TY  - JOUR
AU  - Miljković, Đorđe
AU  - Blazevski, Jana
AU  - Petković, Filip
AU  - Djedović, Neda
AU  - Momcilović, Miljana
AU  - Stanisavljević, Suzana
AU  - Jevtic, Bojan
AU  - Mostarica-Stojković, Marija
AU  - Spasojević, Ivan
PY  - 2015
UR  - http://rimsi.imsi.bg.ac.rs/handle/123456789/891
AB  - 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-gamma 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-kappa B 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.
PB  - Amer Assoc Immunologists, Bethesda
T2  - Journal of Immunology
T1  - A Comparative Analysis of Multiple Sclerosis-Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate
EP  - 2503
IS  - 6
SP  - 2493
VL  - 194
DO  - 10.4049/jimmunol.1402302
ER  - 

@article{
author = "Miljković, Đorđe and Blazevski, Jana and Petković, Filip and Djedović, Neda and Momcilović, Miljana and Stanisavljević, Suzana and Jevtic, Bojan and Mostarica-Stojković, Marija and Spasojević, Ivan",
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-gamma 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-kappa B 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.",
publisher = "Amer Assoc Immunologists, Bethesda",
journal = "Journal of Immunology",
title = "A Comparative Analysis of Multiple Sclerosis-Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate",
pages = "2503-2493",
number = "6",
volume = "194",
doi = "10.4049/jimmunol.1402302"
}

Miljković, Đ., Blazevski, J., Petković, F., Djedović, N., Momcilović, M., Stanisavljević, S., Jevtic, B., Mostarica-Stojković, M.,& Spasojević, I.. (2015). A Comparative Analysis of Multiple Sclerosis-Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate. in Journal of Immunology
Amer Assoc Immunologists, Bethesda., 194(6), 2493-2503.
https://doi.org/10.4049/jimmunol.1402302

Miljković Đ, Blazevski J, Petković F, Djedović N, Momcilović M, Stanisavljević S, Jevtic B, Mostarica-Stojković M, Spasojević I. A Comparative Analysis of Multiple Sclerosis-Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate. in Journal of Immunology. 2015;194(6):2493-2503.
doi:10.4049/jimmunol.1402302 .

Miljković, Đorđe, Blazevski, Jana, Petković, Filip, Djedović, Neda, Momcilović, Miljana, Stanisavljević, Suzana, Jevtic, Bojan, Mostarica-Stojković, Marija, Spasojević, Ivan, "A Comparative Analysis of Multiple Sclerosis-Relevant Anti-Inflammatory Properties of Ethyl Pyruvate and Dimethyl Fumarate" in Journal of Immunology, 194, no. 6 (2015):2493-2503,
https://doi.org/10.4049/jimmunol.1402302 . .

TY  - CONF
AU  - Miljković, Đorđe
AU  - Petković, Filip
AU  - Blazevski, Jana
AU  - Momcilović, Miljana
AU  - Djedović, Neda
AU  - Mostarica-Stojković, Marija
AU  - Spasojević, Ivan
PY  - 2014
UR  - http://rimsi.imsi.bg.ac.rs/handle/123456789/811
AB  - The ongoing success of dimethyl fumarate (DMF; Tecfidera) opens a perspective for further development of the redox strategy in multiple sclerosis (MS) treatment. The mechanisms of anti-inflammatory and neuroprotective effects of DMF involve the formation of adducts with redox-sensitive thiol switches on the surface of T cell resulting in suppressed activity, proliferation and pro-inflammatory cytokine release, and the activation of antioxidative defense in the central nervous system (CNS) cells. Ethyl pyruvate (EP) appears to be a safer non-toxic redox analogue of DMF, as they share common molecular targets. We examined the effects of EP on CNS resident cells (astrocytes, microglia) and encephalitogenic T cells, as well as its influence on the clinical course of actively induced experimental autoimmune encephalomyelitis (EAE). Astrocytes and microglia were stimulated with pro-inflammatory cytokines and treated with EP in vitro. Encephalitogenic immune cells were isolated from draining lymph nodes of rats that were immunized with myelin basic protein (MBP) and complete Freund's adjuvant (CFA) and treated with EP in vivo. EP modulated cytokine generation in the examined cells in an anti-inflammatory manner: (i) the production of interleukin (IL)-6, but not IL-10, was down-regulated in astrocytes; (ii) the release of IL-6, tumor necrosis factor and nitric oxide from microglial cells was reduced; (iii) the production of interferon-gamma and IL-17, but not IL-10, was suppressed in lymph node cells isolated from MBP + CFA-immunized rats. In addition, EP alleviated EAE course in rats, delaying the onset, shortening the relapse, and lowering clinical scores. These results imply that EP has a potency to inhibit inflammation in the CNS. While further studies on the effect of EP on the CNS inflammation are warranted, we believe that EP might be applicable and beneficial in MS treatment.
PB  - Elsevier Science Bv, Amsterdam
C3  - Journal of Neuroimmunology
T1  - Effect of ethyl pyruvate on central nervous system inflammation
EP  - 224
IS  - 1-2
SP  - 223
VL  - 275
DO  - 10.1016/j.jneuroim.2014.08.600
ER  - 

