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Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases

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

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 36338

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Special Issue Editors

Dr. Lee Wei Lim

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Guest Editor

Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Interests: neuromodulation; depression; dementia; cellular and molecular neuroscience
Special Issues, Collections and Topics in MDPI journals

Dr. Luca Aquili

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Co-Guest Editor

College of Health and Education, Discipline of Psychology, Murdoch University, Perth 6150, Australia
Interests: neuropsychology; cognition; cellular and molecular neuroscience
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleague,

This Special Issue of the journal Molecules publishes original research and timely review articles on current approaches of cutting-edge medicinal chemistry in neurological and psychiatric diseases. This section targets molecular, cellular, and biochemical methods to identify disease biomarkers and to study the pathogenesis of the central nervous system with a specific focus on neurological disorders, mood and anxiety disorders, schizophrenia, autism, and others.

In particular (but not exclusively), this Special Issue invites contributions that report on:

Studies related to the pathophysiology and basic mechanisms of neuropsychiatric diseases;
The current approaches of cutting-edge medicinal chemistry, including state-of-the-art neurochemistry, neuropharmacology, optogenetic, chemogenetic, CRISPR-Cas9, etc.;
Biological activity and neuropharmacology studies;
Contemporary ethnopharmacological and ethnomedicinal studies of natural products

Dr. Lee Wei Lim
Dr. Luca Aquili
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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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

neurochemistry
chemical
neuropharmacology
natural products
neurology
neuropsychiatry

Published Papers (13 papers)

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Research

Jump to: Review

21 pages, 12114 KiB

Open AccessArticle

New Triazine Derivatives as Serotonin 5-HT₆ Receptor Ligands

by Dorota Łażewska, Małgorzata Więcek, Grzegorz Satała, Paulina Chałupnik, Ewa Żesławska, Ewelina Honkisz-Orzechowska, Monika Tarasek, Gniewomir Latacz, Wojciech Nitek, Ewa Szymańska and Jadwiga Handzlik

Molecules 2023, 28(3), 1108; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28031108 - 22 Jan 2023

Cited by 3 | Viewed by 1709

Abstract

Since the number of people with Alzheimer’s disease (AD) continues to rise, new and effective drugs are urgently needed to not only slow down the progression of the disease, but to stop or even prevent its development. Serotonin 5-HT₆ receptor (5-HT₆R) ligands are still a promising therapeutic target for the treatment of AD. 1,3,5-Triazine derivatives, as novel structures lacking an indole or a sulfone moiety, have proven to be potent ligands for this receptor. In present work, new derivatives of the compound MST4 (4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine), the potent 5-HT₆R antagonist (K_i = 11 nM) with promising ADMET and in vivo properties, were designed. The synthesized compounds were tested for their affinity towards 5-HT₆R and other receptor (off)targets (serotonin 5-HT_2A, 5-HT₇ and dopamine D₂). Based on the new results, 4-(2-tert-butylphenoxy)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) was selected for extended in vitro studies as a potent and selective 5-HT₆R ligand (K_i = 13 nM). Its ability to permeate the blood–brain barrier (BBB) and its hepatotoxicity were evaluated. In addition, X-ray crystallography and solubility studies were also performed. The results obtained confirm that 6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine derivatives, especially compound 3, are promising structures for further pharmacological studies as 5-HT₆R ligands. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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16 pages, 7527 KiB

Open AccessArticle

Impact of the Substitution Pattern at the Basic Center and Geometry of the Amine Fragment on 5-HT₆ and D₃R Affinity in the 1H-Pyrrolo[3,2-c]quinoline Series

by Katarzyna Grychowska, Wojciech Pietruś, Ludmiła Kulawik, Ophélie Bento, Grzegorz Satała, Xavier Bantreil, Frédéric Lamaty, Andrzej J. Bojarski, Joanna Gołębiowska, Agnieszka Nikiforuk, Philippe Marin, Séverine Chaumont-Dubel, Rafał Kurczab and Paweł Zajdel

Molecules 2023, 28(3), 1096; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28031096 - 21 Jan 2023

