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Antioxidants
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Role of Natural Antioxidants on Neuroprotection
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Role of Natural Antioxidants on Neuroprotection

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: 30 September 2025 | Viewed by 11093

Special Issue Editors

Dr. Mercedes Villacampa

E-Mail Website
Guest Editor
The Organic and Medicinal Chemistry Section in the Department of Chemistry in Pharmaceutical Sciences, School of Pharmacy, Universidad Complutense of Madrid, 28040 Madrid, Spain
Interests: neurodegenerative diseases; PROTACs; mechanochemistry
Special Issues, Collections and Topics in MDPI journals
Dr. José Carlos Menéndez

E-Mail Website
Guest Editor
The Organic and Medicinal Chemistry Section in the Department of Chemistry in Pharmaceutical Sciences, School of Pharmacy, Universidad Complutense of Madrid, 28040 Madrid, Spain
Interests: neurodegenerative diseases; drug discovery; sustainable synthesis
Special Issues, Collections and Topics in MDPI journals
Dr. Ángel Cores

E-Mail Website
Guest Editor
The Organic and Medicinal Chemistry Section in the Department of Chemistry in Pharmaceutical Sciences, School of Pharmacy, Universidad Complutense of Madrid, 28040 Madrid, Spain
Interests: neurodegenerative diseases; medicinal chemistry; pseudo-natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The quest for effective neuroprotective strategies has led to significant interest in natural antioxidants due to their potential to combat oxidative stress, a major contributor to neurodegenerative diseases. Oxidative stress results from an imbalance between free radicals and antioxidants in the body, leading to neuronal damage and the progression of conditions such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS). Natural antioxidants, including polyphenols, flavonoids, certain vitamins, and carotenoids, have shown promise in mitigating oxidative damage and enhancing brain health. These compounds, derived from fruits, vegetables, and other plant sources, have been extensively studied for their ability to neutralize free radicals, induce the secondary antioxidant response, reduce inflammation, and modulate the signaling pathways involved in neurodegeneration.

This Special Issue, "Role of Natural Antioxidants on Neuroprotection", aims to gather cutting-edge research and comprehensive reviews on the neuroprotective effects of natural antioxidants. We invite researchers to contribute original studies and review articles that explore the mechanisms of action, efficacy, and therapeutic potential of these bioactive agents in preventing and treating neurodegenerative diseases. By compiling this body of work, we seek to advance our understanding of how natural antioxidants can be harnessed to protect neural health and improve the quality of life for individuals affected by neurodegenerative conditions.

Dr. Mercedes Villacampa
Dr. José Carlos Menéndez
Dr. Ángel Cores
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

  • drug design
  • polyphenols
  • oxidative stress
  • Nrf2 induction
  • neuroinflammation
  • neurodegenerative diseases

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Published Papers (5 papers)

