A novel IKKα inhibitor, noraristeromycin, blocks the chronic inflammation associated with collagen-induced arthritis in mice.

Abstract:

OBJECTIVES:To evaluate the therapeutic efficacy of a novel inhibitor for IκB kinase alpha (IKKα), noraristeromycin (NAM), for murine experimental model of rheumatoid arthritis, collagen- induced arthritis (CIA). METHODS:NAM has been chemically synthesized as reported earlier. CIA was induced in DBA/1JNCrlj mice by intradermal inoculation of bovine type II collagen (col II) together with Freund Complete Adjuvant. Following the Day 21 booster injection of col II with Freund Incomplete Adjuvant, the animals were monitored for the development of arthritis and clinically evaluated. NAM was administered orally at different doses prior to induction (prophylactic protocol) or after the emergence of definitive arthritis (therapeutic protocol). RESULTS:Here we demonstrate the experimental evidence that oral administration of NAM could completely prevent the occurrence of experimental arthritis in CIA mouse model at 0.3 mg/kg with ED50 value of approximately 0.1 mg/kg twice daily. Moreover, twice daily oral therapeutic dosage of 1 mg/kg of NAM significantly inhibited the paw swelling and disease progression even after the occurrence of experimental CIA. In addition, NAM exhibited an excellent pharmacokinetics in mice and oral administration of NAM could suppress the production of TNFα elicited by lipopolysaccharide (LPS) in a dose-dependent manner. CONCLUSIONS:These results indicated that IKKα inhibition is an effective novel therapy for the treatment of chronic inflammatory processes such as those associated with RA and other related conditions.

journal_name

Mod Rheumatol

journal_title

Modern rheumatology

authors

Ito M,Hamano T,Komatsu T,Asamitsu K,Yamakawa T,Okamoto T

doi

10.3109/14397595.2013.879416

subject

Has Abstract

pub_date

2014-09-01 00:00:00

pages

775-80

issue

5

eissn

1439-7595

issn

1439-7609

journal_volume

24

pub_type

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