Abstract
Current study was designed to evaluate protective effect of mangiferin and its interaction with low dose of nitric oxide (NO) modulators in complete Freund’s adjuvant (CFA) inoculated rats. Male wistar rats (200–300 g, n = 8 per group) were used in the study. On day ‘‘0’’ of study arthritis was induced in rats by injecting 0.2 ml CFA in sub-planter region of right hind paw of animals. Treatment with methotrexate (5 mg/kg), mangiferin (10–30 mg/kg) alone and in combination with NO modulators was given (i.p.) from days 14 to 28. After 28 days, blood and joint synovial fluid was collected for biochemical analysis and rat paws were excised to estimate MDA and SOD in tissue (paw) homogenates. CFA inoculation significantly increases (1) arthritic index, (2) ankle diameter, (3) paw volume, and (4) serum TNF-α, IL-6, IL-1β, and synovial TNF-α levels (p < 0.001). The serum Th1 (IFN-γ) and Th2 (IL-4) cytokine levels, MDA levels in rat paw tissue homogenates and serum NF-κB levels were also found significantly increased. Significant decrease in serum IL-10 levels and SOD activity was found after CFA inoculation. These CFA-induced arthritic changes, cytokine profile, and oxidative stress markers were significantly reversed by mangiferin (10–30 mg/kg) treatment alone and in combination with l-arginine and l-NAME nitric oxide modulators (p < 0.05). Treatment with methotrexate (5 mg/kg) also significantly reversed these adjuvant changes (p < 0.05). However, effect of methotrexate was less marked as compared to mangiferin (30 mg/kg) alone and in combination with l-NAME (10 mg/kg), but was comparable or slightly better than mangiferin (10 and 20 mg/kg). Thus, on the basis of our findings, we can suggest that interaction of mangiferin with nitric oxide modulators may have therapeutic value for chronic inflammatory disease such as RA.
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Abbreviations
- CFA:
-
Complete Freund’s adjuvant
- TNF-α:
-
Tumor necrosis factor alpha
- IL:
-
Interleukin
- NEMO:
-
NF-κB essential modulator
- L-NAME:
-
Nω-nitro-arginine methyl ester hydrochloride
- TRAF:
-
TNF-receptor-associated factor
- TRADD:
-
TNF-receptor-type 1-associated death domain
- IFN:
-
Interferon
- IKK:
-
Inhibitory kappa kinase
References
Aggarwal BB (2004) Nuclear factor-kappaB: the enemy within. Cancer Cell 6:203–208. https://doi.org/10.1016/j.ccr.2004.09.003
Ahmad A, Padhye S, Sarkar FH (2012) Role of novel nutraceuticals garcinol, plumbagin and mangiferin in the prevention and therapy of human malignancies: mechanisms of anticancer activity. In: Sarkar FH (ed) Nutraceuticals and Cancer. Springer Netherlands, Dordrecht, pp 179–199. https://doi.org/10.1007/978-94-007-2630-7_10
Ahn KS, Aggarwal BB (2005) Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann NY Acad Sci 1056:218–233. https://doi.org/10.1196/annals.1352.026
Bulugonda RK, Kumar KA, Gangappa D, Beeda H, Philip GH, Muralidhara Rao D, Faisal SM (2017) Mangiferin from Pueraria tuberosa reduces inflammation via inactivation of NLRP3 inflammasome. Sci Rep 7:42683. https://doi.org/10.1038/srep42683
Carlson BC, Jansson AM, Larsson A, Bucht A, Lorentzen JC (2000) The endogenous adjuvant squalene can induce a chronic T-cell-mediated arthritis in rats. Am J Pathol 156:2057–2065. https://doi.org/10.1016/S0002-9440(10)65077-8
Dou W et al (2014) Mangiferin attenuates the symptoms of dextran sulfate sodium-induced colitis in mice via NF-kappaB and MAPK signaling inactivation. Int Immunopharmacol 23:170–178. https://doi.org/10.1016/j.intimp.2014.08.025
du Plessis-Stoman D, du Preez J, van de Venter M (2011) Combination treatment with oxaliplatin and mangiferin causes increased apoptosis and downregulation of NFkappaB in cancer cell lines. Afr J Tradition Complement Altern Med AJTCAM 8:177–184
Garcia-Rivera D, Delgado R, Bougarne N, Haegeman G, Berghe WV (2011) Gallic acid indanone and mangiferin xanthone are strong determinants of immunosuppressive anti-tumour effects of Mangifera indica L. bark in MDA-MB231 breast cancer cells. Cancer Lett 305:21–31. https://doi.org/10.1016/j.canlet.2011.02.011
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15 N]nitrate in biological fluids. Anal Biochem 126:131–138
Guo HW et al (2014) Mangiferin attenuates TH1/TH2 cytokine imbalance in an ovalbumin-induced asthmatic mouse model. PLoS One 9:e100394. https://doi.org/10.1371/journal.pone.0100394
