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Role of Bioactives in Neurodegenerative Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (10 July 2023) | Viewed by 23941

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Dr. Lefteris Zacharia

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Department of Life and Health Sciences, University of Nicosia, Nicosia 1700, Cyprus
Interests: hormones; tau hyper phosphorylation; Aβ aggregation inhibitors; adrenoreceptors; peptides; natural compounds; neurodegeneration

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases (amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease) lack disease modifying therapeutics. In an effort to identify therapeutics for these diseases, researchers focus on the effects of diverse types of compounds on neurodegeneration, and study their mechanisms of action. Ultimately, the aim is to identify novel compounds with disease-modifying properties, and to contribute to the endeavor of finding much-needed effective therapeutics for these diseases. Such compounds may be “bioactive” compounds, which are defined as substances of natural or synthetic origin that have biological activity.

The aim of this Special Issue is to gather manuscripts (reviews or original research articles) that highlight the role of bioactive substances in neurodegenerative diseases. We welcome the submission of papers discussing bioactive substances that target Aβ, tau, BACE, acetylcholinesterase, oxidative stress/free radicals, a-Synuclein, dopaminergic/cholinergic neurons, mitochondria, neurodegenerative signaling pathways, apoptotic pathways, or other targets related to the pathogenesis of neurodegenerative diseases. The studies can be in vitro or in vivo and may include new or traditional targets that highlight the role of such bioactive compounds in these diseases. In this regard, I invite you to submit your articles on the “Role of Bioactives in Neurodegenerative diseases”, whether these are natural or synthetic, small molecules, peptides, peptidomimetics, natural compounds or even plant extracts/phytochemicals. This Special Issue will generally discuss the role of bioactives in neurodegenerative diseases and gather information on the different bioactives and their effect on old or novel targets for these diseases.

Importantly, the exact active ingredient of natural-origin extracts must be reported in the submitted research manuscripts, since papers describing the effects of mixed extracts of natural origin are not within the scope of the journal.

Dr. Lefteris Zacharia
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

Aβ
tau
hormones
bioactives
BACE
neurodegeneration
oxidative stress

Published Papers (12 papers)

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Editorial

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4 pages, 145 KiB

Open AccessEditorial

Role of Bioactives in Neurodegenerative Diseases

by Lefteris C. Zacharia

Int. J. Mol. Sci. 2024, 25(9), 4951; https://doi.org/10.3390/ijms25094951 - 1 May 2024

Viewed by 309

Abstract

Neurodegenerative diseases (NDs) affect millions worldwide, with the two most prevalent being Alzheimer’s and Parkinson disease [...] Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

Research

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21 pages, 5957 KiB

Open AccessArticle

Stealth Liposomes Encapsulating a Potent ACAT1/SOAT1 Inhibitor F12511: Pharmacokinetic, Biodistribution, and Toxicity Studies in Wild-Type Mice and Efficacy Studies in Triple Transgenic Alzheimer’s Disease Mice

by Adrianna L. De La Torre, Thao N. Huynh, Catherine C. Y. Chang, Darcy B. Pooler, Dylan B. Ness, Lionel D. Lewis, Sanjana Pannem, Yichen Feng, Kimberley S. Samkoe, William F. Hickey and Ta Yuan Chang

Int. J. Mol. Sci. 2023, 24(13), 11013; https://doi.org/10.3390/ijms241311013 - 2 Jul 2023

Cited by 1 | Viewed by 1797

Abstract

Cholesterol is essential for cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is catalyzed by the enzymes acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 being the primary isoenzyme in most cells in humans. In Alzheimer’s Disease, CEs accumulate in vulnerable brain regions. Therefore, ACATs may be promising targets for treating AD. F12511 is a high-affinity ACAT1 inhibitor that has passed phase 1 safety tests for antiatherosclerosis. Previously, we developed a nanoparticle system to encapsulate a large concentration of F12511 into a stealth liposome (DSPE-PEG₂₀₀₀ with phosphatidylcholine). Here, we injected the nanoparticle encapsulated F12511 (nanoparticle F) intravenously (IV) in wild-type mice and performed an HPLC/MS/MS analysis and ACAT enzyme activity measurement. The results demonstrated that F12511 was present within the mouse brain after a single IV but did not overaccumulate in the brain or other tissues after repeated IVs. A histological examination showed that F12511 did not cause overt neurological or systemic toxicity. We then showed that a 2-week IV delivery of nanoparticle F to aging 3xTg AD mice ameliorated amyloidopathy, reduced hyperphosphorylated tau and nonphosphorylated tau, and reduced neuroinflammation. This work lays the foundation for nanoparticle F to be used as a possible therapy for AD and other neurodegenerative diseases. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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13 pages, 1526 KiB

