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


CONCLUSIONS
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.
Webster
Elizabeth L
EL
Integrative Neural-Immune Program, Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Bethesda 20892, USA.
Barrientos
Ruth M
RM
Contoreggi
Carlo
C
Isaac
Mitchel G
MG
Ligier
Sophie
S
Gabry
K Eddie
KE
Chrousos
George P
GP
McCarthy
Edward F
EF
Rice
Kenner C
KC
Gold
Philip W
PW
Sternberg
Esther M
EM
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology*; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D015999:Multivariate Analysis; D011336:Probability; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D012016:Reference Values; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D003346:Corticotropin-Releasing Hormone