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.

Sepsis-associated encephalopathy: a vicious cycle of immunosuppression

“…Monocytes/macrophages Decreasing the number of monocytes; polarization of M2 phenotype; increasing production of IL-10; reducing phagocytic capability [43], [44], [45] Neutrophils Impairment in ROS production; reduction of phagocytosis; shortening life-span as a result of spontaneous apoptosis [43,[46][47][48][49] Dendritic cells Decreasing number of circulating DCs; anergic response to TLR3 and TLR4 stimulations; incapable of priming effective cellular immune response; disturbed infiltration and aberrant phenotypic differentiation [50][51][52][53] T lymphocytes Reducing proportion of peripheral T cells; disturbing response to antigens; polarization of anti-inflammatory phenotypes; inducing imbalance between Tregs and proinflammatory phenotypes of T cells [54][55][56][57][58] sepsis, but they are rarely found in the normal brain [66]. Neutrophils accumulating in the central nervous system jeopardize brain cells by releasing inflammatory cytokines, increasing the activity of myeloperoxidase, and promoting oxidative damage [74]. Taken together, the balance between infiltration and withdrawal of neutrophils is of great importance for the development of SAE.…”

Postconditioning with Sevoflurane or Propofol Alleviate Lipopolysaccharide-Induced Neuroinflammation, but Exert Dissimilar Effects on NR2B Subunit and Cognition

“…Surgery or trauma can cause systemic in ammation, and damage the brain-blood barrier, eventually induce neuroin ammation [52], which has been proved to be highly associated with postoperative cognitive dysfunction [8,9,53]. Intracerebroventricular injection of LPS can mimic neuroin ammation induced by surgery or trauma in animal studies [25,54].…”

The surviving sepsis campaign: basic/translational science research priorities

“…Cognitive defects that may be analogous to those present in patients with sepsis have been identified following CLP in rodents. These abnormalities have been attributed to a number of underlying causes, including neuroinflammation, a number of different brain regions, most notably the hippocampus and basal forebrain, and in some cases have been amenable to treatment [28,168,[222][223][224][225][226][227][228][229][230][231]. However, the relevance of these abnormalities to human sepsis is unknown.…”