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Neuroprotective Effect of Food and Natural Bioactive Compounds

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 56147

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Dear Colleagues,

The neurodegenerative diseases are becoming more relevant in our society. They are different in their pathophysiology and partly determined by the extension of the lifespan.

At present, although there is an increase in research activity on this topic, an effective neuroprotective treatment is still absent. Epidemiological and biochemical studies highlight a significant neuroprotective role of nutrition and natural bioactive compounds suggesting them as potential therapeutic agents.

Indeed, studies suggest that some natural bioactive components, such as polyphenols, terpenes, vitamins, peptides, carbohydrates, can positively prevent, delay, or mitigate the neurodegenerative disorders.

Nevertheless, the cellular and molecular mechanisms underlying these effects are not yet completely understood. Neuroprotection, by nutrition/bioactive compounds, has been proposed to prevent the onset and progress of diseases by targeting oxidative stress, neurotrophic factor reduction, mitochondrial deficit, apoptosis process and abnormal protein accumulation.

In order to design effective therapies, it is fundamental to conduct studies aimed to increase understanding on the bioavailability and pharmacokinetic properties of bioactive compounds.

In this regard, it should be considered that the bioactivity of natural compounds is influenced by metabolic transformations. Also, a dependence on the food matrix as well as on the physiology/anatomy of the consumer, and the type of compound, was highlighted in the assessment of the bioavailability of the bioactive compounds.

Therefore, therapeutic strategies should be assess to develop new delivery systems in order to improve systemic bioavailability and brain penetrance.

This Special Issue of the Molecules, will include a selection of original articles and reviews aimed to expanding our knowledge on the neuroprotective effects of food/natural compounds, concerning several aspects on different neurodegenerative models.

Prof. Antonia Patruno
Dr. Mirko Pesce
Guest Editors

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Keywords

  • neurodegenerative diseases
  • neuroprotection
  • natural bioactive compound
  • polyphenols

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Published Papers (10 papers)

