Abstract:The pathophysiology of multiple sclerosis (MS) involves several components: redox, inflammatory/autoimmune, vascular, and neurodegenerative. All of them are supported by the intertwined lines of evidence, and none of them should be written off. However, the exact mechanisms of MS initiation, its development, and progression are still elusive, despite the impressive pace by which the data on MS are accumulating. In this review, we will try to integrate the current facts and concepts, focusing on the role of red… Show more
“…Finally, EP and DMF are capable of providing a more direct antioxidative protection via scavenging superoxide and hydroxyl radical, which have the central place in MS-related neurodegenerative processes, such as "slow burning" of demyelinated neurons and oxidative damage directly inflicted by cytotoxic cells (5). Emerging data imply that EP might be an effective antiinflammatory agent in vivo.…”
Section: Discussionmentioning
confidence: 99%
“…The activity of DMF appears to be prevalently based on redox properties, that is, binding to thiols via Michael-type addition (3). DMF turns off thiol redox switches on T cell membrane, whereas in neurons and astrocytes, DMF targets specific thiol moieties, which leads to activation of Nrf2-controled set of antioxidative enzymes, NAD(P)H: quinine oxidoreductase 1 and glutathione-related enzymes, and downregulation of transcription factor NF-kB (2,4,5). These pharmacological strategies-targeting of redox switches to suppress T cell activity (6)(7)(8), and activation of endogenous antioxidative system instead of frequently futile application of exogenous antioxidants (9)-are rather new and hold promise of further therapeutic relevance.…”
mentioning
confidence: 99%
“…We have noted recently that ethyl pyruvate (EP) might represent a DMF redox analog, and therefore could be of interest in MS treatment (5). EP forms Michael-type adducts with thiols, activates Nrf2 in astrocytes, and inhibits NF-kB-dependent transcription in different cell types, including LPS-stimulated BV2 (microglial) cells and macrophage-like RAW 264.7 cells (10-13).…”
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.
“…Finally, EP and DMF are capable of providing a more direct antioxidative protection via scavenging superoxide and hydroxyl radical, which have the central place in MS-related neurodegenerative processes, such as "slow burning" of demyelinated neurons and oxidative damage directly inflicted by cytotoxic cells (5). Emerging data imply that EP might be an effective antiinflammatory agent in vivo.…”
Section: Discussionmentioning
confidence: 99%
“…The activity of DMF appears to be prevalently based on redox properties, that is, binding to thiols via Michael-type addition (3). DMF turns off thiol redox switches on T cell membrane, whereas in neurons and astrocytes, DMF targets specific thiol moieties, which leads to activation of Nrf2-controled set of antioxidative enzymes, NAD(P)H: quinine oxidoreductase 1 and glutathione-related enzymes, and downregulation of transcription factor NF-kB (2,4,5). These pharmacological strategies-targeting of redox switches to suppress T cell activity (6)(7)(8), and activation of endogenous antioxidative system instead of frequently futile application of exogenous antioxidants (9)-are rather new and hold promise of further therapeutic relevance.…”
mentioning
confidence: 99%
“…We have noted recently that ethyl pyruvate (EP) might represent a DMF redox analog, and therefore could be of interest in MS treatment (5). EP forms Michael-type adducts with thiols, activates Nrf2 in astrocytes, and inhibits NF-kB-dependent transcription in different cell types, including LPS-stimulated BV2 (microglial) cells and macrophage-like RAW 264.7 cells (10-13).…”
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.
“…It seems T H 1 and T H 17 cells are the main pathogenic populations in the immunopathogenesis of MS (Jadidi-Niaragh & Mirshafiey 2011b). Although there are no DC in a healthy CNS, other antigen-presenting cells (APC) like macrophages, microglia, B cells, endothelial cells and astrocytes can prime autoreactive Tcells at the disease initiation stage (Ransohoff & Engelhardt 2012;Miljković & Spasojević 2013;Yazdani et al 2013). Interestingly, it was reported that microglia and macrophages could differentiate into DC-like cells (Ponomarev et al 2005).…”
Section: Multiple Sclerosismentioning
confidence: 99%
“…The cleavage of extracellular matrix by these enzymes not only damages the CNS parenchyma and BBB integrity, but also creates several protein fragments, which may act as chemoattractants and immunomodulators (Weathington et al 2006). Altogether, these events disturb BBB integrity and recruit various leukocytes into the CNS (Miljković & Spasojević 2013) (Figure 1).…”
Multiple sclerosis (MS) is an autoimmune neurodegenerative disease characterized with immunopathobiological events, including lymphocytic infiltration into the central nervous system (CNS), microglia activation, demyelination and axonal degeneration. Although several neuroprotective drugs have been designed for the treatment of MS, complete remission is yet matter of debate. Therefore, development of novel therapeutic approaches for MS is of a high priority in immunological research. Nanomedicine is a recently developed novel medical field, which is applicable in both diagnosis and treatment of several cancers and autoimmune diseases. Although there is a marked progress in neuroimaging through using nanoparticles, little is known regarding the therapeutic potential of nanomedicine in neurological disorders, particularly MS. Moreover, the majority of data is limited to the MS related animal models. In this review, we will discuss about the brain targeting potential of different nanoparticles as well as the role of nanomedicine in the diagnosis and treatment of MS and its animal model, experimental autoimmune encephalomyelitis.
ARTICLE HISTORY
Multiple sclerosis (MS) is a life‐threading disease that poses a great threat to the human being lifestyle. Having said extensive research in the realm of underlying mechanisms and treatment procedures, no definite remedy has been found. Over the past decades, many medicines have been disclosed to alleviate the symptoms and marking of MS. Meanwhile, the substantial efficacy of herbal medicines including curcumin must be underscored. Accumulated documents demonstrated the fundamental role of curcumin in the induction of the various signaling pathways. According to evidence, curcumin can play a role in mitochondrial dysfunction and apoptosis, autophagy, and mitophagy. Also, by targeting the signaling pathways AMPK, PGC‐1α/PPARγ, and PI3K/Akt/mTOR, curcumin interferes with the metabolism of MS. The anti‐inflammatory, antioxidant, and immune regulatory effects of this herbal compound are involved in its effectiveness against MS. Thus, the present review indicates the molecular and metabolic pathways associated with curcumin's various pharmacological actions on MS, as well as setting into context the many investigations that have noted curcumin‐mediated regulatory effects in MS.
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