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A comparative analysis of multiple sclerosis-relevant anti-inflammatory properties of ethyl pyruvate and dimethyl fumarate.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2015 Mar 15; Vol. 194 (6), pp. 2493-503. Date of Electronic Publication: 2015 Feb 13. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Subjects :
- Animals
Anti-Inflammatory Agents pharmacology
Astrocytes cytology
Astrocytes drug effects
Astrocytes metabolism
Cell Survival drug effects
Cells, Cultured
Cytokines metabolism
Dimethyl Fumarate
Disease Models, Animal
Dose-Response Relationship, Drug
Female
Flow Cytometry
Humans
Immunoblotting
Leukocytes, Mononuclear cytology
Leukocytes, Mononuclear drug effects
Leukocytes, Mononuclear metabolism
Lipopolysaccharides pharmacology
Lymph Nodes cytology
Lymph Nodes metabolism
Macrophages cytology
Macrophages drug effects
Macrophages metabolism
Microglia cytology
Microglia drug effects
Microglia metabolism
NF-kappa B metabolism
Rats
Reactive Oxygen Species metabolism
Spinal Cord cytology
Spinal Cord metabolism
Encephalomyelitis, Autoimmune, Experimental drug therapy
Fumarates pharmacology
Multiple Sclerosis drug therapy
Pyruvates pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 194
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 25681336
- Full Text :
- https://doi.org/10.4049/jimmunol.1402302