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Research

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14 pages, 2663 KiB  
Article
Phenolic Characterization and Neuroprotective Properties of Grape Pomace Extracts
by Annalisa Chiavaroli, Marwa Balaha, Alessandra Acquaviva, Claudio Ferrante, Amelia Cataldi, Luigi Menghini, Monica Rapino, Giustino Orlando, Luigi Brunetti, Sheila Leone, Lucia Recinella and Viviana di Giacomo
Molecules 2021, 26(20), 6216; https://doi.org/10.3390/molecules26206216 - 14 Oct 2021
Cited by 18 | Viewed by 2360
Abstract
Vitis vinifera (grape) contains various compounds with acknowledged phytochemical and pharmacological properties. Among the different parts of the plant, pomace is of particular interest as a winemaking industry by-product. A characterization of the water extract from grape pomace from Montepulciano d’Abruzzo variety (Villamagna [...] Read more.
Vitis vinifera (grape) contains various compounds with acknowledged phytochemical and pharmacological properties. Among the different parts of the plant, pomace is of particular interest as a winemaking industry by-product. A characterization of the water extract from grape pomace from Montepulciano d’Abruzzo variety (Villamagna doc) was conducted, and the bioactive phenolic compounds were quantified through HPLC-DAD-MS analysis. HypoE22, a hypothalamic cell line, was challenged with an oxidative stimulus and exposed to different concentrations (1 µg/mL−1 mg/mL) of the pomace extract for 24, 48, and 72 h. In the same conditions, cells were exposed to the sole catechin, in a concentration range (5–500 ng/mL) consistent with the catechin level in the extract. Cell proliferation was investigated by MTT assay, dopamine release through HPLC-EC method, PGE2 amount by an ELISA kit, and expressions of neurotrophin brain-derived neurotrophic factor (BDNF) and of cyclooxygenase-2 (COX-2) by RT-PCR. The extract reverted the cytotoxicity exerted by the oxidative stimulus at all the experimental times in a dose-dependent manner, whereas the catechin was able to revert the oxidative stress-induced depletion of dopamine 48 h and 72 h after the stimulus. The extract and the catechin were also effective in preventing the downregulation of BDNF and the concomitant upregulation of COX-2 gene expression. In accordance, PGE2 release was augmented by the oxidative stress conditions and reverted by the administration of the water extract from grace pomace and catechin, which were equally effective. These results suggest that the neuroprotection induced by the extract could be ascribed, albeit partially, to its catechin content. Full article
(This article belongs to the Special Issue Neuroprotective Effect of Food and Natural Bioactive Compounds)
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16 pages, 3141 KiB  
Article
Neurorescue Effects of Frondoside A and Ginsenoside Rg3 in C. elegans Model of Parkinson’s Disease
by Pawanrat Chalorak, Tanatcha Sanguanphun, Tanapol Limboonreung and Krai Meemon
Molecules 2021, 26(16), 4843; https://doi.org/10.3390/molecules26164843 - 10 Aug 2021
Cited by 20 | Viewed by 3487
Abstract
Parkinson’s disease (PD) is a currently incurable neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and α-synuclein aggregation. Accumulated evidence indicates that the saponins, especially from ginseng, have neuroprotective effects against neurodegenerative disorders. Interestingly, saponin [...] Read more.
