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Neuroprotective Potential of Natural Products: A Shield against Brain Decay

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (25 February 2025) | Viewed by 14673

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Dr. Alessandro Maugeri

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Department of Health Sciences, University "Magna Græcia" of Catanzaro, 88100 Catanzaro, Italy
Interests: natural products; molecular pharmacology; cancer; inflammation; neuroprotection
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Prof. Dr. Michele Navarra

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Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, viale Annunziata, I-98168 Messina, Italy
Interests: natural products; molecular pharmacology; cancer; inflammation; neuroprotection
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Dr. Santa Cirmi

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Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
Interests: natural products; molecular pharmacology; cancer; inflammation; neuroprotection
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Special Issue Information

Dear Colleagues,

The mechanisms underlying the sophisticated regulation of the nervous system are complex and in perfect balance. Aging is the leading cause of its impairment, yet any other element (i.e., environmental toxicants, alcohol, high-fat diets, tobacco, recreational drugs, etc.) able to interfere with this process can cause severe adverse health outcomes. Neurodegeneration arises from the failure of the body to counteract these toxic stimuli, although we can count on a wide plethora of inner defensive mechanisms. The plant kingdom has always been a treasure trove of uncountable chemical entities endowed with interesting pharmacological activities, among which neuroprotective properties can be found. Therefore, a current strategy to boost our defenses against neurodegeneration is the intake of natural drugs, also in the form of extracts to exploit the potential synergism of their components.

The aim of this Special Issue is to gather the recent evidence on the neuroprotective properties of natural products, whether single compounds or extracts, upon the comprehensive chemical characterization of these products, assessed in preclinical (i.e., in vitro and in vivo) or clinical settings. Authors are encouraged to contribute with original research articles, reviews, systematic reviews, and meta-analyses.

Dr. Alessandro Maugeri
Prof. Dr. Michele Navarra
Dr. Santa Cirmi
Guest Editors

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Keywords

neuroprotection
natural products
extract
oxidative stress
degenerative diseases
adjuvant therapies

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Published Papers (8 papers)

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Research

28 pages, 38752 KiB

Open AccessArticle

Role of Thymus ciliatus (Thyme) to Ameliorate the Acute Neurotoxicity Induced by Bisphenol A: In Vivo Supported with Virtual Study

by Dallal Kourat, Djallal Eddine H. Adli, Mostapha Brahmi, Faisal K. Alkholifi, Faten F. Bin Dayel, Wafaa Arabi, Marie-Laure Fauconnier, Bakhta Bouzouira, Khaled Kahloula, Miloud Slimani and Sherouk Hussein Sweilam

Pharmaceuticals 2025, 18(4), 509; https://doi.org/10.3390/ph18040509 - 31 Mar 2025

Viewed by 447

Abstract

Background/Objectives: The purpose of this research was to investigate the effects of bisphenol A (BPA) exposure on neurobehavioral testing in young Wistar rats and to evaluate the therapeutic potential of Thymus ciliatus (TEO) essential oil to attenuate the damage induced by this chemical toxin. Methods: The essential oil was extracted by hydro-distillation (yield of 2.26%), and the characterization by GC-MS indicates that the major components of Thymus ciliatus oil are thymol (63.33%), p-cymene (13.4%), and σ-terpinene (6.69%). Acute BPA intoxication was induced with a dose of 50 mg/kg orally for 60 days. The neurobehavioral evaluation, performed using a comprehensive set of tests including the forced swim test, dark/light box, Morris water maze, open field test, and sucrose preference test, clearly demonstrated that bisphenol A (BPA) exposure induced significant neurobehavioral impairments. Results: These impairments included reduced exploratory behavior indicative of heightened stress, anxiety, and depressive-like states, as well as deficits in memory and learning. Furthermore, BPA intoxication was associated with metabolic disturbances such as hyperglycemia along with histopathological evidence of brain tissue damage. However, TEO treatment attenuated these adverse effects by restoring neurobehavioral function. Molecular docking analysis revealed an affinity between the major essential oils identified in T. ciliatus, BPA, and the 5HT2C receptor and the MAO, AChE, and BChE enzymes, suggesting a potential mechanism underlying BPA’s effects on behavior and memory. In addition, TEO also showed an interaction with these molecules, suggesting a therapeutic potential against BPA. These findings underscore the promising role of TEO in mitigating the poisonous effects of BPA and pave the way for additional research into the molecular mechanisms and therapeutic uses of natural bioactive compounds for the prevention and treatment of toxic diseases. Thymol, the major compound in TEO, exhibited activity related to the dopamine and serotonin pathways, so it could have potential antidepressant properties. Conclusions: Thymol might be a promising candidate for the treatment of neurodegenerative and neurological disorders such as depression, Parkinson’s disease, and Alzheimer’s disease while also preventing histological damage in the brain. Full article

