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Properties of DMF in NDs. (A) shows the mechanism of action of DMF through Keap1/Nrf2/ARE pathway; (B) provides a table which summarizes the main effects of DMF in NDs (specifically for AD, PD, HD, ALS).
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Neurodegenerative diseases (NDs) represents debilitating conditions characterized by degeneration of neuronal cells in specific brain areas, causing disability and death in patients. In the pathophysiology of NDs, oxidative stress, apoptosis and neuroinflammation have a key role, as demonstrated by in vivo and in vitro models. Therefore, the use of...
Contexts in source publication
Context 1
... to the results obtained from clinical studies, in 2013 DMF was licensed as an oral therapeutic agent for the treatment of relapsing forms of multiple sclerosis [96,97]. Furthermore, it has been disclosed that DMF and MMF act on Kelch-like ECH associating protein 1 (Keap1), an Nrf2 activator (Figure 2A), which works on both antioxidant and inflammatory pathways [98], promoting the attenuation of pro-inflammatory cytokine production [99] and the modulation of microglia and astrocytes [100]. Antioxidants 2020, 9, x FOR PEER REVIEW promoting the attenuation of pro-inflammatory cytokine production [99] and the modulation of microglia and astrocytes [100]. ...
Context 2
... considering the cross-talk that exists between NF-kB and Nrf2 pathways provides DMF the ability to counteract the inflammation. Given these considerations, the use of DMF could improve the management of many pathologies including the NDs ( Figure 2B); this thesis is supported by different research articles that demonstrate the efficacy of DMF in many in vitro and in vivo models of NDs. ...
Context 3
... considering the cross-talk that exists between NF-kB and Nrf2 pathways provides DMF the ability to counteract the inflammation. Given these considerations, the use of DMF could improve the management of many pathologies including the NDs ( Figure 2B); this thesis is supported by different research articles that demonstrate the efficacy of DMF in many in vitro and in vivo models of NDs. ...
Citations
... DMF, an antioxidant, can significantly enhance the resistance of tissue cells to oxidative stress and reduce mitochondrial damage (39) in patients with neurodegenerative diseases (40) and ischemia-reperfusion injury (41). ...
... As discussed earlier, the Nrf2 pathway activation has a protective effect on cells subjected to oxidative stress conditions such as those that occur during PD [81] or COVID-19 infection [109,110]. Apart from multiple sclerosis, DMF also shows an anti-in ammatory and antioxidative effects in various animal and in vitro models of PD [111,112]. During the COVID-19 pandemic, many studies suggested that infected multiple sclerosis patients could continue their treatment with DMF [113][114][115]. ...
Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) is a highly pathogenic and contagious coronavirus that first surfaced in late 2019. The genome encodes four major structural proteins, non-structural proteins and accessory proteins. The nucleocapsid (N) protein of SARS-CoV-2 is an evolutionarily conserved RNA-binding protein that is abundant and plays a critical role in packaging the viral genome. Researchers have explored its potential as a target for therapeutic purposes. People with pre-existing neurological conditions like Parkinson’s disease (PD) and dementia have been recognised as a high-risk population for severe COVID-19 illness as SARS-CoV-2 has been reported to cause deterioration of the symptoms of these diseases. This study aims to identify the shared human interactors of SARS-CoV-2 N protein, PD and dementia. Proteins involved were retrieved from databases, and protein-protein interaction networks were created and visualized in Cytoscape. Individual intersection networks of SARS-CoV-2 N protein with PD and dementia resulted in 46 and 26 proteins, respectively, while intersection networks of SARS-CoV-2 N protein, PD and dementia resulted in 15 common proteins. Seed proteins were identified from network clusters and their Gene Ontology (GO) analysis revealed their involvement in several biological processes. Valosin-containing-protein (VCP) was found to be the only seed protein involved during the co-occurrence of SARS-CoV-2 N protein infection, PD and dementia and is mainly concerned with the regulation of the ubiquitin-proteasome system (UPS). Further, gene enrichment analysis of the identified 15 common proteins was conducted using the DAVID tool, followed by the identification of 7 druggable targets using the Therapeutic Target Database (TTD) and DrugBank. Studying the biological functions of the identified host-protein interactors is crucial for understanding the progression of the disease at a molecular level. Moreover, approved therapeutic compounds against the potential drug target proteins can also be utilized to develop effective treatments.
