Rheumatoid arthritis (RA) is a disorder linked with chronic synovial inflammation; it is untreatable and is characterized by hyperplasia and continuous inflammation. RA is highly prevalent globally [1]. The pathogenesis of RA has not been completely elucidated [2]. Inflammation is revealed as the principal factor for RA; therefore, its treatment mainly comprises anti-inflammatory therapy [3,4]. Macrophages are a part of innate immunity and are responsible for initiating and modulating adaptive immunity; therefore, these are critically involved in inflammatory diseases [5]. Multiple investigations have demonstrated that macrophages are associated with RA, and multiple macrophages exist in RA joint tissue [6]. Murine macrophage RAW 264.7 cell induced by lipopolysaccharides (LPS) is a classical in-vitro model for RA-associated inflammatory research [7]. Recently, studies showed that macrophages migrate toward the sites of inflammation in a two-dimensional (2D) or three-dimensional (3D) manner and release multiple pro-inflammatory cytokines in large quantities to initiate inflammatory responses [8]. The migration of macrophages is necessary for their entrance and participation in the inflammatory sites and pathologic mechanisms, respectively [9]. Inhibiting this migration can also be a potential anti-inflammatory strategy for RA treatment [10].

Recently, prolonged administration of clinical drugs (such as anti-rheumatic drugs, glucocorticoids, etc.) for RA treatment have reported to cause unavoidable adverse effects [11]. Since natural products have minimum toxicity and side effects, the search for these novel and efficient anti-arthritic natural agents has become an area of interest [12].

Curcumin (1, 7-bis (4-hydroxy-3- methoxyphenyl)-1, 6-heptadiene-3,5-dione) is isolated from the roots of Zingiberaceae and Araceae and has many curcuminoids including bisdemethoxycurcumin (BDMC, Fig. 1A) and curcumin (Cur, Fig. 1B) [13]. Previous research indicates that BDMC, a Cur derivative, has shown better stability under biological conditions and enhanced cellular uptake than Cur [14]. Cur has been known for its therapeutic effect on the development of RA [15]. It is thought to impede the stimulation of nuclear factor kappa-B (NF-κB) and pro-inflammatory gene levels by impeding the degeneration of the inhibitory molecule I-kappa B kinase α (IκBa) [16]. Inhibiting the stimulation of NF-κB subsequently down-regulates the levels of cyclooxygenase-2 (COX-2), thereby suppressing the inflammatory process [17]. Moreover, Cur modulates the inflammatory reaction by down-regulating COX-2 activity, which suppresses the secretion of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-a), interleukin (IL)-1, −2, −6 [18]. In our previous study, BDMC has been proved to inhibit the migration of endothelial cells of the human umbilical vein induced by vascular endothelial growth factor in-vitro, suggesting its beneficial effect on the treatment of RA [19].

BDMC is indicated to possess anti-inflammatory, anti-mutagenic, anti-tumor, and anti-oxidant activities [20,21]. Although Cur has been reported for its anti-inflammatory activity, there is no research that demonstrates the therapeutic effects and underlying mechanisms of BDMC on the treatment of RA. Here, Cur was kept as a positive control, and the therapeutic efficacy of BDMC was explored using LPS-stimulated RAW 264.7 cell and adjuvant-induced arthritis (AIA) rat model in hopes of identifying a promising therapeutic potential of BDMC for the treatment of RA.