Cited by 1 | Viewed by 1551

Abstract

Salt bridge (SB, double-charge-assisted hydrogen bonds) formation is one of the strongest molecular non-covalent interactions in biological systems, including ligand–receptor complexes. In the case of G-protein-coupled receptors, such an interaction is formed by the conserved aspartic acid (D3.32) residue and the basic moiety of the aminergic ligand. This study aims to determine the influence of the substitution pattern at the basic nitrogen atom and the geometry of the amine moiety at position 4 of 1H-pyrrolo[3,2-c]quinoline on the quality of the salt bridge formed in the 5-HT₆ receptor and D₃ receptor. To reach this goal, we synthetized and biologically evaluated a new series of 1H-pyrrolo[3,2-c]quinoline derivatives modified with various amines. The selected compounds displayed a significantly higher 5-HT₆R affinity and more potent 5-HT₆R antagonist properties when compared with the previously identified compound PZ-1643, a dual-acting 5-HT₆R/D₃R antagonist; nevertheless, the proposed modifications did not improve the activity at D₃R. As demonstrated by the in silico experiments, including molecular dynamics simulations, the applied structural modifications were highly beneficial for the formation and quality of the SB formation at the 5-HT₆R binding site; however, they are unfavorable for such interactions at D₃R. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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19 pages, 7068 KiB

Open AccessArticle

In Silico Evaluation and In Vitro Determination of Neuroprotective and MAO-B Inhibitory Effects of Pyrrole-Based Hydrazones: A Therapeutic Approach to Parkinson’s Disease

by Magdalena Kondeva-Burdina, Emilio Mateev, Borislav Angelov, Virginia Tzankova and Maya Georgieva

Molecules 2022, 27(23), 8485; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27238485 - 2 Dec 2022

Cited by 5 | Viewed by 1721

Abstract

Parkinson’s disease is a huge burden in modern medicinal practice. A serious drawback of current antiparkinsonian therapy is its symptomatic nature. This directed our investigations in the search for new more potent derivatives, affecting not only the loss of dopaminergic neurons but also the oxidative damage of neuronal cells. Thus in vitro neurotoxicity and neuroprotective analysis on a group of N-pyrrolyl hydrazide–hydrazones were performed. The neurotoxicity of the target derivatives was determined on a subcellular level in isolated rat synaptosomes, mitochondria and microsomes determining their effect on cellular vitality, GSH depletion and MDA production. The neuroprotective effects of the evaluated hydrazones were measured in three models of induced oxidative stress: 6-OHDA, t-BuOOH and Fe²⁺/AA-induced lipid peroxidation. Molecular docking simulations along with in vitro evaluation of MAO-B inhibitory potential of the target molecules were also performed. The results identified the ethyl 5-(4-bromophenyl)-1-(3-hydrazinyl-3-oxopropyl)-2-methyl-1H-pyrrole-3-carboxylate (12) as the most promising compound with the lowest neurotoxicity and highest neuroprotection on all evaluated parameters and inhibiting the hMAOB enzyme by 50%, comparable with the activity of the reference, Selegiline. The compatibility of the in silico and in vitro evaluations is a good prerequisite for these methods to be applied in future assessment of pyrrole-based compounds as anti-Parkinson agents. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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15 pages, 1751 KiB

Open AccessArticle

New, Eco-Friendly Method for Synthesis of 3-Chlorophenyl and 1,1′-Biphenyl Piperazinylhexyl Trazodone Analogues with Dual 5-HT_1A/5-HT₇ Affinity and Its Antidepressant-like Activity

by Przemysław Zaręba, Anna Partyka, Gniewomir Latacz, Grzegorz Satała, Paweł Zajdel and Jolanta Jaśkowska

Molecules 2022, 27(21), 7270; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27217270 - 26 Oct 2022

