Please use this identifier to cite or link to this item: https://hdl.handle.net/1/1773
Title: A novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammation
Authors: Mathew, Geetha ;Sharma, A.;Pickering, R.J.;Rosado, C.J.;Lemarie, J.;Mudgal, J.;Thambi, M.;Sebastian, S.;Jandeleit-Dahm, K.A.;de Haan, J.B.;Unnikrishnan, M.K.
Affliation: Central Coast Local Health District
Gosford Hospital
Issue Date: Oct-2018
Source: 52(10):1140-1157
Journal title: Free Radical Research
Department: Pharmacy
Abstract: Inflammation is a protective immune response against invading pathogens, however, dysregulated inflammation is detrimental. As the complex inflammatory response involves multiple mediators, including the involvement of reactive oxygen species, concomitantly targeting proinflammatory and antioxidant check-points may be a more rational strategy. We report the synthesis and anti-inflammatory/antioxidant activity of a novel indanedione derivative DMFO. DMFO scavenged reactive oxygen species (ROS) in in-vitro radical scavenging assays and in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In acute models of inflammation (carrageenan-induced inflammation in rat paw and air pouch), DMFO effectively reduced paw oedema and leucocyte infiltration with an activity comparable to diclofenac. DMFO stabilised mast cells (MCs) in in-vitro A23187 and compound 48/80-induced assays. Additionally, DMFO stabilised MCs in an antigen (ovalbumin)-induced MC degranulation model in-vivo, without affecting serum IgE levels. In a model of chronic immune-mediated inflammation, Freund's adjuvant-induced arthritis, DMFO reduced arthritic score and contralateral paw oedema, and increased the pain threshold with an efficacy comparable to diclofenac but without being ulcerogenic. Additionally, DMFO significantly reduced serum TNFalpha levels. Mechanistic studies revealed that DMFO reduced proinflammatory genes (IL1beta, TNFalpha, IL6) and protein levels (COX2, MCP1), with a concurrent increase in antioxidant genes (NQO1, haem oxygenase 1 (HO-1), Glo1, Nrf2) and protein (HO-1) in LPS-stimulated macrophages. Importantly, the anti-inflammatory/antioxidant effect on gene expression was absent in primary macrophages isolated from Nrf2 KO mice suggesting an Nrf2-targeted activity, which was subsequently confirmed using siRNA transfection studies in RAW macrophages. Therefore, DMFO is a novel, orally-active, safe (even at 2 g/kg p.o.), a small molecule which targets Nrf2 in ameliorating inflammation.
URI: https://elibrary.cclhd.health.nsw.gov.au/cclhdjspui/handle/1/1773
DOI: 10.1080/10715762.2018.1533636
Pubmed: https://www.ncbi.nlm.nih.gov/pubmed/30422019
ISSN: 1029-2470
Publicaton type: Journal Article
Keywords: Drug Therapy
Appears in Collections:Health Service Research

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