Sinomenine increases adenosine A2A receptor and inhibits NF-κB to inhibit arthritis in adjuvant-induced-arthritis rats and fibroblast-like synoviocytes through α7nAChR

Abstract

Sinomenine (SIN) is a clinical drug for treating rheumatoid arthritis (RA) in China. Our previous study found SIN inhibited inflammation via alpha7 nicotinic acetylcholine receptor (α7nAChR) in macrophages in vitro. Adenosine receptor A2A has anti‐inflammatory and immunosuppressive function. However, the mechanisms of SIN acting on α7nAChR and the effect on adenosine A2A receptor (A2AR) in RA are not clear. In the present study, the effects of SIN on adjuvant‐induced‐arthritis (AIA) rats in vivo and on fibroblast‐like synoviocytes (FLSs) in vitro were investigated. Indomethacin (Indo) and methotrexate (MTX), the clinical anti‐arthritis drugs, were used as controls. Nicotine (Nic), a specific agonist of α7nAChR, was used as a control for targeting α7nAChR. Alpha‐bungarotoxin (α‐BTX), the antagonist of α7nAChR or small interference RNA (siRNA) was used to block or knock down α7nAChR. Results showed that SIN decreased arthritis index, hind paw volume, erythrocyte sedimentation (ESR) and serum TNF‐α in AIA rats, and α‐BTX attenuated the earlier‐mentioned effects of SIN and Nic, but not Indo and MTX. The expressions of A2AR in synovium declined in AIA rats, but remarkably increased after the intervention of SIN. The expression of A2AR decreased by LPS or TNF‐α, but increased by SIN; cAMP also increased by SIN in FLSs in vitro. SIN inhibited the expression of MCP‐1, IL‐6, and vascular endothelial growth factor in LPS‐induced FLSs. SIN inhibited the activation of NF‐κB. Meanwhile, α‐BTX or α7nAChR siRNA blocked the earlier‐mentioned effects of SIN in FLSs. Results suggested the expressions of A2AR in synovium and FLSs are negatively correlated with the arthritis progression of AIA rats and the activation of FLSs. SIN increases A2AR and inhibits the activation of NF‐κB pathway via α7nAChR in AIA rats and FLSs.

Bioactivities and Mechanisms of Action of Sinomenine and Its Derivatives: A Comprehensive Review

“…et al reported that SIN (200 µM) inhibited MCP-1, IL-6, and vascular endothelial growth factor, increased A 2A R in synovial tissue of AIA rats and FLSs, and inhibited the NF-κB pathway via α7nAChR, thereby alleviating arthritis. SIN (120 mg/kg) also decreased the arthritis index in vivo [ 127 ]. Local and systemic inflammation are characteristics of rheumatoid arthritis (RA), a chronic autoimmune disease.…”

Magnoflorine Ameliorates Collagen-Induced Arthritis by Suppressing the Inflammation Response via the NF-κB/MAPK Signaling Pathways

“…Recent studies have shown that sinomenine regulated the secretion of inflammatory cytokines and macrophage subsets, and inhibited the activation of the nuclear factor-kappa B (NF-κB) pathway in fibroblast-like synoviocytes (FLS). 7,8 To date, the effects of Mag on macrophage in RA have not been reported.…”

Synthesis and biological evaluation of novel sinomenine derivatives as anti-inflammatory and analgesic agent

“…et Wils., has long been known as an anti-inammatory drug. [15][16][17][18][19] SIN has been reported to inhibit the production of proinammatory mediators, such as TNF-a, nitric oxide (NO) and IL-6, both in vitro and in vivo. [20][21][22] Therefore, SIN was regarded as lead compounds in the drug research, especially for anti-inammatory medicines, while low activity had limited its clinical application.…”