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:

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.

• Authors: Philipp Guenthoer, Kerstin Fuchs, Gerald Reischl, Leticia Quintanilla-Martinez, Irene Gonzalez-Menendez, Stefan Laufer, Bernd J Pichler, Manfred Kneilling
• Journal: Inflammopharmacology (Inflammopharmacology) Vol. 27 Issue 6 Pg. 1217-1227 (Dec 2019) ISSN: 1568-5608 [Electronic] Switzerland
• PMID: 31037574 (Publication Type: Evaluation Study, Journal Article)

Chemical References

• Dibenzocycloheptenes
• Imidazoles
• LN950
• Protein Kinase Inhibitors
• Pyridines
• skepinone-L
• fluoromisonidazole
• Misonidazole
• Mitogen-Activated Protein Kinase 10
• p38 Mitogen-Activated Protein Kinases
• Glucose-6-Phosphate Isomerase

Topics

• Animals
• Arthritis, Experimental (diagnostic imaging, drug therapy)
• Dibenzocycloheptenes (pharmacology, therapeutic use)
• Disease Models, Animal
• Glucose-6-Phosphate Isomerase (immunology)
• Imidazoles (pharmacology, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Misonidazole (analogs & derivatives, pharmacokinetics)
• Mitogen-Activated Protein Kinase 10 (antagonists & inhibitors)
• Positron-Emission Tomography
• Protein Kinase Inhibitors (therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)