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Research

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23 pages, 4791 KiB  
Article
A Novel Gastrodin Derivative with Neuroprotection Promotes NGF-Mimic Activity by Targeting INSR and ACTN4 to Activate PI3K/Akt Signaling Pathway in PC12 Cells
by Jiayuan Zeng, Jianxia Mo, Makoto Muroi, Hiroyuki Osada, Lan Xiang and Jianhua Qi
Antioxidants 2025, 14(3), 344; https://doi.org/10.3390/antiox14030344 - 14 Mar 2025
Viewed by 632
Abstract
Gastrodin (gas) has been shown to promote neuroprotection and reverse Alzheimer’s disease (AD) pathology. However, its high effective dose limits its potential in treating AD. In this study, a bioassay system using PC12 cells and the nerve growth factor (NGF)-mimic effect was employed [...] Read more.
Gastrodin (gas) has been shown to promote neuroprotection and reverse Alzheimer’s disease (AD) pathology. However, its high effective dose limits its potential in treating AD. In this study, a bioassay system using PC12 cells and the nerve growth factor (NGF)-mimic effect was employed to investigate the structure–activity relationship of gas derivatives. Among the synthesized compounds, GAD037 demonstrated the highest NGF-mimic activity, surpassing gas. Additionally, GAD037 exhibited significant neuroprotective effects, reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, thereby improving the survival of PC12 cells under oxidative stress. It also protected cells from Aβ-induced toxicity. Target protein identification and mechanistic studies revealed that insulin receptor (INSR) and alpha-actinin-4 (ACTN4) are potential targets of GAD037, confirmed through specific inhibitors, small interfering RNA (siRNA) analysis, a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). Moreover, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and rat sarcoma (Ras)/protooncogene serine–threonine protein kinase (Raf)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways were found to be involved in the NGF-mimic activity of GAD037. In conclusion, GAD037 exhibits superior NGF-mimic and neuroprotective activities compared to gas, suggesting its potential as a lead compound for anti-AD applications. Full article
(This article belongs to the Special Issue Role of Natural Antioxidants on Neuroprotection)
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17 pages, 10721 KiB  
Article
Ethyl Acetate Fraction of Chestnut Honey Attenuates Scopolamine-Induced Cognitive Impairment in Mice and Glutamate-Induced Neurotoxicity in HT22 Cells
by Yun Hee Jeong, Wei Li, Hye Jin Yang, Se-Gun Kim, Hong Min Choi, Jang-Gi Choi and You-Chang Oh
Antioxidants 2024, 13(11), 1346; https://doi.org/10.3390/antiox13111346 - 2 Nov 2024
Viewed by 1390
Abstract
Chestnut honey has various benefits, such as antioxidative, anti-inflammatory, immunomodulatory, antibacterial, and antiviral effects. However, the effects of chestnut honey or the ethyl acetate fraction of chestnut honey (EACH) on neurodegenerative diseases and their related cognitive impairment and neurotoxicity have not yet been [...] Read more.
Chestnut honey has various benefits, such as antioxidative, anti-inflammatory, immunomodulatory, antibacterial, and antiviral effects. However, the effects of chestnut honey or the ethyl acetate fraction of chestnut honey (EACH) on neurodegenerative diseases and their related cognitive impairment and neurotoxicity have not yet been established. Therefore, in this study, we investigated the mitigating effect of the EACH on scopolamine (SCO)-injected cognitive decline in mice and glutamate-exposed neurotoxicity in HT22 cells. EACH administration significantly reversed SCO-induced cognitive decline in mice, as demonstrated through the Morris water maze and passive avoidance tests. The EACH treatment showed a significant alleviation effect by recovering more than 80% of the cell viability decrease induced by glutamate exposure in the HT22 neuronal cell model. Furthermore, the EACH significantly reduced reactive oxygen species accumulation, lactate dehydrogenase release, mitochondrial depolarization, and neuronal apoptosis. The EACH regulated the level of apoptosis-related proteins, induced the nuclear translocation of nuclear factor-E2-related factor 2 (Nrf-2) and the expression of related antioxidant proteins, and induced the phosphorylation of tropomyosin-related kinase receptor B (TrkB)/cAMP-calcium response element-binding protein (CREB) and the expression of brain-derived neurotrophic factor. These data indicate that the EACH can prevent neurons from oxidative damage and improve cognitive dysfunction by activating Nrf-2 and TrkB/CREB signaling pathways. Therefore, the EACH demonstrates potential therapeutic value in mitigating oxidative stress-induced neurotoxicity, cognitive decline, and related neurodegenerative diseases. Full article
(This article belongs to the Special Issue Role of Natural Antioxidants on Neuroprotection)
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21 pages, 5941 KiB  
Article
Bioactivated Glucoraphanin Modulates Genes Involved in Necroptosis on Motor-Neuron-like Nsc-34: A Transcriptomic Study
by Aurelio Minuti, Alessandra Trainito, Agnese Gugliandolo, Ivan Anchesi, Luigi Chiricosta, Renato Iori, Emanuela Mazzon and Marco Calabrò
Antioxidants 2024, 13(9), 1111; https://doi.org/10.3390/antiox13091111 - 14 Sep 2024
Cited by 1 | Viewed by 1617
Abstract
Research on bioactive compounds has grown recently due to their health benefits and limited adverse effects, particularly in reducing the risk of chronic diseases, including neurodegenerative conditions. According to these observations, this study investigates the activity of sulforaphane (RS-GRA) on an in vitro [...] Read more.
Research on bioactive compounds has grown recently due to their health benefits and limited adverse effects, particularly in reducing the risk of chronic diseases, including neurodegenerative conditions. According to these observations, this study investigates the activity of sulforaphane (RS-GRA) on an in vitro model of differentiated NSC-34 cells. We performed a transcriptomic analysis at various time points (24 h, 48 h, and 72 h) and RS-GRA concentrations (1 µM, 5 µM, and 10 µM) to identify molecular pathways influenced by this compound and the effects of dosage and prolonged exposure. We found 39 differentially expressed genes consistently up- or downregulated across all conditions. Notably, Nfe2l2, Slc1a5, Slc7a11, Slc6a9, Slc6a5, Sod1, and Sod2 genes were consistently upregulated, while Ripk1, Glul, Ripk3, and Mlkl genes were downregulated. Pathway perturbation analysis showed that the overall dysregulation of these genes results in a significant increase in redox pathway activity (adjusted p-value 1.11 × 10−3) and a significant inhibition of the necroptosis pathway (adjusted p-value 4.64 × 10−3). These findings suggest RS-GRA’s potential as an adjuvant in neurodegenerative disease treatment, as both increased redox activity and necroptosis inhibition may be beneficial in this context. Furthermore, our data suggest two possible administration strategies, namely an acute approach with higher dosages and a chronic approach with lower dosages. Full article
(This article belongs to the Special Issue Role of Natural Antioxidants on Neuroprotection)
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17 pages, 4323 KiB  
Article
Unveiling the Therapeutic Potential of Kelulut (Stingless Bee) Honey in Alzheimer’s Disease: Findings from a Rat Model Study
by Ammara Shaikh, Fairus Ahmad, Seong Lin Teoh, Jaya Kumar and Mohamad Fairuz Yahaya
Antioxidants 2024, 13(8), 926; https://doi.org/10.3390/antiox13080926 - 30 Jul 2024
Cited by 1 | Viewed by 2024
Abstract
Alzheimer’s disease (AD) poses a major worldwide health challenge because of its profound impact on cognitive abilities and overall well-being. Despite extensive research and numerous clinical trials, therapeutic options remain limited. Our study aimed to investigate the potential of Kelulut honey (KH) as [...] Read more.
Alzheimer’s disease (AD) poses a major worldwide health challenge because of its profound impact on cognitive abilities and overall well-being. Despite extensive research and numerous clinical trials, therapeutic options remain limited. Our study aimed to investigate the potential of Kelulut honey (KH) as a novel therapeutic agent for addressing the multifactorial pathology of AD. We tried to evaluate the disease-attenuating and neuroprotective potential of KH in the intrahippocampally induced AD rat model by utilizing histochemistry and enzyme-linked immunosorbent assay (ELISA) studies. A total of 26 male Sprague Dawley rats weighing ~280–380 g were randomly divided into three groups: Control, AD-induced (Aβ), and AD-induced and treated with KH (Aβ+KH). The latter two groups underwent stereotaxic surgery, where 6.25 µg of amyloid β1–42 peptides were injected intrahippocampally. One-week post-surgery, KH was administered to the treatment group at a dose of 1 g/kg body weight for a period of four weeks, after which the rats went through behavior tests. After completion of behavior analysis, the rats were sacrificed, and the brains were processed for histochemistry and ELISA studies. The open field test analysis demonstrated that KH improved the locomotion of Aβ+KH compared to Aβ (p = 0.0013). In comparison, the Morris water maze did not show any nootropic effects on cognition with a paradoxical increase in time spent in the target quadrant by the Aβ group (p = 0.029). Histochemical staining showed markedly increased Congo-red-stained amyloid plaques, which were significantly reduced in dentate gyrus of Aβ+KH compared to Aβ (p < 0.05). Moreover, significantly higher apoptosis was seen in the Aβ group compared to Aβ+KH (p < 0.01) and control groups (p < 0.001). Furthermore, the ELISA studies deduced more phosphorylated tau in the diseased group compared to Aβ+KH (p = 0.038) and controls (p = 0.016). These findings suggest that KH consumption for twenty-eight days has the potential to attenuate the pathological burden of disease while exerting neuroprotective effects in rodent models of AD. Full article
(This article belongs to the Special Issue Role of Natural Antioxidants on Neuroprotection)
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Review

