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The effects of β-d-mannuronic acid (M2000), as a novel NSAID, on COX1 and COX2 activities and gene expression in ankylosing spondylitis patients and the murine monocyte/macrophage, J774 cell line

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Abstract

Ankylosing spondylitis (AS) is a debilitating chronic inflammatory disease with genetic predisposition, which is characterized by the involvement of spine and sacroiliac joints. Due to the relatively unsuccessful treatments, we designed β-d-mannuronic (M2000) with the beneficial effects in various experimental models as a novel non-steroidal anti-inflammatory drug (NSAID). The aims of our present study were: first, to compare the therapeutic effects of M2000, as a novel designed NSAID, with naproxen and placebo in Iranian patients with AS during 12 weeks; second, to evaluate the effect of M2000 on gene expression of cyclooxygenase enzyme (COX-1/COX-2), a key enzyme in the initiation of inflammatory pathways in AS patients; and third, to assess the activity of COX-1 and COX-2 enzymes in the presence/absence of M2000 at the different doses in the murine macrophage, J774 cell line. This was a sub-study of phase II, randomized, placebo-controlled trial with three treatment arms: M2000, naproxen, and placebo. The outcome measures were the mean changes from baseline to week 12. The gene expression was assessed by real-time PCR. The COX-1 and COX-2 activities were evaluated by ELISA in J774 cell line induced by LPS and arachidonic acid (AA). Our findings demonstrated that M2000 had beneficial therapeutic effects on pain, stiffness, and inflammation, whereas no adverse effects were observed following the use of M2000 after 12 weeks. The analysis of gene expression showed that M2000 could effectively reduce the expression levels of COX-1 and COX-2 in comparison with untreated patients. In addition, the enzymatic activities in the presence of M2000 were significantly less than LPS- and AA-treated groups. Our results indicate that M2000, as a novel designed NSAID with immunosuppressive properties, can be considered as one of the therapeutic options for the treatment of inflammatory diseases without adverse events.

Clinical trial identifier IRCT2013062213739N1/http://www.IRCT.ir.

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Authors and Affiliations

  1. Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Box: 14155-6446, Tehran, Iran

    Fahimeh Jafarnezhad-Ansariha, Mohammad Javad Fattahi & Abbas Mirshafiey

  2. Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

    Mir Saeed Yekaninejad

  3. Rheumatology Research Centre, Tehran University of Medical Sciences, Tehran, Iran

    Ahmad-reza Jamshidi, Mahdi Vojdanian, Mahdi Mahmoudi & Seyed Naser Hashemi

  4. Department of Immunology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Reza Mansouri

  5. Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammad Javad Fattahi

  6. Department of Immunology, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Fahimeh Jafarnezhad-Ansariha & Reza Mansouri

  7. Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand

    Bernd H. A. Rehm

  8. Department of Clinical Research, Nagasaki Kawatana Medical Center, Nagasaki, Japan

    Hidenori Matsuo

  9. Department of Neurology, Nagasaki Kawatana Medical Center, Nagasaki, Japan

    Hidenori Matsuo

  10. Department of Biological and Environmental Sciences, University of Messina, Messina, Italy

    Emanuela Esposito & Salvatore Cuzzocrea

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  1. Fahimeh Jafarnezhad-Ansariha
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  2. Mir Saeed Yekaninejad
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  3. Ahmad-reza Jamshidi
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  4. Reza Mansouri
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  7. Mohammad Javad Fattahi
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  8. Seyed Naser Hashemi
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  9. Bernd H. A. Rehm
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  10. Hidenori Matsuo
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  11. Emanuela Esposito
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  12. Salvatore Cuzzocrea
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  13. Abbas Mirshafiey
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Corresponding authors

Correspondence to Ahmad-reza Jamshidi or Abbas Mirshafiey.

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Jafarnezhad-Ansariha, F., Yekaninejad, M.S., Jamshidi, Ar. et al. The effects of β-d-mannuronic acid (M2000), as a novel NSAID, on COX1 and COX2 activities and gene expression in ankylosing spondylitis patients and the murine monocyte/macrophage, J774 cell line. Inflammopharmacol 26, 375–384 (2018). https://doi.org/10.1007/s10787-017-0386-4

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