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Newly Developed Drugs for Alzheimer's Disease

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

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 17065

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Prof. Dr. Kamil Kuca

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Department of Chemistry, Faculty of Science, University of Hradec Králové, 50003 Hradec Králové, Czech Republic
Interests: toxins; drug design and development; antidotes for pesticide and nerve agent intoxications; Alzheimer’s disease; detergents as disinfectants, decontamination means; nanotechnology; health economics and pharmacoeconomics
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Dr. Martin Valis

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Neurology Clinic, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Interests: brain damage; neurology; Alzheimer’s disease
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Dr. Eugenie Nepovimova

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Department of Chemistry, Faculty of Science, University of Hradec Králové, 50003 Hradec Králové, Czech Republic
Interests: Alzheimer’s disease; antiaging drugs; nerve agent antidotes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Searching for novel drugs for the treatment of Alzheimer’s disease (AD) has become a main task of current developed societies. There novel drug candidates were/are and will be designed, synthesized and tested in many parts of the world. Despite tremendous advances in the understanding of many aspects of AD pathogenesis, there are no proven disease-modifying therapies, and the only available ones are minimally effective symptomatic therapies.

AD is associated with an enzyme acetylcholinesterase (AChE), which is a target for the development of novel drug candidates for these diseases.

In this Special Issue of International Journal of Molecular Sciences, we would like to discuss all chemico-biological aspects are behind Alzheimer’s disease, and related diseases.

Prof. Dr. Kamil Kuca
Dr. Martin Valis
Dr. Eugenie Nepovimova
Guest Editors

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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

alzheimer’s disease
drug development
therapy
treatment
biomarkers
pathophysiology
mechanism
novel drugs
preclinical
drug candidate

Published Papers (5 papers)

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Research

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23 pages, 3627 KiB

Open AccessArticle

Cannabidiol Enhances Microglial Beta-Amyloid Peptide Phagocytosis and Clearance via Vanilloid Family Type 2 Channel Activation

by Shaobin Yang, Yaqin Du, Xiaoqian Zhao, Qi Tang, Wei Su, Yuemeng Hu and Peng Yu

Int. J. Mol. Sci. 2022, 23(10), 5367; https://doi.org/10.3390/ijms23105367 - 11 May 2022

Cited by 16 | Viewed by 2569

Abstract

Alzheimer’s disease (AD) is associated with the accumulation and aggregation of amyloid in the brain. The cation channel TRPV2 may mediate the pathological changes in mild cognitive impairment. A high-affinity agonist of TRPV2 named cannabidiol is one of the candidate drugs for AD. However, the molecular mechanism of cannabidiol via TRPV2 in AD remains unknown. The present study investigated whether cannabidiol enhances the phagocytosis and clearance of microglial Aβ via the TRPV2 channel. We used a human dataset, mouse primary neuron and microglia cultures, and AD model mice to evaluate TRPV2 expression and the ability of microglial amyloid-β phagocytosis in vivo and in vitro. The results revealed that TRPV2 expression was reduced in the cortex and hippocampus of AD model mice and AD patients. Cannabidiol enhanced microglial amyloid-β phagocytosis through TRPV2 activation, which increased the mRNA expression of the phagocytosis-related receptors, but knockdown of TRPV2 or Trem2 rescued the expression. TRPV2-mediated effects were also dependent on PDK1/Akt signaling, a pathway in which autophagy was indispensable. Furthermore, cannabidiol treatment successfully attenuated neuroinflammation while simultaneously improving mitochondrial function and ATP production via TRPV2 activation. Therefore, TRPV2 is proposed as a potential therapeutic target in AD, while CBD is a promising drug candidate for AD. Full article

(This article belongs to the Special Issue Newly Developed Drugs for Alzheimer's Disease)

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21 pages, 4665 KiB

Open AccessArticle

Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies

by Abdullah Al Mamun, Filip Pidaný, Daniela Hulcová, Jana Maříková, Tomáš Kučera, Monika Schmidt, Maria Carmen Catapano, Martina Hrabinová, Daniel Jun, Lubica Múčková, Jiří Kuneš, Jiří Janoušek, Rudolf Andrýs, Lucie Nováková, Rozálie Peřinová, Negar Maafi, Ondřej Soukup, Jan Korábečný and Lucie Cahlíková

Int. J. Mol. Sci. 2021, 22(15), 8308; https://doi.org/10.3390/ijms22158308 - 02 Aug 2021

Cited by 7 | Viewed by 2770

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1–20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC₅₀ values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC₅₀ value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score. Full article

(This article belongs to the Special Issue Newly Developed Drugs for Alzheimer's Disease)

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21 pages, 3883 KiB

Open AccessArticle

Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells

by Monika Hudáčová, Slávka Hamuľaková, Eva Konkoľová, Rastislav Jendželovský, Jana Vargová, Juraj Ševc, Peter Fedoročko, Ondrej Soukup, Jana Janočková, Veronika Ihnatova, Tomáš Kučera, Petr Bzonek, Nikola Novakova, Daniel Jun, Lucie Junova, Jan Korábečný, Kamil Kuča and Mária Kožurková

Int. J. Mol. Sci. 2021, 22(8), 3830; https://doi.org/10.3390/ijms22083830 - 07 Apr 2021

Cited by 4 | Viewed by 2818

Abstract

A series of novel C4-C7-tethered biscoumarin derivatives (12a–e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC₅₀ = 6.30 µM) and butyrylcholinesterase (BChE, IC₅₀ = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease. Full article

(This article belongs to the Special Issue Newly Developed Drugs for Alzheimer's Disease)

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Review

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20 pages, 27404 KiB

Open AccessReview

Neuropharmacology of Cevimeline and Muscarinic Drugs—Focus on Cognition and Neurodegeneration

by Patrik Oleksak, Michal Novotny, Jiri Patocka, Eugenie Nepovimova, Jakub Hort, Jan Pavlik, Blanka Klimova, Martin Valis and Kamil Kuca

Int. J. Mol. Sci. 2021, 22(16), 8908; https://doi.org/10.3390/ijms22168908 - 18 Aug 2021

Cited by 3 | Viewed by 3811

Abstract

At present, Alzheimer’s disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-β (Aβ) peptide in the cerebral spinal fluid of Alzheimer’s patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD. Full article

(This article belongs to the Special Issue Newly Developed Drugs for Alzheimer's Disease)

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18 pages, 1161 KiB

Open AccessReview

Highlighting Immune System and Stress in Major Depressive Disorder, Parkinson’s, and Alzheimer’s Diseases, with a Connection with Serotonin

by Ana Salomé Correia, Armando Cardoso and Nuno Vale

Int. J. Mol. Sci. 2021, 22(16), 8525; https://doi.org/10.3390/ijms22168525 - 07 Aug 2021

Cited by 18 | Viewed by 3572

Abstract

There is recognition that both stress and immune responses are important factors in a variety of neurological disorders. Moreover, there is an important role of several neurotransmitters that connect these factors to several neurological diseases, with a special focus in this paper on serotonin. Accordingly, it is known that imbalances in stressors can promote a variety of neuropsychiatric or neurodegenerative pathologies. Here, we discuss some facts that link major depressive disorder, Alzheimer’s, and Parkinson’s to the stress and immune responses, as well as the connection between these responses and serotonergic signaling. These are important topics of investigation which may lead to new or better treatments, improving the life quality of patients that suffer from these conditions. Full article

(This article belongs to the Special Issue Newly Developed Drugs for Alzheimer's Disease)

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