Antioxidant and Anti-inflammatory Effect of Nrf2 Inducer Dimethyl Fumarate in Neurodegenerative Diseases

Abstract

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 molecules with antioxidant and anti-inflammatory activities represents a possible strategy for the treatment of NDs. Many studies demonstrated the beneficial effects of fumaric acid esters (FAEs) to counteract neuroinflammation and oxidative stress. Among these molecules, dimethyl fumarate (DMF) showed a valid therapeutic approach to slow down neurodegeneration and relieve symptoms in patients with NDs. DMF is a methyl ester of fumaric acid and acts as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation. Therefore, this review aims to examine the potential beneficial effects of DMF to counteract oxidative stress and inflammation in patients with NDs.

Atorvastatin Attenuates Isoflurane-Induced Activation of ROS-p38MAPK/ATF2 Pathway, Neuronal Degeneration, and Cognitive Impairment of the Aged Mice

“…Accumulating evidence indicates that oxidative stress and inflammation may contribute to anesthetic-induced neurotoxicity in the aged brain ( Wu et al, 2015 ; Xu et al, 2020 ). Excessive oxidative stress and inflammation could promote the inflammatory factors release, which would damage the integrity of blood brain barrier and activate microglia, further lead to inflammatory cascades and cellular apoptosis ( Otani and Shichita, 2020 ; Scuderi et al, 2020 ). In our study, 1.5% isoflurane could promote oxidative stress and inflammation in the aged brain, with an increase in ROS, MDA, IL-1β, and TNF-α as well as a decrease in SOD.…”

“…Isoflurane is commonly used in the clinic ( Kumar et al, 2019 ; Peyton et al, 2020 ; Warren et al, 2020 ), which has also been reported to induces neuroinflammation, neuronal apoptosis, and cognitive impairment ( Cui et al, 2020 ; Neghab et al, 2020 ). Anesthesia and surgery induce systemic inflammatory response and oxidative stress, which could enter the brain through a variety of pathways [either passing directly through the blood brain barrier (BBB) or destroying the BBB] or sending signals to the brain ( Otani and Shichita, 2020 ; Scuderi et al, 2020 ). The increase of proinflammatory cytokines in the brain will over-activate microglia cells and induce more inflammatory substances to be released in the brain, resulting in nerve cell damage with a vicious cycle ( Bathini et al, 2020 ; Jeong et al, 2020 ).…”

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

“…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).…”

“…In this study, we determined whether DMF would induce antioxidant and anti-inflammatory responses within the brains of rhesus macaques during SIV infection, which is the non-human primate model of HIV infection. Studies in various rodent models of neurodegeneration and neuroinflammation have shown that DMF administration results in antioxidative and anti-inflammatory effects in the rodent brain (reviewed in [ 37 ]), with excellent tissue penetration [ 38 ]. We used the rhesus macaque CD8 + T lymphocyte depletion model of pathogenic SIV infection, as this model shows consistent brain inflammation and oxidative stress associated with a relatively rapid progression (weeks) to severe SIV-induced immune deficiency [ 39 ].…”

Properties of a New Food Supplement Containing Actinia equina Extract

“…Nrf2 is an important cytoprotective transcription factor that has a fundamental role in cellular homeostasis; it promotes the transcription of various anti-oxidant enzymes that contrast oxidative stress conditions present in the cellular environment [ 60 , 61 ].…”