Cited by 2 | Viewed by 1361

Abstract

Serotonin 5-HT_1A and 5-HT₇ receptors play an important role in the pathogenesis and pharmacotherapy of depression. Previously identified N-hexyl trazodone derivatives, 2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride (7a·HCl), with high affinity for 5-HT_1AR and 2-(6-(4-([1,1′-biphenyl]-2-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride (7b·HCl), a dual-acting 5-HT_1A/5-HT₇ receptor ligand, were prepared with a new microwave-assisted method. The protocol for the synthesis of 7a and 7b involved reductive alkylation under a mild reducing agent. We produced the final compounds with yield of 56–63% using ethanol or 51–56% in solvent-free conditions in 4 min. We then determined the 5-HT₇R binding mode for compounds 7a and 7b using in silico methods and assessed the preliminary ADME and safety properties (hepatotoxicity and CYP3A4 inhibition) using in vitro methods for 7a·HCl and 7b·HCl. Furthermore, we evaluated antidepressant-like activity of the dual antagonist of 5-HT_1A/5-HT₇ receptors (7b·HCl) in the forced swim test (FST) in mice. The 5-HT_1AR ligand (7a·HCl) with a much lower affinity for 5-HT₇R compared to that of 7b·HCl was tested comparatively. Both compounds showed antidepressant activity, while 5-HT_1A/5-HT₇ double antagonist 7b·HCl showed a stronger and more specific response. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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13 pages, 1631 KiB

Open AccessArticle

Europinidin Inhibits Rotenone-Activated Parkinson’s Disease in Rodents by Decreasing Lipid Peroxidation and Inflammatory Cytokines Pathways

by Ali Altharawi, Khalid M. Alharthy, Hassan N. Althurwi, Faisal F. Albaqami, Sami I. Alzarea, Fahad A. Al-Abbasi, Muhammad Shahid Nadeem and Imran Kazmi

Molecules 2022, 27(21), 7159; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27217159 - 23 Oct 2022

Cited by 9 | Viewed by 1966

Abstract

Background: Europinidin is a derivative of delphinidin obtained from the plants Plumbago Europea and Ceratostigma plumbaginoides. This herb has wide medicinal applications in treating various diseases but there are very few studies available on this bioactive compound. Considering this background, the present study is designed for the evaluation of Europinidin against Parkinson’s disease. Aim: The investigation aims to assess the effect of Europinidin in the rotenone-activated Parkinson’s paradigm. Methods: To evaluate neuroprotective activity, rotenone (1.5 mg/kg s.c) and europinidin (10 mg/kg and 20 mg/kg) was administered in rats for 21 days. The behavioural parameters were performed before sacrificing the rats. On the 22nd day, all the rats were assessed for biochemical markers (SOD, GSH, MDA, Catalase), neurotransmitter levels (Dopamine, 5-HIAA, DOPAC, and HVA levels), and neuroinflammatory markers (IL-6, IL-1β and TNF-α). Results: It was found that rotenone produced significant (p < 0.001) oxidative damage, a cholinergic deficit, dopaminergic loss, and a rise in neuroinflammatory markers in rats. Conclusion: The study concludes that europinidin possesses anti-oxidant and anti-inflammatory properties. The results suggest the therapeutic role of europinidin against rotenone-activated behavioural, biochemical, and neuroinflammatory alterations in rats. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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16 pages, 25051 KiB

Open AccessArticle

Nano-PSO Administration Attenuates Cognitive and Neuronal Deficits Resulting from Traumatic Brain Injury

by Doaa Qubty, Kati Frid, Meirav Har-Even, Vardit Rubovitch, Ruth Gabizon and Chaim G Pick

Molecules 2022, 27(9), 2725; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092725 - 23 Apr 2022

Cited by 5 | Viewed by 2236

Abstract

Traumatic Brain Injury (TBI), is one of the most common causes of neurological damage in young populations. It is widely considered as a risk factor for neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s (PD) disease. These diseases are characterized in part by the accumulation of disease-specific misfolded proteins and share common pathological features, such as neuronal death, as well as inflammatory and oxidative damage. Nano formulation of Pomegranate seed oil [Nano-PSO (Granagard ^TM)] has been shown to target its active ingredient to the brain and thereafter inhibit memory decline and neuronal death in mice models of AD and genetic Creutzfeldt Jacob disease. In this study, we show that administration of Nano-PSO to mice before or after TBI application prevents cognitive and behavioral decline. In addition, immuno-histochemical staining of the brain indicates that preventive Nano-PSO treatment significantly decreased neuronal death, reduced gliosis and prevented mitochondrial damage in the affected cells. Finally, we examined levels of Sirtuin1 (SIRT1) and Synaptophysin (SYP) in the cortex using Western blotting. Nano-PSO consumption led to higher levels of SIRT1 and SYP protein postinjury. Taken together, our results indicate that Nano-PSO, as a natural brain-targeted antioxidant, can prevent part of TBI-induced damage. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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15 pages, 2142 KiB

