Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase
- 289 Downloads
Pro-inflammatory cytokines like TNF-α activate sphingosine kinase (SK). Therefore, inhibition of SK is a potential molecular target for the treatment of rheumatoid arthritis.
The primary goal of this study was to assess the efficacy of ABC249640 (a selective SK-2 inhibitor) in two models of rodent arthritis. A secondary goal was to evaluate the pharmacological profile of ABC294640, when given in combination with methotrexate.
The efficacy of ABC294640 was determined by paw diameter/volume measurements, histological evaluations, and micro-CT analyses.
ABC294640 attenuated both collagen-induced arthritis in mice, as well as adjuvant-induced arthritis in rats. With the adjuvant arthritis model, the prophylactic efficacy profile of ABC294640 was similar to indomethacin. Of note, ABC294640 reduced the bone and cartilage degradation, associated with adjuvant-induced arthritis. Rats treated with a suboptimal dose of MTX (50 μg/kg/day) in combination with ABC249640 (100 mg/kg/day) had better anti-arthritis effects in the adjuvant model, than treatment with either agent alone.
Our results suggest that ABC249640 is an orally available drug candidate with a good pre-clinical efficacy profile for the prevention and/or treatment of RA.
KeywordsSphingosine kinase Arthritis Rodents ABC-294640
- Maines LW, Fitzpatrick LR, Green CL et al (2010) Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn’s disease. Inflammopharmacology [PMID:2015210]Google Scholar
- Oliver SJ, Brain E (1996) Combination therapy in rheumatoid arthritis: the animal model perspective. J Rheumatol 23(Suppl 4):56–60Google Scholar
- Pendley CE, Fitzpatrick LR, Ewing RW et al (1993) The gastrin/cholecystokinin-B receptor antagonist reduces basal acid secretion and prevents gastrointestinal damage by aspirin, ethanol and cysteamine in the rat. JPET 265:1348–1354Google Scholar
- Schopf LR, Anderson K, Jeffee BD (2006) Rat models of arthritis: similarities, differences, advantages and disadvantages in the identification of novel therapeutics. In: Stevenson CS, Marshall LA, Morgan DW (eds) in vivo models of inflammation, vol 1. Birkhauser Verlag, Boston, USA, pp 1–34Google Scholar
- Smith CD, French KJ, Zhuang Y (2008) Sphingosine kinase inhibitors. US Patent Number 7,338,961Google Scholar
- Taha TA, Hannun YA, Obedi LM (2006) Sphingosine kinase: biochemical and cellular regulation and role in disease. J Biochem Mol Bio 39:113–131Google Scholar