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Therapeutic Agents for Neurodegenerative Disorders

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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 2023) | Viewed by 31826

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Dr. Andrea Kwakowsky

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Guest Editor

Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
Interests: neurotrasmitters; estrogens; neurotrophins; neurodegenerative disorders; drug discovery and development
Special Issues, Collections and Topics in MDPI journals

Dr. Margaret Ryan

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Guest Editor

Brain Health Research Centre, University of Otago, PO Box 56, Dunedin, New Zealand
Interests: Dr. Ryan's interest is in how memories are formed and stored in the brain at the molecular level and how this may be altered in Alzheimer's disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue of Molecules provides a forum for the dissemination of the most recent findings on therapeutic agents for neurodegenerative diseases.

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as amyotrophic lateral sclerosis pose extraordinary challenges for drug development. There is a great need for therapies to prevent and/or slow the progression of these disorders. The etiology of most neurodegenerative diseases is still unknown, but several factors are thought to contribute to the neurodegenerative process, such as oxidative stress, excitotoxicity, protein aggregation, vascular dysfunction, and neuroinflammation. These processes culminate in the death of specific neuronal populations, leading to cognitive and/or motor impairments, and they offer many potential therapeutic targets. Most current treatments for these disorders target single aspects of disease pathology. However, this strategy has yet to fulfil expectations in clinical trials, and focus has now turned toward therapeutics which target multiple aspects underlying neurodegeneration to ensure future treatment success. A number of these therapeutic targets also serve multiple roles as biomarkers and as theranostics. Drug designs have also shifted from treating neurodegenerative diseases at later stages of disease progression to focusing on preventive strategies at early stages of disease development.

We welcome the submission of research and review articles on the advances in every aspect of drug discovery in the field of neurodegenerative diseases.

Dr. Andrea Kwakowsky
Dr. Margaret Ryan
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

Beta amyloid
Tau
Alpha-synuclein
Huntingtin
Autophagy
Neuromodulators
Neurotrophins
Natural compounds
Neuroinflammation
Vascular dysfunction
Neuronal death
Drug development
Therapeutic biomarkers
Blood–brain barrier
Small-molecule therapeutics
Theranostics

Related Special Issue

Therapeutic Agents for Neurodegenerative Disorders in Molecules (2 articles)

Published Papers (8 papers)

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Research

Jump to: Review

14 pages, 7177 KiB

Open AccessArticle

Various Energetic Metabolism of Microglia in Response to Different Stimulations

by Xiaohui Liu, Ning Jiang and Wenxia Zhou

Molecules 2023, 28(11), 4501; https://doi.org/10.3390/molecules28114501 - 1 Jun 2023

Cited by 1 | Viewed by 1512

Abstract

The activation of the microglia plays an important role in the neuroinflammation induced by different stimulations associated with Alzheimer’s disease (AD). Different stimulations, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and cytokines, trigger a consequence of activation in the microglia with diverse changes of the microglial cell type response in AD. The activation of the microglia is often accompanied by metabolic changes in response to PAMPs, DAMPs and cytokines in AD. Actually, we do not know the distinct differences on the energetic metabolism of microglia when subject to these stimuli. This research assessed the changes of the cell type response and energetic metabolism in mouse-derived immortalized cells (BV-2 cells) induced by a PAMP (LPS), DAMPs (Aβ and ATP) and a cytokine (IL-4) in mouse-derived immortalized cells (BV-2 cells) and whether the microglial cell type response was improved by targeting the metabolism. We uncovered that LPS, a proinflammatory stimulation of PAMPs, modified the morphology from irregular to fusiform, with stronger cell viability, fusion rates and phagocytosis in the microglia accompanied by a metabolic shift to the promotion of glycolysis and the inhibition of oxidative phosphorylation (OXPHOS). Aβ and ATP, which are two known kinds of DAMPs that trigger microglial sterile activation, induced the morphology from irregular to amoebic, and significantly decreased others in the microglia, accompanied by boosting or reducing both glycolysis and OXPHOS. Monotonous pathological changes and energetic metabolism of microglia were observed under IL-4 exposure. Further, the inhibition of glycolysis transformed the LPS-induced proinflammatory morphology and decreased the enhancement of LPS-induced cell viability, the fusion rate and phagocytosis. However, the promotion of glycolysis exerted a minimal effect on the changes of morphology, the fusion rate, cell viability and phagocytosis induced by ATP. Our study reveals that microglia induced diverse pathological changes accompanied by various changes in the energetic metabolism in response to PAMPs, DAMPs and cytokines, and it may be a potential application of targeting the cellular metabolism to interfere with the microglia-mediated pathological changes in AD. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurodegenerative Disorders)