Parkinson’s disease (PD) is a currently incurable neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and α-synuclein aggregation. Accumulated evidence indicates that the saponins, especially from ginseng, have neuroprotective effects against neurodegenerative disorders. Interestingly, saponin can also be found in marine organisms such as the sea cucumber, but little is known about its effect in neurodegenerative disease, including PD. In this study, we investigated the anti-Parkinson effects of frondoside A (FA) from Cucumaria frondosa and ginsenoside Rg3 (Rg3) from Panax notoginseng in C. elegans PD model. Both saponins were tested for toxicity and optimal concentration by food clearance assay and used to treat 6-OHDA-induced BZ555 and transgenic α-synuclein NL5901 strains in C. elegans. Treatment with FA and Rg3 significantly attenuated DAergic neurodegeneration induced by 6-OHDA in BZ555 strain, improved basal slowing rate, and prolonged lifespan in the 6-OHDA-induced wild-type strain with downregulation of the apoptosis mediators, egl-1 and ced-3, and upregulation of sod-3 and cat-2. Interestingly, only FA reduced α-synuclein aggregation, rescued lifespan in NL5901, and upregulated the protein degradation regulators, including ubh-4, hsf-1, hsp-16.1 and hsp-16.2. This study indicates that both FA and Rg3 possess beneficial effects in rescuing DAergic neurodegeneration in the 6-OHDA-induced C. elegans model through suppressing apoptosis mediators and stimulating antioxidant enzymes. In addition, FA could attenuate α-synuclein aggregation through the protein degradation process. Full article
(This article belongs to the Special Issue Neuroprotective Effect of Food and Natural Bioactive Compounds)
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19 pages, 2924 KiB  
Article
Beneficial Effects of Cyclic Ether 2-Butoxytetrahydrofuran from Sea Cucumber Holothuria scabra against Aβ Aggregate Toxicity in Transgenic Caenorhabditis elegans and Potential Chemical Interaction
by Taweesak Tangrodchanapong, Nilubon Sornkaew, Laphatrada Yurasakpong, Nakorn Niamnont, Chanin Nantasenamat, Prasert Sobhon and Krai Meemon
Molecules 2021, 26(8), 2195; https://doi.org/10.3390/molecules26082195 - 11 Apr 2021
Cited by 11 | Viewed by 3859
Abstract
The pathological finding of amyloid-β (Aβ) aggregates is thought to be a leading cause of untreated Alzheimer’s disease (AD). In this study, we isolated 2-butoxytetrahydrofuran (2-BTHF), a small cyclic ether, from Holothuria scabra and demonstrated its therapeutic potential against AD through the attenuation [...] Read more.
The pathological finding of amyloid-β (Aβ) aggregates is thought to be a leading cause of untreated Alzheimer’s disease (AD). In this study, we isolated 2-butoxytetrahydrofuran (2-BTHF), a small cyclic ether, from Holothuria scabra and demonstrated its therapeutic potential against AD through the attenuation of Aβ aggregation in a transgenic Caenorhabditis elegans model. Our results revealed that amongst the five H. scabra isolated compounds, 2-BTHF was shown to be the most effective in suppressing worm paralysis caused by Aβ toxicity and in expressing strong neuroprotection in CL4176 and CL2355 strains, respectively. An immunoblot analysis showed that CL4176 and CL2006 treated with 2-BTHF showed no effect on the level of Aβ monomers but significantly reduced the toxic oligomeric form and the amount of 1,4-bis(3-carboxy-hydroxy-phenylethenyl)-benzene (X-34)-positive fibril deposits. This concurrently occurred with a reduction of reactive oxygen species (ROS) in the treated CL4176 worms. Mechanistically, heat shock factor 1 (HSF-1) (at residues histidine 63 (HIS63) and glutamine 72 (GLN72)) was shown to be 2-BTHF’s potential target that might contribute to an increased expression of autophagy-related genes required for the breakdown of the Aβ aggregate, thus attenuating its toxicity. In conclusion, 2-BTHF from H. scabra could protect C. elegans from Aβ toxicity by suppressing its aggregation via an HSF-1-regulated autophagic pathway and has been implicated as a potential drug for AD. Full article
(This article belongs to the Special Issue Neuroprotective Effect of Food and Natural Bioactive Compounds)
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15 pages, 1541 KiB  
Article
