39:1677–1684
Cattell V (2002) Nitric oxide and glomerulonephritis. Kidney Int 61:816–821
Cattell V, Cook T, Moncada S et al (1990) Glomeruli synthetise nitrite in experimental nephrotoxic nephritis. Kidney Int 38:1056–1060
Chade AR, Rodrı´guez-Porcel M, Grande JP Krier et al (2002) Distinct renal injury in early atherosclerosis and renovascular disease. Circulation 106:1165–1171
Chakravarty N (1993) Inhibition of histamine release from mast cells by Nigellone. Ann Allergy 70:237–242
Daba MH, Abdel Rahman MS (1988) Hepatoprotective activity of thymoquinone in isolated rat hepatocytes. Toxicol Lett 16:23–29
Dijoseph JF, Walter TL, Hartman DA et al (1993) Kidney dysfunction in the arthritic rat. Int J Immunopharmacol 15:933–941
Dougados M, Awada H, Amor B et al (1988) Cyclosporin in rheumatoid arthritis: a double blind, placebo controlled study in 52 patients. Ann Rheum Dis 47:127–133
El-Alfy TS, El-Fatatry HM, Tooma MA et al (1975) Isalation and structure assignment of an antimicrobial principle from the volatile oil of Nigella sativa L.seeds Pharmazie 30:109–111
El-Kadi A, Kandil O, Tabuni AM et al (1987) Nigella cell mediated immunity. Arch AIDS Res 1:232–233
El-Tahir KE, Ashour MM, Al-Harbi MM et al (1993) The cardiovascular actions of the volatile oil of the black seed (Nigella sativa) in rats: elucidation of the mechanism(s) of action. Gen Pharmacol 24:1123–1131
Farrell AJ, Blake DR, Palmer RM et al (1992) Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann Rheum Dis 51:1219–1222
Furusu A, Miyazaki M, Abe K et al (1998) Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis. Kidney Int 53:1760–1768
Franch MA, Moreno JJ, Castell et al (1990) M urinary N-acetyl-beta-d-glucosaminidase as a marker of renal injury in adjuvant arthritis. Res Exp Med (Berl) 190:213–218
Houghton PJ, Zarka R, Heras B et al (1995) Fixed oil of Nigella sativa and derived thymoquinone inhibit eicosanoid generation in leucocytes and membrane lipid peroxidation. Planta Med 61:33–36
Hsu SM, Raine L, Fanger H et al (1981) Use of Avidin-Biotin-Peroxidase complex (ABC) in immunperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577–580
Jansen A, Cook T, Taylor GM et al (1994) Induction of nitric oxide synthase in rat immune complex glomerulonephritis. Kidney Int 45:1215–1219
Kashem A, Endoh M, Yano N et al (1996) Expression of inducible-NOS in human glomerulonephritis: the possible source is infiltrating monocytes/macrophages. Kidney Int 50:392–399
Kone BC, Baylis C (1997) Biosynthesis and homeostatic roles of nitric oxide in the normal kidney. Am J Physiol 272:F561–78
Kruk I, Michalska T, Lichszteld K et al (2000) The effect of thymol and its derivatives on reactions generating reactive oxygen species. Chemosphere 41:1059–1064
Lopez-Franco O Suzuki Y Sanjuan et al (2002) Nuclear factor-kappa B inhibitors as potential novel anti-inflammatory agents for the treatment of immune glomerulonephritis. Am J Pathol 161:1497–1505
Mahfouz M, El-Dakhakhny M (1960) The isolation of a crystalline active principle from Nigella sativa L. seeds J Pharm Sci UAR 1:1–19
Maiti S, Chen G (2003) Methotrexate is a novel inducer of rat liver and intestinal sulfotransferases. Arch Biochem Biophys 418:161–168
Nagi MN, Mansour MA (2000) Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity in rats: a possible mechanism of protection. Pharmacol Res 41:283–289
Nagi MN, Alam K, Badary OA et al (1999) Thymoquinone protects against carbon tetrachloride hepatotoxicity in mice via an antioxidant mechanism. Biochem Mol Biol Int 47:153–159
Nathan C (1997) Inducible nitric oxide synthase: What difference does it make? J Clin Invest 100:2417–2423
Peacock DJ, Banquerigo ML, Brahn E et al (1992) Angiogenesis inhibition suppresses collagen arthritis. J Exp Med 175:1135–1138
van Rijthoven AW, Dijkmans BA, Goei The HS et al (1986) Cyclosporin treatment for rheumatoid arthritis: a placebo controlled, double blind, multicentre study. Ann Rheum Dis 45:726–731
Romero JC, Strick DM (1993) Nitric oxide and renal function. Curr Opin Nephrol Hypertens 2:114–121
Rovensky J, Svik K, Stancikova M et al (2002) Treatment of experimental adjuvant arthritis with the combination of methotrexate and lyophilized Enterococcus faecium enriched with organic selenium. Folia Microbiol (Praha) 47:573–578
Rovensky J, Svik K, Stancikova M et al (2003) Effect of immunostimulatory ribomunyl on the preventive treatment of rat adjuvant arthritis with cyclosporine and methotrexate. J Rheumatol 30:2027–2032
Sakurai H, Kohsaka H, Liu MF et al (1995) Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest 96:2357– 2363
Thompson RN, Watts C, Edelman J et al (1984) A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol 11:760–763
Trentham DE, Townes AS, Kang AH et al (1977) Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med 146:857–868
Vengerovskii AI, Saratikov AS, Tikhonova NM et al (1977) Structural and metabolic disorders in the heart, liver and kidneys in adjuvant disease. Arkh Patol 39:72–77
Weinblatt ME , Coblyn JS, Fox DA et al (1985) Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 312:818–822
Williams HJ, Willkens RF, Samuelson CO Jr et al (1985) Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 28:721–730
Yang CW, Yu CC, Ko YC et al (1998) Aminoguanidine reduces glomerular inducible nitric oxide synthase (iNOS) and transforming growth factor-1 (TGF-1) mRNA expression and diminishes glomerulosclerosis in NZB/WF1 mice. Clin Exp Immunol 113:258–264
Yassuda Filho P, Bracht A, Ishii-Iwamoto EL et al (2003) The urea cycle in the liver of arthritic rats. Mol Cell Biochem 243:97–106
Yocum DE, Klippel JH, Wilder RL et al (1998) Cyclosporin A in severe, treatment-refractory rheumatoid arthritis. A randomized study. Ann Intern Med 109:863–869
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Budancamanak, M., Kanter, M., Demirel, A. et al. Protective effects of thymoquinone and methotrexate on the renal injury in collagen-induced arthritis. Arch Toxicol 80, 768–776 (2006). https://doi.org/10.1007/s00204-006-0094-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-006-0094-0