(This article belongs to the Special Issue Neuroprotective Potential of Natural Products: A Shield against Brain Decay)

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18 pages, 6122 KiB

Open AccessArticle

GABA_A Receptors Are Involved in the Seizure Blockage Prompted by a Polyphenol-Rich Extract of White Grape Juice in Rodents

by Alessandro Maugeri, Rita Citraro, Antonio Leo, Caterina Russo, Michele Navarra and Giovambattista De Sarro

Pharmaceuticals 2025, 18(2), 186; https://doi.org/10.3390/ph18020186 - 30 Jan 2025

Viewed by 742

Abstract

Background/Objectives: Polyphenols have been suggested to possess anticonvulsant properties, which can be exploited as tools in novel strategies against epilepsy. Along that line, the aim of this study was to investigate the effects of a polyphenol-rich extract of white grape juice (WGJe) in different rodent models of epilepsy, exploring its putative mechanism of action. Methods: In this study, we employed pentylenetetrazole (PTZ)-injected ICR-CD1 mice, audiogenic seizure (AGS)-susceptible DBA/2 mice and WAG/Rij rats. Seizures were monitored and scored, while absence was assessed by electroencephalogram. The open-field test was employed to assess the anxiolytic effects of WGJe. In order to assess the involvement of the GABA_A receptor, we used the antagonist flumazenil in AGS-susceptible DBA/2 mice. Computational analyses were employed to evaluate the interaction of the main polyphenols of WGJe and GABA_A receptors. Results: Our results showed that the intraperitoneal injection of WGJe hindered tonic seizures in PTZ-injected ICR-CD1 mice. In WAG/Rij rats, WGJe did not elicit any significant effects on spike-wave discharges compared to untreated rats. In AGS-susceptible DBA/2 mice, WGJe significantly hampered both clonic and tonic seizures, as well as induced anxiolytic effects. Interestingly, when administering WGJe with flumazenil to DBA/2 mice, we noted that the observed effects were mediated by the GABA_A receptor. Moreover, docking simulations confirmed that the main polyphenols of WGJe are able to interact with the benzodiazepine sites located in both extracellular and transmembrane domains in the GABA_A receptor. Conclusions: This study outlines the mechanism underlying the anti-epileptic activity of WGJe, thus supporting its potential role in the management of epilepsy. Full article

(This article belongs to the Special Issue Neuroprotective Potential of Natural Products: A Shield against Brain Decay)

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33 pages, 4427 KiB

Open AccessArticle

Therapeutic Efficacy of Lavandula dentata’s Oil and Ethanol Extract in Regulation of the Neuroinflammation, Histopathological Alterations, Oxidative Stress, and Restoring Balance Treg Cells Expressing FoxP3+ in a Rat Model of Epilepsy

by Aziza Antar, Eman S. Abdel-Rehiem, Areej A. Al-Khalaf, Abdelaziz S. A. Abuelsaad, Mohamed Abdel-Gabbar, Gaber M. G. Shehab and Ayman M. Abdel-Aziz

Pharmaceuticals 2025, 18(1), 35; https://doi.org/10.3390/ph18010035 - 31 Dec 2024