Open AccessArticle

Determination and Comparison of Soybean Lecithin and Bovine Brain Plasmalogens Effects in Healthy Male Wistar Rats

by Yuliya S. Sidorova, Varuzhan A. Sarkisyan, Nikita A. Petrov, Yuliya V. Frolova and Alla A. Kochetkova

Int. J. Mol. Sci. 2023, 24(8), 7643; https://doi.org/10.3390/ijms24087643 - 21 Apr 2023

Viewed by 1459

Abstract

The aim of this study was to investigate the effects of soybean lecithin and plasmalogens concentrating on a variety of physiological tests and biochemical analyses in healthy Wistar rats. For six weeks, male Wistar rats were given a standard diet that included plasmalogens or soybean lecithin. We measured anxiety levels, overall exploratory activity, short- and long-term memory, cognitive abilities, and grip strength. Lecithin increased significantly anxiety and enhanced memory and cognitive functions. Plasmalogens significantly improved appetite and increased grip strength. When compared to plasmalogens, lecithin significantly raised HDL levels while lowering LDL levels. The plasmalogens group showed a significant increase in the C16:0DMA/C16:0 ratio, which led us to assume that plasmalogen consumption could increase their synthesis in neural tissue. The study’s findings imply that, despite their various modes of action, soy lecithin and plasmalogens may both be significant nutritional components for enhancing cognitive functions. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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18 pages, 8438 KiB

Open AccessArticle

New Thienobenzo/Naphtho-Triazoles as Butyrylcholinesterase Inhibitors: Design, Synthesis and Computational Study

by Milena Mlakić, Ida Selec, Irena Ćaleta, Ilijana Odak, Danijela Barić, Ana Ratković, Krešimir Molčanov and Irena Škorić

Int. J. Mol. Sci. 2023, 24(6), 5879; https://doi.org/10.3390/ijms24065879 - 20 Mar 2023

Cited by 3 | Viewed by 1452

Abstract

This study aims to test the inhibition potency of new thienobenzo/naphtho-triazoles toward cholinesterases, evaluate their inhibition selectivity, and interpret the obtained results by molecular modeling. The synthesis of 19 new thienobenzo/naphtho-triazoles by two different approaches resulted in a large group of molecules with different functionalities in the structure. As predicted, most prepared molecules show better inhibition of the enzyme butyrylcholinesterase (BChE), considering that the new molecules were designed according to the previous results. Interestingly, the binding affinity of BChE for even seven new compounds (1, 3, 4, 5, 6, 9, and 13) was similar to that reported for common cholinesterase inhibitors. According to computational study, the active thienobenzo- and naphtho-triazoles are accommodated by cholinesterases through H-bonds involving one of the triazole’s nitrogens, π-π stacking between the aromatic moieties of the ligand and aromatic residues of the active sites of cholinesterases, as well as π-alkyl interactions. For the future design of cholinesterase inhibitors and search for therapeutics for neurological disorders, compounds with a thienobenzo/naphtho-triazole skeleton should be considered. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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14 pages, 2786 KiB

Open AccessArticle

Effect of Ovocystatin on Amyloid β 1-42 Aggregation—In Vitro Studies

by Bartłomiej Stańczykiewicz, Tomasz M. Goszczyński, Paweł Migdał, Marta Piksa, Krzysztof Pawlik, Jakub Gburek, Krzysztof Gołąb, Bogusława Konopska and Agnieszka Zabłocka

Int. J. Mol. Sci. 2023, 24(6), 5433; https://doi.org/10.3390/ijms24065433 - 12 Mar 2023