Open AccessArticle

Neuroprotective Effects of Green Tea Seed Isolated Saponin Due to the Amelioration of Tauopathy and Alleviation of Neuroinflammation: A Therapeutic Approach to Alzheimer’s Disease

by Muhammad Imran Khan, Muhammad Zubair Khan, Jin Hyuk Shin, Tai Sun Shin, Young Bok Lee, Min Yong Kim and Jong Deog Kim

Molecules 2022, 27(7), 2079; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27072079 - 24 Mar 2022

Cited by 6 | Viewed by 2514

Abstract

Tauopathy is one of the major causes of neurodegenerative disorders and diseases such as Alzheimer’s disease (AD). Hyperphosphorylation of tau proteins by various kinases leads to the formation of PHF and NFT and eventually results in tauopathy and AD; similarly, neuroinflammation also exaggerates and accelerates neuropathy and neurodegeneration. Natural products with anti-tauopathy and anti-neuroinflammatory effects are highly recommended as safe and feasible ways of preventing and /or treating neurodegenerative diseases, including AD. In the present study, we isolated theasaponin E1 from ethanol extract of green tea seed and evaluated its therapeutic inhibitory effects on tau hyper-phosphorylation and neuroinflammation in neuroblastoma (SHY-5Y) and glioblastoma (HTB2) cells, respectively, to elucidate the mechanism of the inhibitory effects. The expression of tau-generating and phosphorylation-promoting genes under the effects of theasaponin E1 were determined and assessed by RT- PCR, ELISA, and western blotting. It was found that theasaponin E1 reduced hyperphosphorylation of tau and Aβ concentrations significantly, and dose-dependently, by suppressing the expression of GSK3 β, CDK5, CAMII, MAPK, EPOE4(E4), and PICALM, and enhanced the expression of PP1, PP2A, and TREM2. According to the ELISA and western blotting results, the levels of APP, Aβ, and p-tau were reduced by treatment with theasaponin E1. Moreover, theasaponin E1 reduced inflammation by suppressing the Nf-kB pathway and dose-dependently reducing the levels of inflammatory cytokines such as IL-1beta, IL-6, and TNF-alpha etc. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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16 pages, 2214 KiB

Open AccessArticle

In Vitro and Computational Studies of Perezone and Perezone Angelate as Potential Anti-Glioblastoma Multiforme Agents

by Maricarmen Hernández-Rodríguez, Pablo I. Mendoza Sánchez, Joel Martínez, Martha E. Macías Pérez, Erika Rosales Cruz, Teresa Żołek, Dorota Maciejewska, René Miranda Ruvalcaba, Elvia Mera Jiménez and María I. Nicolás-Vázquez

Molecules 2022, 27(5), 1565; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27051565 - 26 Feb 2022

Cited by 2 | Viewed by 1941

Abstract

Glioblastoma multiforme (GBM) represents the most malignant type of astrocytoma, with a life expectancy of two years. It has been shown that Poly (ADP-ribose) polymerase 1 (PARP-1) protein is over-expressed in GBM cells, while its expression in healthy tissue is low. In addition, perezone, a phyto-compound, is a PARP-1 inhibitor with anti-neoplastic activity. As a consequence, in the present study, both in vitro and computational evaluations of perezone and its chemically related compound, perezone angelate, as anti-GBM agents were performed. Hence, the anti-proliferative assay showed that perezone angelate induces higher cytotoxicity in the GBM cell line (U373 IC₅₀ = 6.44 μM) than perezone (U373 IC₅₀ = 51.20 μM) by induction of apoptosis. In addition, perezone angelate showed low cytotoxic activity in rat glial cells (IC₅₀ = 173.66 μM). PARP-1 inhibitory activity (IC₅₀ = 5.25 μM) and oxidative stress induction by perezone angelate were corroborated employing in vitro studies. In the other hand, the performed docking studies allowed explaining the PARP-1 inhibitory activity of perezone angelate, and ADMET studies showed its probability to permeate cell membranes and the blood–brain barrier, which is an essential characteristic of drugs to treat neurological diseases. Finally, it is essential to highlight that the results confirm perezone angelate as a potential anti-GBM agent. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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Review

