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01-12-2019 | Arthritis | Original Article

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

Authors: Philipp Guenthoer, Kerstin Fuchs, Gerald Reischl, Leticia Quintanilla-Martinez, Irene Gonzalez-Menendez, Stefan Laufer, Bernd J. Pichler, Manfred Kneilling

Published in: Inflammopharmacology | Issue 6/2019

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.

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Title: 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
Authors: Philipp Guenthoer
Kerstin Fuchs
Gerald Reischl
Leticia Quintanilla-Martinez
Irene Gonzalez-Menendez
Stefan Laufer
Bernd J. Pichler
Manfred Kneilling
Publication date: 01-12-2019
Publisher: Springer International Publishing
Keywords: Arthritis
Rheumatoid Arthritis
Positron Emission Tomography
Published in: Inflammopharmacology / Issue 6/2019
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-019-00593-6

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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

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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