Natural Bioactive Compounds and Neurological Disorders: Exploiting Resources from Nature

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 42010

Special Issue Editors


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Guest Editor
Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy
Interests: drug development; neuroprotective agents; multitarget ligands; natural-based derivatives; anticancer drug; efflux pump inhibition

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Guest Editor
Department of Pharmacy, University of Pisa, Pisa, Italy
Interests: drug discovery; multitarget ligands; antioxidants; neuroprotective agents; autophagy; anticancer; kinase inhibitor
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Pharmacy, University of Pisa, Pisa, Italy
Interests: drug discovery; neurodegeneration; autophagy; drug design

Special Issue Information

Nature has represented for millennia the main source of unique bioactive substances, significantly contributing to the treatment of a large number of diseases. Not surprisingly, pharmaceutical research has been largely inspired by nature, accomplishing big efforts to develop new pharmacological agents based or derived from natural products (NPs). Indeed, the rich polypharmacological profile of NPs offers an interesting instrument for developing innovative treatments for complex diseases, such as neurological disorders (NDs).

NDs constitute a heterogeneous group of pathologies affecting the central and the peripheral nervous systems, with a vast and complex symptomatology. Given their estimated incidence of more than 1 billion people worldwide and no efficacious pharmacological therapy available, there is a high request of new pharmaceutical options able to counteract their insurgence and progression. To help reaching this goal, this Special Issue aims at collecting relevant studies focusing on: (i) identification, design, and synthesis of NP-inspired derivatives, able to target specific NDs mechanisms, (ii) PK/PD profiling of NPs, and (iii) drug delivery system application to improve NPs’ biopharmaceutical properties.

The journal Pharmaceuticals invites experts in the field to contribute to this Special Issue with both reviews and original research articles focusing on exploiting natural products to develop innovative pharmaceutical tools for neurological disorders.

Dr. Simona Sestito
Prof. Dr. Simona Rapposelli
Dr. Massimiliano Runfola
Guest Editors

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Keywords

  • neurological disorders
  • neuroprotective agents
  • neuronal injury
  • phytochemical screening
  • natural products
  • phenotypic drug discovery
  • mechanism of action
  • nanoparticles
  • drug delivery
  • natural bioactive products
  • autophagic promoters
  • ADMET optimization

Published Papers (13 papers)

