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Cysteinyl leukotriene receptor antagonism: a promising pharmacological strategy for lowering the severity of arthritis

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Abstract

Background and aims

Though cyclooxygenase inhibitors are employed in rheumatoid arthritis treatment, modulators of leukotrienes are underexplored. We investigated the therapeutic potential of montelukast, a known cysteinyl leukotriene receptor-1 (CysLT1) inhibitor in an experimental rat model of arthritis.

Methods

Arthritis was induced in rats, and montelukast (5 mg/kg body wt.) was administered prophylactically (PAM) and therapeutically (TAM) through oral route.

Results and discussion

Blood and joint tissue markers of oxidative stress (lipid peroxidation, protein carbonyls, and nitric oxides) were significantly (p < 0.05) reduced in montelukast administered rats. Paw inflammation, RA markers (RF and CRP), eicosanoids (PGE2, LTB4, and LTC4), cytokines (IL-1β and MCP-1), activity of hydrolytic enzymes (collagenase, elastase, and hyaluronidase), expression of matrix metalloproteinases (MMP), and EP-4 receptor were significantly (p < 0.05) reduced in montelukast administered rats. This study established that leukotriene inhibition through montelukast lowered the severity of arthritis and thus a potential strategy for reducing the severity of arthritis.

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Abbreviations

CRP:

C-reactive protein

CysLT-1:

Cysteinyl leukotriene receptor-1

DNPH:

2, 4-Dinitrophenylhydrazine

EP-4:

Prostaglandin E2 receptor

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

MCP-1:

Monocyte chemoattractant protein-1

MDA:

Malondialdehyde

RA:

Rheumatoid arthritis

RF:

Rheumatoid factor

TBA:

Thiobarbituric acid

TNF-α:

Tumor necrosis factor-α

References

  • Abramson SB, Amin A (2002) Blocking the effects of IL-1 in rheumatoid arthritis protects bone and cartilage. Rheumatology 41(9):972–980

    Article  CAS  Google Scholar 

  • Bieth J, Spiess B, Wermuth CG (1974) The synthesis and analytical use of a highly sensitive and convenient substrate of elastase. Biochem Med 11(4):350–357

    Article  CAS  Google Scholar 

  • Bosnjak B, Stelzmueller B, Erb KJ, Epstein MM (2011) Treatment of allergic asthma: modulation of Th2 cells and their responses. Respir Res 12(1):114

    Article  CAS  Google Scholar 

  • Bousquet J, Demoly P, Humbert M (2009) Montelukast in guidelines and beyond. Adv Ther 26(6):575–587

    Article  Google Scholar 

  • Brand D, Latham KA, Rosloniec EF (2007) Collagen-induced arthritis. Nat Protoc 2(5):1269–1275

    Article  CAS  Google Scholar 

  • Bray MA, Cunningham FM, Ford-Hutchinson AW, Smith MJ (1981) Leukotriene B4: a mediator of vascular permeability. Br J Pharmacol 72(3):483–486

    Article  CAS  Google Scholar 

  • Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R (2003) Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 32(1–2):23–38

    Article  Google Scholar 

  • Goronzy JJ, Weyand CM (2009) Developments in the scientific understanding of rheumatoid arthritis. Arthritis Res Ther 11(5):249

    Article  Google Scholar 

  • Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite and [15N] nitrate in biological fluids. Anal Biochem 126(1):131–138

    Article  CAS  Google Scholar 

  • Gruenwald J, Graubaum HJ, Hansen K, Grube B (2004) Efficacy and tolerability of a combination of lyprinol and high concentrations of EPA and DHA in inflammatory rheumatoid disorders. Adv Ther 21(3):197–201

    Article  CAS  Google Scholar 

  • Gubitosi-Klug RA, Talahalli R, Du Y, Nadler JL, Kern TS (2008) 5-Lipoxygenase, but not 12/15-lipoxygenase, contributes to degeneration of retinal capillaries in a mouse model of diabetic retinopathy. Diabetes 57(5):1387–1393

    Article  CAS  Google Scholar 

  • Hamid Q, Tulic MK, Liu MC, Moqbel R (2003) Inflammatory cells in asthma: mechanisms and implications for therapy. J Aller Clin Immunol 111(1):S5–S17

    Article  CAS  Google Scholar 

  • Honda T, Segi-Nishida E, Miyachi Y, Narumiya S (2006) Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis. J Exp Med 203(2):325–335

    Article  CAS  Google Scholar 

  • Kahlenberg JM, Fox DA (2011) Advances in the medical treatment of rheumatoid arthritis. Hand Clin 27(1):11–20