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23 pages, 6885 KiB

Open AccessArticle

A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway

by Ying Han, Le Chen, Jingyun Liu, Jie Chen, Chunyang Wang, Yu Guo, Xuebin Yu, Chenghong Zhang, Haiying Chu and Haiying Ma

Molecules 2022, 27(13), 4160; https://doi.org/10.3390/molecules27134160 - 29 Jun 2022

Cited by 12 | Viewed by 2689

Abstract

As a neurodegenerative disease, Alzheimer’s disease (AD) seriously affects the health of older people. Changes in synapses occur first over the course of the disease, perhaps even before the formation of Aβ plaques. Histone deacetylase (HDAC) mediates the damage of Aβ oligomers to dendritic spines. Therefore, we examined the relationship between HDAC activity and synaptic defects using an HDAC inhibitor (HDACI), BG45, in the human neuroblastoma SH-SY5Y cell line with stable overexpression of Swedish mutant APP (APPsw) and in APP/PS1 transgenic mice during this study. The cells were treated with 15 μM BG45 and the APP/PS1 mice were treated with 30 mg/kg BG45. We detected the levels of synapse-related proteins, HDACs, tau phosphorylation, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors using Western blotting and immunohistochemistry. We also measured the expression of cytoskeletal proteins in the cell model. The mRNA levels of the glutamate ion receptor alginate subunit 2 (GRIK2), sodium voltage-gated channel beta subunit (SCN3B), synaptophysin (SYP), Grm2 (the gene encoding glutamate receptor subunit 2 (GluR2)), Grid2IP, glutamate receptor interacting protein 1 (GRIP1), and GRIP2 were detected to explore the effects of the HDACI on regulating the expression of synaptic proteins and AMPA receptors. According to our studies, the expressions of HDAC1, HDAC2, and HDAC3 were increased, which were accompanied by the downregulation of the synapse-related proteins SYP, postsynaptic dendritic protein (PSD-95), and spinophilin as early as 24 h after transfection with the APPsw gene. BG45 upregulated the expression of synapse-related proteins and repaired cytoskeletal damage. In vivo, BG45 alleviated the apoptosis-mediated loss of hippocampal neurons, upregulated synapse-related proteins, reduced Aβ deposition and phosphorylation of tau, and increased the levels of the synapse-related genes GRIK2, SCN3B, SYP, Grm2, and Grid2IP. BG45 increased the expression of the AMPA receptor subunits GluA1, GluA2, and GluA3 on APPsw-transfected cells and increased GRIP1 and GRIP2 expression and AMPA receptor phosphorylation in vivo. Based on these results, HDACs are involved in the early process of synaptic defects in AD models, and BG45 may rescue synaptic damage and the loss of hippocampal neurons by specifically inhibiting HDAC1, HDAC2, and HDAC3, thereby modulating AMPA receptor transduction, increasing synapse-related gene expression, and finally enhancing the function of excitatory synapses. BG45 may be considered a potential drug for the treatment of early AD in further studies. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurodegenerative Disorders)

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12 pages, 1967 KiB

Open AccessArticle

Identification of Potential Anti-Neuroinflammatory Inhibitors from Antarctic Fungal Strain Aspergillus sp. SF-7402 via Regulating the NF-κB Signaling Pathway in Microglia

by Thao Quyen Cao, Zhiming Liu, Linsha Dong, Hwan Lee, Wonmin Ko, Le Ba Vinh, Nguyen Quoc Tuan, Youn-Chul Kim, Jae Hak Sohn, Joung Han Yim, Dong-Sung Lee and Hyuncheol Oh

Molecules 2022, 27(9), 2851; https://doi.org/10.3390/molecules27092851 - 29 Apr 2022

Cited by 1 | Viewed by 2053

Abstract

Microglia play a significant role in immune defense and tissue repair in the central nervous system (CNS). Microglial activation and the resulting neuroinflammation play a key role in the pathogenesis of neurodegenerative disorders. Recently, inflammation reduction strategies in neurodegenerative diseases have attracted increasing attention. Herein, we discovered and evaluated the anti-neuroinflammatory potential of compounds from the Antarctic fungi strain Aspergillus sp. SF-7402 in lipopolysaccharide (LPS)-stimulated BV2 cells. Four metabolites were isolated from the fungi through chemical investigations, namely, 5-methoxysterigmatocystin (1), sterigmatocystin (2), aversin (3), and 6,8-O-dimethylversicolorin A (4). Their chemical structures were elucidated by extensive spectroscopic analysis and HR-ESI-MS, as well as by comparison with those reported in literature. Anti-neuroinflammatory effects of the isolated metabolites were evaluated by measuring the production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in LPS-activated microglia at non-cytotoxic concentrations. Sterigmatocystins (1 and 2) displayed significant effects on NO production and mild effects on TNF-α and IL-6 expression inhibition. The molecular mechanisms underlying this activity were investigated using Western blot analysis. Sterigmatocystin treatment inhibited NO production via downregulation of inducible nitric oxide synthase (iNOS) expression in LPS-stimulated BV2 cells. Additionally, sterigmatocystins reduced nuclear translocation of NF-κB. These results suggest that sterigmatocystins present in the fungal strain Aspergillus sp. are promising candidates for the treatment of neuroinflammatory diseases. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurodegenerative Disorders)