ACTH(6–9)PGP Peptide Protects SH-SY5Y Cells from H2O2, tert-Butyl Hydroperoxide, and Cyanide Cytotoxicity via Stimulation of Proliferation and Induction of Prosurvival-Related Genes
by Mikhail G. Akimov, Elena V. Fomina-Ageeva, Polina V. Dudina, Ludmila A. Andreeva, Nikolay F. Myasoyedov and Vladimir V. Bezuglov
Molecules 2021, 26(7), 1878; https://doi.org/10.3390/molecules26071878 - 26 Mar 2021
Cited by 9 | Viewed by 2140
Abstract
Stabilized melanocortin analog peptide ACTH(6–9)PGP (HFRWPGP) possesses a wide range of neuroprotective activities. However, its mechanism of action remains poorly understood. In this paper, we present a study of the proproliferative and cytoprotective activity of the adrenocorticotropic hormone fragment 6–9 (HFRW) linked with [...] Read more.
Stabilized melanocortin analog peptide ACTH(6–9)PGP (HFRWPGP) possesses a wide range of neuroprotective activities. However, its mechanism of action remains poorly understood. In this paper, we present a study of the proproliferative and cytoprotective activity of the adrenocorticotropic hormone fragment 6–9 (HFRW) linked with the peptide prolyine–glycyl–proline on the SH-SY5Y cells in the model of oxidative stress-related toxicity. The peptide dose-dependently protected cells from H2O2, tert-butyl hydroperoxide, and KCN and demonstrated proproliferative activity. The mechanism of its action was the modulation of proliferation-related NF-κB genes and stimulation of prosurvival NRF2-gene-related pathway, as well as a decrease in apoptosis. Full article
(This article belongs to the Special Issue Neuroprotective Effect of Food and Natural Bioactive Compounds)
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11 pages, 1691 KiB  
Article
Neuroprotective Effects of Thymoquinone by the Modulation of ER Stress and Apoptotic Pathway in In Vitro Model of Excitotoxicity
by Elisa Landucci, Costanza Mazzantini, Daniela Buonvicino, Domenico E. Pellegrini-Giampietro and Maria Camilla Bergonzi
Molecules 2021, 26(6), 1592; https://doi.org/10.3390/molecules26061592 - 13 Mar 2021
Cited by 24 | Viewed by 2175
Abstract
Experimental evidence indicates that the activation of ionotropic glutamate receptors plays an important role in neurological disorders’ models such as epilepsy, cerebral ischemia and trauma. The glutamate receptor agonist kainic acid (KA) induces seizures and excitotoxic cell death in the CA3 region of [...] Read more.
Experimental evidence indicates that the activation of ionotropic glutamate receptors plays an important role in neurological disorders’ models such as epilepsy, cerebral ischemia and trauma. The glutamate receptor agonist kainic acid (KA) induces seizures and excitotoxic cell death in the CA3 region of the hippocampus. Thymoquinone (TQ) is the most important component of the essential oil obtained from black cumin (Nigella sativa L.) seeds. It has many pharmacological actions including antioxidant, anti-inflammatory, and anti-apoptotic effects. TQ was used in an in vitro experimental model of primary cultures where excitotoxicity was induced. Briefly, rat organotypic hippocampal slices were exposed to 5 µM KA for 24 h. Cell death in the CA3 subregions of slices was quantified by measuring propidium iodide fluorescence. The cross-talk between TQ, ER stress and apoptotic pathways was investigated by Western blot. In untreated slices TQ (10 µM) induced a significant increase on the PSD95 levels and it decreased the excitotoxic injury induced by KA. Additionally, TQ was able to ameliorate the KA-induced increase in unfolded proteins GRP78 and GRP94 expression. Finally, TQ was able to partially rescue the reduction of the KA-induced apoptotic pathway activation. Our results suggest that TQ modulates the processes leading to post-kainate neuronal death in the CA3 hippocampal area. Full article
(This article belongs to the Special Issue Neuroprotective Effect of Food and Natural Bioactive Compounds)
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Review

