Abstract
BackgroundCytosolic phospholipase A2 group IVA (cPLA2α)-deficient mice are resistant to collagen-induced arthritis, suggesting that cPLA2α is an important therapeutic target. Here, the anti-inflammatory effects of the AVX001 and AVX002 cPLA2α inhibitors were investigated.MethodsIn vitro enzyme activity was assessed by a modified Dole assay. Effects on inhibiting IL-1β-induced release of arachidonic acid (AA) and prostaglandin E2 (PGE2) were measured using SW982 synoviocyte cells. In vivo effects were studied in prophylactic and therapetic murine collagen-induced arthritis models and compared to methotrexate (MTX) and Enbrel, commonly used anti-rheumatic drugs. The in vivo response to treatment was evaluated in terms of the arthritis index (AI), histopathology scores and by plasma levels of PGE2 following 14 and 21 days of treatment.ResultsBoth cPLA2α inhibitors are potent inhibitors of cPLA2α in vitro. In synoviocytes, AVX001 and AVX002 reduce, but do not block, release of AA or PGE2 synthesis. In both CIA models, the AI and progression of arthritis were significantly lower in the mice treated with AVX001, AVX002, Enbrel and MTX than in non- treated mice. Several histopathology parameters of joint damage were found to be significantly reduced by AVX001 and AVX002 in both prophylactic and therapeutic study modes; namely articular cavity and peripheral tissue inflammatory cell infiltration; capillary and synovial hyperplasia; articular cartilage surface damage; and periostal and endochondral ossification. In comparison, MTX did not significantly improve any histopathology parameters and Enbrel only improved ossification. Finally, as a biomarker of inflammation and as an indication that AVX001 and AVX002 blocked the cPLA2α target, we determined that plasma levels of PGE2 were significantly reduced in response to the AVX inhibitors and MTX, but not Enbrel.ConclusionsAVX001 and AVX002 display potent anti-inflammatory activity and disease-modifying properties in cellular and in vivo models. The in vivo effects of AVX001 and AVX002 were comparable to, or superior, to those of MTX and Enbrel. Taken together, this study suggests that cPLA2α inhibitors AVX001 and AVX002 are promising small molecule disease-modifying anti-rheumatic therapies.
Highlights
Rheumatoid arthritis (RA) is an autoimmune and systemic inflammatory disease affecting 0.5–1% of the population worldwide
As previously shown by a vesicular in vitro assay [11], AVX001 and AVX002 are potent in inhibiting Cytosolic phospholipase A2 protein (cPLA2α) activity
This finding was confirmed by the mixed micelle in vitro assay, in which a 0.091 mol fraction of the inhibitors yielded at least 90% inhibition, corresponding to the ΧI(50) values 0.0072 for AVX001 and 0.0052 for AVX002
Summary
Rheumatoid arthritis (RA) is an autoimmune and systemic inflammatory disease affecting 0.5–1% of the population worldwide. Excessive levels of pro-inflammatory cytokines including tumor necrosis factor (TNF) and interleukin 1β (IL-1β) are found in the joint [2, 4]. In the synovium in RA, TNF and IL-1β elicit a variety of biological effects on inflammation and joint destruction [4]. TNF has been found to regulate the expression and pathophysiological function of many factors that contribute to inflammation and joint destruction; e.g. the interleukin IL-6, the chemokines IL-8 and CCL2/MCP-1 [5, 6] and the matrix metalloproteinases MMP1 and MMP3 [7]. The anti-inflammatory effects of the AVX001 and AVX002 cPLA2α inhibitors were investigated
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