Protective effect of RC-3095, an antagonist of the gastrin-releasing peptide receptor, in experimental arthritis

Abstract

Objective. To evaluate the antiinflammatory effects of RC-3095 in 2 experimental models of arthritis, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), and to determine the mechanisms of action involved.Methods. RC-3095 was administered daily to mice with CIA and mice with AIA, after induction of disease with methylated bovine serum albumin. Disease incidence and severity were assessed using a clinical index and evaluation of histologic features, respectively. In mice with CIA, gastrin-releasing peptide receptor (GRPR) was detected by immunohistochemical analysis, while in mice with AIA, migration of neutrophils, presence of glycosaminoglycans, and lymphocyte proliferation, determined using the MTT assay, were assessed. Expression of cytokines interleukin-17 (IL-17), IL-1␤, and tumor necrosis factor ␣ (TNF␣) was evaluated in all mouse knees using enzyme-linked immunosorbent assay. Treg cell production was assessed by flow cytometry in the joints of mice with AIA.Results. In mice with AIA, administration of RC-3095 reduced neutrophil migration, mechanical hypernociception, and proteoglycan loss. These findings were associated with inhibition of the levels of all 3 proinflammatory cytokines, decreased lymphocyte proliferation, and increased Treg cell numbers. In the CIA model, treatment with RC-3095 led to a significant reduction in arthritis clinical scores and the severity of disease determined histologically. Synovial inflammation, synovial hyperplasia, pannus formation, and extensive erosive changes were all dramatically reduced in the arthritic mice treated with RC-3095. Furthermore, arthritic mice treated with RC-3095 showed a significant reduction in the concentrations of IL-17, IL-1␤, and TNF␣, and showed a diminished expression of GRPR.Conclusion. These findings suggest that the GRP pathway has a significant role in chronic arthritis, and its inhibition can be explored as a possible therapeutic strategy in rheumatoid arthritis.

Anti-inflammatory Effects of a Small Molecule Gastrin-Releasing Peptide Receptor Antagonist on Adjuvant-Induced Rheumatoid Arthritis in Rats

“…of IL-1β and TNF-α in different inflammation models, and they can be inhibited by administration of a GRPR antagonist, RC-3095. 7,10,26 Both serum IL-1β and TNF-α concentration were significantly inhibited by administration of all three dosages of RH-1402.…”

“…[6][7][8][9] More recently, it has been reported that releasing of GRP closely related to the progression and severity of chronic inflammatory diseases, including RA, and administration of GRPR antagonist have anti-inflammatory effects in inflammation models. 7,[10][11][12] RC-3095 is a synthetic polypeptide BN/GRP antagonist with the MW of Chemical and Pharmaceutical Bulletin Advance Publication 1106.32. Studies showed that RC-3095 could be an attractive and safe candidate compound for future trials in GRPR-related diseases, including specific types of cancer and chronic inflammatory diseases.…”

“…Studies showed that RC-3095 could be an attractive and safe candidate compound for future trials in GRPR-related diseases, including specific types of cancer and chronic inflammatory diseases. 7,10,[13][14] Administration of RC-3095 suppressed the growth of CFPAC-1 human pancreatic cancers and MDA-MB-435 breast cancers in nude mice, and the protein levels of basic fibroblast growth factor (bFGF), insulin-like growth factors (IGF-II) and vascular endothelial growth factor (VEGF) in the tumors largely reduced. [13][14] Previous researches also showed that RC-3095 have protective effects in experimental RA models of collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), and it was associated with a substantial reduction in levels of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β).…”

“…[13][14] Previous researches also showed that RC-3095 have protective effects in experimental RA models of collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), and it was associated with a substantial reduction in levels of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). 7,10 As a polypeptide, RC-3095 is difficult to synthesize and use, there may be a limitation of its application.…”

IL-17: a potential therapeutic target for rheumatoid arthritis?

“…Splenocytes were stimulated with phorbol myristate acetate in the presence of propolis extract in vitro found concentration-dependent declines in IL-17 expression and propolis significantly inhibited the differentiation of Th17 cells. On the other hand, CIA and antigen-induced arthritis (AIA) mouse model treated with RC-3095 showed a significant reduction in the concentrations of IL-17, IL-1β, and TNF-α [4]. Furthermore, treatment with bosentan markedly ameliorated the clinical aspects of CIA, reduced joint damage, leukocyte infiltration and pro-inflammatory cytokine levels (IL-1β, TNF-α, and IL-17) in the joint tissues [5].…”