Mathew, Geetha and Jacob, Anija and Ega, Durgashivaprasad and Reddy, ND and Unnikrishnan, MK (2013) 6b,11b-Dihydroxy-6b,11b-dihydro-7 H -indeno[1,2- b ]naphtho[2,1- d ]furan-7-one (DHFO), a small Molecule Targeting NF- κ B, Demonstrates Therapeutic Potential in Immunopathogenic Chronic in Flammatory Conditions. International Immunopharmacology, 15 (1). pp. 182-189.

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Abstract

6b,11b-Dihydroxy-6b,11b-dihydro-7 H -indeno[1,2- b naphtho[2,1- d ]furan-7-one (DHFO), an easily synthesisable, orallybioavailableandrelativelynon-toxicsmallmolecul esynthesisedinourlab,waspreviouslyreportedtopossess anti-oxidant, 5-lipoxyge nase inhibitory, anti-in fl ammatory and peripheral analgesic activities. The present work deals with exploration of DHFO's efficacy in immunopathogenic chronic in flammatory conditions — arthritis and al-lergy.Incarrageenan-inducedin lammatory airpouch, which resembles the arthritic synovium, DHFO effectivelyre- duced in flammatory redness and swelling and neutrophil in filtration. In complete Freund's adjuvant-induced arthritis, DHFO significantly decreased paw oedema and nitrite levels with efficacy comparable to diclofenac.DHFO inhibited neutrophil activation (observed as decrea sed myeloperoxidase levels), in both the in vivo models of in flammation. Interestingly, DHFO did not ulcerate the gastrointestinal tract, while diclofenac was observed to be extremely ulcerogenic. In antigen-induced active and passive anaphylaxis (allergy) models, DHFO dose- dependently prevented mesenteric mast cell (MC) degranulation with efficacy comparable to ketotifen. DHFO also inhibited compound 48/80 (C48/80)-induced paw oed ema and peritoneal MC degranulation. DHFO stabilised p815 murine MCs stimulated by C48/80 and calcium ionophore — A23187, indicating an action downstream of cal- cium mobilisation. DHFO's anti-allergic mechanism could be two-pronged involving (1) inhibition of IgE production and/or (2) MC stabilisation. DHFO inhibited lipopolysaccharide (LPS)-induced pro-in flammatory medi- ator release (ROS, NO, IL-6 levels) and COX2 expression in RAW264.7 murine macrop hages. Protein expression studies con firmed DHFO's ability to reduce nuclear levels of NF-κ B in LPS-stimulated macrophages. Thus, DHFO is a promising non-ulcerogenic synthetic small molecule lead for immunopathogenic chronic in flammatory conditions.

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