... When reperfusion occurs, massive ROS attack on Keap1 leads to Nrf2 release and translocation into the nucleus, where it binds to the appropriate transcriptional precursor and initiates target gene transcription. Thus, enhancers of the Keap1/Nrf2 system may have neuroprotective effects by increasing PPP levels in astrocytes [210][211][212]. Dimethyl fumarate, an Nrf2 activator, has been evaluated to reduce the proinflammatory effects of astrocytes following cerebral ischemia [213] and has shown neuroprotective effects [214]. ...
Ischemic stroke is a leading cause of disability and death worldwide. However, the clinical efficacy of recanalization therapy as a preferred option is significantly hindered by reperfusion injury. The transformation between different phenotypes of gliocytes is closely associated with cerebral ischemia/reperfusion injury (CI/RI). Moreover, gliocyte polarization induces metabolic reprogramming, which refers to the shift in gliocyte phenotype and the overall transformation of the metabolic network to compensate for energy demand and building block requirements during CI/RI caused by hypoxia, energy deficiency, and oxidative stress. Within microglia, the pro-inflammatory phenotype exhibits upregulated glycolysis, pentose phosphate pathway, fatty acid synthesis, and glutamine synthesis, whereas the anti-inflammatory phenotype demonstrates enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation. Reactive astrocytes display increased glycolysis but impaired glycogenolysis and reduced glutamate uptake after CI/RI. There is mounting evidence suggesting that manipulation of energy metabolism homeostasis can induce microglial cells and astrocytes to switch from neurotoxic to neuroprotective phenotypes. A comprehensive understanding of underlying mechanisms and manipulation strategies targeting metabolic pathways could potentially enable gliocytes tobe reprogrammed toward beneficial functions while opening new therapeutic avenues for CI/RI treatment. This review provides an overview of current insights into metabolic reprogramming mechanisms in microglia and astrocytes within the pathophysiological context of CI/RI, along with potential pharmacological targets. Herein, we emphasize the potential of metabolic reprogramming of gliocytes as a therapeutic target for CI/RI and aim to offer a novel perspective in the treatment of CI/RI.
... Fumaric acid and its derivatives are among the wellknown antioxidants that provide various health benefits due to their potent free radical scavenging properties, anti-inflammatory and immunomodulatory effects. 26,27 These data in the literature may be related to the wound healing activity of Salvia tomentosa due to its high fumaric acid content. ...
Antioxidant activity, antimicrobial potency and components of the aerial parts (leaf, stem, flower and mixture) of Salvia tomentosa Miller were determined qualitatively and quantitatively in this study. Aqueous extracts of Salvia tomentosa (ST) were prepared by using the flower, leaf and stem parts and all the above-ground parts of the plant (flower-leafstem mixture) for this purpose. The radical scavenging activity, total antioxidant/oxidant status, antimicrobial potential, phenolic substances and qualitative/quantitative analyzes of the components in the extracts were determined. ST-stem phenolic acid amount (599 ± 34 mg gallic acid equivalent (GAE)/g extract) was found to be close to the standard substance caffeic acid (651 ±3 1 mg GAE/g extract). Total antioxidant status of ST-mix (3.4 ± 0.1 mmol Trolox Equiv./L) and ST-stem (3.4 ± 0.1 mmol Trolox Equiv./L) and natural antioxidant Vitamin C (3.6 ± 0.1 mmol Trolox Equiv./L) were not statistically different. The extract produced by using S. tomentosa aerial parts (flower-stem-leaf) showed stronger antioxidant and antimicrobial activity than the aqueous extracts obtained separately from the flower, stem and leaf of the plant. However, it was determined that the components of the separately prepared flower, stem and leaf extracts and the extract components obtained from the aerial parts were largely similar. At the same time, it was observed that there were significant differences in the presence of these components.
... Our study attempted for the first time to link these treatments to NRF2 functional genetic polymorphism in an in vitro model of ASD treatment using the pharmacological NRF2 inductor dimethyl fumarate (DMF). The latter represents a subscription drug to treat Parkinson's disease and a candidate drug under evaluation for Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis [24][25][26]. We believe that thorough justification of re-purposing of the DMF drug to treat ASD on a personalized base is currently highly desirable. ...
... This is the case, for example, with physical exercise and several phytochemicals including curcumin from turmeric, diallyl sulfide from garlic, resveratrol from grapes, epicatechin from cocoa or green tea and sulforaphane from cruciferous vegetables like broccoli, cauliflower, and kale (11), all of which generate a mild oxidative stress that, in turn, upregulates endogenous antioxidant defense systems, such as reduced glutathione (12). This is also the case with dimethyl fumarate (DMF), an electrophilic compound, which has been approved for the treatment of relapsing multiple sclerosis in the United States and Europe, and which is under investigation in cancer and other neurodegenerative diseases like Alzheimer's, and Parkinson's (13). Like RRx-001, DMF induces an initial oxidative burst through alkylation of thiols and depletion of glutathione (GSH) that activates Nrf2 and ultimately increases GSH levels (14). ...
