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Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis

Authors
  • Kirpotina, Liliya N.1
  • Schepetkin, Igor A.1
  • Hammaker, Deepa2
  • Kuhs, Amanda2
  • Khlebnikov, Andrei I.3, 4
  • Quinn, Mark T.1
  • 1 Department of Microbiology and Immunology, Montana State University, Bozeman, MT , (United States)
  • 2 Division of Rheumatology, Allergy, and Immunology, School of Medicine, University of California, San Diego, La Jolla, CA , (United States)
  • 3 Kizhner Research Center, Tomsk Polytechnic University, Tomsk
  • 4 Research Institute of Biological Medicine, Altai State University, Barnaul
Type
Published Article
Journal
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Publication Date
Jul 24, 2020
Volume
11
Identifiers
DOI: 10.3389/fphar.2020.01145
PMID: 32792961
PMCID: PMC7394103
Source
PubMed Central
Keywords
License
Unknown

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease involving joint and bone damage that is mediated in part by proteases and cytokines produced by synovial macrophages and fibroblast-like synoviocytes (FLS). Although current biological therapeutic strategies for RA have been effective in many cases, new classes of therapeutics are needed. We investigated anti-inflammatory properties of the natural alkaloid tryptanthrin (TRYP) and its synthetic derivative tryptanthrin-6-oxime (TRYP-Ox). Both TRYP and TRYP-Ox inhibited matrix metalloproteinase (MMP)-3 gene expression in interleukin (IL)-1β-stimulated primary human FLS, as well as IL-1β–induced secretion of MMP-1/3 by FLS and synovial SW982 cells and IL-6 by FLS, SW982 cells, human umbilical vein endothelial cells (HUVECs), and monocytic THP-1 cells, although TRYP-Ox was generally more effective and had no cytotoxicity in vitro . Evaluation of the therapeutic potential of TRYP and TRYP-Ox in vivo in murine arthritis models showed that both compounds significantly attenuated the development of collagen-induced arthritis (CIA) and collagen-antibody–induced arthritis (CAIA), with comparable efficacy. Collagen II (CII)-specific antibody levels were similarly reduced in TRYP- and TRYP-Ox-treated CIA mice. TRYP and TRYP-Ox also suppressed proinflammatory cytokine production by lymph node cells from CIA mice, with TRYP-Ox being more effective in inhibiting IL-17A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and receptor activator of nuclear factor-κB ligand (RANKL). Thus, even though TRYP-Ox generally had a better in vitro profile, possibly due to its ability to inhibit c-Jun N-terminal kinase (JNK), both TRYP and TRYP-Ox were equally effective in inhibiting the clinical symptoms and damage associated with RA. Overall, TRYP and/or TRYP-Ox may represent potential new directions for the pursuit of novel treatments for RA.

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