Cited by 2 | Viewed by 1694

Abstract

Amyloid β peptides (Aβ) aggregating in the brain have a potential neurotoxic effect and are believed to be a major cause of Alzheimer’s disease (AD) development. Thus, inhibiting amyloid polypeptide aggregation seems to be a promising approach to the therapy and prevention of this neurodegenerative disease. The research presented here is directed at the determination of the inhibitory activity of ovocystatin, the cysteine protease inhibitor isolated from egg white, on Aβ42 fibril genesis in vitro. Thioflavin-T (ThT) assays, which determine the degree of aggregation of amyloid peptides based on fluorescence measurement, circular dichroism spectroscopy (CD), and transmission electron microscopy (TEM) have been used to assess the inhibition of amyloid fibril formation by ovocystatin. Amyloid beta 42 oligomer toxicity was measured using the MTT test. The results have shown that ovocystatin possesses Aβ42 anti-aggregation activity and inhibits Aβ42 oligomer toxicity in PC12 cells. The results of this work may help in the development of potential substances able to prevent or delay the process of beta-amyloid aggregation—one of the main reasons for Alzheimer’s disease. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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18 pages, 2528 KiB

Open AccessArticle

Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration

by Jennifer Nhieu, Liming Milbauer, Thomas Lerdall, Fatimah Najjar, Chin-Wen Wei, Ryosuke Ishida, Yue Ma, Hiroyuki Kagechika and Li-Na Wei

Int. J. Mol. Sci. 2023, 24(5), 4980; https://doi.org/10.3390/ijms24054980 - 4 Mar 2023

Cited by 4 | Viewed by 1922

Abstract

All-trans-retinoic Acid (atRA) is the principal active metabolite of Vitamin A, essential for various biological processes. The activities of atRA are mediated by nuclear RA receptors (RARs) to alter gene expression (canonical activities) or by cellular retinoic acid binding protein 1 (CRABP1) to rapidly (minutes) modulate cytosolic kinase signaling, including calcium calmodulin-activated kinase 2 (CaMKII) (non-canonical activities). Clinically, atRA-like compounds have been extensively studied for therapeutic applications; however, RAR-mediated toxicity severely hindered the progress. It is highly desirable to identify CRABP1-binding ligands that lack RAR activity. Studies of CRABP1 knockout (CKO) mice revealed CRABP1 to be a new therapeutic target, especially for motor neuron (MN) degenerative diseases where CaMKII signaling in MN is critical. This study reports a P19-MN differentiation system, enabling studies of CRABP1 ligands in various stages of MN differentiation, and identifies a new CRABP1-binding ligand C32. Using the P19-MN differentiation system, the study establishes C32 and previously reported C4 as CRABP1 ligands that can modulate CaMKII activation in the P19-MN differentiation process. Further, in committed MN cells, elevating CRABP1 reduces excitotoxicity-triggered MN death, supporting a protective role for CRABP1 signaling in MN survival. C32 and C4 CRABP1 ligands were also protective against excitotoxicity-triggered MN death. The results provide insight into the potential of signaling pathway-selective, CRABP1-binding, atRA-like ligands in mitigating MN degenerative diseases. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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12 pages, 1812 KiB

Open AccessArticle

Paeoniflorin Attenuates Lipopolysaccharide-Induced Cognitive Dysfunction by Inhibition of Amyloidogenesis in Mice

by Hui Wen Meng, Ji-Hyun Kim, Hyun Young Kim, Ah Young Lee and Eun Ju Cho

Int. J. Mol. Sci. 2023, 24(5), 4838; https://doi.org/10.3390/ijms24054838 - 2 Mar 2023

Cited by 2 | Viewed by 1649

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease, associated with progressive cognitive impairment and memory loss. In the present study, we examined the protective effects of paeoniflorin against memory loss and cognitive decline in lipopolysaccharide (LPS)-induced mice. Treatment with paeoniflorin alleviated LPS-induced neurobehavioral dysfunction, as confirmed by behavioral tests, including the T-maze test, novel-object recognition test, and Morris water maze test. LPS stimulated the amyloidogenic pathway-related proteins (amyloid precursor protein, APP; β-site APP cleavage enzyme, BACE; presenilin1, PS1; presenilin2, PS2) expression in the brain. However, paeoniflorin decreased APP, BACE, PS1, and PS2 protein levels. Therefore, paeoniflorin reverses LPS-induced cognitive impairment via inhibition of the amyloidogenic pathway in mice, which suggests that paeoniflorin may be useful in the prevention of neuroinflammation related to AD. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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22 pages, 3923 KiB

