Acmella uliginosa (Sw.) Cass hampers complete Freund's adjuvant-induced arthritis in rats by inhibiting the VEGF axis.

Rheumatoid arthritis (RA), which is characterized by joint inflammation, is associated with excessive angiogenesis. Acmella uliginosa (Sw) Cass, known as "Subang nenek" in Malaysia, is traditionally used to treat various inflammatory conditions. This study examined the anti-arthritic effects and underlying mechanisms of A. uliginosa leaf ethanolic extract (AULE) and its hexane-fractionated extract (AULH) in arthritic rats induced with complete Freund's adjuvant (CFA) for 28 d. Weekly evaluations were conducted for parameters including paw volume, body weight, and arthritic score, while hematological, biochemical, and the levels of various mediators (COX-2, 5-LOX, VEGF) were assessed upon termination of the study. The phytochemical composition of the extracts was analyzed via GC-MS to identify the bioactive compounds linked to anti-arthritic activity. AULE and AULH showed significant anti-arthritic effects, with AULH showing slightly higher potency. The anti-arthritic effects were mediated through modulation of the VEGF axis, implicating angiogenesis. COX-2 and 5-LOX protein levels were significantly reduced by both extracts. No notable variations in body mass, weights of target organs, and blood-related and biochemical indicators were observed in the extract-treated groups compared to the control rats, indicating possible nontoxic effects. Phytochemical analysis identified bioactive compounds, such as spilanthol and phytol, which underwent molecular docking studies and were identified as the main contributors to anti-arthritic activity via COX-2 and 5-LOX inhibition. However, VEGF inhibition was attributed to other compounds present in the extracts. A. uliginosa leaf extract show potential as a natural RA treatment, with effects mediated through the modulation of the VEGF axis and angiogenesis.