title: A comparative analysis of multiple sclerosis-relevant anti-inflammatory properties of ethyl pyruvate and dimethyl fumarate.
abstract: Dimethyl fumarate (DMF), a new drug for multiple sclerosis (MS) treatment, acts against neuroinflammation via mechanisms that are triggered by adduct formation with thiol redox switches. Ethyl pyruvate (EP), an off-the-shelf agent, appears to be a redox analog of DMF, but its immunomodulatory properties have not been put into the context of MS therapy. In this article, we examined and compared the effects of EP and DMF on MS-relevant activity/functions of T cells, macrophages, microglia, and astrocytes. EP efficiently suppressed the release of MS signature cytokines, IFN-γ and IL-17, from human PBMCs. Furthermore, the production of these cytokines was notably decreased in encephalitogenic T cells after in vivo application of EP to rats. Production of two other proinflammatory cytokines, IL-6 and TNF, and NO was suppressed by EP in macrophages and microglia. Reactive oxygen species production in macrophages, microglia activation, and the development of Ag-presenting phenotype in microglia and macrophages were constrained by EP. The release of IL-6 was reduced in astrocytes. Finally, EP inhibited the activation of transcription factor NF-κB in microglia and astrocytes. Most of these effects were also found for DMF, implying that EP and DMF share common targets and mechanisms of action. Importantly, EP had in vivo impact on experimental autoimmune encephalomyelitis, an animal model of MS. Treatment with EP resulted in delay and shortening of the first relapse, and lower clinical scores, whereas the second attack was annihilated. Further studies on the possibility to use EP as an MS therapeutic are warranted.
authors: Department of Immunology, Institute for Biological Research "Siniša Stanković," University of Belgrade, 11000 Belgrade, Serbia; djordjem@ibiss.bg.ac.rs.
authors: Djordje
authors: D
authors: Miljković
authors: Department of Immunology, Institute for Biological Research "Siniša Stanković," University of Belgrade, 11000 Belgrade, Serbia;
authors: Jana
authors: J
authors: Blaževski
authors: Department of Immunology, Institute for Biological Research "Siniša Stanković," University of Belgrade, 11000 Belgrade, Serbia;
authors: Filip
authors: F
authors: Petković
authors: Department of Immunology, Institute for Biological Research "Siniša Stanković," University of Belgrade, 11000 Belgrade, Serbia;
authors: Neda
authors: N
authors: Djedović
authors: Department of Immunology, Institute for Biological Research "Siniša Stanković," University of Belgrade, 11000 Belgrade, Serbia;
authors: Miljana
authors: M
authors: Momčilović
authors: Department of Immunology, Institute for Biological Research "Siniša Stanković," University of Belgrade, 11000 Belgrade, Serbia;
authors: Suzana
authors: S
authors: Stanisavljević
authors: Department of Immunology, Institute for Biological Research "Siniša Stanković," University of Belgrade, 11000 Belgrade, Serbia;
authors: Bojan
authors: B
authors: Jevtić
authors: Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; and.
authors: Marija
authors: M
authors: Mostarica Stojković
authors: Life Sciences Department, Institute for Multidisciplinary Research, University of Belgrade, 11030 Belgrade, Serbia.
authors: Ivan
authors: I
authors: Spasojević
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D000069462:Dimethyl Fumarate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D005434:Flow Cytometry; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy*; D016328:NF-kappa B / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005650:Fumarates; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011773:Pyruvates; D017382:Reactive Oxygen Species; C046522:ethyl pyruvate; D000069462:Dimethyl Fumarate