RRx-001 is a shape shifting small molecule with Fast Track designation for the prevention/amelioration of chemoradiation-induced severe oral mucositis (SOM) in newly diagnosed Head and Neck cancer. It has been intentionally developed or “engineered” as a chimeric single molecular entity that targets multiple redox-based mechanisms. Like an antibody drug conjugate (ADC), RRx-001 contains, at one end a “targeting” moiety, which binds to the NLRP3 inflammasome and inhibits it as well as Kelch-like ECH-associated protein 1 (KEAP1), the negative regulator of Nrf2, and, at the other end, a conformationally constrained, dinitro containing 4 membered ring, which fragments under conditions of hypoxia and reduction to release therapeutically active metabolites i.e., the payload. This “payload”, which is delivered specifically to hypoperfused and inflamed areas, includes nitric oxide, nitric oxide related species and carbon-centered radicals. As observed with ADCs, RRx-001 contains a backbone amide “linker” attached to a binding site, which correlates with the F ab region of an antibody, and to the dinitroazetidine payload, which is microenvironmentally activated. However, unlike ADCs, whose large size impacts their pharmacokinetic properties, RRx-001 is a nonpolar small molecule that easily crosses cell membranes and the blood brain barrier (BBB) and distributes systemically. This short review is organized around the de novo design and in vivo pro-oxidant/pro-inflammatory and antioxidant/anti-inflammatory activity of RRx-001, which, in turn, depends on the reduced to oxidized glutathione ratio and the oxygenation status of tissues.
... Parkinson's disease (PD) represents the second-most common neurodegenerative disease, affecting every year about 5 million people worldwide [1]. PD, as a motor disorder, presents symptoms that include tremors, stiffness, bradykinesia, and difficulty walking; however, the pathology presents several clinical signs that also involve cognitive disorders, behavioral complications, dementia, and impaired emotional recognition in the advanced stages [2]. ...
Parkinson’s disease (PD) is a disorder that is characterized by progressive and selective neuronal injury and cell death. Recent studies have provided accumulating evidence for a significant role of the immune system and neuroinflammation in PD pathogenesis. On this basis, many scientific articles have highlighted the anti-inflammatory and neuroprotective properties of Antrodia camphorata (AC), an edible fungus containing various bioactive compounds. This study aimed to evaluate the inhibitory effect of AC administration on neuroinflammation and oxidative stress in a murine model of MPTP-induced dopaminergic degeneration. AC (10, 30, 100 mg/kg) was administered daily by oral gavage starting 24 h after the first administration of MPTP, and mice were sacrificed 7 days after MPTP induction. In this study, treatment with AC significantly reduced the alteration of PD hallmarks, increasing tyrosine hydroxylase expression and reducing the number of alpha-synuclein-positive neurons. In addition, AC treatment restored the myelination process of neurons associated with PD and attenuated the neuroinflammatory state. Furthermore, our study demonstrated that AC was able to reduce the oxidative stress induced by MPTP injection. In conclusion, this study highlighted that AC could be a potential therapeutic agent for the treatment of neurodegenerative disorders such as PD.
... Dimethyl fumarate (DMF) was approved for treatment of relapsing-remitting multiple sclerosis (RRMS) in 2013. DMF is currently under study for the treatment of primary neurodegenerative diseases [40][41][42], inflammation-associated diseases [43][44][45][46], and for potential applications to SARS-CoV-2 infection [47][48][49][50][51][52]. DMF and its in vivo metabolite, monomethyl fumarate (MMF), suppress aerobic glycolysis by targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) through irreversible succination of cysteine residues at the active site [53]. ...
... The other immune-modulating effects of DMF and MMF include the induction of a Th1 to Th2 lymphocyte shift, inhibition of pro-inflammatory cytokine signaling, inhibition of nuclear factor kappa B (NF-κB) nuclear translocation, suppression of lymphocyte and endothelial adhesion molecule expression, and lymphocyte and monocyte chemotaxis [62,63]. They are also responsible for the induction of multiple NRF-2-dependent effector genes [40,41]. DMF and MMF mostly affect CD8+ T cells but are also known to affect CD4+ cells to a lesser degree, especially the pro-inflammatory T-helper Th1 and Th17 cells. ...
