An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases

Zgórzyńska, Emilia; Dziedzic, Barbara; Walczewska, Anna

doi:10.3390/ijms22179592

Cited by 99 publications

(87 citation statements)

References 192 publications

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“…Precursors of glutathione biosynthesis, such as N -acetyl- l -cysteine, which have been demonstrated to increase glutathione concentrations following intravenous administration, have also been considered for clinical applications [ 8 , 16 ]. More recently a combination of N -acetylcysteine and a regenerative secretome preparation of mesenchymal stem cells has been suggested [ 17 ].…”

Section: Glutathione As Antioxidantmentioning

confidence: 99%

Neuroprotection against Aminochrome Neurotoxicity: Glutathione Transferase M2-2 and DT-Diaphorase

et al. 2022

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Glutathione is an important antioxidant that plays a crucial role in the cellular protection against oxidative stress and detoxification of electrophilic mutagens, and carcinogens. Glutathione transferases are enzymes catalyzing glutathione-dependent reactions that lead to inactivation and conjugation of toxic compounds, processes followed by subsequent excretion of the detoxified products. Degeneration and loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal neurons generally involves oxidative stress, neuroinflammation, alpha-synuclein aggregation to neurotoxic oligomers, mitochondrial dysfunction, protein degradation dysfunction, and endoplasmic reticulum stress. However, it is still unclear what triggers these neurodegenerative processes. It has been reported that aminochrome may elicit all of these mechanisms and, interestingly, aminochrome is formed inside neuromelanin-containing dopaminergic neurons during neuromelanin synthesis. Aminochrome is a neurotoxic ortho-quinone formed in neuromelanin synthesis. However, it seems paradoxical that the neurotoxin aminochrome is generated during neuromelanin synthesis, even though healthy seniors have these neurons intact when they die. The explanation of this paradox is the existence of protective tools against aminochrome neurotoxicity composed of the enzymes DT-diaphorase, expressed in these neurons, and glutathione transferase M2-2, expressed in astrocytes. Recently, it has been reported that dopaminergic neurons can be protected by glutathione transferase M2-2 from astrocytes, which secrete exosomes containing the protective enzyme.

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Section: Glutathione As Antioxidantmentioning

confidence: 99%

Neuroprotection against Aminochrome Neurotoxicity: Glutathione Transferase M2-2 and DT-Diaphorase

et al. 2022

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“…A more detailed description of the molecular mechanism by which iron leads to OS in PD is seen in other reviews (Ke and Qian, 2007;Weinreb et al, 2013;Belaidi and Bush, 2016;Xu et al, 2017;Zucca et al, 2017;Chen et al, 2019). (Zgorzynska et al, 2021). As a core factor, Nrf2 orchestrates the cytoprotective pathway and regulates the expression of several protective genes containing AREs in their promoters, which function to restore homeostasis after combatting OS (Bento-Pereira and Dinkova-Kostova, 2021).…”

Section: Iron Accumulation (Fe 2+ ) and Oxidative Stress In Pdmentioning

confidence: 99%

“…Based on previous works, targeting Keap1/Nrf2/ARE pathway is becoming a strong candidate for therapy for neurodegenerative disease ( Zgorzynska et al, 2021 ). As a core factor, Nrf2 orchestrates the cytoprotective pathway and regulates the expression of several protective genes containing AREs in their promoters, which function to restore homeostasis after combatting OS ( Bento-Pereira and Dinkova-Kostova, 2021 ).…”

Section: Nrf2/are Pathway and Pdmentioning

confidence: 99%

Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease

et al. 2021

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Parkinson’s disease (PD) is a complex neurodegenerative disorder featuring both motor and nonmotor symptoms associated with a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress (OS) has been implicated in the pathogenesis of PD. Genetic and environmental factors can produce OS, which has been implicated as a core contributor to the initiation and progression of PD through the degeneration of dopaminergic neurons. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates activation of multiple protective genes, including heme oxygenase-1 (HO-1), which protects cells from OS. Nrf2 has also been shown to exert anti-inflammatory effects and modulate both mitochondrial function and biogenesis. Recently, a series of studies have reported that different bioactive compounds were shown to be able to activate Nrf2/antioxidant response element (ARE) and can ameliorate PD-associated neurotoxin, both in animal models and in tissue culture. In this review, we briefly overview the sources of OS and the association between OS and the pathogenesis of PD. Then, we provided a concise overview of Nrf2/ARE pathway and delineated the role played by activation of Nrf2/HO-1 in PD. At last, we expand our discussion to the neuroprotective effects of pharmacological modulation of Nrf2/HO-1 by bioactive compounds and the potential application of Nrf2 activators for the treatment of PD. This review suggests that pharmacological modulation of Nrf2/HO-1 signaling pathway by bioactive compounds is a therapeutic target of PD.

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“…Nrf2 activators are expected to inhibit the progression of Parkinson disease as well as other neurodegenerative diseases, and many basic studies have been conducted [ 88 , 89 , 90 ]. For example, in a mouse model of Parkinson disease, disease progression was accelerated in Nrf2 knockout mice, compared with wild-type mice [ 90 ].…”

Section: Parkinson Disease and The Keap1/nrf2 Systemmentioning

confidence: 99%

Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease

Takahashi

Mashima

2022

Antioxidants

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Oxidative stress and neuroinflammation are common bases for disease onset and progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of dopaminergic neurons resulting in dopamine depletion, the pathogenesis differs between hereditary and solitary disease forms and is often unclear. In addition to the pathogenicity of alpha-synuclein as a pathological disease marker, the involvement of dopamine itself and its interactions with glial cells (astrocyte or microglia) have attracted attention. Pacemaking activity, which is a hallmark of dopaminergic neurons, is essential for the homeostatic maintenance of adequate dopamine concentrations in the synaptic cleft, but it imposes a burden on mitochondrial oxidative glucose metabolism, leading to reactive oxygen species production. Astrocytes provide endogenous neuroprotection to the brain by producing and releasing antioxidants in response to oxidative stress. Additionally, the protective function of astrocytes can be modified by microglia. Some types of microglia themselves are thought to exacerbate Parkinson disease by releasing pro-inflammatory factors (M1 microglia). Although these inflammatory microglia may further trigger the inflammatory conversion of astrocytes, microglia may induce astrocytic neuroprotective effects (A2 astrocytes) simultaneously. Interestingly, both astrocytes and microglia express dopamine receptors, which are upregulated in the presence of neuroinflammation. The anti-inflammatory effects of dopamine receptor stimulation are also attracting attention because the functions of astrocytes and microglia are greatly affected by both dopamine depletion and therapeutic dopamine replacement in Parkinson disease. In this review article, we will focus on the antioxidative and anti-inflammatory effects of astrocytes and their synergism with microglia and dopamine.

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An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases

Cited by 99 publications

References 192 publications

Neuroprotection against Aminochrome Neurotoxicity: Glutathione Transferase M2-2 and DT-Diaphorase

Neuroprotection against Aminochrome Neurotoxicity: Glutathione Transferase M2-2 and DT-Diaphorase

Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease

Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease

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