Dimethyl Fumarate Alleviates Dextran Sulfate Sodium-Induced Colitis, through the Activation of Nrf2-Mediated Antioxidant and Anti-inflammatory Pathways

Abstract

Oxidative stress and chronic inflammation play critical roles in the pathogenesis of ulcerative colitis (UC) and inflammatory bowel diseases (IBD). A previous study has demonstrated that dimethyl fumarate (DMF) protects mice from dextran sulfate sodium (DSS)-induced colitis via its potential antioxidant capacity, and by inhibiting the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. This study aims to clarify the nuclear factor erythroid 2-related factor 2/antioxidant responsive element (Nrf2/ARE) pathway pharmacological activation and anti-inflammatory effect by DMF, through focusing on other crucial antioxidant enzymes and inflammatory mediator, including glutamate-cysteine ligase catalytic subunit (GCLC), glutathione peroxidase (GPX) and cyclooxygenase-2 (COX-2), in a DSS-induced colitis mouse model. The oral administration of DMF attenuated the shortening of colons and alleviated colonic inflammation. Furthermore, the expression of key antioxidant enzymes, including GCLC and GPX, in the colonic tissue were significantly increased by DMF administration. In addition, protein expression of the inflammatory mediator, COX-2, was reduced by DMF administration. Our results suggest that DMF alleviates DSS-induced colonic inflammatory damage, likely via up-regulating GCLC and GPX and down-regulating COX-2 protein expression in colonic tissue.

Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?

“…In most instances, experimental rodent models of colitis have been used to demonstrate the efficacy of DMF for mitigating colon injury, pro-inflammatory cytokine and adhesion molecule production and NF-κB signalling [ 7 ]. Furthermore, DMF exerts efficacy in IBD through induction of the Nrf2-mediated antioxidant response involving increased superoxide dismutase (SOD) expression to reduce lipid peroxidation [ 7 , 36 ]. MMF has also been shown to suppress or completely prevent gastric ulceration in rats [ 88 ] highlighting FAEs as potent gastro-protective agents.…”

“…By reversing mitochondrial TCA cycle flux, there is novel evidence that FAEs might exert at least a portion of their immunomodulatory action through generating succinyl-carnitine esters or other metabolites as well [ 31 , 32 ]. The collective Nrf2-inducing and immuno-modulatory properties of DMF and other FAEs, have demonstrated therapeutic efficacy across multiple body systems such as the central nervous [ 10 , 33 ], cardiovascular [ 34 , 35 ], gastrointestinal [ 7 , 36 , 37 ], immune [ 5 , 38 ] and integumentary [ 39 , 40 ] systems. Thus, the prospective clinical impact of DMF and its esters is extensive.…”

Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?

“…there is a well-established association between IBD development/progression and inflammation, several groups injury, pro-inflammatory cytokine and adhesion molecule production and NF-κB signalling [7]. Furthermore, DMF exerts efficacy in IBD through induction of the Nrf2-mediated antioxidant response involving increased superoxide dismutase (SOD) expression to reduce lipid peroxidation [7,33]. MMF has also been shown to suppress or completely prevent gastric ulceration in rats [86] highlighting FAEs as potent gastro-protective agents.…”

“…In addition to the activation of Nrf2, MMF also interacts with HCAR2, which strongly modulates anti-inflammatory activity, particularly in primary and accessory immune cells [29]. The collective Nrf2-inducing and immune-modulatory properties of DMF and other FAEs, has demonstrated therapeutic efficacy across multiple body systems such as the central nervous [10,30], cardiovascular [31,32], gastrointestinal [7,33,34], immune [5,35] and integumentary [36,37] systems. Thus, the prospective clinical impact of DMF and its esters is extensive.…”

Dynamic Evaluation of Compound Ento-PB for the Repair of Mucosal Ulcer in Dogs With Acetic Acid-induced Experimental Colitis 

“…The occurrence and development of UC are largely due to chronic in ammation, and massive in ltration of immune cells, and accompanied by increased production of pro-in ammatory mediators, including IL-1β, TNF-α, and COX-2, and decreased production of anti-in ammatory factors such as IL-10 [29,30]. Many evidences indicated that cytokines TNF-α and IL-1β play important roles in intestinal in ammation and barrier dysfunction [31].…”