Abstract
IntroductionPreviously, secretory phospholipase A2 (sPLA2) inhibition has been used as an adjunct to conventional rheumatoid arthritis therapy in human clinical trials without significant improvement of arthritic pathology. In this study, we compared the efficacy of a potent and orally active group IIa secretory phospholipase A2 inhibitor (sPLA2I) to conventional anti-arthritic agents; infliximab, leflunomide and prednisolone, in a rat model of antigen-induced arthritis.MethodsInitially, to establish efficacy and dose-response, rats were orally dosed with the sPLA2I (1 and 5 mg/kg) two days prior to arthritis induction, and then daily throughout the 14-day study period. In the second trial, rats were orally dosed with the sPLA2I (5 and 10 mg/kg/day) beginning two days after the induction of arthritis, at the peak of joint swelling. Separate groups of rats were also dosed with the tumour necrosis factor-alpha (TNF-α) inhibitor infliximab (single 3 mg/kg i.v. injection), leflunomide (10 mg/kg/day, oral) or prednisolone (1 mg/kg/day, oral) at this same time point and used as comparative treatments.ResultsIn the pathology prevention trial, both 1 and 5 mg/kg dose groups of sPLA2I demonstrated a significant reduction in joint swelling and gait disturbances; however, only the higher 5 mg/kg dose resulted in significantly reduced histopathology scores. In the post-induction trial, rats dosed with sPLA2I showed a significant improvement in joint swelling and gait scoring, whereas none of the conventional therapeutics achieved a significant decrease in both of these two disease markers. Histopathological scoring at the end-point of the study demonstrated significantly reduced median scores in rats treated with 10 mg/kg sPLA2I and leflunomide.ConclusionsThe results from this study suggest a pathogenic role for sPLA2 enzymes in this model of arthritis in rats, and the potential clinical utility of sPLA2 inhibition as a safer, and more effective, alternative to conventional anti-arthritic therapeutics.
Highlights
Secretory phospholipase A2 inhibition has been used as an adjunct to conventional rheumatoid arthritis therapy in human clinical trials without significant improvement of arthritic pathology
We have previously reported that a synthetic small molecule inhibitor of group IIa secretory phospholipase A2 (sPLA2) (sPLA2I; 5-(4benzyloxyphenyl)-4S-(7-phenylheptanoylamino)-pentanoic acid) is orally active and has therapeutic efficacy in rat models of intestinal ischemia-reperfusion injury [19] and inflammatory bowel disease [20]
We demonstrate that inhibition of sPLA2 IIa alleviates the clinical signs and pathological changes associated with Rheumatoid arthritis (RA), with a greater reliability than some conventional anti-rheumatoid therapies
Summary
Secretory phospholipase A2 (sPLA2) inhibition has been used as an adjunct to conventional rheumatoid arthritis therapy in human clinical trials without significant improvement of arthritic pathology. We compared the efficacy of a potent and orally active group IIa secretory phospholipase A2 inhibitor (sPLA2I) to conventional anti-arthritic agents; infliximab, leflunomide and prednisolone, in a rat model of antigen-induced arthritis. As opposed to cytosolic PLA2 enzymes which have physiological functions within virtually all cells [4], secretory PLA2 (sPLA2) enzymes are known to be active during inflammation, and have been an attractive target for anti-inflammatory drug development [3]. Correlations have been found between serum levels of sPLA2 and clinical markers of disease such as the number of active and effused joints, erythrocyte sedimentation rate, Lansbury index, elevated platelet count, and low hemoglobin in RA patients [10,11]. Intra-articular injections of human recombinant sPLA2 caused acute inflammatory arthritic-like symptoms in rats [13] and rabbits [14], transgenic mice over-expressing human sPLA2 did not spontaneously develop arthritis [15,16]
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