Jarazo Dietrich S, Fass MI, Jacobo PV, Sobarzo CM, Lustig L, Theas MS (2015) Inhibition of NOS-NO system prevents autoimmune orchitis development in rats: relevance of NO released by testicular macrophages in germ cell apoptosis and testosterone secretion. PloS One 10:e0128709. https://doi.org/10.1371/journal.pone.0128709
Jung JS, Jung K, Kim DH, Kim HS (2012) Selective inhibition of MMP-9 gene expression by mangiferin in PMA-stimulated human astroglioma cells: involvement of PI3 K/Akt and MAPK signaling pathways. Pharmacol Res 66:95–103. https://doi.org/10.1016/j.phrs.2012.02.013
Lee DM, Weinblatt ME (2001) Rheumatoid arthritis. Lancet 358:903–911. https://doi.org/10.1016/S0140-6736(01)06075-5
Leiro J, Arranz JA, Yanez M, Ubeira FM, Sanmartin ML, Orallo F (2004) Expression profiles of genes involved in the mouse nuclear factor-kappa B signal transduction pathway are modulated by mangiferin. Int Immunopharmacol 4:763–778. https://doi.org/10.1016/j.intimp.2004.03.002
Li J et al (2010) The anti-arthritic effects of synthetic melittin on the complete Freund’s adjuvant-induced rheumatoid arthritis model in rats. Am J Chin Med 38:1039–1049. https://doi.org/10.1142/S0192415X10008457
Liu SH, Wong CS, Chang DM (2005) Increased monocyte chemoattractant protein-1 in knee joints of rats with adjuvant-induced arthritis: in vivo microdialysis. J Rheumatol 32:2205–2211
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Mahmoud-Awny M, Attia AS, Abd-Ellah MF, El-Abhar HS (2015) Mangiferin mitigates gastric ulcer in ischemia/reperfused rats: involvement of PPAR-gamma, NF-kappaB and Nrf2/HO-1 signaling pathways. PLoS One 10:e0132497. https://doi.org/10.1371/journal.pone.0132497
Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474
Mathew AJ, Antony J, Eremenco S, Paul BV, Jayakumar B, Philip J (2009) Health-related quality of life in rheumatoid arthritis patients in South India. Singap Med J 50:800–803
Matkowski A, Kus P, Goralska E, Wozniak D (2013) Mangiferin—a bioactive xanthonoid, not only from mango and not just antioxidant. Mini Rev Med Chem 13:439–455
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Pal R, Chaudhary MJ, Tiwari PC, Babu S, Pant KK (2015) Protective role of theophylline and their interaction with nitric oxide (NO) in adjuvant-induced rheumatoid arthritis in rats. Int Immunopharmacol 29:854–862. https://doi.org/10.1016/j.intimp.2015.08.031
Pal R, Chaudhary MJ, Tiwari PC, Nath R, Babu S, Pant KK (2016) Pharmacological studies on the anti-inflammatory and immunomodulatory role of pentoxifylline and its interaction with nitric oxide (NO) in experimental arthritis in rats. Inflammopharmacology 24:221–231. https://doi.org/10.1007/s10787-016-0281-4
Philippe L, Gegout-Pottie P, Guingamp C, Bordji K, Terlain B, Netter P, Gillet P (1997) Relations between functional, inflammatory, and degenerative parameters during adjuvant arthritis in rats. Am J Physiol 273:R1550–1556
Rajendran P, Jayakumar T, Nishigaki I, Ekambaram G, Nishigaki Y, Vetriselvi J, Sakthisekaran D (2013) Immunomodulatory effect of mangiferin in experimental animals with benzo(a)pyrene-induced lung carcinogenesis. Int J Biomed Sci IJBS 9:68–74
Rajendran P, Rengarajan T, Nishigaki I, Ekambaram G, Sakthisekaran D (2014) Potent chemopreventive effect of mangiferin on lung carcinogenesis in experimental Swiss albino mice. J Cancer Res Therap 10:1033–1039. https://doi.org/10.4103/0973-1482.137966
Sarkar A, Sreenivasan Y, Ramesh GT, Manna SK (2004) beta-D-Glucoside suppresses tumor necrosis factor-induced activation of nuclear transcription factor kappaB but potentiates apoptosis. J Biol Chem 279:33768–33781. https://doi.org/10.1074/jbc.M403424200
Wooley PH, Luthra HS, Stuart JM, David CS (1981) Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. J Exp Med 154:688–700
Acknowledgements
Authors would like to thank Professor R. K. Dixit, Department of Pharmacology and Therapeutics, KGMU, Lucknow for his expert suggestions and English editing. Authors have not received any kind of assistance and have no relation with Sigma-Aldrich chemical Co. USA from which mangiferin was purchased.
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Pal, R., Chaudhary, M.J., Tiwari, P.C. et al. Pharmacological and biochemical studies on protective effects of mangiferin and its interaction with nitric oxide (NO) modulators in adjuvant-induced changes in arthritic parameters, inflammatory, and oxidative biomarkers in rats. Inflammopharmacol 27, 291–299 (2019). https://doi.org/10.1007/s10787-018-0507-8
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DOI: https://doi.org/10.1007/s10787-018-0507-8