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Research

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18 pages, 1443 KiB  
Article
Will Cannabigerol Trigger Neuroregeneration after a Spinal Cord Injury? An In Vitro Answer from NSC-34 Scratch-Injured Cells Transcriptome
by Andrea Valeri, Luigi Chiricosta, Agnese Gugliandolo, Federica Pollastro and Emanuela Mazzon
Pharmaceuticals 2022, 15(2), 117; https://doi.org/10.3390/ph15020117 - 19 Jan 2022
Cited by 8 | Viewed by 3918
Abstract
Spinal cord injury affects the lives of millions of people around the world, often causing disability and, in unfortunate circumstances, death. Rehabilitation can partly improve outcomes and only a small percentage of patients, typically the least injured, can hope to return to normal [...] Read more.
Spinal cord injury affects the lives of millions of people around the world, often causing disability and, in unfortunate circumstances, death. Rehabilitation can partly improve outcomes and only a small percentage of patients, typically the least injured, can hope to return to normal living conditions. Cannabis sativa is gaining more and more interest in recent years, even though its beneficial properties have been known for thousands of years. Cannabigerol (CBG), extracted from C. sativa, is defined as the “mother of all cannabinoids” and its properties range from anti-inflammatory to antioxidant and neuroprotection. Using NSC-34 cells to model spinal cord injury in vitro, our work evaluated the properties of CBG treatments in motor neuron regeneration. While pre-treatment can modulate oxidative stress and increase antioxidant enzyme genes, such as Tnx1, decreasing Nos1 post-treatment seems to induce regeneration genes by triggering different pathways, such as Gap43 via p53 acetylation by Ep300 and Ddit3 and Xbp1 via Bdnf signaling, along with cytoskeletal remodeling signaling genes Nrp1 and Map1b. Our results indicate CBG as a phytocompound worth further investigation in the field of neuronal regeneration. Full article
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23 pages, 9257 KiB  
Article
Extracellular Vesicle Delivery of Neferine for the Attenuation of Neurodegenerative Disease Proteins and Motor Deficit in an Alzheimer’s Disease Mouse Model
by Bin Tang, Wu Zeng, Lin Lin Song, Hui Miao Wang, Li Qun Qu, Hang Hong Lo, Lu Yu, An Guo Wu, Vincent Kam Wai Wong and Betty Yuen Kwan Law
Pharmaceuticals 2022, 15(1), 83; https://doi.org/10.3390/ph15010083 - 10 Jan 2022
Cited by 22 | Viewed by 3671
Abstract
Exosomes are nano-extracellular vesicles with diameters ranging from 30 to 150 nm, which are secreted by the cell. With their role in drug cargo loading, exosomes have been applied to carry compounds across the blood–brain barrier in order to target the central nervous [...] Read more.
Exosomes are nano-extracellular vesicles with diameters ranging from 30 to 150 nm, which are secreted by the cell. With their role in drug cargo loading, exosomes have been applied to carry compounds across the blood–brain barrier in order to target the central nervous system (CNS). In this study, high-purity exosomes isolated by the ultra-high-speed separation method were applied as the natural compound carrier, with the loading efficiency confirmed by UHPLC-MS analysis. Through the optimization of various cargo loading methods using exosomes, this study compared the efficiency of different ways for the separation of exosomes and the exosome encapsulation of natural compounds with increasing molecular weights via extensive in vitro and in vivo efficacy studies. In a pharmacokinetic study, our data suggested that the efficiency of compound’s loading into exosomes is positively correlated to its molecular weight. However, with a molecular weight of greater than 1109 Da, the exosome-encapsulated natural compounds were not able to pass through the blood–brain barrier (BBB). In vitro cellular models confirmed that three of the selected exosome-encapsulated natural compounds—baicalin, hederagenin and neferine—could reduce the level of neurodegenerative disease mutant proteins—including huntingtin 74 (HTT74), P301L tau and A53T α-synuclein (A53T α-syn)—more effectively than the compounds alone. With the traditional pharmacological role of the herbal plant Nelumbo nucifera in mitigating anxiety, exosome-encapsulated-neferine was, for the first time, reported to improve the motor deficits of APP/PS1 (amyloid precursor protein/ presenilin1) double transgenic mice, and to reduce the level of β-amyloid (Aβ) in the brain when compared with the same concentration of neferine alone. With the current trend in advocating medicine–food homology and green healthcare, this study has provided a rationale from in vitro to in vivo for the encapsulation of natural compounds using exosomes for the targeting of BBB permeability and neurodegenerative diseases in the future. Full article
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11 pages, 3301 KiB  
Article
Oleanolic Acid Alleviates Cerebral Ischemia/Reperfusion Injury via Regulation of the GSK-3β/HO-1 Signaling Pathway
by Kaili Lin, Zhang Zhang, Zhu Zhang, Peili Zhu, Xiaoli Jiang, Ying Wang, Qiudi Deng, Ken Kin Lam Yung and Shiqing Zhang
Pharmaceuticals 2022, 15(1), 1; https://doi.org/10.3390/ph15010001 - 21 Dec 2021
Cited by 11 | Viewed by 3411
Abstract
