Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: Role of CRH in peripheral inflammation

Elizabeth L. Webster, Ruth M. Barrientos, Carlo Contoreggi, Mitchel G. Isaac, Sophie Ligier, K. Eddie Gabry, George P. Chrousos, Edward F. McCarthy, Kenner C. Rice, Philip W. Gold, Esther M. Sternberg

Research output: Contribution to journalArticlepeer-review

Abstract

Objective. To determine whether a corticotropin releasing hormone (CRH) type 1-specific receptor antagonist, antalarmin, would alter the progression of inflammation in adjuvant induced arthritis (AIA) susceptible LEW/N rats by blocking local CRH mediated inflammatory responses or render AIA resistant F344/N rats more susceptible to AIA by blocking central CRH, thus reducing secretion of endogenous glucocorticoids. Methods. F344/N and LEW/N rats were assigned to either drug or vehicle groups and treated with 20 mg/kg antalarmin or vehicle alone BID-for 25 days by intraperitoneal injection. Arthritis was induced in both antalarmin and vehicle treated LEW/N and F344/N rats by subcutaneous injections at the base of the tail of incomplete Freund's adjuvant containing 10 mg/ml heat killed Mycobacterium tuberculosis. Control F344/N and LEW/N rats were maintained on either antalarmin or vehicle. Results. Chronic blockade of CRH-R1 with systemic antalarmin significantly ameliorated AIA in LEW/N rats, reducing the severity of inflammation in peripheral joints, evidenced by clinical and histopathology scores, and weight loss associated with disease onset. Antalarmin neither induced nor exacerbated arthritis expression in F344/N or LEW/N rats, despite suppression of levels of adjuvant induced corticosterone, the major antiinflammatory glucocorticoid in rats. Conclusion. Systemic blockade of CRH-R1 appeared to predominantly block peripheral proinflammatory effects of immune CRH, rather than the systemic glucocorticoid mediated antiinflammatory effects of hypothalamic CRH. Results indicate that chronic treatment with a CRH antagonist attenuates progressive inflammation induced degeneration of synovia, cartilage, and bone in arthritic joints, suggesting that antalarmin may have therapeutic potential in treatment of human autoimmune and inflammatory disorders.

Original languageEnglish (US)
Pages (from-to)1252-1261
Number of pages10
JournalJournal of Rheumatology
Volume29
Issue number6
StatePublished - 2002
Externally publishedYes

Keywords

  • Adjuvant induced arthritis
  • Corticotropin releasing hormone receptor antagonist
  • Glucocorticoids
  • Inflammation
  • Rats

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

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