A novel combination of astilbin and low-dose methotrexate respectively targeting A(2A)AR and its ligand adenosine for the treatment of collagen-induced arthritis

作者：Ma, Yuxiang; Gao, Zhe; Xu, Fang; Liu, Li; Luo, Qiong; Shen, Yan; Wu, Xuefeng; Wu, Xingxin; Sun, Yang; Wu, Xudong^*; Xu, Qiong^*

来源：Biochemical Pharmacology, 2018, 153: 269-281.

DOI：10.1016/j.bcp.2018.01.033

• Rheumatoid arthritis
• MTX combination therapy
• Adenosine
• A(2A)AR
• Astilbin

Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment with frequently serious adverse effects. Therefore, combination of low-dose MTX with other drugs is often used in clinic. In this study, we investigated the improvement of astilbin and low-dose MTX combination on collagen-induced arthritis in DBA/1J mice. Results showed that the clinic score, incidence rate, paw swelling, pathological changes of joints and rheumatoid factors were more alleviated in combination therapy than MTX or astilbin alone group. Elevated antibodies (IgG, IgG1, IgG2a, IgM and anti-collagen IgG) and pro-inflammatory cytokines (IL-1 beta, IL-6, TNF-alpha, IFN-gamma and IL-17A) in serum were significantly inhibited, while anti-inflammatory cytokine, IL-10, was enhanced by combination therapy. Further studies indicated that combination therapy significantly decreased Th1 and Th17 cell differentiation and increased Treg cell differentiation. Mechanisms analysis demonstrated combination therapy greatly inhibited Con A-activated MAPK and inflammatory transcriptional signals. Moreover, MTX activated adenosine release and astilbin specifically up-regulated A(2A) adenosine receptor (A(2A)AR) expression simultaneously, which most probably contributed to the synergistic efficacy of combination therapy. ZM241385, a specific antagonist of A(2A)AR, greatly blocked the effects of combination therapy on T cell functions and downstream pathways. All these findings suggest that astilbin is a valuable candidate for low-dose MTX combined therapy in RA via increasing A(2A)AR/adenosine system and decreasing ERK/NFKB/STATs signals.

• 出版日期2018-7
• 单位南京大学; 医药生物技术国家重点实验室