Alzheimer’s Disease (AD) is a debilitating disease that leads to severe cognitive impairment and functional decline. The role of tau hyperphosphorylation and amyloid plaque deposition in the pathophysiology of AD has been well described; however, neuroinflammation and oxidative stress related to sustained microglial activation is thought to play a significant role in the disease process as well. NRF-2 has been identified in modulating the effects of inflammation and oxidative stress in AD. Activation of NRF-2 leads to an increased production of antioxidant enzymes, including heme oxygenase, which has been shown to have protective effects in neurodegenerative disorders such as AD. Dimethyl fumarate and diroximel fumarate (DMF) have been approved for the use in relapsing–remitting multiple sclerosis. Research indicates that they can modulate the effects of neuroinflammation and oxidative stress through the NRF-2 pathway, and as such, could serve as a potential therapeutic option in AD. We propose a clinical trial design that could be used to assess DMF as a treatment option for AD.
... In the present study, DMF was able to directly or indirectly or both affect oxidative and inflammatory markers, and thereby ameliorating manic behaviors in the KET model of MLB. The role of DMF as an inducer of Nrf2 in oxidative and inflammatory pathways in neurodegenerative diseases has been reported by Scuderi et al. (2020). However, the effects of DMF in controlling OS and inflammation can be extended to other neurological diseases such as BD. ...
Medications for treating bipolar disorder (BD) are limited and can cause side effects if used chronically. Therefore, efforts are being made to use new agents in the control and treatment of BD. Considering the antioxidant and anti-inflammatory effects of dimethyl fumarate (DMF), this study was performed to examine the role of DMF on ketamine (KET)-induced manic-like behavior (MLB) in rats. Forty-eight rats were randomly divided into eight groups, including three groups of healthy rats: normal, lithium chloride (LiCl) (45 mg/kg, p.o.), and DMF (60 mg/kg, p.o.), and five groups of MLB rats: control, LiCl, and DMF (15, 30, and 60 mg/kg, p.o.), which received KET at a dose of 25 mg/kg, i.p. The levels of total sulfhydryl groups (total SH), thiobarbituric acid reactive substances (TBARS), nitric oxide (NO), and tumor necrosis factor-alpha (TNF-α), as well as the activity of antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the prefrontal cortex (PFC) and hippocampus (HPC), were measured. DMF prevented hyperlocomotion (HLM) induced by KET. It was found that DMF could inhibit the increase in the levels of TBARS, NO, and TNF-α in the HPC and PFC of the brain. Furthermore, by examining the amount of total SH and the activity of SOD, GPx, and CAT, it was found that DMF could prevent the reduction of the level of each of them in the brain HPC and PFC. DMF pretreatment improved the symptoms of the KET model of mania by reducing HLM, oxidative stress, and modulating inflammation.
... In the present study, DMF was able to directly or indirectly or both affect oxidative and inflammatory markers, and thereby ameliorating manic behaviors in the KET model of MLB. The role of DMF as an inducer of Nrf2 in oxidative and inflammatory pathways in neurodegenerative diseases has been reported by Scuderi et al. (2020). However, the effects of DMF in controlling OS and inflammation can be extended to other neurological diseases such as BD. ...
Medications for treating bipolar disorder (BD) are limited and can cause side efects if used chronically. Therefore, eforts are
being made to use new agents in the control and treatment of BD. Considering the antioxidant and anti-infammatory efects
of dimethyl fumarate (DMF), this study was performed to examine the role of DMF on ketamine (KET)-induced manic-like
behavior (MLB) in rats. Forty-eight rats were randomly divided into eight groups, including three groups of healthy rats:
normal, lithium chloride (LiCl) (45 mg/kg, p.o.), and DMF (60 mg/kg, p.o.), and fve groups of MLB rats: control, LiCl, and
DMF (15, 30, and 60 mg/kg, p.o.), which received KET at a dose of 25 mg/kg, i.p. The levels of total sulfhydryl groups (total
SH), thiobarbituric acid reactive substances (TBARS), nitric oxide (NO), and tumor necrosis factor-alpha (TNF-α), as well
as the activity of antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase
(GPx) in the prefrontal cortex (PFC) and hippocampus (HPC), were measured. DMF prevented hyperlocomotion (HLM)
induced by KET. It was found that DMF could inhibit the increase in the levels of TBARS, NO, and TNF-α in the HPC and
PFC of the brain. Furthermore, by examining the amount of total SH and the activity of SOD, GPx, and CAT, it was found
that DMF could prevent the reduction of the level of each of them in the brain HPC and PFC. DMF pretreatment improved
the symptoms of the KET model of mania by reducing HLM, oxidative stress, and modulating infammation.