Oleanolic acid (OA), a bioactive ingredient of Panax ginseng, exhibits neuroprotective pharmacological effects. However, the protective role of OA in cerebral ischemia and involved mechanisms remain unclear. This study attempted to explore the therapeutic effects of OA both in vitro and in [...] Read more.
Oleanolic acid (OA), a bioactive ingredient of Panax ginseng, exhibits neuroprotective pharmacological effects. However, the protective role of OA in cerebral ischemia and involved mechanisms remain unclear. This study attempted to explore the therapeutic effects of OA both in vitro and in vivo. OA attenuated cytotoxicity and overproduction of intracellular reactive oxygen species (ROS) by regulation of glycogen synthase kinase-3β (GSK-3β)/heme oxygenase-1 (HO-1) signal in oxygen-glucose deprivation/reoxygenation (OGD/R)-exposed SH-SY5Y cells. Additionally, OA administration significantly reduced the area of cerebral infarction and the neurological scores in the rat models of cerebral ischemia with middle cerebral artery occlusion (MCAO). The OA administration group showed a higher percentage of Nissl+ and NeuN+ cells, along with lower TUNEL+ ratios in the infarct area of MCAO rats. Moreover, OA administration reduced ROS production while it suppressed the GSK-3β activation and upregulated the HO-1 expression in infarcted tissue. Our results illustrated that OA significantly counteracted cerebral ischemia-mediated injury through antioxidant effects induced by the regulation of the GSK-3β/HO-1 signaling pathway, implicating OA as a promising neuroprotective drug for the therapy of ischemic stroke. Full article
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17 pages, 2716 KiB  
Article
Rhaponticum uniflorum and Serratula centauroides Extracts Attenuate Emotional Injury in Acute and Chronic Emotional Stress
by Larisa N. Shantanova, Daniil N. Olennikov, Irinchey E. Matkhanov, Sergey M. Gulyaev, Anyuta A. Toropova, Irina G. Nikolaeva and Sergey M. Nikolaev
Pharmaceuticals 2021, 14(11), 1186; https://doi.org/10.3390/ph14111186 - 19 Nov 2021
Cited by 8 | Viewed by 2191
Abstract
In modern life, the use of plant stress-protectors has taken on particular significance due to the wide distribution of neurosis-like and neurotic diseases caused by neuroendocrine-immune system imbalance. Special attention has been paid to the plants containing ecdysteroids, i.e., hormone-like bioactive substances with [...] Read more.
In modern life, the use of plant stress-protectors has taken on particular significance due to the wide distribution of neurosis-like and neurotic diseases caused by neuroendocrine-immune system imbalance. Special attention has been paid to the plants containing ecdysteroids, i.e., hormone-like bioactive substances with high adaptogenic activity. The article deals with the study of bioactivity of two plant extracts as Rhaponticum uniflorum (L.) DC. and Serratula centauroides L. with a high content of ecdysteroids and phenolic compounds. The models of acute and chronic emotional stress in white rats were used to estimate the stress-protective activity of R. uniflorum and S. centauroides extracts. Both extracts showed the stress-protective effect via inhibiting the development of signs induced by single and long-term effects of stress factors. In acute stress, the development of Selye's triad signs was less pronounced against the background of the plant remedies introduction. In chronic stress, the extracts prevented the development of anxiety-depressive syndrome. Besides, R. uniflorum and S. centauroides extracts banned the development of stress-induced injuries in the brain cortex and had a neuroprotective effect on ischemia against chronic stress. The stress-protective effects of both plant extracts were based on a decrease of hyperactivation of the central stress-promoting systems (sympathoadrenal, hypothalamic-pituitary-adrenal) due to their GABA-mimetic effects. Peripheral mechanisms were connected with the inhibition of free radical oxidation processes and with an increase in the endogenous antioxidant system activity. Thus, R. uniflorum and S. centauroides extracts have a high potential to increase non-specific body resistance against acute and chronic emotional stress effects. Full article
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11 pages, 2216 KiB  
Article
The Inhibitory Effects of Terminalia catappa L. Extract on the Migration and Invasion of Human Glioblastoma Multiforme Cells
by Hsiao-Hang Chung, Ming-Ju Hsieh, Yih-Shou Hsieh, Pei-Ni Chen, Chung-Po Ko, Nuo-Yi Yu, Chiao-Wen Lin and Shun-Fa Yang
Pharmaceuticals 2021, 14(11), 1183; https://doi.org/10.3390/ph14111183 - 19 Nov 2021
Cited by 5 | Viewed by 2047
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive and common types of brain tumor. Due to its high proliferation ability, a high lethality rate has been observed with this malignant glial tumor. Terminalia catappa L. (T. catappa) is currently [...] Read more.