Open AccessArticle

LUHMES Cells: Phenotype Refinement and Development of an MPP⁺-Based Test System for Screening Antiparkinsonian Drugs

by Sergei V. Beliakov, Victor Blokhin, Sergey A. Surkov and Michael V. Ugrumov

Int. J. Mol. Sci. 2023, 24(1), 733; https://doi.org/10.3390/ijms24010733 - 1 Jan 2023

Viewed by 2762

Abstract

The low effectiveness of symptomatic pharmacotherapy for Parkinson’s disease (PD), which compensates for dopamine (DA) deficiency under degeneration of nigrostriatal dopaminergic (DAergic) neurons, could apparently be improved with neuroprotective therapy, which slows down neurodegeneration and PD progression. For this, it is necessary to have a DAergic cell line for the development of a PD model to screen neuroprotectors. We used immortalized human embryonic mesencephalon LUHMES cells (LCs) differentiated into DAergic neurons. The aim of this study was to characterize the phenotype of differentiated LCs and develop an 1-methyl-4-phenylpyridinium iodide (MPP⁺)-based test system for screening neuroprotectors. Using polymerase chain reaction (PCR) and immunocytochemistry, it has been shown that all differentiated LCs express genes and synthesize proteins characteristic of all neurons (microtubule-associated protein 2, bIII-tubulin, synaptotagmin 1) and specifically of DAergic neurons (tyrosine hydroxylase, aromatic L-amino acid decarboxylase, DA transporter, vesicular monoamine transporter 2). Furthermore, LCs are able to produce a small amount of DA, but under special conditions. To assess the mechanisms of neurodegeneration and neuroplasticity under the influence of toxins and antiparkinsonian drugs, including neuroprotectors, we have developed an LCs-based MPP⁺ PD model and proposed an original panel of markers for testing functional and structural cell disorders. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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Review

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21 pages, 1832 KiB

Open AccessReview

DHA/EPA (Omega-3) and LA/GLA (Omega-6) as Bioactive Molecules in Neurodegenerative Diseases

by Christina Kousparou, Maria Fyrilla, Anastasis Stephanou and Ioannis Patrikios

Int. J. Mol. Sci. 2023, 24(13), 10717; https://doi.org/10.3390/ijms241310717 - 27 Jun 2023

Cited by 11 | Viewed by 3348

Abstract

Neurodegenerative diseases are characterized by neuroinflammation, neuronal depletion and oxidative stress. They coincide with subtle chronic or flaring inflammation, sometimes escalating with infiltrations of the immune system cells in the inflamed parts causing mild to severe or even lethal damage. Thus, neurodegenerative diseases show all features of autoimmune diseases. Prevalence of neurodegenerative diseases has dramatically increased in recent decades and unfortunately, the therapeutic efficacy and safety profile of available drugs is moderate. The beneficial effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) polyunsaturated fatty acids (omega-3 PUFAs) are nowadays highlighted by a plethora of studies. They play a role in suppression of inflammation, gene expression, cellular membrane fluidity/permeability, immune functionality and intracellular/exocellular signaling. The role of omega-6 polyunsaturated fatty acids, such as linoleic acid (LA), gamma linolenic acid (GLA), and arachidonic acid (AA), on neuroprotection is controversial, as some of these agents, specifically AA, are proinflammatory, whilst current data suggest that they may have neuroprotective properties as well. This review provides an overview of the existing recent clinical studies with respect to the role of omega-3 and omega-6 PUFAs as therapeutic agents in chronic, inflammatory, autoimmune neurodegenerative diseases as well as the dosages and the period used for testing. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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19 pages, 1692 KiB

Open AccessReview

A Systematic Review of the Effects of Capsaicin on Alzheimer’s Disease

by Deborah Inyang, Tasneem Saumtally, Chinelo Nonyerem Nnadi, Sharmila Devi and Po-Wah So

Int. J. Mol. Sci. 2023, 24(12), 10176; https://doi.org/10.3390/ijms241210176 - 15 Jun 2023

