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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Selective Glucocorticoid Receptor Agonists for the Treatment of Inflammatory Bowel Disease: Studies in Mice with Acute Trinitrobenzene Sulfonic Acid Colitis

Kerstin C. Reuter, Christian R. Grunwitz, Bettina M. Kaminski, Dieter Steinhilber, Heinfried H. Radeke and Jürgen Stein
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 68-80; DOI: https://doi.org/10.1124/jpet.111.183947
Kerstin C. Reuter
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Christian R. Grunwitz
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Bettina M. Kaminski
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Dieter Steinhilber
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Heinfried H. Radeke
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Jürgen Stein
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Abstract

Despite being a mainstay of inflammatory bowel disease (IBD) therapy, glucocorticoids (GCs) still carry significant risks with respect to unwanted side effects. Alternative drugs with a more favorable risk/benefit ratio than common GCs are thus highly desirable for the management of IBD. New and supposedly selective glucocorticoid receptor (GR) agonists (SEGRAs), with dissociated properties, have been described as promising candidates for circumventing therapeutic problems while still displaying full beneficial anti-inflammatory potency. Here, we report on compound A [CpdA; (2-((4-acetophenyl)-2-chloro-N-methyl)ethylammonium-chloride)] and N-(4-methyl-1-oxo-1H-2,3-benzoxazine-6-yl)-4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-2-(trifluoromethyl)-4-methylpentanamide (ZK216348), two GR agonists for the treatment of experimental colitis. Their therapeutic and anti-inflammatory effects were tested in the acute trinitrobenzene sulfonic acid-mediated colitis model in mice against dexamethasone (Dex). In addition to their influence on immunological pathways, a set of possible side effects, including impact on glucose homeostasis, steroid resistance, and induction of apoptosis, was surveyed. Our results showed that, comparable with Dex, treatment with CpdA and ZK216348 reduced the severity of wasting disease, macroscopic and microscopic damage, and colonic inflammation. However, both SEGRAs exhibited no GC-associated diabetogenic effects, hypothalamic pituitary adrenal axis suppression, or development of glucocorticoid resistance. In addition, CpdA and ZK216348 showed fewer transactivating properties and successfully dampened T helper 1 immune response. Unlike ZK216348, the therapeutic benefit of CpdA was lost at higher doses because of toxic apoptotic effects. In conclusion, both SEGRAs acted as potent anti-inflammatory agents with a significantly improved profile compared with classic GCs. Although CpdA revealed a narrow therapeutic window, both GR agonists might be seen as a starting point for a future IBD treatment option.

Footnotes

  • This work was supported by a graduate scholarship grant from the Deutsche Forschungsgemeinschaft [Grant GRK 757] (to K.C.R. and B.M.K.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.183947.

  • ABBREVIATIONS:

    GC
    glucocorticoid
    GR
    GC receptor
    SEGRA
    selective GR agonist
    BW
    body weight
    COX
    cyclooxygenase
    CpdA
    compound A
    Dex
    dexamethasone
    ELISA
    enzyme-linked immunosorbent assay
    FACS
    fluorescence-activated cell sorting
    FCS
    fetal calf serum
    FL
    full length
    G-6-P
    glucose-6-phosphatase
    GRE
    glucocorticoid response element
    HEK
    human embryonic kidney
    HPA
    hypothalamic pituitary adrenal
    IBD
    inflammatory bowel disease
    IFN
    interferon
    IL
    interleukin
    LPS
    lipopolysaccharide
    Luc
    luciferase
    MCP-1
    monocyte chemotactic protein-1
    MLN
    mesenteric lymph node
    MPO
    myeloperoxidase
    MR
    mineralocorticoid receptor
    NF-κB
    nuclear factor-κB
    PARP
    poly(ADP-ribose) polymerase
    PBMC
    peripheral blood mononuclear cell
    PBS
    phosphate-buffered saline
    PEPCK
    phosphoenolpyruvate carboxykinase
    PCR
    polymerase chain reaction
    qPCR
    quantitative PCR
    PR
    progesterone receptor
    TAT
    tyrosine aminotransferase
    Th
    T helper
    TNBS
    trinitrobenzene sulfonic acid
    TNF
    tumor necrosis factor
    TUNEL
    terminal deoxynucleotidyl transferase dUTP nick-end labeling
    ZK216348
    N-(4-methyl-1-oxo-1H-2,3-benzoxazine-6-yl)-4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-2-(trifluoromethyl)-4-methylpentanamide
    RU-486
    11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

  • Received May 13, 2011.
  • Accepted January 9, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

SEGRAs in Experimental IBD

Kerstin C. Reuter, Christian R. Grunwitz, Bettina M. Kaminski, Dieter Steinhilber, Heinfried H. Radeke and Jürgen Stein
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 68-80; DOI: https://doi.org/10.1124/jpet.111.183947

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

SEGRAs in Experimental IBD

Kerstin C. Reuter, Christian R. Grunwitz, Bettina M. Kaminski, Dieter Steinhilber, Heinfried H. Radeke and Jürgen Stein
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 68-80; DOI: https://doi.org/10.1124/jpet.111.183947
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