Glioblastoma multiforme (GBM) is one of the most aggressive and common types of brain tumor. Due to its high proliferation ability, a high lethality rate has been observed with this malignant glial tumor. Terminalia catappa L. (T. catappa) is currently known to have anti-inflammatory and anti-carcinogenesis effects. However, few studies have examined the mechanisms of the leaf extracts of T. catappa (TCE) on GBM cells. In the current study, we demonstrated that TCE can significantly inhibit the migration and invasion capabilities of GBM cell lines without showing biotoxic effects. Matrix metalloproteinases-2 (MMP-2) activity and protein expression were attenuated by reducing the p38 phosphorylation involved in the mitogen-activated protein kinase (MAPK) pathway. By treating with TCE and/or p38 inhibitor (SB203580), we confirmed that p38 MAPK is involved in the inhibition of cell migration. In conclusion, our results demonstrated that TCE inhibits human GBM cell migration and MMP-2 expression by regulating the p38 pathway. These results reveal that TCE contains potent therapeutic compounds which could be applied for treating GBM brain tumors. Full article
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16 pages, 2600 KiB  
Article
Esculetin Provides Neuroprotection against Mutant Huntingtin-Induced Toxicity in Huntington’s Disease Models
by Letizia Pruccoli, Carlo Breda, Gabriella Teti, Mirella Falconi, Flaviano Giorgini and Andrea Tarozzi
Pharmaceuticals 2021, 14(10), 1044; https://doi.org/10.3390/ph14101044 - 13 Oct 2021
Cited by 3 | Viewed by 2366
Abstract
Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene. This mutation leads to the production of mutant HTT (mHTT) protein which triggers neuronal death through several mechanisms. Here, we [...] Read more.
Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene. This mutation leads to the production of mutant HTT (mHTT) protein which triggers neuronal death through several mechanisms. Here, we investigated the neuroprotective effects of esculetin (ESC), a bioactive phenolic compound, in an inducible PC12 model and a transgenic Drosophila melanogaster model of HD, both of which express mHTT fragments. ESC partially inhibited the progression of mHTT aggregation and reduced neuronal death through its ability to counteract the oxidative stress and mitochondria impairment elicited by mHTT in the PC12 model. The ability of ESC to counteract neuronal death was also confirmed in the transgenic Drosophila model. Although ESC did not modify the lifespan of the transgenic Drosophila, it still seemed to have a positive impact on the HD phenotype of this model. Based on our findings, ESC may be further studied as a potential neuroprotective agent in a rodent transgenic model of HD. Full article
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13 pages, 1084 KiB  
Article
The Protective Effect of Bergamot Polyphenolic Fraction (BPF) on Chemotherapy-Induced Neuropathic Pain
by Sara Ilari, Filomena Lauro, Luigino Antonio Giancotti, Valentina Malafoglia, Concetta Dagostino, Micaela Gliozzi, Antonia Condemi, Jessica Maiuolo, Francesca Oppedisano, Ernesto Palma, Carlo Tomino, Daniela Salvemini, Vincenzo Mollace and Carolina Muscoli
Pharmaceuticals 2021, 14(10), 975; https://doi.org/10.3390/ph14100975 - 25 Sep 2021
Cited by 7 | Viewed by 2825
Abstract
Paclitaxel is a chemotherapeutic drug used for cancer treatment. Chemotherapy-induced peripheral neuropathy (CIPN) is a common major dose-limiting side effect of many chemotherapeutic agents, including paclitaxel. CIPN is accompanied by mechanical and thermal hypersensitivity that resolves within weeks, months, or years after drug [...] Read more.
Paclitaxel is a chemotherapeutic drug used for cancer treatment. Chemotherapy-induced peripheral neuropathy (CIPN) is a common major dose-limiting side effect of many chemotherapeutic agents, including paclitaxel. CIPN is accompanied by mechanical and thermal hypersensitivity that resolves within weeks, months, or years after drug termination. To date, there is no available preventive strategy or effective treatment for CIPN due to the fact that its etiology has not been fully explained. It is clear that free radicals are implicated in many neurodegenerative diseases and recent studies have shown the important role of oxidative stress in development of CIPN. Here, we observed how, in rats, the administration of a natural antioxidant such as the bergamot polyphenolic extract (BPF), can play a crucial role in reducing CIPN. Paclitaxel administration induced mechanical allodynia and thermal hyperalgesia, which began to manifest on day seven, and reached its lowest levels on day fifteen. Paclitaxel-induced neuropathic pain was associated with nitration of proteins in the spinal cord including MnSOD, glutamine synthetase, and glutamate transporter GLT-1. This study showed that the use of BPF, probably by inhibiting the nitration of crucial proteins involved in oxidative stress, improved paclitaxel-induced pain behaviors relieving mechanical allodynia, thermal hyperalgesia, thus preventing the development of chemotherapy-induced neuropathic pain. Full article
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16 pages, 6333 KiB  
Article
Antioxidant and Anti-Inflammatory Potential of Thymoquinone and Lycopene Mitigate the Chlorpyrifos-Induced Toxic Neuropathy
by Mohamed Aboubakr, Said M. Elshafae, Ehab Y. Abdelhiee, Sabreen E. Fadl, Ahmed Soliman, Afaf Abdelkader, Mohamed M. Abdel-Daim, Khaled A. Bayoumi, Roua S. Baty, Enas Elgendy, Amira Elalfy, Bodour Baioumy, Samah F. Ibrahim and Ahmed Abdeen
Pharmaceuticals 2021, 14(9), 940; https://doi.org/10.3390/ph14090940 - 20 Sep 2021
Cited by 40 | Viewed by 3343
Abstract
CPF (chlorpyrifos) is an organophosphate pesticide used in agricultural and veterinary applications. Our experiment aimed to explore the effects of thymoquinone (TQ) and/or lycopene (LP) against CPF-induced neurotoxicity. Wistar rats were categorized into seven groups: first group served as a control (corn oil [...] Read more.