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17 pages, 866 KiB  
Review
Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection
by Osama Elsallabi, Antonia Patruno, Mirko Pesce, Amelia Cataldi, Simone Carradori and Marialucia Gallorini
Molecules 2022, 27(3), 738; https://doi.org/10.3390/molecules27030738 - 23 Jan 2022
Cited by 23 | Viewed by 5784
Abstract
Like other organs, brain functions diminish with age. Furthermore, for a variety of neurological disorders—including Alzheimer’s disease—age is one of the higher-risk factors. Since in many Western countries the average age is increasing, determining approaches for decreasing the effects of aging on brain [...] Read more.
Like other organs, brain functions diminish with age. Furthermore, for a variety of neurological disorders—including Alzheimer’s disease—age is one of the higher-risk factors. Since in many Western countries the average age is increasing, determining approaches for decreasing the effects of aging on brain function is taking on a new urgency. Neuroinflammation and oxidative stress are two convoluted key factors in brain aging and chronic neurodegenerative diseases. The diverseness of factors, causing an age-related decrease in brain functions, requires identifying small molecules that have multiple biological activities that can affect all these factors. One great source of these small molecules is related to polyphenolic flavonoids. Recently, 3,3′,4′,7-tetrahydroxyflavone (fisetin) has been reported as a potent senotherapeutic capable of extending lifespan by reducing peroxidation levels and enhancing antioxidant cell responses. The neuroprotective effects of fisetin have been shown in several in vitro and in vivo models of neurological disorders due to its actions on multiple pathways associated with different neurological disorders. The present work aims to collect the most recent achievements related to the antioxidant and neuroprotective effects of fisetin. Moreover, in silico pharmacokinetics, pharmacodynamics, and toxicity of fisetin are also comprehensively described along with emerging novel drug delivery strategies for the amelioration of this flavonol bioavailability and chemical stability. Full article
(This article belongs to the Special Issue Neuroprotective Effect of Food and Natural Bioactive Compounds)
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14 pages, 1929 KiB  
Review
Synergistic Action of Membrane-Bound and Water-Soluble Antioxidants in Neuroprotection
by Stephanie K. Polutchko, Gabrielle N. E. Glime and Barbara Demmig-Adams
Molecules 2021, 26(17), 5385; https://doi.org/10.3390/molecules26175385 - 04 Sep 2021
Cited by 12 | Viewed by 4451
Abstract
Prevention of neurodegeneration during aging, and support of optimal brain function throughout the lifespan, requires protection of membrane structure and function. We review the synergistic action of different classes of dietary micronutrients, as well as further synergistic contributions from exercise and stress reduction, [...] Read more.
Prevention of neurodegeneration during aging, and support of optimal brain function throughout the lifespan, requires protection of membrane structure and function. We review the synergistic action of different classes of dietary micronutrients, as well as further synergistic contributions from exercise and stress reduction, in supporting membrane structure and function. We address membrane-associated inflammation involving reactive oxygen species (ROS) that produce immune regulators from polyunsaturated fatty acids (PUFAs) of membrane phospholipids. The potential of dietary micronutrients to maintain membrane fluidity and prevent chronic inflammation is examined with a focus on synergistically acting membrane-soluble components (zeaxanthin, lutein, vitamin E, and omega-3 PUFAs) and water-soluble components (vitamin C and various phenolics). These different classes of micronutrients apparently operate in a series of intertwined oxidation-reduction cycles to protect membrane function and prevent chronic inflammation. At this time, it appears that combinations of a balanced diet with regular moderate exercise and stress-reduction practices are particularly beneficial. Effective whole-food-based diets include the Mediterranean and the MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay diet, where DASH stands for Dietary Approaches to Stop Hypertension). Full article
(This article belongs to the Special Issue Neuroprotective Effect of Food and Natural Bioactive Compounds)
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26 pages, 3136 KiB  
Review
Neuroprotective Potential of Limonene and Limonene Containing Natural Products
by Lujain Bader Eddin, Niraj Kumar Jha, M. F. Nagoor Meeran, Kavindra Kumar Kesari, Rami Beiram and Shreesh Ojha
Molecules 2021, 26(15), 4535; https://doi.org/10.3390/molecules26154535 - 27 Jul 2021
Cited by 50 | Viewed by 7891
Abstract
Limonene is a monoterpene confined to the family of Rutaceae, showing several biological properties such as antioxidant, anti-inflammatory, anticancer, antinociceptive and gastroprotective characteristics. Recently, there is notable interest in investigating the pharmacological effects of limonene in various chronic diseases due to its [...] Read more.
