Dimethyl fumarate attenuates liver injury in a mouse model of cecal ligation and puncture by modulating inflammatory, angiogenic and pyroptotic pathways

Background: Sepsis is a prevalent ailment that significantly affects hospitalized individuals around the globe. It is characterized by uncontrolled inflammatory responses resulting in organ injury and leading to high morbidity and mortality. The liver, a vital organ, is affected by sepsis, resulting in liver dysfunction. Dimethyl fumarate (DMF), which is approved for the treatment of multiple sclerosis, has anti-inflammatory and neuroprotective properties through the inhibition of multiple inflammatory mediators. Hence, the present study aimed to assess the hepatoprotective potential of DMF against sepsis.

Methods: Four groups of mice (6 Animals per group) were divided into a sham group, which was subjected to only anaesthesia and a midline abdominal incision; the cecal ligation and puncture (CLP) group was anaesthetized and underwent an abdominal incision followed by the ligation of the cecum under the ileocecal valve and perforation twice with a needle; the vehicle group was given a solvent of DMF 1 h before the CLP, and the CLP group received 50 mg/kg of DMF via intraperitoneal (IP) injection 1 h before CLP. Following the procedure (24 h post-CLP), the mice were given unrestricted access to food and drink throughout the day. Serum was used to measure the levels of angiopoietin 2, AST and ALT. Enzyme-linked immunosorbent assay (ELISA) was used to investigate the levels of TNF-α, IL-6, MIF, ICAM-1, F2-isoprostanes, VEGF, and Caspase 11 in liver tissues. To evaluate the degree of liver damage, a biopsy of the liver was performed.

Results: The results revealed that mice exposed to CLP had high levels of AST and ALT in comparison with sham mice. Furthermore, levels of TNF-α, IL-6, MIF, ICAM-1, F2-isoprostanes, VEGF, and Caspase 11 in liver tissues were also notably elevated as compared with sham mice. The levels of these parameters were significantly decreased in septic mice pre-treated with DMF. Mice with CLP showed a severe degree of liver damage as compared with sham mice. DMF pre-treatment mitigated liver injury.

Conclusion: This study suggests that DMF has hepatoprotective effects on septic mice via the modulation of inflammation, adhesion molecules, angiopoietin 2 and Pyroptosis.

CLP; DMF; Endotoxaemia; Hepatoprotective; Oxidative stress; Sepsis; VEGF.