CPF (chlorpyrifos) is an organophosphate pesticide used in agricultural and veterinary applications. Our experiment aimed to explore the effects of thymoquinone (TQ) and/or lycopene (LP) against CPF-induced neurotoxicity. Wistar rats were categorized into seven groups: first group served as a control (corn oil only); second group, TQ (10 mg/kg); third group, LP (10 mg/kg); fourth group, CPF (10 mg/kg) and deemed as CPF toxic control; fifth group, TQ + CPF; sixth group, (LP + CPF); and seventh group, (TQ + LP + CPF). CPF intoxication inhibited acetylcholinesterase (AchE), decreased glutathione (GSH) content, and increased levels of malondialdehyde (MDA), an oxidative stress biomarker. Furthermore, CPF impaired the activity of antioxidant enzymes including superoxide dismutase (SOD) and catalase (CAT) along with enhancement of the level of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β. CPF evoked apoptosis in brain tissue. TQ or LP treatment of CPF-intoxicated rats greatly improved AchE activity, oxidative state, inflammatory responses, and cell death. Co-administration of TQ and LP showed better restoration than their sole treatment. In conclusion, TQ or LP supplementation may alleviate CPF-induced neuronal injury, most likely due to TQ or LPs’ antioxidant, anti-inflammatory, and anti-apoptotic effects. Full article
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24 pages, 9012 KiB  
Article
Caesalpinia mimosoides Leaf Extract Promotes Neurite Outgrowth and Inhibits BACE1 Activity in Mutant APP-Overexpressing Neuronal Neuro2a Cells
by Panthakarn Rangsinth, Chatrawee Duangjan, Chanin Sillapachaiyaporn, Ciro Isidoro, Anchalee Prasansuklab and Tewin Tencomnao
Pharmaceuticals 2021, 14(9), 901; https://doi.org/10.3390/ph14090901 - 4 Sep 2021
Cited by 10 | Viewed by 3537
Abstract
Alzheimer’s disease (AD) is implicated in the imbalance of several proteins, including Amyloid-β (Aβ), amyloid precursor protein (APP), and BACE1. APP overexpression interferes with neurite outgrowth, while BACE1 plays a role in Aβ generation. Medicinal herbs with effects on neurite outgrowth stimulation and [...] Read more.
Alzheimer’s disease (AD) is implicated in the imbalance of several proteins, including Amyloid-β (Aβ), amyloid precursor protein (APP), and BACE1. APP overexpression interferes with neurite outgrowth, while BACE1 plays a role in Aβ generation. Medicinal herbs with effects on neurite outgrowth stimulation and BACE1 inhibition may benefit AD. This study aimed to investigate the neurite outgrowth stimulatory effect, along with BACE1 inhibition of Caesalpinia mimosoides (CM), using wild-type (Neuro2a) and APP (Swedish mutant)-overexpressing (Neuro2a/APPSwe) neurons. The methanol extract of CM leaves stimulated neurite outgrowth in wild-type and APP-overexpressing cells. After exposure to the extract, the mRNA expression of the neurite outgrowth activation genes growth-associated protein-43 (GAP-43) and teneurin-4 (Ten-4) was increased in both Neuro2a and Neuro2a/APPSwe cells, while the mRNA expression of neurite outgrowth negative regulators Nogo receptor (NgR) and Lingo-1 was reduced. Additionally, the extract suppressed BACE1 activity in the APP-overexpressing neurons. Virtual screening demonstrated that quercetin-3′-glucuronide, quercetin-3-O-glucoside, clausarinol, and theogallin were possible inhibitors of BACE1. ADMET was analyzed to predict drug-likeness properties of CM-constituents. These results suggest that CM extract promotes neurite outgrowth and inhibits BACE1 activity in APP-overexpressing neurons. Thus, CM may serve as a source of drugs for AD treatment. Additional studies for full identification of bioactive constituents and to confirm the neuritogenesis in vivo are needed for translation into clinic of the present findings. Full article
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20 pages, 2016 KiB  
Article
Multi-Target Actions of Acridones from Atalantia monophylla towards Alzheimer’s Pathogenesis and Their Pharmacokinetic Properties
by Pitchayakarn Takomthong, Pornthip Waiwut, Chavi Yenjai, Aonnicha Sombatsri, Prasert Reubroycharoen, Luo Lei, Ren Lai, Suchada Chaiwiwatrakul and Chantana Boonyarat
Pharmaceuticals 2021, 14(9), 888; https://doi.org/10.3390/ph14090888 - 31 Aug 2021
Cited by 11 | Viewed by 2666
Abstract
Ten acridones isolated from Atalantia monophylla were evaluated for effects on Alzheimer’s disease pathogenesis including antioxidant effects, acetylcholinesterase (AChE) inhibition, prevention of beta-amyloid (Aβ) aggregation and neuroprotection. To understand the mechanism, the type of AChE inhibition was investigated in vitro and binding interactions [...] Read more.
Ten acridones isolated from Atalantia monophylla were evaluated for effects on Alzheimer’s disease pathogenesis including antioxidant effects, acetylcholinesterase (AChE) inhibition, prevention of beta-amyloid (Aβ) aggregation and neuroprotection. To understand the mechanism, the type of AChE inhibition was investigated in vitro and binding interactions between acridones and AChE or Aβ were explored in silico. Drug-likeness and ADMET parameters were predicted in silico using SwissADME and pKCSM programs, respectively. All acridones showed favorable drug-likeness and possessed multifunctional activities targeting AChE function, Aβ aggregation and oxidation. All acridones inhibited AChE in a mixed-type manner and bound AChE at both catalytic anionic and peripheral anionic sites. In silico analysis showed that acridones interfered with Aβ aggregation by interacting at the central hydrophobic core, C-terminal hydrophobic region, and the key residues 41 and 42. Citrusinine II showed potent multifunctional action with the best ADMET profile and could alleviate neuronal cell damage induced by hydrogen peroxide and Aβ1-42 toxicity. Full article
