ArticleArthritis research & therapy2019
Cytosolic group IVA phospholipase A2 inhibitors, AVX001 and AVX002, ameliorate collagen-induced arthritis.
Article in Arthritis research & therapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 17 citations in OpenAlex.
- Targeting phospholipase A2 with arachidonyl trifluoromethyl ketone modulates macrophage activation during Japanese encephalitis virus infection.Medical microbiology and immunology · 2026Article
- Inhibition of DYRK1B BY C81 impedes inflammatory processes in leukocytes by reducing STAT3 activity.Cellular and molecular life sciences : CMLS · 2025Article
- Induction of long-term hyperexcitability by memory-related cAMP signaling in isolated nociceptor cell bodies.bioRxiv : the preprint server for biology · 2024Article
- Functions and mechanisms of cytosolic phospholipase ANeural regeneration research · 2023Review
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- Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod.Frontiers in pharmacology · 2022Review
- Baicalein Induces Apoptosis of Rheumatoid Arthritis Synovial Fibroblasts through Inactivation of the PI3K/Akt/mTOR Pathway.Evidence-based complementary and alternative medicine : eCAM · 2022Article
- Inhibition of Cytosolic Phospholipase A2α Induces Apoptosis in Multiple Myeloma Cells.Molecules (Basel, Switzerland) · 2021Article
- Robust COX-2-mediated prostaglandin response may drive arthralgia and bone destruction in patients with chronic inflammation post-chikungunya.PLoS neglected tropical diseases · 2021Article
- Pharmacokinetics-Based Chronoefficacy ofFrontiers in pharmacology · 2021Article
- cPLABiomolecules · 2020Article
- Berberine Suppresses Colonic Inflammation in Dextran Sulfate Sodium-Induced Murine Colitis Through Inhibition of Cytosolic Phospholipase A2 Activity.Frontiers in pharmacology · 2020Article
- Cytosolic Phospholipase A2 Alpha Regulates TLR Signaling and Migration in Metastatic 4T1 Cells.International journal of molecular sciences · 2019Article
- Induction of long-term hyperexcitability by memory-related cAMP signaling in isolated nociceptor cell bodies.Neurobiology of pain (Cambridge, Mass.)Article
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3 authors at 2 institutions in 2 countries.
Funding
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.
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