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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, and ESTHER M. STERNBERG
ABSTRACT.
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. (J Rheumatol 2002;29:1252-61) Key Indexing Terms:
CORTICOTROPIN RELEASING HORMONE RECEPTOR ANTAGONIST
From the Integrative Neural-Immune Program, Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda; Clinical Neuroendocrinology Branch, NIMH, NIH, Bethesda; Brain Imaging Unit, National Institute on Drug Abuse (NIDA), Baltimore; Pediatric Endocrinology Section, Pediatric and Reproductive Endocrinology Branch (PREB), National Institute of Child Health and Human Development (NICHD), Bethesda; Department of Orthopedic Surgery, Johns Hopkins Medical School, Baltimore; and Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD), NIH, Bethesda, Maryland, USA. E.L. Webster, PhD, Integrative Neural-Immune Program, Clinical Neuroendocrinology Branch, NIMH; R.M. Barrientos, PhD, Integrative Neural-Immune Program, NIMH (currently University of Colorado at Boulder, Boulder, CO); C. Contoreggi, MD, Brain Imaging Unit, NIDA; M.G. Isaac, MD, Integrative Neural-Immune Program, NIMH; (currently University of Kansas Medical Center, Kansas City, KS); S. Ligier, MD, Integrative Neural-Immune Program, NIMH (currently Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada); K.E. Gabry, MD, PhD, Clinical Neuroendocrinology Branch, NIMH; G.P. Chrousos, MD, Pediatric Endocrinology Section, PREB, NICHD; E.F. McCarthy, MD, Department of Orthopedic Surgery, Johns Hopkins Medical School; K.C. Rice, PhD, Chief, Laboratory of Medicinal Chemistry, NIDDKD; P.W. Gold, MD, Chief, Clinical Neuroendocrinology Branch, NIMH; E.M. Sternberg, MD, Director, Integrative Neural-Immune Program, Chief, Section on Neuroendocrine Immunology and Behavior, NIMH. Address reprint requests to Dr. E.M. Sternberg, National Institute of Mental Health, 36 Convent Drive, MSC 4020, Bldg. 36, Bethesda, MD 20892. Submitted July 9, 2001; revision accepted December 6, 2001.
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