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12 pages, 4476 KiB  
Article
Chirality-Dependent Anti-Inflammatory Effect of Glutathione after Spinal Cord Injury in an Animal Model
by Seong-Jun Kim, Wan-Kyu Ko, Gong-Ho Han, Daye Lee, Yuhan Lee, Seung-Hun Sheen, Je-Beom Hong and Seil Sohn
Pharmaceuticals 2021, 14(8), 792; https://doi.org/10.3390/ph14080792 - 12 Aug 2021
Cited by 6 | Viewed by 2421
Abstract
Neuroinflammation forms a glial scar following a spinal cord injury (SCI). The injured axon cannot regenerate across the scar, suggesting permanent paraplegia. Molecular chirality can show an entirely different bio-function by means of chiral-specific interaction. In this study, we report that d-chiral glutathione [...] Read more.
Neuroinflammation forms a glial scar following a spinal cord injury (SCI). The injured axon cannot regenerate across the scar, suggesting permanent paraplegia. Molecular chirality can show an entirely different bio-function by means of chiral-specific interaction. In this study, we report that d-chiral glutathione (D-GSH) suppresses the inflammatory response after SCI and leads to axon regeneration of the injured spinal cord to a greater extent than l-chiral glutathione (L-GSH). After SCI, axon regrowth in D-GSH-treated rats was significantly increased compared with that in L-GSH-treated rats (*** p < 0.001). Secondary damage and motor function were significantly improved in D-GSH-treated rats compared with those outcomes in L-GSH-treated rats (** p < 0.01). Moreover, D-GSH significantly decreased pro-inflammatory cytokines and glial fibrillary acidic protein (GFAP) via inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway compared with L-GSH (*** p < 0.001). In primary cultured macrophages, we found that D-GSH undergoes more intracellular interaction with activated macrophages than L-GSH (*** p < 0.001). These findings reveal a potential new regenerative function of chiral GSH in SCI and suggest that chiral GSH has therapeutic potential as a treatment of other diseases. Full article
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17 pages, 3343 KiB  
Article
Merging the Multi-Target Effects of Kleeb Bua Daeng, a Thai Traditional Herbal Formula in Unpredictable Chronic Mild Stress-Induced Depression
by Juthamart Maneenet, Orawan Monthakantirat, Supawadee Daodee, Chantana Boonyarat, Yutthana Chotritthirong, Pakakrong Kwankhao, Supaporn Pitiporn, Suresh Awale and Yaowared Chulikhit
Pharmaceuticals 2021, 14(7), 659; https://doi.org/10.3390/ph14070659 - 9 Jul 2021
Cited by 7 | Viewed by 3838
Abstract
Major depressive disorder (MDD) is a common and debilitating psychiatric disease characterized by persistent low mood, lack of energy, hypoactivity, anhedonia, decreased libido, and impaired cognitive and social functions. However, the multifactorial etiology of MDD remains largely unknown due the complex interaction between [...] Read more.
Major depressive disorder (MDD) is a common and debilitating psychiatric disease characterized by persistent low mood, lack of energy, hypoactivity, anhedonia, decreased libido, and impaired cognitive and social functions. However, the multifactorial etiology of MDD remains largely unknown due the complex interaction between genetics and environment involved. Kleeb Bua Daeng (KBD) is a Thai traditional herbal formula that has been used to promote brain health. It consists of a 1:1:1 ratio of the aerial part of Centella asiatica, Piper nigrum fruit, and the petals of Nelumbo nucifera. According to the pharmacological activities of the individual medicinal plants, KBD has good potential as a treatment for MDD. The present study investigated the antidepressant activity of KBD in an unpredictable chronic mild stress (UCMS) mouse model. Daily administration of KBD to UCMS mice ameliorated both anhedonia, by increasing 2% sucrose intake, and hopeless behavior, by reducing immobility times in the forced swimming test (FST) and tail suspension test (TST) without any effect on locomotor activity. The mechanism of KBD activity was multi-modal. KBD promoted neurogenesis by upregulation of brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element binding (CREB) mRNA expression in the frontal cortex and hippocampus. Daily treatment with KBD significantly reversed UCMS-induced HPA axis dysregulation by upregulating the glucocorticoid receptor (GR) while downregulating serum- and glucocorticoid-inducible kinase 1 (SGK1) and FK506 binding protein 5 (FKBP5) mRNA expression. KBD treatment also normalized proinflammatory cytokine expression including tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-1β and IL-6. KBD and its component extracts also exhibited an inhibitory effect in vitro on monoamine oxidase (MAO) A and B. The multiple antidepressant actions of KBD emphasize its potential as an effective, novel treatment for MDD. Full article
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Review

