Therapeutic Effect of the Immunomodulator, FTY720 in Rheumatoid Arthritis Rat Model: Sphingolipids Perspective (FTY720 in Rheumatoid Arthritis, FTY720 on RA)
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- Category: Vol. 84, December 2016
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Therapeutic Effect of the Immunomodulator, FTY720 in Rheumatoid Arthritis Rat Model: Sphingolipids Perspective (FTY720 in Rheumatoid Arthritis, FTY720 on RA), REHAB E. ABO EL-GHEIT
Abstract
Introduction: Rheumatoid Arthritis (RA) is the most common autoimmune inflammatory arthritis. Fingolimod (FTY-720) is a Sphingosine 1-Phosphate (SIP) receptor mod-ulator, reported to have a therapeutic effect in autoimmune disease models.
Aim: To evaluate the potential therapeutic effect of fin-golimod on established rat model of RA and its possible underlying mechanisms.
Experimental Protocol: The arthritic model was established by subcutaneous immunization of female albino rats with Muramyl Dipeptide (MDP) and bovine type II collagen (C-II) (MCIA model). Rats were boosted with a second collagen-MDP emulsion 60 days after the first immunization. Rats were evaluated for arthritis severity using a macroscopic scoring system.
From the day of onset of arthritis symptom, the MDP/CII challenged rats, with similar arthritis scores, were randomly divided into three groups; arthritic control, FTY-treated and prednisolone (pred, was chosen as the positive drug) treated arthritic groups. Treatment was continued up to day 90. With non immunized rats were taken as non-arthritic negative control group.
Assessment of RA was performed by measuring serum rheumatoid factor-Immunoglobulin M (RF-IgM), Cartilage Oligomeric Matrix Protein (COMP) as specific rheumatoid biomarkers, Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) as inflammatory biomarkers to asses disease severity and activity. Blood and Synovial Fluid (SF) total and differential leukocytes were counted. Spleen and thymus indices were recorded while SIP levels were assayed in blood, spleen and thymus. Paws Cyclooxygenase-2 (COX-2) and Prostaglandin-E2 (PG-E2) proteins were quantified.
Results: Compared to normal control group, the arthritic rats displayed dramatic increase in blood inflammatory cells with massive joint cellular infiteration, increased arthritis scores, spleen and thymus indices, flaring in disease activity with cartilage erosion, upregulated paw COX-2/PGE2 protein levels together with increased SIP levels and high SIP gradient between blood and thymus, spleen.The anti-inflammatory and chondroprotective effects of FTY-720, similar to pred, was associated with decreased arthritis scores, recruitment of leukocytes into the inflamed joint, paw COX-2/PGE2 levels, and spleen index. Unlike the non significant effect of FTY-720 on thymus index, it was decreased under pred treatment. There were non significant change in SIP level and gradient in pred treated group while SIP level was increased with obliterated gradient with FTY 720 treatment, compared to the MCIA challenged female albino rats.
Conclusion: FTY720 was as potent as pred for suppressing arthritis, mostly through modulation of SIP signaling and COX-2/PG-E2 axis suggesting FTY 720 may be an effective candidate drug for treating human with RA.