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22 pages, 3831 KiB

Open AccessReview

Computer-Aided Drug Design towards New Psychotropic and Neurological Drugs

by Georgia Dorahy, Jake Zheng Chen and Thomas Balle

Molecules 2023, 28(3), 1324; https://doi.org/10.3390/molecules28031324 - 30 Jan 2023

Cited by 12 | Viewed by 5463

Abstract

Central nervous system (CNS) disorders are a therapeutic area in drug discovery where demand for new treatments greatly exceeds approved treatment options. This is complicated by the high failure rate in late-stage clinical trials, resulting in exorbitant costs associated with bringing new CNS drugs to market. Computer-aided drug design (CADD) techniques minimise the time and cost burdens associated with drug research and development by ensuring an advantageous starting point for pre-clinical and clinical assessments. The key elements of CADD are divided into ligand-based and structure-based methods. Ligand-based methods encompass techniques including pharmacophore modelling and quantitative structure activity relationships (QSARs), which use the relationship between biological activity and chemical structure to ascertain suitable lead molecules. In contrast, structure-based methods use information about the binding site architecture from an established protein structure to select suitable molecules for further investigation. In recent years, deep learning techniques have been applied in drug design and present an exciting addition to CADD workflows. Despite the difficulties associated with CNS drug discovery, advances towards new pharmaceutical treatments continue to be made, and CADD has supported these findings. This review explores various CADD techniques and discusses applications in CNS drug discovery from 2018 to November 2022. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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28 pages, 43996 KiB

Open AccessReview

A Review on Recent Approaches on Molecular Docking Studies of Novel Compounds Targeting Acetylcholinesterase in Alzheimer Disease

by Stergiani-Chrysovalanti Peitzika and Eleni Pontiki

Molecules 2023, 28(3), 1084; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28031084 - 21 Jan 2023

Cited by 18 | Viewed by 3638

Abstract

Alzheimer’s disease (AD), a neurodegenerative brain disorder that affects millions of people worldwide, is characterized by memory loss and cognitive decline. Low levels of acetylcholine and abnormal levels of beta-amyloid, T protein aggregation, inflammation, and oxidative stress, have been associated with AD, and therefore, research has been oriented towards the cholinergic system and primarily on acetylcholinesterase (AChE) inhibitors. In this review, we are focusing on the discovery of AChE inhibitors using computer-based modeling and simulation techniques, covering the recent literature from 2018–2022. More specifically, the review discusses the structures of novel, potent acetylcholinesterase inhibitors and their binding mode to AChE, as well as the physicochemical requirements for the design of potential AChE inhibitors. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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24 pages, 4028 KiB

Open AccessReview

Allosteric Modulators of Dopamine D₂ Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

by Agnieszka A. Kaczor, Tomasz M. Wróbel and Damian Bartuzi

Molecules 2023, 28(1), 178; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28010178 - 25 Dec 2022

Cited by 7 | Viewed by 2492

Abstract

Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays a hot topic in medicinal chemistry. Allosteric modulators, i.e., compounds which bind in a receptor site topologically distinct from orthosteric sites, exhibit a number of advantages. They are more selective, safer and display a ceiling effect which prevents overdosing. Allosteric modulators of dopamine D₂ receptor are potential drugs against a number of psychiatric and neurological diseases, such as schizophrenia and Parkinson’s disease. In this review, an insightful summary of current research on D₂ receptor modulators is presented, ranging from their pharmacology and structural aspects of ligand-receptor interactions to their synthesis. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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21 pages, 834 KiB