Cited by 1 | Viewed by 1161

Abstract

Background/Objectives: Despite the availability of antiepileptic drugs (AEDs) that can manage seizures, they often come with cognitive side effects. Furthermore, the role of oxidative stress and neuroinflammatory responses in epilepsy and the limitations of current AEDs necessitate exploring alternative therapeutic options. Medicinal plants, e.g., Lavandula dentata L., are rich in phenolic compounds and may provide neuroprotective and anti-inflammatory benefits. However, limited research evaluates their effectiveness in modulating neuroinflammation and histopathological changes in epilepsy models. Therefore, the current study hypothesized that treating Lavandula dentata L. extract or essential oils may reduce neuroinflammatory responses and mitigate histopathological changes in the brain, providing a natural alternative or adjunct therapy for epilepsy management. Methods: Five groups of male Wistar rats were used: control, pilocarpine-treated epileptic, valproic acid (VPA-treated epileptic), L. dentata extract, and essential oils. Numerous electrolyte levels, monoamine levels, neurotransmitter levels, and the mRNA expression of specific gate channel subtypes were evaluated in homogenate brain tissue. Additionally, histological changes in various brain regions were investigated. Results: The investigation revealed that the extract and essential oils obtained from L. dentata L. exhibited the ability to improve the modulation of electrolytes and ions across voltage- and ligand-gated ion channels. Furthermore, it was revealed that they could decrease neuronal excitability by facilitating repolarization. Moreover, L. dentata’s oil and ethanol extract re-balances T-reg/Th-17 cytokines, restoring the pro/anti-inflammatory cytokines and Treg markers, e.g., FOXP3 and CTLA-4, to their normal level. Conclusions: The present work confirms that the extract and essential oils of L. dentata L. have different activities to ameliorate the progression of histopathological alterations. Therefore, when used in conjunction with other AEDs, the extract and essential oils of L. dentata can slow the progression of epileptogenesis. Full article

(This article belongs to the Special Issue Neuroprotective Potential of Natural Products: A Shield against Brain Decay)

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21 pages, 3481 KiB

Open AccessArticle

Corema album Berry Juice as a Protective Agent Against Neurodegeneration

by Antonio Canoyra, Carmen Martín-Cordero, Dolores Muñoz-Mingarro, Antonio J. León-González, Richard B. Parsons and Nuria Acero

Pharmaceuticals 2024, 17(11), 1535; https://doi.org/10.3390/ph17111535 - 15 Nov 2024

Cited by 1 | Viewed by 1160

Abstract

Background/Objectives: Corema album berries are edible fruits from the Iberian Atlantic coast, characterized by a rich polyphenolic composition, which endows their juice with potential protective effects against neurodegeneration. This study aimed to evaluate the potential of the relatively lesser-known C. album berries as a novel neuroprotective agent against neurodegenerative diseases. Methods: The phenolic compounds of the juice were characterized using UHPLC-HRMS (Orbitrap). The SH-SY5Y neuroblastoma line was used to determine the preventive effect of the juice against H₂O₂-induced oxidative stress. Furthermore, neuronal cells were differentiated into dopaminergic and cholinergic lines and exposed to 6-hydroxydopamine and okadaic acid, respectively, to simulate in vitro models of Parkinson’s disease and Alzheimer’s disease. The ability of the juice to enhance neuronal viability under toxic conditions was examined. Additionally, its inhibitory effects on neuroprotective-related enzymes, including MAO-A and MAO-B, were assessed in vitro. Results: Phytochemical characterization reveals that 5-O-caffeoylquinic acid constitutes 80% of the total phenolic compounds. Higher concentrations of the juice effectively protected both differentiated and undifferentiated SH-SY5Y cells from H₂O₂-induced oxidative damage, reducing oxidative stress by approximately 20% and suggesting a dose-dependent mechanism. Moreover, the presence of the juice significantly enhanced the viability of dopaminergic and cholinergic cells exposed to neurotoxic agents. In vitro, the juice inhibited the activity of MAO-A (IC₅₀ = 87.21 µg/mL) and MAO-B (IC₅₀ = 56.50 µg/mL). Conclusions: While these findings highlight C. album berries as a promising neuroprotective agent, further research is required to elucidate its neuroprotective mechanisms in cell and animal models and, ultimately, in human trials. Full article

(This article belongs to the Special Issue Neuroprotective Potential of Natural Products: A Shield against Brain Decay)

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31 pages, 5582 KiB

Open AccessArticle

Potential Therapeutic Properties of Olea europaea Leaves from Selected Cultivars Based on Their Mineral and Organic Profiles

by Natália M. de Oliveira, Jorge Machado, Maria Helena Chéu, Lara Lopes, M. Fátima Barroso, Aurora Silva, Sara Sousa, Valentina F. Domingues and Clara Grosso

Pharmaceuticals 2024, 17(3), 274; https://doi.org/10.3390/ph17030274 - 22 Feb 2024

