Treatment with dimethyl fumarate ameliorates liver ischemia/reperfusion injury

Abstract

AIMTo investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI).METHODSRats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined.RESULTSHistological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham vs CTL, P < 0.0001; CTL vs DMF, P < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L vs CTL 10592 ± 1152 U/L, P = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L vs CTL 26.0 ± 1.0 μmol/L, P = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg vs CTL 18.3 ± 0.6 nmol/mg, P = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL vs CTL 6.0 ± 0.5 mU/mL, P = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold vs 0.17 ± 0.06-fold, P = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group.CONCLUSIONDMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI.

Hemin reduces postoperative ileus in a heme oxygenase 1‐dependent manner while dimethyl fumarate does without heme oxygenase 1‐induction

“…Oral administration of 25 mg kg ‐1 DMF twice a day for 2 days before induction of liver I/R injury in rats resulted in a significant reduction of MPO activity and NF‐κB protein expression in liver tissue of DMF‐treated animals compared to non‐treated animals. However, administration of DMF for only 2 days did not result in a significant increase in HO‐1 protein levels . Similar beneficial effects of DMF were observed in a rat model of myocardial I/R injury after administration of 10 mg kg ‐1 DMF intravenously 90 minutes, and immediately before induction of myocardial ischemia.…”

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

“…Our previous study, exploring the effects of DMF on attenuating chronic pancreatitis, has shown that HO-1 expression was significantly upregulated in pancreatic tissue after incubation in DMF [10]. Similarly, we demonstrated that the oral administration of DMF prevented tissue damage in liver ischemia/reperfusion injury by increasing the expression of antioxidant enzymes, including catalase (CAT) and glutamate-cysteine ligase modifier subunit (GCLM), but not GCLC, GPX, HO-1 or NQO-1, suggesting that the mechanism of DMF action could be tissue specific [11]. Moreover, liver tissues treated with DMF had decreased expression levels of inflammation mediators NF-kB and cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines and chemokines, including cluster of differentiation 86 (CD86), IL-6, interleukin 10 (IL-10), TNF-a, etc.…”

“…Moreover, liver tissues treated with DMF had decreased expression levels of inflammation mediators NF-kB and cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines and chemokines, including cluster of differentiation 86 (CD86), IL-6, interleukin 10 (IL-10), TNF-a, etc. [11] This study aimed to clarify the pharmacological effects of DMF on nuclear factor erythroid 2-related factor 2/antioxidant responsive element (Nrf2/ARE) pathway activation and the anti-inflammatory system, by focusing on other crucial antioxidant enzymes and inflammatory mediators, including GCLC, GPX and COX-2 in the DSS-induced colitis mouse model.…”

Potential Benefits of Nrf2/Keap1 Targeting in Pancreatic Islet Cell Transplantation

“…Nevertheless, liver and renal tissue damage secondary to ischemia/reperfusion has been studied in the presence of Nrf2 activator pretreatment, and the results are promising. Our group looked at the effect of DMF pretreatment in rats that were subjected to ischemia for 1 h and reperfusion for 2 h [87]. Rats that received orally-administered DMF (25 mg/kg, 2x/day) pretreatment had a significant decrease in levels of MDA (p = 0.0009), increased expression of CAT (p = 0.03) and Glutamate-Cysteine Ligase Modifier Subunit (GCLM) (p = 0.04), decreased neutrophils and markers of inflammation, superior endothelial function and histopathological integrity (p = 0.02), and increased ATP levels (apoptosis consumes NAD + ) (p = 0.02) [87].…”