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Antioxidants
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Role of Nrf2 in Neurodegenerative Diseases
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Role of Nrf2 in Neurodegenerative Diseases

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 17345

Special Issue Editors

Dr. Agueda A. Rostagno

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Guest Editor
Department of Pathology, Grossman School of Medicine, New York University, New York, NY 10016, USA
Interests: Alzheimer's disease; amyloidosis; neurodegenerative disorders; mitochondrial dysfunction; oxidative stress; cerebral amyloid angiopathy; neuroinflammation
Prof. Dr. Jorge Ghiso

E-Mail Website
Guest Editor
Department of Pathology, Grossman School of Medicine, New York University, New York, NY 10016, USA
Interests: Alzheimer disease; neurodegenerative disorders; systemic and cerebral amyloidoses; aging; proteomics; post-translational modifications; blood-brain-barrier; amyloid; neurofibrillary tangles; cerebral amyloid angiopathy; cerebral hemorrhage; translational approaches; mouse models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent decades, the incidence of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, vascular dementia, and amyotrophic lateral sclerosis, among others, has remarkably increased worldwide. Despite extensive research, the complex molecular mechanisms driving the pathogenesis of these disorders have not been fully elucidated and disease-modifying therapeutic strategies remain to be discovered. Among the different pathways compromised in this diverse group of neurodegenerative diseases, mounting evidence highlights a central role of mitochondrial detrimental changes, oxidative stress, altered cerebral glucose metabolism, and metabolic/bioenergetic shifts that frequently precede cognitive abnormalities. The central element interlinking these complex pathways is Nrf2 (nuclear factor erythroid 2-related factor 2), a critical transcription factor that coordinates the expression of more than 500 cytoprotective and metabolic genes modulating inducible defence systems and regulating not only the antioxidant response but also mitochondria functioning as well as multiple points of the cell intermediary metabolism.

This Special Issue aims to provide insight into the role of Nrf2 in the interplay between the multifaceted molecular pathways linking metabolic/bioenergetic alterations, neuroinflammatory mechanisms, vascular dysfunction, and cognitive impairment associated with neurodegeneration. Manuscripts addressing the clinical implications and therapeutic potential of targeting the Nrf2 signaling pathway in neurodegenerative conditions are also of interest. We welcome contributions in the form of original research articles, reviews, and perspectives.

Dr. Agueda A. Rostagno
Prof. Dr. Jorge Ghiso
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Nrf2 pathway
  • nuclear factor erythroid 2-related factor 2
  • neuroprotection
  • Parkinson’s disease
  • Alzheimer’s disease
  • neurodegenerative diseases
  • neuroinflammation
  • metabolic/bioenergetic alterations
  • oxidative stress
  • mitochondria
  • amyotrophic lateral sclerosis

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Published Papers (5 papers)