Cited by 2 | Viewed by 2500

Abstract

Olive leaves are consumed as an extract or as a whole herbal powder with several potential therapeutic benefits attributed to polyphenols, tocopherol’s isomers, and flavonoids, among others. This study assessed the potential variance in the functional features presented by olive leaves from three different Portuguese cultivars—Cobrançosa, Madural, and Verdeal—randomly mix-cultivated in the geographical area of Vale de Salgueiros. Inorganic analysis determined their mineral profiles while an organic analysis measured their total phenolic and flavonoid content, and scanned their phenolic and tocopherol and fatty acid composition. The extracts’ biological activity was tested by determining their antimicrobial and antioxidant power as well as their ability to inhibit acetylcholinesterase, butyrylcholinesterase, MAO-A/B, and angiotensin-I-converting enzyme. The inorganic profiles showed them to be an inexpensive source able to address different mineral deficiencies. All cultivars appear to have potential for use as possible antioxidants and future alternative antibiotics against some multidrug-resistant microorganisms, with caution regarding the arsenic content in the Verdeal cultivar. Madural’s extract displayed properties to be considered a natural multitarget treatment for Alzheimer’s and Parkinson’s diseases, depression, and cardiometabolic and dual activity for blood pressure modulation. This work indicates that randomly cultivating different cultivars significantly modifies the leaves’ composition while keeping their multifaceted therapeutic value. Full article

(This article belongs to the Special Issue Neuroprotective Potential of Natural Products: A Shield against Brain Decay)

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23 pages, 12177 KiB

Open AccessArticle

Modulation of Gut Microbiome Community Mitigates Multiple Sclerosis in a Mouse Model: The Promising Role of Palmaria palmata Alga as a Prebiotic

by Shimaa Mohammad Yousof, Badrah S. Alghamdi, Thamer Alqurashi, Mohammad Zubair Alam, Reham Tash, Imrana Tanvir and Lamis AbdelGadir Kaddam

Pharmaceuticals 2023, 16(10), 1355; https://doi.org/10.3390/ph16101355 - 25 Sep 2023

Cited by 5 | Viewed by 2382

Abstract

Background: Red marine algae have shown the potential to reduce inflammation, influence microbiota, and provide neuroprotection. Objective: To examine the prebiotic properties of Palmaria palmata aqueous extract (Palmaria p.) and its potential as a neuroprotective agent in multiple sclerosis (MS). Methods: eighty-eight adult Swiss mice were divided into four male and four female groups, including a control group (distilled water), Palmaria p.-treated group (600 mg/kg b.w.), cuprizone (CPZ)-treated group (mixed chow 0.2%), and a group treated with both CPZ and Palmaria p. The experiment continued for seven weeks. CPZ treatment terminated at the end of the 5th week, with half of the mice sacrificed to assess the demyelination stage. To examine the spontaneous recovery, the rest of the mice continued until the end of week seven. Behavioral (grip strength (GS) and open field tests (OFT)), microbiome, and histological assessments for general morphology of corpus callous (CC) were all conducted at the end of week five and week 7. Results: Palmaria p. can potentially protect against CPZ-induced MS with variable degrees in male and female Swiss mice. This protection was demonstrated through three key findings: (1) increased F/B ratio and expansion of the beneficial Lactobacillus, Proteobacteria, and Bactriodia communities. (2) Protection against the decline in GS induced by CPZ and prevented CPZ-induced anxiety in OFT. (3) Preservation of structural integrity. Conclusions: Because of its propensity to promote microbiota alterations, its antioxidant activity, and its content of −3 fatty acids, Palmaria p. could be a promising option for MS patients and could be beneficial as a potential probiotic for the at-risk groups as a preventive measure against MS. Full article

(This article belongs to the Special Issue Neuroprotective Potential of Natural Products: A Shield against Brain Decay)

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15 pages, 4022 KiB

Open AccessArticle

Gypenoside-14 Reduces Depression via Downregulation of the Nuclear Factor Kappa B (NF-kB) Signaling Pathway on the Lipopolysaccharide (LPS)-Induced Depression Model

by Yaqun Jiang, Xiang Cheng, Ming Zhao, Tong Zhao, Mengya Zhang, Zibi Shi, Xiangpei Yue, Yanan Geng, Jiayue Gao, Chengbo Wang, Junli Yang and Lingling Zhu

