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

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-RI 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.

• Authors: 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
• Journal: The Journal of rheumatology (J Rheumatol) Vol. 29 Issue 6 Pg. 1252-61 (Jun 2002) ISSN: 0315-162X [Print] Canada
• PMID: 12064844 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Pyrimidines
• Pyrroles
• Receptors, Corticotropin-Releasing Hormone
• antalarmin
• Corticotropin-Releasing Hormone

Topics

• Animals
• Arthritis, Experimental (drug therapy, pathology)
• Corticotropin-Releasing Hormone (antagonists & inhibitors, pharmacology)
• Disease Models, Animal
• Female
• Immunohistochemistry
• Male
• Multivariate Analysis
• Probability
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• Rats
• Rats, Inbred F344
• Rats, Inbred Lew
• Receptors, Corticotropin-Releasing Hormone (metabolism)
• Reference Values
• Sensitivity and Specificity
• Treatment Outcome