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14 pages, 1029 KiB  
Review
Multi-Target Approach of Murraya koenigii Leaves in Treating Neurodegenerative Diseases
by Mario A. Tan, Niti Sharma and Seong Soo A. An
Pharmaceuticals 2022, 15(2), 188; https://doi.org/10.3390/ph15020188 - 2 Feb 2022
Cited by 11 | Viewed by 3560
Abstract
Neurodegenerative diseases (NDs) mainly affect neurons and gradually lead to a loss of normal motor and cognitive functions. Atypical protein homeostasis—misfolding, aggregations and accumulations, oxidative stress, inflammation, and apoptosis—are common features in most NDs. To date, due to the complex etiology and pathogenesis [...] Read more.
Neurodegenerative diseases (NDs) mainly affect neurons and gradually lead to a loss of normal motor and cognitive functions. Atypical protein homeostasis—misfolding, aggregations and accumulations, oxidative stress, inflammation, and apoptosis—are common features in most NDs. To date, due to the complex etiology and pathogenesis of NDs, no defined treatment is available. There has been increasing interest in plant extracts as potential alternative medicines as the presence of various active components may exert synergistic and multi-pharmacological effects. Murraya koenigii (Rutaceae) is utilized in Ayurvedic medicine for various ailments. Pharmacological studies evidenced its potential antioxidant, anti-inflammatory, anticancer, hepatoprotective, immunomodulatory, antimicrobial, and neuroprotective activities, among others. In line with our interest in exploring natural agents for the treatment of neurodegenerative diseases, this review presents an overview of literature concerning the mechanisms of action and the safety profile of significant bioactive components present in M. koenigii leaves to support further investigations into their neuroprotective therapeutic potential. Full article
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