@conference{
author = "Miljković, Đorđe and Petković, Filip and Blazevski, Jana and Momcilović, Miljana and Djedović, Neda and Mostarica-Stojković, Marija and Spasojević, Ivan",
year = "2014",
abstract = "The ongoing success of dimethyl fumarate (DMF; Tecfidera) opens a perspective for further development of the redox strategy in multiple sclerosis (MS) treatment. The mechanisms of anti-inflammatory and neuroprotective effects of DMF involve the formation of adducts with redox-sensitive thiol switches on the surface of T cell resulting in suppressed activity, proliferation and pro-inflammatory cytokine release, and the activation of antioxidative defense in the central nervous system (CNS) cells. Ethyl pyruvate (EP) appears to be a safer non-toxic redox analogue of DMF, as they share common molecular targets. We examined the effects of EP on CNS resident cells (astrocytes, microglia) and encephalitogenic T cells, as well as its influence on the clinical course of actively induced experimental autoimmune encephalomyelitis (EAE). Astrocytes and microglia were stimulated with pro-inflammatory cytokines and treated with EP in vitro. Encephalitogenic immune cells were isolated from draining lymph nodes of rats that were immunized with myelin basic protein (MBP) and complete Freund's adjuvant (CFA) and treated with EP in vivo. EP modulated cytokine generation in the examined cells in an anti-inflammatory manner: (i) the production of interleukin (IL)-6, but not IL-10, was down-regulated in astrocytes; (ii) the release of IL-6, tumor necrosis factor and nitric oxide from microglial cells was reduced; (iii) the production of interferon-gamma and IL-17, but not IL-10, was suppressed in lymph node cells isolated from MBP + CFA-immunized rats. In addition, EP alleviated EAE course in rats, delaying the onset, shortening the relapse, and lowering clinical scores. These results imply that EP has a potency to inhibit inflammation in the CNS. While further studies on the effect of EP on the CNS inflammation are warranted, we believe that EP might be applicable and beneficial in MS treatment.",
publisher = "Elsevier Science Bv, Amsterdam",
journal = "Journal of Neuroimmunology",
title = "Effect of ethyl pyruvate on central nervous system inflammation",
pages = "224-223",
number = "1-2",
volume = "275",
doi = "10.1016/j.jneuroim.2014.08.600"
}

Miljković, Đ., Petković, F., Blazevski, J., Momcilović, M., Djedović, N., Mostarica-Stojković, M.,& Spasojević, I.. (2014). Effect of ethyl pyruvate on central nervous system inflammation. in Journal of Neuroimmunology
Elsevier Science Bv, Amsterdam., 275(1-2), 223-224.
https://doi.org/10.1016/j.jneuroim.2014.08.600

Miljković Đ, Petković F, Blazevski J, Momcilović M, Djedović N, Mostarica-Stojković M, Spasojević I. Effect of ethyl pyruvate on central nervous system inflammation. in Journal of Neuroimmunology. 2014;275(1-2):223-224.
doi:10.1016/j.jneuroim.2014.08.600 .

Miljković, Đorđe, Petković, Filip, Blazevski, Jana, Momcilović, Miljana, Djedović, Neda, Mostarica-Stojković, Marija, Spasojević, Ivan, "Effect of ethyl pyruvate on central nervous system inflammation" in Journal of Neuroimmunology, 275, no. 1-2 (2014):223-224,
https://doi.org/10.1016/j.jneuroim.2014.08.600 . .