Protective effect of RC-3095, an antagonist of the gastrin-releasing peptide receptor, in experimental arthritis
P. G. Oliveira
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Search for more papers by this authorR. Grespan
Universidade de São Paulo–Ribeirão Preto, Ribeirão Preto, Brazil
Search for more papers by this authorL. G. Pinto
Universidade de São Paulo–Ribeirão Preto, Ribeirão Preto, Brazil
Search for more papers by this authorL. Meurer
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Search for more papers by this authorJ. C. T. Brenol
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Search for more papers by this authorR. Roesler
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Drs. Roesler and Schwartsmann are listed as inventors in a provisional patent application for the therapeutic use of gastrin-releasing peptide receptor antagonists in the treatment of inflammatory conditions.
Search for more papers by this authorG. Schwartsmann
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Drs. Roesler and Schwartsmann are listed as inventors in a provisional patent application for the therapeutic use of gastrin-releasing peptide receptor antagonists in the treatment of inflammatory conditions.
Search for more papers by this authorF. Q. Cunha
Universidade de São Paulo–Ribeirão Preto, Ribeirão Preto, Brazil
Search for more papers by this authorCorresponding Author
R. M. Xavier
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Hospital de Clínicas de Porto Alegre, Serviço de Reumatologia, Rua Ramiro Barcellos 2350, Sala 645, 90035-003 Porto Alegre, BrazilSearch for more papers by this authorP. G. Oliveira
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Search for more papers by this authorR. Grespan
Universidade de São Paulo–Ribeirão Preto, Ribeirão Preto, Brazil
Search for more papers by this authorL. G. Pinto
Universidade de São Paulo–Ribeirão Preto, Ribeirão Preto, Brazil
Search for more papers by this authorL. Meurer
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Search for more papers by this authorJ. C. T. Brenol
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Search for more papers by this authorR. Roesler
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Drs. Roesler and Schwartsmann are listed as inventors in a provisional patent application for the therapeutic use of gastrin-releasing peptide receptor antagonists in the treatment of inflammatory conditions.
Search for more papers by this authorG. Schwartsmann
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Drs. Roesler and Schwartsmann are listed as inventors in a provisional patent application for the therapeutic use of gastrin-releasing peptide receptor antagonists in the treatment of inflammatory conditions.
Search for more papers by this authorF. Q. Cunha
Universidade de São Paulo–Ribeirão Preto, Ribeirão Preto, Brazil
Search for more papers by this authorCorresponding Author
R. M. Xavier
Hospital de Clinicas de Porto Alegre and Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Hospital de Clínicas de Porto Alegre, Serviço de Reumatologia, Rua Ramiro Barcellos 2350, Sala 645, 90035-003 Porto Alegre, BrazilSearch for more papers by this authorAbstract
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-1β, and tumor necrosis factor α (TNFα) 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-1β, and TNFα, 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.
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