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17 pages, 3071 KiB

Open AccessArticle

In Silico Screening of Natural Compounds for Candidates 5HT6 Receptor Antagonists against Alzheimer’s Disease

by Tijana Bojić, Milan Sencanski, Vladimir Perovic, Jelena Milicevic and Sanja Glisic

Molecules 2022, 27(9), 2626; https://doi.org/10.3390/molecules27092626 - 19 Apr 2022

Cited by 4 | Viewed by 3039

Abstract

Alzheimer’s disease (AD), a devastating neurodegenerative disease, is the focus of pharmacological research. One of the targets that attract the most attention for the potential therapy of AD is the serotonin 5HT6 receptor, which is the receptor situated exclusively in CNS on glutamatergic and GABAergic neurons. The neurochemical impact of this receptor supports the hypothesis about its role in cognitive, learning, and memory systems, which are of critical importance for AD. Natural products are a promising source of novel bioactive compounds with potential therapeutic potential as a 5HT6 receptor antagonist in the treatment of AD dementia. The ZINC—natural product database was in silico screened in order to find the candidate antagonists of 5-HT6 receptor against AD. A virtual screening protocol that includes both short-and long-range interactions between interacting molecules was employed. First, the EIIP/AQVN filter was applied for in silico screening of the ZINC database followed by 3D QSAR and molecular docking. Ten best candidate compounds were selected from the ZINC Natural Product database as potential 5HT6 Receptor antagonists and were proposed for further evaluation. The best candidate was evaluated by molecular dynamics simulations and free energy calculations. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurodegenerative Disorders)

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8 pages, 2066 KiB

Open AccessArticle

Molecular Modeling and Experimental Evaluation of Non-Chiral Components of Bergamot Essential Oil with Inhibitory Activity against Human Monoamine Oxidases

by Raffaella Catalano, Francesca Procopio, Daniel Chavarria, Sofia Benfeito, Stefano Alcaro, Fernanda Borges and Francesco Ortuso

Molecules 2022, 27(8), 2467; https://doi.org/10.3390/molecules27082467 - 11 Apr 2022

Cited by 4 | Viewed by 2600

Abstract

Human monoamine oxidases (hMAOs) are well-established targets for the treatment of neurological disorders such as depression, Parkinson’s disease and Alzheimer’s disease. Despite the efforts carried out over the years, few selective and reversible MAO inhibitors are on the market. Thus, a continuous search for new compounds is needed. Herein, MAO inhibitors were searched among the non-chiral constituents of Bergamot Essential Oil (BEO) with the aid of computational tools. Accordingly, molecular modeling simulations were carried out on both hMAO-A and hMAO-B for the selected constituents. The theoretically predicted target recognition was then used to select the most promising compounds. Among the screened compounds, Bergamottin, a furocoumarin, showed selective hMAO-B inhibitory activity, fitting its active site well. Molecular dynamics simulations were used to deeply analyze the target recognition and to rationalize the selectivity preference. In agreement with the computational results, experimental studies confirmed both the hMAO inhibition properties of Bergamottin and its preference for the isoform B. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurodegenerative Disorders)

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24 pages, 6684 KiB

Open AccessArticle

Beta-Amyloid (Aβ_1-42) Increases the Expression of NKCC1 in the Mouse Hippocampus

by Patricia Lam, Chitra Vinnakota, Beatriz Calvo-Flores Guzmán, Julia Newland, Katie Peppercorn, Warren P. Tate, Henry J. Waldvogel, Richard L. M. Faull and Andrea Kwakowsky

Molecules 2022, 27(8), 2440; https://doi.org/10.3390/molecules27082440 - 10 Apr 2022