Cited by 5 | Viewed by 2271

Abstract

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterised by cognitive impairment, and amyloid-β plaques and neurofibrillary tau tangles at neuropathology. Capsaicin is a spicy-tasting compound found in chili peppers, with anti-inflammatory, antioxidant, and possible neuroprotective properties. Capsaicin intake has been associated with greater cognitive function in humans, and attenuating aberrant tau hyperphosphorylation in a rat model of AD. This systematic review discusses the potential of capsaicin in improving AD pathology and symptoms. A systematic analysis was conducted on the effect of capsaicin on AD-associated molecular changes, cognitive and behaviour resulting in 11 studies employing rodents and/or cell cultures, which were appraised with the Cochrane Risk of Bias tool. Ten studies showed capsaicin attenuated tau deposition, apoptosis, and synaptic dysfunction; was only weakly effective on oxidative stress; and had conflicting effects on amyloid processing. Eight studies demonstrated improved spatial and working memory, learning, and emotional behaviours in rodents following capsaicin treatment. Overall, capsaicin showed promise in improving AD-associated molecular, cognitive, and behavioural changes in cellular and animal models, and further investigations are recommended to test the readily available bioactive, capsaicin, to treat AD. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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17 pages, 742 KiB

Open AccessReview

Parkinson’s Disease: From Genetics and Epigenetics to Treatment, a miRNA-Based Strategy

by Elena Paccosi and Luca Proietti-De-Santis

Int. J. Mol. Sci. 2023, 24(11), 9547; https://doi.org/10.3390/ijms24119547 - 31 May 2023

Cited by 7 | Viewed by 2216

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, characterized by an initial and progressive loss of dopaminergic neurons of the substantia nigra pars compacta via a potentially substantial contribution from protein aggregates, the Lewy bodies, mainly composed of α-Synuclein among other factors. Distinguishing symptoms of PD are bradykinesia, muscular rigidity, unstable posture and gait, hypokinetic movement disorder and resting tremor. Currently, there is no cure for PD, and palliative treatments, such as Levodopa administration, are directed to relieve the motor symptoms but induce severe side effects over time. Therefore, there is an urgency for discovering new drugs in order to design more effective therapeutic approaches. The evidence of epigenetic alterations, such as the dysregulation of different miRNAs that may stimulate many aspects of PD pathogenesis, opened a new scenario in the research for a successful treatment. Along this line, a promising strategy for PD treatment comes from the potential exploitation of modified exosomes, which can be loaded with bioactive molecules, such as therapeutic compounds and RNAs, and can allow their delivery to the appropriate location in the brain, overcoming the blood–brain barrier. In this regard, the transfer of miRNAs within Mesenchymal stem cell (MSC)-derived exosomes has yet to demonstrate successful results both in vitro and in vivo. This review, besides providing a systematic overview of both the genetic and epigenetic basis of the disease, aims to explore the exosomes/miRNAs network and its clinical potential for PD treatment. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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12 pages, 1306 KiB

Open AccessReview

GM1 Ganglioside as a Disease-Modifying Therapeutic for Parkinson’s Disease: A Multi-Functional Glycosphingolipid That Targets Multiple Parkinson’s Disease-Relevant Pathogenic Mechanisms

by Jay S. Schneider

Int. J. Mol. Sci. 2023, 24(11), 9183; https://doi.org/10.3390/ijms24119183 - 24 May 2023

Cited by 2 | Viewed by 1559

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting millions of patients worldwide. Many therapeutics are available for treating PD symptoms but there is no disease-modifying therapeutic that has been unequivocally shown to slow or stop the progression of the disease. There are several factors contributing to the failure of many putative disease-modifying agents in clinical trials and these include the choice of patients and clinical trial designs for disease modification trials. Perhaps more important, however, is the choice of therapeutic, which for the most part, has not taken into account the multiple and complex pathogenic mechanisms and processes involved in PD. This paper discusses some of the factors contributing to the lack of success in PD disease-modification trials, which have mostly investigated therapeutics with a singular mechanism of action directed at one of the many PD pathogenic processes, and suggests that an alternative strategy for success may be to employ multi-functional therapeutics that target multiple PD-relevant pathogenic mechanisms. Evidence is presented that the multi-functional glycosphingolipid GM1 ganglioside may be just such a therapeutic. Full article

(This article belongs to the Special Issue Role of Bioactives in Neurodegenerative Diseases)

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