    Article  Google Scholar 

  • Kang JH, Lim H, Yim DSM (2018) Montelukast inhibits RANKL-induced osteoclast formation and bone loss via CysLTR1 and P2Y12. Mol Med Rep 18(2):2387–2398

    CAS  PubMed  Google Scholar 

  • Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, Russell A, Dougados M, Emery P, Nuamah IF, Williams GR, Becker JC, Hagerty DT, Moreland LW (2003) Treatment of rheumatoid arthritis by selective inhibition of T cell activation with fusion protein CTLA4Ig. N Engl J Med 349(20):1907–1915

    Article  CAS  Google Scholar 

  • Lin CR, Amaya F, Barrett L, Wang H, Takada J, Samad TA, Woolf CJ (2006) Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity. J Pharmacol Exp Ther 319(3):1096–1103

    Article  CAS  Google Scholar 

  • Lokesh BR, Hsieh HL, Kinsella JE (1986) Alterations in the lipids and prostaglandins in mouse spleen following the ingestion of menhaden oil. Ann Nutr Metab 30(6):357–364

    Article  CAS  Google Scholar 

  • Martel-Pelletier J, Pelletier JP, Fahmi H (2003) Cyclooxygenase-2 and prostaglandins in articular tissues. Semin Arthritis Rheum 33(3):155–167

    Article  CAS  Google Scholar 

  • Mathews MB, Dorfman A (1955) Inhibition of hyaluronidase. Physiol Rev 35(2):381–402

    Article  CAS  Google Scholar 

  • McInnes IB, Schet G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365(23):2205–2219

    Article  CAS  Google Scholar 

  • Mesquita CS, Oliveira R, Bento F, Geraldo D, Rodrigues JV, Marcos JC (2014) Simplified 2, 4-dinitrophenylhydrazine spectrophotometric assay for quantification of carbonyls in oxidized proteins. Anal Biochem 458:69–71

    Article  CAS  Google Scholar 

  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358

    Article  CAS  Google Scholar 

  • Ong CK, Lirk P, Tan CH, Seymour RA (2007) An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res 5(1):19–34

    Article  CAS  Google Scholar 

  • Sakurai H, Kohsaka H, Liu MF, Higashiyama H, Hirata Y, Kanno K, Saito I, Miyasaka N (1995) Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest 96(5):2357–2363

    Article  CAS  Google Scholar 

  • Schett G, Gravallese E (2012) Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol 8(11):656–664

    Article  CAS  Google Scholar 

  • Shah R, Raska KJr, Tiku ML (2005) The presence of molecular markers of in vivo lipid peroxidation in osteoarthritic cartilage: a pathogenic role in osteoarthritis. Arthritis Rheum 52(9):2799–2807

    Article  CAS  Google Scholar 

  • Shaw T, Quan J, Totoritis M (2003) B cell therapy for rheumatoid arthritis: the rituximab (anti-CD20) experience. Ann Rheum Dis 62(2):55–59

    Google Scholar 

  • Sheibanie AF, Khayrullina T, Safadi FF, Ganea D (2007) Prostaglandin E2 exacerbates collagen-induced arthritis in mice through the inflammatory interleukin-23/interleukin-17 axis. Arthritis Rheum 56(8):2608–2619

    Article  CAS  Google Scholar 

  • Sprague AH, Khalil RA (2009) Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 78(6):539–552

    Article  CAS  Google Scholar 

  • Van Wart HE, Steinbrink DR (1981) A continuous spectrophotometric assay for clostridium histolyticum collagenase. Anal Biochem 113(2):356–365

    Article  Google Scholar 

  • Vijaykumar M, Sambaiah K, Lokesh BR (1999) The anhydrous milk fat lowers serum prostaglandins and secretion of leukotrienes by rat peritoneal macrophages. Prostaglandins Leukot Essent Fatty Acids 61(4):249–254

    Article  Google Scholar 

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Acknowledgements

The authors thank the Council of Scientific and Industrial Research, New Delhi and Department of Biotechnology, New Delhi for their financial support.

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Author notes

  1. Nayana Venugopal and Pooja Acharya contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, 570020, India

    Nayana Venugopal, Pooja Acharya, Mehrdad Zarei & Ramaprasad Ravichandra Talahalli

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  1. Nayana Venugopal
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  2. Pooja Acharya
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  3. Mehrdad Zarei
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  4. Ramaprasad Ravichandra Talahalli
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Correspondence to Ramaprasad Ravichandra Talahalli.

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Venugopal, N., Acharya, P., Zarei, M. et al. Cysteinyl leukotriene receptor antagonism: a promising pharmacological strategy for lowering the severity of arthritis. Inflammopharmacol 27, 923–931 (2019). https://doi.org/10.1007/s10787-019-00618-0

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  • DOI: https://doi.org/10.1007/s10787-019-00618-0

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