Open AccessReview

Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence

by Efthalia Angelopoulou, Efstratios-Stylianos Pyrgelis and Christina Piperi

Molecules 2022, 27(23), 8448; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27238448 - 2 Dec 2022

Cited by 11 | Viewed by 3712

Abstract

Neurodegenerative diseases constitute a broad range of central nervous system disorders, characterized by neuronal degeneration. Alzheimer’s disease, Parkinson’s disease, amyolotrophic lateral sclerosis (ALS), and progressive forms of multiple sclerosis (MS) are some of the most frequent neurodegenerative diseases. Despite their diversity, these diseases share some common pathophysiological mechanisms: the abnormal aggregation of disease-related misfolded proteins, autophagosome–lysosome pathway dysregulation, impaired ubiquitin–proteasome system, oxidative damage, mitochondrial dysfunction and excessive neuroinflammation. There is still no effective drug that could halt the progression of neurodegenerative diseases, and the current treatments are mainly symptomatic. In this regard, the development of novel multi-target pharmaceutical approaches presents an attractive therapeutic strategy. Ibudilast, an anti-inflammatory drug firstly developed as an asthma treatment, is a cyclic nucleotide phosphodiesterases (PDEs) inhibitor, which mainly acts by increasing the amount of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), while downregulating the pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF) and Toll-like receptor 4 (TLR-4). The preclinical evidence shows that ibudilast may act neuroprotectively in neurodegenerative diseases, by suppressing neuroinflammation, inhibiting apoptosis, regulating the mitochondrial function and by affecting the ubiquitin–proteasome and autophagosome–lysosome pathways, as well as by attenuating oxidative stress. The clinical trials in ALS and progressive MS also show some promising results. Herein, we aim to provide an update on the emerging preclinical and clinical evidence on the therapeutic potential of ibudilast in these disorders, discuss the potential challenges and suggest the future directions. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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22 pages, 2295 KiB

Open AccessReview

Green Tea Catechins Attenuate Neurodegenerative Diseases and Cognitive Deficits

by Obaid Afzal, Mahmood Hassan Dalhat, Abdulmalik S. A. Altamimi, Rabia Rasool, Sami I. Alzarea, Waleed Hassan Almalki, Bibi Nazia Murtaza, Saima Iftikhar, Shamaila Nadeem, Muhammad Shahid Nadeem and Imran Kazmi

Molecules 2022, 27(21), 7604; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27217604 - 6 Nov 2022

Cited by 21 | Viewed by 4429

Abstract

Neurodegenerative diseases exert an overwhelming socioeconomic burden all around the globe. They are mainly characterized by modified protein accumulation that might trigger various biological responses, including oxidative stress, inflammation, regulation of signaling pathways, and excitotoxicity. These disorders have been widely studied during the last decade in the hopes of developing symptom-oriented therapeutics. However, no definitive cure has yet been discovered. Tea is one of the world’s most popular beverages. The same plant, Camellia Sinensis (L.).O. Kuntze, is used to make green, black, and oolong teas. Green tea has been most thoroughly studied because of its anti-cancer, anti-obesity, antidiabetic, anti-inflammatory, and neuroprotective properties. The beneficial effect of consumption of tea on neurodegenerative disorders has been reported in several human interventional and observational studies. The polyphenolic compounds found in green tea, known as catechins, have been demonstrated to have many therapeutic effects. They can help in preventing and, somehow, treating neurodegenerative diseases. Catechins show anti-inflammatory as well as antioxidant effects via blocking cytokines’ excessive production and inflammatory pathways, as well as chelating metal ions and free radical scavenging. They may inhibit tau protein phosphorylation, amyloid beta aggregation, and release of apoptotic proteins. They can also lower alpha-synuclein levels and boost dopamine levels. All these factors have the potential to affect neurodegenerative disorders. This review will examine catechins’ neuroprotective effects by highlighting their biological, pharmacological, antioxidant, and metal chelation abilities, with a focus on their ability to activate diverse cellular pathways in the brain. This review also points out the mechanisms of catechins in various neurodegenerative and cognitive diseases, including Alzheimer’s, Parkinson’s, multiple sclerosis, and cognitive deficit. Full article

(This article belongs to the Special Issue Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases)

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