Dimethyl Fumarate Limits Neuroinflammation and Oxidative Stress and Improves Cognitive Impairment After Polymicrobial Sepsis

Abstract

Sepsis is caused by a dysregulated host response to infection, often associated with acute central nervous system (CNS) dysfunction, which results in long-term cognitive impairment. Dimethyl fumarate (DMF) is an important agent against inflammatory response and reactive species in CNS disorders. Evaluate the effect of DMF on acute and long-term brain dysfunction after experimental sepsis in rats. Male Wistar rats were submitted to the cecal ligation and puncture (CLP) model. The groups were divided into sham (control) + vehicle, sham + NAC, sham + DMF, CLP + vehicle, CLP + NAC, and CLP + DMF. The animals were treated with DMF (15 mg/kg at 0 and 12 h after CLP, per gavage) and the administration of n-acetylcysteine (NAC) (20 mg/kg; 3, 6, and 12 h after CLP, subcutaneously) was used as positive control. Twenty-four hours after CLP, cytokines, myeloperoxidase (MPO), nitrite/nitrate (N/N), oxidative damage to lipids and proteins, and antioxidant enzymes were evaluated in the hippocampus, total cortex, and prefrontal cortex. At 10 days after sepsis induction, behavioral tests were performed to assess cognitive damage. We observed an increase in cytokine levels, MPO activity, N/N concentration, and oxidative damage, a reduction in SOD and GPx activity in the brain structures, and cognitive damage in CLP rats. DMF treatment was effective in reversing these parameters. DMF reduces sepsis-induced neuroinflammation, oxidative stress, and cognitive impairment in rats subjected to the CLP model.

Keywords: Cognitive impairment; Dimethyl fumarate; Neuroinflammation; Oxidative stress; Sepsis.