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Research

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12 pages, 2019 KiB  
Communication
A Highly Potent Apomorphine Derivative Enhancing Neurite Outgrowth via Nrf2 Activation
by Tamaki Ishima, Hitoshi Osaka, Ryozo Nagai and Kenichi Aizawa
Antioxidants 2025, 14(5), 537; https://doi.org/10.3390/antiox14050537 - 29 Apr 2025
Viewed by 45
Abstract
Apomorphine (APO), a dopamine agonist, activates nuclear factor erythroid 2-related factor 2 (Nrf2) and exerts antioxidant effects, making it a promising candidate for neuroprotection against oxidative stress. This study evaluated neuroplasticity-enhancing properties of newly synthesized APO derivatives, focusing on their ability to promote [...] Read more.
Apomorphine (APO), a dopamine agonist, activates nuclear factor erythroid 2-related factor 2 (Nrf2) and exerts antioxidant effects, making it a promising candidate for neuroprotection against oxidative stress. This study evaluated neuroplasticity-enhancing properties of newly synthesized APO derivatives, focusing on their ability to promote neurite outgrowth in PC12 cells under nerve growth factor (NGF) stimulation. D55, an APO derivative, retains the hydroxyl group at APO’s 11th position while substituting the 10th with an ethoxy group. D55 exhibited the highest potency (EC50 = 0.5661 nM), significantly enhancing neurite outgrowth. APO demonstrated the highest efficacy (Emax ~10-fold increase), while edaravone (Eda) required higher concentrations (EC50 = 22.5 nM) for moderate effects (Emax ~4-fold increase). D30, in which the 11th hydroxyl was replaced with a methoxy group, had no effect. Neurite outgrowth-promoting effects of APO, D55, and Eda were significantly attenuated by Nrf2 siRNA knockdown, confirming that their neuroplasticity effects are Nrf2-mediated. These findings confirm that D55 is a highly potent Nrf2-activating compound with strong neuroprotective potential, providing new insights into its therapeutic applications for neurodegenerative diseases associated with oxidative stress. Full article
(This article belongs to the Special Issue Role of Nrf2 in Neurodegenerative Diseases)
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19 pages, 4304 KiB  
Article
diAcCA, a Pro-Drug for Carnosic Acid That Activates the Nrf2 Transcriptional Pathway, Shows Efficacy in the 5xFAD Transgenic Mouse Model of Alzheimer’s Disease
by Piu Banerjee, Yubo Wang, Lauren N. Carnevale, Parth Patel, Charlene K Raspur, Nancy Tran, Xu Zhang, Ravi Natarajan, Amanda J. Roberts, Phil S. Baran and Stuart A. Lipton
Antioxidants 2025, 14(3), 293; https://doi.org/10.3390/antiox14030293 - 28 Feb 2025
Cited by 1 | Viewed by 11190
Abstract
The antioxidant/anti-inflammatory compound carnosic acid (CA) is a phenolic diterpene found in the herbs rosemary and sage. Upon activation, CA manifests electrophilic properties to stimulate the Nrf2 transcriptional pathway via reaction with Keap1. However, purified CA is readily oxidized and thus highly unstable. [...] Read more.
The antioxidant/anti-inflammatory compound carnosic acid (CA) is a phenolic diterpene found in the herbs rosemary and sage. Upon activation, CA manifests electrophilic properties to stimulate the Nrf2 transcriptional pathway via reaction with Keap1. However, purified CA is readily oxidized and thus highly unstable. To develop CA as an Alzheimer’s disease (AD) therapeutic, we synthesized pro-drug derivatives, among which the di-acetylated form (diAcCA) showed excellent drug-like properties. diAcCA converted to CA in the stomach prior to absorption into the bloodstream, and exhibited improved stability and bioavailability as well as comparable pharmacokinetics (PK) and efficacy to CA. To test the efficacy of diAcCA in AD transgenic mice, 5xFAD mice (or littermate controls) received the drug for 3 months, followed by behavioral and immunohistochemical studies. Notably, in addition to amyloid plaques and tau tangles, a hallmark of human AD is synapse loss, a major correlate to cognitive decline. The 5xFAD animals receiving diAcCA displayed synaptic rescue on immunohistochemical analysis accompanied by improved learning and memory in the water maze test. Treatment with diAcCA reduced astrocytic and microglial inflammation, amyloid plaque formation, and phospho-tau neuritic aggregates. In toxicity studies, diAcCA was as safe or safer than CA, which is listed by the FDA as “generally regarded as safe”, indicating diAcCA is suitable for human clinical trials in AD. Full article
(This article belongs to the Special Issue Role of Nrf2 in Neurodegenerative Diseases)
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16 pages, 3869 KiB  
Article
α-Cyclodextrin/Moringin Induces an Antioxidant Transcriptional Response Activating Nrf2 in Differentiated NSC-34 Motor Neurons
by Agnese Gugliandolo, Gabriella Calì, Claudia Muscarà, Osvaldo Artimagnella, Patrick Rollin, Daniele Perenzoni, Renato Iori, Emanuela Mazzon and Luigi Chiricosta
Antioxidants 2024, 13(7), 813; https://doi.org/10.3390/antiox13070813 - 6 Jul 2024
Cited by 1 | Viewed by 1523
Abstract
Oxidative stress is a common feature of neurodegenerative diseases. Different natural compounds mediate neuroprotective effects by activating the Nrf2 antioxidant response. Some isothiocyanates are Nrf2 activators, including Moringin (MOR). In this study, the transcriptional profile of differentiated NSC-34 motor neurons was evaluated after [...] Read more.
Oxidative stress is a common feature of neurodegenerative diseases. Different natural compounds mediate neuroprotective effects by activating the Nrf2 antioxidant response. Some isothiocyanates are Nrf2 activators, including Moringin (MOR). In this study, the transcriptional profile of differentiated NSC-34 motor neurons was evaluated after treatment for 48 h and 96 h with concentrations of 0.5, 5, and 10 µM of a new MOR formulation obtained with α-cyclodextrin (α-CD). All the concentrations increased gene expression and cytoplasmic protein levels of Nrf2 at 96 h. However, the highest dose also increased nuclear Nrf2 levels at 96 h. Then, Nrf2 interactors were selected using STRING, and common biological process (BP) terms between the groups were evaluated. α-CD/MOR was able to modulate BP related to responses to oxidative stress, proteostasis, and autophagy. Specifically, the treatment with 10 µM of α-CD/MOR for 96 h induced genes involved in glutathione synthesis and proteasome subunits and reduced the expression of genes related to endoplasmic reticulum stress. Moreover, this group showed the lowest levels of the apoptotic markers Bax, cleaved caspase 9, and cleaved caspase 3. These results indicate the beneficial effects of prolonged α-CD/MOR supplementation that are mediated, at least in part, by Nrf2 activation. Then, α-CD/MOR could be a valuable treatment against neurodegenerative diseases, in particular motor neuron degeneration. Full article
(This article belongs to the Special Issue Role of Nrf2 in Neurodegenerative Diseases)
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Review

