Exploring the Use of Dimethyl Fumarate as Microglia Modulator for Neurodegenerative Diseases Treatment

Rosito, Maria; Testi, Claudia; Parisi, Giacomo; Cortese, Barbara; Baiocco, Paola; Angelantonio, Silvia Di

doi:10.3390/antiox9080700

Cited by 31 publications

(25 citation statements)

References 171 publications

(240 reference statements)

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“…During the present study we have observed an increase of S 40 phosphorylation of Nrf2 and induction of GCLm expression. GCL is a transcriptional Nrf2 target and an enzyme of central importance for the maintenance of intracellular GSH levels in microglia [80]. In agreement with the induction of GCLm protein expression also GSH levels increased in LPA treated cells (Figure 8), a finding indicative of the induction of a protective pathway to counteract damage of endogenous macromolecules [81].…”

Section: Discussionsupporting

confidence: 74%

Lysophosphatidic Acid Induces Aerobic Glycolysis, Lipogenesis, and Increased Amino Acid Uptake in BV-2 Microglia

Joshi

Plastira

Bernhart

et al. 2021

IJMS

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Lysophosphatidic acid (LPA) species are a family of bioactive lipids that transmit signals via six cognate G protein-coupled receptors, which are required for brain development and function of the nervous system. LPA affects the function of all cell types in the brain and can display beneficial or detrimental effects on microglia function. During earlier studies we reported that LPA treatment of microglia induces polarization towards a neurotoxic phenotype. In the present study we investigated whether these alterations are accompanied by the induction of a specific immunometabolic phenotype in LPA-treated BV-2 microglia. In response to LPA (1 µM) we observed slightly decreased mitochondrial respiration, increased lactate secretion and reduced ATP/ADP ratios indicating a switch towards aerobic glycolysis. Pathway analyses demonstrated induction of the Akt-mTOR-Hif1α axis under normoxic conditions. LPA treatment resulted in dephosphorylation of AMP-activated kinase, de-repression of acetyl-CoA-carboxylase and increased fatty acid content in the phospholipid and triacylglycerol fraction of BV-2 microglia lipid extracts, indicating de novo lipogenesis. LPA led to increased intracellular amino acid content at one or more time points. Finally, we observed LPA-dependent generation of reactive oxygen species (ROS), phosphorylation of nuclear factor erythroid 2–related factor 2 (Nrf2), upregulated protein expression of the Nrf2 target regulatory subunit of glutamate-cysteine ligase and increased glutathione synthesis. Our observations suggest that LPA, as a bioactive lipid, induces subtle alterations of the immunometabolic program in BV-2 microglia.

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Section: Discussionsupporting

confidence: 74%

Lysophosphatidic Acid Induces Aerobic Glycolysis, Lipogenesis, and Increased Amino Acid Uptake in BV-2 Microglia

Joshi

Plastira

Bernhart

et al. 2021

IJMS

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“…DMF targets the Nrf2/ARE pathway, which involves multiple genes that protect cells from oxidative stress and injury [ 37 , 54 , 55 , 56 , 57 , 58 , 59 ], including antioxidant enzymes, such as NQO1 [ 60 ], GPX1 [ 61 ], PRDX1 [ 62 ], and HO-1 [ 63 ]. We quantified the antioxidant enzyme expression in eleven brain regions ( Figure 4 ), as well as the spleen ( Figure 5 ), thymus, and liver ( Figure S1 ), and observed higher NQO1 ( p < 0.01), GPX1 ( p < 0.001), and HO-1 ( p < 0.05) expression in the brains of DMF-treated animals compared to untreated animals (via comparing the means of expression from each region in each group using a paired t -test, Figure 4 B,D,F,H,J).…”

Section: Resultsmentioning

confidence: 99%

Dimethyl Fumarate, an Approved Multiple Sclerosis Treatment, Reduces Brain Oxidative Stress in SIV-Infected Rhesus Macaques: Potential Therapeutic Repurposing for HIV Neuroprotection

