Extracts and pimaradienoic acid from Eleutherococcus trifoliatus L. S. Y. Hu for the treatment of Rheumatoid Arthritis by modulating NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of Eleutherococcus trifoliatus L. S. Y. Hu (E. trifoliatus) in Yi ethnomedicine to treat rheumatic diseases can be traced back hundreds of years. However, its pharmacological mechanism and possible material basis remain unknown.

AIM OF THE STUDY: The aim of this study is to explore the effective components and mechanisms of E. trifoliatus in the treatment of rheumatoid arthritis.

MATERIALS AND

METHODS

Arthritic rats induced with FCA were treated with E. trifoliatus extracts (ETPE, ETEA, ETNBA) or methotrexate (MTX) for 30 days. The arthritis index, paw edema, organ indices, histopathology, serum cytokines (IL-1β, IL-6, TNF-α, IL-10, PGE2, NO), and synovial MMPs/NF-κB were assessed. The active ETPE fraction was separated, and the main compound, pimaradienoic acid (PA), was identified. PA's effects on MH7A cells were evaluated using CCK-8, Transwell, flow cytometry, ELISA, and Western blot.

RESULTS

ETPE significantly reduced AI scores, paw swelling, thymic/splenic indices, synovial hyperplasia, inflammatory infiltration (p < 0.05 vs. model), and serum pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, PGE2, NO, p < 0.05 vs. model) while increasing IL-10 in FCA rats (p < 0.05 vs. model). It also downregulated synovial MMP-2, MMP-9, and NF-κB (p < 0.05 vs. model). A high content and active ent-pimarane diterpenoid, pimaradienoic acid (PA), was isolated from ETPE. PA inhibited MH7A proliferation (IC50 = 69.13 ± 6.82 μM), migration, invasion, and induced G2/M cell cycle arrest and apoptosis (p < 0.01). PA treatment reduced VEGF, MMP-2, MMP-9, IL-1β, and NF-κB secretion (p < 0.05), downregulated Bcl-2, NF-κB p65, and IKKα protein expression, and upregulated Bax (p < 0.01).

CONCLUSIONS

ETPE is the main anti-RA fraction in E. trifoliatus, contains the active constituent PA, which alleviates RA by inhibiting synoviocyte proliferation, migration, and inflammation through NF-κB suppression and apoptosis promotion. This supports E. trifoliatus' traditional use and highlights PA as a promising anti-RA candidate.