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37 pages, 7050 KiB  
Review
Role of Plant Phytochemicals: Resveratrol, Curcumin, Luteolin and Quercetin in Demyelination, Neurodegeneration, and Epilepsy
by Mikołaj Grabarczyk, Weronika Justyńska, Joanna Czpakowska, Ewa Smolińska, Aleksandra Bielenin, Andrzej Glabinski and Piotr Szpakowski
Antioxidants 2024, 13(11), 1364; https://doi.org/10.3390/antiox13111364 - 7 Nov 2024
Cited by 9 | Viewed by 4500
Abstract
Polyphenols are an important group of biologically active compounds present in almost all food sources of plant origin and are primarily known for their anti-inflammatory and antioxidative capabilities. Numerous studies have indicated their broad spectrum of pharmacological properties and correlations between their increased [...] Read more.
Polyphenols are an important group of biologically active compounds present in almost all food sources of plant origin and are primarily known for their anti-inflammatory and antioxidative capabilities. Numerous studies have indicated their broad spectrum of pharmacological properties and correlations between their increased supply in the human diet and lower prevalence of various disorders. The positive effects of polyphenols application are mostly discussed in terms of cardiovascular system well-being. However, in recent years, they have also increasingly mentioned as prophylactic and therapeutic factors in the context of neurological diseases, being able to suppress the progression of such disorders and soothe accompanying symptoms. Among over 8000 various compounds, that have been identified, the most widely examined comprise resveratrol, curcumin, luteolin and quercetin. This review focuses on in vitro assessments, animal models and clinical trials, reflecting the most actual state of knowledge, of mentioned polyphenols’ medicinal capabilities in epilepsy, demyelinating and neurodegenerative diseases of the central nervous system. Full article
(This article belongs to the Special Issue Role of Natural Antioxidants on Neuroprotection)
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