title: 6b,11b-Dihydroxy-6b,11b-dihydro-7H-indeno[1,2-b]naphtho[2,1-d]furan-7-one (DHFO), a small molecule targeting NF-κB, demonstrates therapeutic potential in immunopathogenic chronic inflammatory conditions.
abstract: 6b,11b-Dihydroxy-6b,11b-dihydro-7H-indeno[1,2-b]naphtho[2,1-d]furan-7-one (DHFO), an easily synthesisable, orally bioavailable and relatively non-toxic small molecule synthesised in our lab, was previously reported to possess anti-oxidant, 5-lipoxygenase inhibitory, anti-inflammatory and peripheral analgesic activities. The present work deals with exploration of DHFO's efficacy in immunopathogenic chronic inflammatory conditions - arthritis and allergy. In carrageenan-induced inflammatory air pouch, which resembles the arthritic synovium, DHFO effectively reduced inflammatory redness and swelling and neutrophil infiltration. 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 decreased myeloperoxidase levels), in both the in vivo models of inflammation. 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 oedema and peritoneal MC degranulation. DHFO stabilised p815 murine MCs stimulated by C48/80 and calcium ionophore-A23187, indicating an action downstream of calcium 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-inflammatory mediator release (ROS, NO, IL-6 levels) and COX2 expression in RAW264.7 murine macrophages. Protein expression studies confirmed DHFO's ability to reduce nuclear levels of NF-κB in LPS-stimulated macrophages. Thus, DHFO is a promising non-ulcerogenic synthetic small molecule lead for immunopathogenic chronic inflammatory conditions.
authors.affiliation: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India. geeth_math@yahoo.co.in
authors.forename: Geetha
authors.initials: G
authors.lastname: Mathew
authors.forename: Anija
authors.initials: A
authors.lastname: Jacob
authors.forename: Ega
authors.initials: E
authors.lastname: Durgashivaprasad
authors.forename: N D
authors.initials: ND
authors.lastname: Reddy
authors.forename: M K
authors.initials: MK
authors.lastname: Unnikrishnan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000941:Antigens / Q000276:immunology; D001168:Arthritis / Q000188:drug therapy* / Q000378:metabolism; D002351:Carrageenan; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004487:Edema / Q000188:drug therapy; D005620:Freund's Adjuvant; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use*; D006636:Histamine Release / Q000187:drug effects; D006967:Hypersensitivity / Q000188:drug therapy* / Q000378:metabolism; D007192:Indenes / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D044967:Serum / Q000276:immunology; D012756:Sheep; D003189:p-Methoxy-N-methylphenethylamine
chemical_list: C581818:6b,11b-dihydroxy-6b,11b-dihydro-7H-indeno(1,2-b)naphtho(2,1-d)furan-7-one; D000893:Anti-Inflammatory Agents; D000941:Antigens; D005663:Furans; D007192:Indenes; D015850:Interleukin-6; D016328:NF-kappa B; D009281:Naphthalenes; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D003189:p-Methoxy-N-methylphenethylamine; D002351:Carrageenan; D005620:Freund's Adjuvant; D009195:Peroxidase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2