Cited by 8 | Viewed by 2974

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder with an increasing need for developing disease-modifying treatments as current therapies only provide marginal symptomatic relief. Recent evidence suggests the γ-aminobutyric acid (GABA) neurotransmitter system undergoes remodeling in AD, disrupting the excitatory/inhibitory (E/I) balance in the brain. Altered expression levels of K-Cl-2 (KCC2) and N-K-Cl-1 (NKCC1), which are cation–chloride cotransporters (CCCs), have been implicated in disrupting GABAergic activity by regulating GABA_A receptor signaling polarity in several neurological disorders, but these have not yet been explored in AD. NKCC1 and KCC2 regulate intracellular chloride [Cl⁻]_i by accumulating and extruding Cl⁻, respectively. Increased NKCC1 expression in mature neurons has been reported in these disease conditions, and bumetanide, an NKCC1 inhibitor, is suggested to show potential therapeutic benefits. This study used primary mouse hippocampal neurons to explore if KCC2 and NKCC1 expression levels are altered following beta-amyloid (Aβ_1-42) treatment and the potential neuroprotective effects of bumetanide. KCC2 and NKCC1 expression levels were also examined in 18-months-old male C57BL/6 mice following bilateral hippocampal Aβ_1-42 stereotaxic injection. No change in KCC2 and NKCC1 expression levels were observed in mouse hippocampal neurons treated with 1 nM Aβ_1-42, but NKCC1 expression increased 30-days post-Aβ_1-42-injection in the CA1 region of the mouse hippocampus. Primary mouse hippocampal cultures were treated with 1 nM Aβ_1-42 alone or with various concentrations of bumetanide (1 µM, 10 µM, 100 µM, 1 mM) to investigate the effect of the drug on cell viability. Aβ_1-42 produced 53.1 ± 1.4% cell death after 5 days, and the addition of bumetanide did not reduce this. However, the drug at all concentrations significantly reduced cell viability, suggesting bumetanide is highly neurotoxic. In summary, these results suggest that chronic exposure to Aβ_1-42 alters the balance of KCC2 and NKCC1 expression in a region-and layer-specific manner in mouse hippocampal tissue; therefore, this process most likely contributes to altered hippocampal E/I balance in this model. Furthermore, bumetanide induces hippocampal neurotoxicity, thus questioning its suitability for AD therapy. Further investigations are required to examine the effects of Aβ_1-42 on KCC2 and NKCC1 expression and whether targeting CCCs might offer a therapeutic approach for AD. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurodegenerative Disorders)

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Review

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41 pages, 1499 KiB

Open AccessReview

Neuroprotective Effect of Caffeine in Alzheimer’s Disease

by Y Mukish M Yelanchezian, Henry J. Waldvogel, Richard L. M. Faull and Andrea Kwakowsky

Molecules 2022, 27(12), 3737; https://doi.org/10.3390/molecules27123737 - 10 Jun 2022

Cited by 14 | Viewed by 6455

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia, predicted to be the most significant health burden of the 21st century, with an estimated 131.5 million dementia patients by the year 2050. This review aims to provide an overview of the effect of caffeine on AD and cognition by summarizing relevant research conducted on this topic. We searched the Web of Science core collection and PubMed for studies related to the effect of caffeine on AD and cognition using title search terms: caffeine; coffee; Alzheimer’s; cognition. There is suggestive evidence from clinical studies that caffeine is neuroprotective against dementia and possibly AD (20 out of 30 studies support this), but further studies, such as the “ideal” study proposed in this review, are required to prove this link. Clinical studies also indicate that caffeine is a cognitive normalizer and not a cognitive enhancer. Furthermore, clinical studies suggest the neuroprotective effect of caffeine might be confounded by gender. There is robust evidence based on in vivo and in vitro studies that caffeine has neuroprotective properties in AD animal models (21 out of 22 studies support this), but further studies are needed to identify the mechanistic pathways mediating these effects. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurodegenerative Disorders)

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14 pages, 2284 KiB

Open AccessReview

FNDC5/Irisin: Physiology and Pathophysiology

by Rashid Waseem, Anas Shamsi, Taj Mohammad, Md. Imtaiyaz Hassan, Syed Naqui Kazim, Anis Ahmad Chaudhary, Hassan Ahmed Rudayni, Mohammed Al-Zharani, Faizan Ahmad and Asimul Islam

Molecules 2022, 27(3), 1118; https://doi.org/10.3390/molecules27031118 - 8 Feb 2022

Cited by 59 | Viewed by 9215

Abstract

A sedentary lifestyle or lack of physical activity increases the risk of different diseases, including obesity, diabetes, heart diseases, certain types of cancers, and some neurological diseases. Physical exercise helps improve quality of life and reduces the risk of many diseases. Irisin, a hormone induced by exercise, is a fragmented product of FNDC5 (a cell membrane protein) and acts as a linkage between muscles and other tissues. Over the past decade, it has become clear that irisin is a molecular mimic of exercise and shows various beneficial effects, such as browning of adipocytes, modulation of metabolic processes, regulation of bone metabolism, and functioning of the nervous system. Irisin has a role in carcinogenesis; numerous studies have shown its impact on migration, invasion, and proliferation of cancer cells. The receptor of irisin is not completely known; however, in some tissues it probably acts via a specific class of integrin receptors. Here, we review research from the past decade that has identified irisin as a potential therapeutic agent in the prevention or treatment of various metabolic-related and other diseases. This article delineates structural and biochemical aspects of irisin and provides an insight into the role of irisin in different pathological conditions. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurodegenerative Disorders)

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