Limonene is a monoterpene confined to the family of Rutaceae, showing several biological properties such as antioxidant, anti-inflammatory, anticancer, antinociceptive and gastroprotective characteristics. Recently, there is notable interest in investigating the pharmacological effects of limonene in various chronic diseases due to its mitigating effect on oxidative stress and inflammation and regulating apoptotic cell death. There are several available studies demonstrating the neuroprotective role of limonene in neurodegenerative diseases, including Alzheimer’s disease, multiple sclerosis, epilepsy, anxiety, and stroke. The high abundance of limonene in nature, its safety profile, and various mechanisms of action make this monoterpene a favorable molecule to be developed as a nutraceutical for preventive purposes and as an alternative agent or adjuvant to modern therapeutic drugs in curbing the onset and progression of neurodegenerative diseases. This manuscript presents a comprehensive review of the available scientific literature discussing the pharmacological activities of limonene or plant products containing limonene which attribute to the protective and therapeutic ability in neurodegenerative disorders. This review has been compiled based on the existing published articles confined to limonene or limonene-containing natural products investigated for their neurotherapeutic or neuroprotective potential. All the articles available in English or the abstract in English were extracted from different databases that offer an access to diverse journals. These databases are PubMed, Scopus, Google Scholar, and Science Direct. Collectively, this review emphasizes the neuroprotective potential of limonene against neurodegenerative and other neuroinflammatory diseases. The available data are indicative of the nutritional use of products containing limonene and the pharmacological actions and mechanisms of limonene and may direct future preclinical and clinical studies for the development of limonene as an alternative or complementary phytomedicine. The pharmacophore can also provide a blueprint for further drug discovery using numerous drug discovery tools. Full article
(This article belongs to the Special Issue Neuroprotective Effect of Food and Natural Bioactive Compounds)
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45 pages, 1244 KiB  
Review
Attenuation of Nrf2/Keap1/ARE in Alzheimer’s Disease by Plant Secondary Metabolites: A Mechanistic Review
by Sajad Fakhri, Mirko Pesce, Antonia Patruno, Seyed Zachariah Moradi, Amin Iranpanah, Mohammad Hosein Farzaei and Eduardo Sobarzo-Sánchez
Molecules 2020, 25(21), 4926; https://doi.org/10.3390/molecules25214926 - 24 Oct 2020
Cited by 50 | Viewed by 5780
Abstract
Alzheimer’s disease (AD) is a progressive neuronal/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated [...] Read more.
Alzheimer’s disease (AD) is a progressive neuronal/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated mechanisms in AD. Amongst the dysregulated pathophysiological pathways in AD, oxidative stress seems to play a critical role in the pathogenesis progression of AD, with a dominant role of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)/antioxidant responsive elements (ARE) pathway. In the present study, a comprehensive review was conducted using the existing electronic databases, including PubMed, Medline, Web of Science, and Scopus, as well as related articles in the field. Nrf2/Keap1/ARE has shown to be the upstream orchestrate of oxidative pathways, which also ameliorates various inflammatory and apoptotic pathways. So, developing multi-target agents with higher efficacy and lower side effects could pave the road in the prevention/management of AD. The plant kingdom is now a great source of natural secondary metabolites in targeting Nrf2/Keap1/ARE. Among natural entities, phenolic compounds, alkaloids, terpene/terpenoids, carotenoids, sulfur-compounds, as well as some other miscellaneous plant-derived compounds have shown promising future accordingly. Prevailing evidence has shown that activating Nrf2/ARE and downstream antioxidant enzymes, as well as inhibiting Keap1 could play hopeful roles in overcoming AD. The current review highlights the neuroprotective effects of plant secondary metabolites through targeting Nrf2/Keap1/ARE and downstream interconnected mediators in combating AD. Full article
(This article belongs to the Special Issue Neuroprotective Effect of Food and Natural Bioactive Compounds)
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27 pages, 1904 KiB  
Review
The Pathology of Parkinson’s Disease and Potential Benefit of Dietary Polyphenols
by Sunisha Aryal, Taylor Skinner, Bronwyn Bridges and John T. Weber
Molecules 2020, 25(19), 4382; https://doi.org/10.3390/molecules25194382 - 24 Sep 2020
Cited by 55 | Viewed by 16657
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by a loss of dopaminergic neurons, leading to bradykinesia, rigidity, tremor at rest, and postural instability, as well as non-motor symptoms such as olfactory impairment, pain, autonomic dysfunction, impaired sleep, fatigue, and [...] Read more.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by a loss of dopaminergic neurons, leading to bradykinesia, rigidity, tremor at rest, and postural instability, as well as non-motor symptoms such as olfactory impairment, pain, autonomic dysfunction, impaired sleep, fatigue, and behavioral changes. The pathogenesis of PD is believed to involve oxidative stress, disruption to mitochondria, alterations to the protein α-synuclein, and neuroinflammatory processes. There is currently no cure for the disease. Polyphenols are secondary metabolites of plants, which have shown benefit in several experimental models of PD. Intake of polyphenols through diet is also associated with lower PD risk in humans. In this review, we provide an overview of the pathology of PD and the data supporting the potential neuroprotective capacity of increased polyphenols in the diet. Evidence suggests that the intake of dietary polyphenols may inhibit neurodegeneration and the progression of PD. Polyphenols appear to have a positive effect on the gut microbiome, which may decrease inflammation that contributes to the disease. Therefore, a diet rich in polyphenols may decrease the symptoms and increase quality of life in PD patients. Full article
(This article belongs to the Special Issue Neuroprotective Effect of Food and Natural Bioactive Compounds)
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