Abstract | BACKGROUND: METHODS: RESULTS: Both 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. CONCLUSIONS:
AVX001 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.
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Authors | A J Feuerherm, E A Dennis, B Johansen |
Journal | Arthritis research & therapy
(Arthritis Res Ther)
Vol. 21
Issue 1
Pg. 29
(01 21 2019)
ISSN: 1478-6362 [Electronic] England |
PMID | 30665457
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- AVX001
- AVX002
- Antirheumatic Agents
- Fatty Acids, Omega-3
- Arachidonic Acid
- Group IV Phospholipases A2
- Dinoprostone
- Etanercept
- Methotrexate
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Topics |
- Animals
- Antirheumatic Agents
(pharmacology)
- Arachidonic Acid
(metabolism)
- Arthritis, Experimental
(metabolism, pathology, prevention & control)
- Cell Line, Tumor
- Dinoprostone
(metabolism)
- Etanercept
(pharmacology)
- Fatty Acids, Omega-3
(chemistry, pharmacology)
- Group IV Phospholipases A2
(antagonists & inhibitors, metabolism)
- Humans
- Male
- Methotrexate
(pharmacology)
- Mice, Inbred DBA
- Molecular Structure
- Synovial Membrane
(cytology, drug effects, metabolism)
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