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Inflammopharmacology

, Volume 27, Issue 6, pp 1217–1227 | Cite as

Evaluation of the therapeutic potential of the selective p38 MAPK inhibitor Skepinone-L and the dual p38/JNK 3 inhibitor LN 950 in experimental K/BxN serum transfer arthritis

  • Philipp Guenthoer
  • Kerstin Fuchs
  • Gerald Reischl
  • Leticia Quintanilla-Martinez
  • Irene Gonzalez-Menendez
  • Stefan Laufer
  • Bernd J. Pichler
  • Manfred KneillingEmail author
Original Article
  • 90 Downloads

Abstract

Background

Mitogen-activated protein kinase (MAPK) signaling plays an important role in inflammatory diseases such as rheumatoid arthritis (RA).The aim of our study was to elucidate the therapeutic potential of the highly selective p38 MAPK inhibitor Skepinone-L and the dual inhibitor LN 950 (p38 MAPK and JNK 3) in the K/BxN serum transfer model of RA. Additionally, we aimed to monitor MAPK treatment non-invasively in vivo using the hypoxia tracer [18F]fluoromisonidazole ([18F]FMISO) and positron emission tomography (PET).

Methods

To induce experimental arthritis, we injected glucose-6-phosphate isomerase autoantibody-containing serum in BALB/c mice. MAPK inhibitor or Sham treatment was administered per os once daily. On days 3 and 6 after arthritis induction, we conducted PET imaging with [18F]FMISO. At the end of the experiment, ankles were harvested for histopathological analysis.

Results

Skepinone-L and LN 950 were applicable to suppress the severity of experimental arthritis confirmed by reduced ankle swelling and histopathological analysis. Skepinone-L (3.18 ± 0.19 mm) and LN 950 (3.40 ± 0.13 mm) treatment yielded a significantly reduced ankle thickness compared to Sham-treated mice (3.62 ± 0.11 mm) on day 5 after autoantibody transfer, a time-point characterized by severe arthritis. Hypoxia imaging with [18F]FMISO revealed non-conclusive results and might not be an appropriate tool to monitor MAPK therapy in experimental RA.

Conclusion

Both the selective p38 MAPK inhibitor Skepinone-L and the dual (p38 MAPK and JNK 3) inhibitor LN 950 exhibited significant therapeutic effects during experimental arthritis. Thus, our study contributes to the ongoing discussion on the use of p38 MAPK as a potential target in RA.

Keywords

Rheumatoid arthritis Mitogen-activated protein kinase Hypoxia imaging PET 

Notes

Acknowledgements

We thank Denis Lamparter, Sandro Aidone and Maren Koenig, Werner Siemens Imaging Center, Laboratory for Preclinical Imaging and Radiopharmacy, University of Tuebingen, for their excellent technical support of the study.

Funding

This work was supported by Werner Siemens Foundation (Zug, Switzerland) and the Interdisciplinary Center for Clinical Research of the University of Tübingen (IZKF) and the DFG through the CRC 156 (project C03).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Supplementary material

10787_2019_593_MOESM1_ESM.docx (703 kb)
Supplementary material 1 (docx 704 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Philipp Guenthoer
    • 1
  • Kerstin Fuchs
    • 1
  • Gerald Reischl
    • 1
  • Leticia Quintanilla-Martinez
    • 2
  • Irene Gonzalez-Menendez
    • 2
  • Stefan Laufer
    • 3
  • Bernd J. Pichler
    • 1
  • Manfred Kneilling
    • 1
    • 4
    Email author
  1. 1.Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging CenterEberhard Karls University of TuebingenTuebingenGermany
  2. 2.Department of PathologyEberhard Karls University of TuebingenTuebingenGermany
  3. 3.Department of Pharmaceutical and Medicinal ChemistryUniversity of TuebingenTuebingenGermany
  4. 4.Department of DermatologyEberhard Karls University of TuebingenTuebingenGermany

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