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Dimethyl Fumarate Modulates Oxidative Stress and Inflammation in Organs After Sepsis in Rats
Amanda Della Giustina1, Sandra Bonfante1, Graciela Freitas Zarbato1
1Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, University of South Santa Catarina, Tubarao, SC, Brazil.
Abstract:
Sepsis is defined as life-threatening organ dysfunction induced by a disrupted host response to infecting pathogens. Evidences suggest that oxidative stress is intrinsically related to sepsis progression. Dimethyl fumarate (DMF) is a novel oral therapeutic agent with anti-oxidant properties which exerts protective effects through activation of nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2). Thus, the aim of this study is to evaluate the effect of DMF in different organs of rats submitted to an animal model of sepsis. Adult male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP) procedure and sham-operated rats was considered control group. The experimental groups were divided into sham + vehicle, sham + DMF, sham + NAC, CLP + vehicle, CLP + DMF, and CLP + NAC. Rats were treated by oral gavage with DMF immediately after and 12 h after surgery, or NAC (s.c.) at 3, 6, and 12 h after surgery. Twenty-four hours after sepsis induction, neutrophil infiltration, nitrite/nitrate concentrations, oxidative damage to lipids and proteins, superoxide dismutase (SOD), and catalase (CAT) activities were evaluated in the heart, liver, lung, and kidney. Septic animals presented increased neutrophil infiltration, NO metabolism, oxidative damage to lipids and proteins, and decreases of SOD and CAT activities, mainly in the heart, liver, and lung, while DMF-treated animals showed significant reduction in neutrophil infiltration, NO metabolism, and oxidative damage followed by increased SOD and CAT activities. DMF is effective in preventing oxidative stress and inflammation in rats 24 h after sepsis induction.
Insights
Dimethyl fumarate (DMF) effectively combats sepsis-induced oxidative stress and inflammation in rats. This antioxidant agent reduces organ damage by activating the Nrf2 pathway, offering a promising therapeutic strategy for sepsis.
Area of Science:
- Biomedical Science
- Pathophysiology
- Pharmacology
Background:
- Sepsis involves life-threatening organ dysfunction due to a dysregulated host response to infection.
- Oxidative stress is a key factor in sepsis progression and associated organ damage.
- Dimethyl fumarate (DMF) is an oral antioxidant that activates the Nrf2 pathway, showing potential therapeutic benefits.
Purpose of the Study:
- To investigate the protective effects of Dimethyl fumarate (DMF) against sepsis-induced organ dysfunction in a rat model.
- To evaluate DMF's impact on oxidative stress, inflammation, and organ damage markers in sepsis.
Main Methods:
- Sepsis was induced in Wistar rats via cecal ligation and puncture (CLP).
- Experimental groups received vehicle, DMF, or N-acetylcysteine (NAC) treatment post-CLP.
- Organs (heart, liver, lung, kidney) were analyzed 24 hours post-sepsis for neutrophil infiltration, NO metabolism, oxidative damage, and antioxidant enzyme activities (SOD, CAT).
Main Results:
- Sepsis induction led to increased neutrophil infiltration, NO metabolism, and oxidative damage, with decreased SOD and CAT activities, particularly in the heart, liver, and lung.
- DMF treatment significantly reduced neutrophil infiltration, NO metabolism, and oxidative damage in septic rats.
- DMF administration also resulted in increased superoxide dismutase (SOD) and catalase (CAT) activities, mitigating sepsis-induced oxidative stress.
Conclusions:
- Dimethyl fumarate (DMF) demonstrates significant efficacy in preventing and reducing oxidative stress and inflammation in a rat model of sepsis.
- DMF's protective effects are linked to its antioxidant properties and activation of the Nrf2 pathway.
- DMF represents a promising therapeutic agent for managing sepsis-related organ dysfunction.
