A novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammation

Mathew, Geetha and Mudgal, Jayesh and Thambi, Magith and Sebastian, Sarine and Unnikrishnan, MK (2018) A novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammation. Free Radical Research, 52 (10). pp. 1140-1157. ISSN 1071-5762

[img] PDF
00005612.pdf - Published Version
Restricted to Registered users only

Download (3MB) | Request a copy

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 TNFa levels. Mechanistic studies revealed that DMFO reduced proinflammatory genes (IL1b, TNFa, 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 LPSstimulated 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.

Item Type: Article
Uncontrolled Keywords: Anti-inflammatory; antioxidant; macrophages; nonulcerogenic; Nrf2.
Subjects: Pharmacy > MCOPS Manipal > Pharmacology
Pharmacy > MCOPS Manipal > Pharmacy Practice
Depositing User: KMC Library
Date Deposited: 05 Jan 2019 07:15
Last Modified: 05 Jan 2019 07:15
URI: http://eprints.manipal.edu/id/eprint/152715

Actions (login required)

View Item View Item