Luteolin in combination with scoparone produces synergistic anti-rheumatoid arthritis effects in cell and mouse models.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by chronic synovitis and progressive erosion of cartilage and bone. Current RA therapies have limitations. We have previously shown that an herbal formula comprising Rosae Multiflorae Fructus (RMF) and Lonicerae Japonicae Flos (LJF) possesses anti-RA effects in rats. We have further found that luteolin (Lu, occurs in LJF) and scoparone (Sco, occurs in RMF) are the main anti-RA compounds of this herbal formula. This study aimed to investigate whether the combination of Lu and Sco (Lu-plus-Sco) has anti-RA effects, and to investigate the acute and subchronic toxicities of this combination. In cell assays, Lu and Sco exerted synergistic effects in inhibiting nitric oxide production in LPS-stimulated RAW264.7 cells, and in suppressing the hyperproliferation of IL-6/sIL-6R-stimulated fibroblast-like synoviocytes. In a collagen-induced arthritis (CIA) mouse model, intragastric administration of Lu-plus-Sco attenuated paw swelling and bone erosion, suppressed synovial hyperplasia, down-regulated serum levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-17), and improved body weight gain. Acute oral dosing toxicity assessments showed that LD50 of Lu-plus-Sco on female and male mice were 1,022.6 mg/kg and 1,298.5 mg/kg (Lu:Sco=1:6), respectively. Sub-chronic toxicity study showed that intragastric gavage with Lu-plus-Sco for 14 days caused liver injury in female mice, while caused kidney injury and reproductive injury in male mice.

In summary, we for the first time demonstrated that Lu-plus-Sco exhibits synergistic anti-RA effects in experimental models. We also demonstrated that a 14-day intragastric administration of Lu-plus-Sco causes toxicities in mice. This study provides pharmacological and toxicological data for developing Lu-plus-Sco into a novel anti-RA agent.