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17 pages, 2479 KiB  
Review
Nrf2-Independent Anti-Inflammatory Effects of Dimethyl Fumarate: Challenges and Prospects in Developing Electrophilic Nrf2 Activators for Neurodegenerative Diseases
by Yasuhiko Izumi and Yutaka Koyama
Antioxidants 2024, 13(12), 1527; https://doi.org/10.3390/antiox13121527 - 13 Dec 2024
Viewed by 1355
Abstract
The NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a potential therapeutic target for central nervous system diseases. This review emphasizes the role of oxidative stress and neuroinflammation in neurodegenerative diseases, highlighting the therapeutic potential of Nrf2 activators such as dimethyl fumarate [...] Read more.
The NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a potential therapeutic target for central nervous system diseases. This review emphasizes the role of oxidative stress and neuroinflammation in neurodegenerative diseases, highlighting the therapeutic potential of Nrf2 activators such as dimethyl fumarate (DMF). DMF, initially administered for treating psoriasis, has demonstrated efficacy in multiple sclerosis and is metabolized to monomethyl fumarate, which may exert significant therapeutic effects. DMF activates the Nrf2-ARE pathway, and recent studies have indicated that its anti-inflammatory effects occur through Nrf2-independent mechanisms. Electrophilic Nrf2 activators, such as DMF, covalently bind to cysteine residues in proteins and modulate their function. We discuss the implications of cysteine residue modifications by DMF, which may cause both therapeutic benefits and potential off-target effects. Furthermore, we propose a chemical proteomics-based drug discovery approach to achieve desired therapeutic effects by selectively covalently modifying cysteines in target proteins. These findings advocate for a broader understanding of the Nrf2-independent mechanisms of electrophilic Nrf2 activators, thereby improving drug discovery strategies that target neurodegenerative diseases while minimizing toxicity. Full article
(This article belongs to the Special Issue Role of Nrf2 in Neurodegenerative Diseases)
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18 pages, 1037 KiB  
Review
Natural Compounds That Activate the KEAP1/Nrf2 Signaling Pathway as Potential New Drugs in the Treatment of Idiopathic Parkinson’s Disease
by Sandro Huenchuguala and Juan Segura-Aguilar
Antioxidants 2024, 13(9), 1125; https://doi.org/10.3390/antiox13091125 - 18 Sep 2024
Cited by 1 | Viewed by 2037
Abstract
Recently, a single-neuron degeneration model has been proposed to understand the development of idiopathic Parkinson’s disease based on (i) the extremely slow development of the degenerative process before the onset of motor symptoms and during the progression of the disease and (ii) the [...] Read more.
Recently, a single-neuron degeneration model has been proposed to understand the development of idiopathic Parkinson’s disease based on (i) the extremely slow development of the degenerative process before the onset of motor symptoms and during the progression of the disease and (ii) the fact that it is triggered by an endogenous neurotoxin that does not have an expansive character, limiting its neurotoxic effect to single neuromelanin-containing dopaminergic neurons. It has been proposed that aminochrome is the endogenous neurotoxin that triggers the neurodegenerative process in idiopathic Parkinson’s disease by triggering mitochondrial dysfunction, oxidative stress, neuroinflammation, dysfunction of both lysosomal and proteasomal protein degradation, endoplasmic reticulum stress and formation of neurotoxic alpha-synuclein oligomers. Aminochrome is an endogenous neurotoxin that is rapidly reduced by flavoenzymes and/or forms adducts with proteins, which implies that it is impossible for it to have a propagative neurotoxic effect on neighboring neurons. Interestingly, the enzymes DT-diaphorase and glutathione transferase M2-2 prevent the neurotoxic effects of aminochrome. Natural compounds present in fruits, vegetables and other plant products have been shown to activate the KEAP1/Nrf2 signaling pathway by increasing the expression of antioxidant enzymes including DT-diaphorase and glutathione transferase. This review analyzes the possibility of searching for natural compounds that increase the expression of DT-diaphorase and glutathione transferase through activation of the KEAP1/Nrf2 signaling pathway. Full article
(This article belongs to the Special Issue Role of Nrf2 in Neurodegenerative Diseases)
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