Pharmaceuticals 2023, 16(8), 1152; https://doi.org/10.3390/ph16081152 - 14 Aug 2023

Cited by 9 | Viewed by 2226

Abstract

Neuroinflammation is a common pathogenetic sign of depression and is closely linked to the development of depression. Many clinical anti-inflammatory drugs act as antidepressants by reducing the neuroinflammatory response. Previous research found that gypenosides and their bioactive compound gypenoside-14 (GP-14) had neuroprotective effects against hypoxia-induced injury and reduced neuroinflammation-related high-altitude cerebral edema. Here we investigated the effects of GP-14 on the lipopolysaccharide (LPS)-induced depression-like behavior model. LPS (0.5 mg/kg) was injected into mice intraperitoneally for 7 consecutive days to induce depression-like behavior, which is considered a model for the exacerbation of depression. GP-14 in the amount of 100 mg/kg was simultaneously administered by gavage for 7 days. In the LPS-induced depression model, GP-14 not only attenuated depression-like behavior but also improved the anxiety-like behavior of the mice. Additionally, GP-14 treatment mitigated learning and cognitive decline in depressed mice. ELISA and immunofluorescence staining results revealed that GP-14 inhibited the upregulation of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), and suppressed the activation of astrocytes induced with LPS, indicating its potent anti-inflammatory effect. GP-14 pretreatment in C8 cells and primary astrocytes can inhibit the activation of the NF-κB signaling pathway and downregulate the levels of pro-inflammatory factors. In summary, our findings showed that GP-14 had significant anti-inflammation and anti-depression properties; thus, GP-14 could be a promising lead compound for treating depression. Full article

(This article belongs to the Special Issue Neuroprotective Potential of Natural Products: A Shield against Brain Decay)

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20 pages, 5361 KiB

Open AccessArticle

Neuroprotective Effects of Albizia lebbeck (L.) Benth. Leaf Extract against Glutamate-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Microglial Cells

by Onuma Phoraksa, Chanika Chimkerd, Parunya Thiyajai, Kunchit Judprasong, Siriporn Tuntipopipat, Tewin Tencomnao, Somsri Charoenkiatkul, Chawanphat Muangnoi and Monruedee Sukprasansap

Pharmaceuticals 2023, 16(7), 989; https://doi.org/10.3390/ph16070989 - 10 Jul 2023

Cited by 8 | Viewed by 2592

Abstract

Endoplasmic reticulum (ER) stress caused by excessive glutamate in the central nervous system leads to neurodegeneration. Albizia lebbeck (L.) Benth. has been reported to possess neuroprotective properties. We aimed to investigate the effect and mechanism of A. lebbeck leaf extracts on glutamate-induced neurotoxicity and apoptosis linked to ER stress using human microglial HMC3 cells. A. lebbeck leaves were extracted using hexane (AHE), mixed solvents, and ethanol. Each different extract was evaluated for cytotoxic effects on HMC3 cells, and then non-cytotoxic concentrations of the extracts were pretreated with the cells, followed by glutamate. Our results showed that AHE treatment exhibited the highest protective effect and was thus selected for finding the mechanistic approach. AHE inhibited the specific ER stress proteins (calpain1 and caspase-12). AHE also suppressed the apoptotic proteins (Bax, cytochrome c, cleaved caspase-9, and cleaved caspase-3); however, it also increased the antiapoptotic Bcl-2 protein. Remarkably, AHE increased cellular antioxidant activities (SOD, CAT, and GPx). To support the activation of antioxidant defense and inhibition of apoptosis in our HMC3 cell model, the bioactive phytochemicals within AHE were identified by HPLC analysis. We found that AHE had high levels of carotenoids (α-carotene, β-carotene, and lutein) and flavonoids (quercetin, luteolin, and kaempferol). Our novel findings indicate that AHE can inhibit glutamate-induced neurotoxicity via ER stress and apoptosis signaling pathways by activating cellular antioxidant enzymes in HMC3 cells, suggesting a potential mechanism for neuroprotection. As such, A. lebbeck leaf might potentially represent a promising source and novel alternative approach for preventing neurodegenerative diseases. Full article

(This article belongs to the Special Issue Neuroprotective Potential of Natural Products: A Shield against Brain Decay)

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