García-Mesa

Vance

et al. 2021

Antioxidants

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Dimethyl fumarate (DMF), an antioxidant/anti-inflammatory drug approved for the treatment of multiple sclerosis, induces antioxidant enzymes, in part through transcriptional upregulation. We hypothesized that DMF administration to simian immunodeficiency virus (SIV)-infected rhesus macaques would induce antioxidant enzyme expression and reduce oxidative injury and inflammation throughout the brain. Nine SIV-infected, CD8+-T-lymphocyte-depleted rhesus macaques were studied. Five received oral DMF prior to the SIV infection and through to the necropsy day. Protein expression was analyzed in 11 brain regions, as well as the thymus, liver, and spleen, using Western blot and immunohistochemistry for antioxidant, inflammatory, and neuronal proteins. Additionally, oxidative stress was determined in brain sections using immunohistochemistry (8-OHdG, 3NT) and optical redox imaging of oxidized flavoproteins containing flavin adenine dinucleotide (Fp) and reduced nicotinamide adenine dinucleotide (NADH). The DMF treatment was associated with no changes in virus replication; higher expressions of the antioxidant enzymes NQO1, GPX1, and HO-1 in the brain and PRDX1 and HO-2 in the spleen; lower levels of 8-OHdG and 3NT; a lower optical redox ratio. The DMF treatment was also associated with increased expressions of cell-adhesion molecules (VCAM-1, ICAM-1) and no changes in HLA-DR, CD68, GFAP, NFL, or synaptic proteins. The concordantly increased brain antioxidant enzyme expressions and reduced oxidative stress in DMF-treated SIV-infected macaques suggest that DMF could limit oxidative stress throughout the brain through effective induction of the endogenous antioxidant response. We propose that DMF could potentially induce neuroprotective brain responses in persons living with HIV.

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“…Among the clinically tested Nrf2 inducers, DMF, also known as BG-12 or Tecfidera ® , is the only drug approved for Relapsing-Remitting Multiple Sclerosis (RRMS) by both Food and Drug Administration and the European Medicines Agency ( 185 ). DMF, a derivative of fumaric acid, exerts immunomodulatory, anti-inflammatory, anti-oxidative, and neuroprotective effects ( 186 ). Furthermore, Linker et al reported that DMF acts on the cysteine 151 on KEAP1 and thus activates Nrf2 ( 104 ).…”

Section: Clinical Trials With Nrf2 Inducers Against Nlrp3 Inflammasom...mentioning

confidence: 99%

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

2022

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The NLRP3 inflammasome is an intracellular multiprotein complex that plays an essential role in the innate immune system by identifying and eliminating a plethora of endogenous and exogenous threats to the host. Upon activation of the NLRP3 complex, pro-inflammatory cytokines are processed and released. Furthermore, activation of the NLRP3 inflammasome complex can induce pyroptotic cell death, thereby propagating the inflammatory response. The aberrant activity and detrimental effects of NLRP3 inflammasome activation have been associated with cardiovascular, neurodegenerative, metabolic, and inflammatory diseases. Therefore, clinical strategies targeting the inhibition of the self-propelled NLRP3 inflammasome activation are required. The transcription factor Nrf2 regulates cellular stress response, controlling the redox equilibrium, metabolic programming, and inflammation. The Nrf2 pathway participates in anti-oxidative, cytoprotective, and anti-inflammatory activities. This prominent regulator, through pharmacologic activation, could provide a therapeutic strategy for the diseases to the etiology and pathogenesis of which NLRP3 inflammasome contributes. In this review, current knowledge on NLRP3 inflammasome activation and Nrf2 pathways is presented; the relationship between NLRP3 inflammasome signaling and Nrf2 pathway, as well as the pre/clinical use of Nrf2 activators against NLRP3 inflammasome activation in disorders of the central nervous system, are thoroughly described. Cumulative evidence points out therapeutic use of Nrf2 activators against NLRP3 inflammasome activation or diseases that NLRP3 inflammasome contributes to would be advantageous to prevent inflammatory conditions; however, the side effects of these molecules should be kept in mind before applying them to clinical practice.

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Exploring the Use of Dimethyl Fumarate as Microglia Modulator for Neurodegenerative Diseases Treatment

Cited by 31 publications

References 171 publications

Lysophosphatidic Acid Induces Aerobic Glycolysis, Lipogenesis, and Increased Amino Acid Uptake in BV-2 Microglia

Lysophosphatidic Acid Induces Aerobic Glycolysis, Lipogenesis, and Increased Amino Acid Uptake in BV-2 Microglia

Dimethyl Fumarate, an Approved Multiple Sclerosis Treatment, Reduces Brain Oxidative Stress in SIV-Infected Rhesus Macaques: Potential Therapeutic Repurposing for HIV Neuroprotection

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

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