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Recent Advances in the Modulation of Cholinergic Signaling
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Recent Advances in the Modulation of Cholinergic Signaling

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 60679

Special Issue Editor

Prof. Dr. Clelia Dallanoce

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Milan, Via Luigi Mangiagalli 25, 20133 Milan, Italy
Interests: rational drug design; organic synthesis; structure-activity relationships; nicotinic acetylcholine receptors; muscarinic acetylcholine receptors; cholinesterase inhibitors; bifunctional and bitopic ligands
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is with great pleasure that I invite you to contribute to the Special Issue “Recent Advances in the Modulation of Cholinergic Signaling,” which will mainly focus on new bioactive compounds able to regulate cholinergic transmission in neuronal and non-neuronal tissues. Since acetylcholine-related functions are impaired in several disorders and pathological conditions, different pharmacological approaches have been explored in view of innovative therapeutic applications. Additional mechanisms of action and/or downstream responses have been more recently associated to receptor targets of the cholinergic system, i.e., nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs), notably allosteric modulation (for both receptor families), biased signaling (for mAChRs) or silent agonism (for nAChRs). Overall, these evidences may enrich the repertoire of therapeutic opportunities for cholinergic ligands, including antitumor, anti-inflammatory, and analgesic activities. On the other hand, molecular fragments of cholinesterase (AChE and BChE) inhibitors are quite frequently incorporated in the structure of various hybrid ligands characterized by a dual or multitarget pharmacological profile, an approach aimed at improving their action on CNS disorders.

Contributions to this Special Issue, in the form of original research articles and short communications, may cover multidisciplinary aspects of the design, synthesis, and biological evaluation of novel small molecules affecting cholinergic neurotransmission as well as their therapeutic potential.

Prof. Dr. Clelia Dallanoce
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. 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

  • drug design
  • organic synthesis
  • biological activity
  • In silico studies
  • nicotinic acetylcholine receptors
  • muscarinic acetylcholine receptors
  • cholinesterase inhibitors
  • allosteric modulators
  • dual-acting ligands
  • therapeutic applications

Published Papers (17 papers)

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Editorial

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4 pages, 199 KiB  
Editorial
Recent Advances in the Modulation of Cholinergic Signaling
by Clelia Dallanoce
Molecules 2022, 27(18), 5971; https://doi.org/10.3390/molecules27185971 - 14 Sep 2022
Cited by 1 | Viewed by 1009
Abstract
In recent years, an impressive number of research studies have been conducted to improve the understanding of the structure and function of the cholinergic system, and significant progress has also been made in elucidating the roles of neuronal and non-neuronal acetylcholine (ACh) in [...] Read more.
In recent years, an impressive number of research studies have been conducted to improve the understanding of the structure and function of the cholinergic system, and significant progress has also been made in elucidating the roles of neuronal and non-neuronal acetylcholine (ACh) in the pathogenesis and treatment of human disease [...] Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)

Research

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25 pages, 2828 KiB  
Article
Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile
by Galina F. Makhaeva, Nadezhda V. Kovaleva, Natalia P. Boltneva, Elena V. Rudakova, Sofya V. Lushchekina, Tatiana Yu. Astakhova, Igor V. Serkov, Alexey N. Proshin, Eugene V. Radchenko, Vladimir A. Palyulin, Jan Korabecny, Ondrej Soukup, Sergey O. Bachurin and Rudy J. Richardson
Molecules 2022, 27(3), 1060; https://doi.org/10.3390/molecules27031060 - 4 Feb 2022
Cited by 10 | Viewed by 2635
Abstract
Using two ways of functionalizing amiridine—acylation with chloroacetic acid chloride and reaction with thiophosgene—we have synthesized new homobivalent bis-amiridines joined by two different spacers—bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) —as potential multifunctional agents for the treatment [...] Read more.
Using two ways of functionalizing amiridine—acylation with chloroacetic acid chloride and reaction with thiophosgene—we have synthesized new homobivalent bis-amiridines joined by two different spacers—bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) —as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug–drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a–c exhibited an IC50(AChE) = 2.9–1.4 µM, IC50(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ42 aggregation. Conjugates 3 had no effect on Aβ42 self-aggregation, whereas compounds 5c–e (m = 4, 5, 6) showed mild (13–17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2–2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood–brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c–e appear promising for future optimization and development as multitarget anti-AD agents. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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9 pages, 1189 KiB  
Communication
The Caenorhabditis elegans DEG-3/DES-2 Channel Is a Betaine-Gated Receptor Insensitive to Monepantel
by Tina V. A. Hansen, Heinz Sager, Céline E. Toutain, Elise Courtot, Cédric Neveu and Claude L. Charvet
Molecules 2022, 27(1), 312; https://doi.org/10.3390/molecules27010312 - 5 Jan 2022
Cited by 5 | Viewed by 2202
Abstract
Natural plant compounds, such as betaine, are described to have nematocidal properties. Betaine also acts as a neurotransmitter in the free-living model nematode Caenorhabditis elegans, where it is required for normal motility. Worm motility is mediated by nicotinic acetylcholine receptors (nAChRs), including [...] Read more.
Natural plant compounds, such as betaine, are described to have nematocidal properties. Betaine also acts as a neurotransmitter in the free-living model nematode Caenorhabditis elegans, where it is required for normal motility. Worm motility is mediated by nicotinic acetylcholine receptors (nAChRs), including subunits from the nematode-specific DEG-3 group. Not all types of nAChRs in this group are associated with motility, and one of these is the DEG-3/DES-2 channel from C. elegans, which is involved in nociception and possibly chemotaxis. Interestingly, the activity of DEG-3/DES-2 channel from the parasitic nematode of ruminants, Haemonchus contortus, is modulated by monepantel and its sulfone metabolite, which belong to the amino-acetonitrile derivative anthelmintic drug class. Here, our aim was to advance the pharmacological knowledge of the DEG-3/DES-2 channel from C. elegans by functionally expressing the DEG-3/DES-2 channel in Xenopus laevis oocytes and using two-electrode voltage-clamp electrophysiology. We found that the DEG-3/DES-2 channel was more sensitive to betaine than ACh and choline, but insensitive to monepantel and monepantel sulfone when used as direct agonists and as allosteric modulators in co-application with betaine. These findings provide important insight into the pharmacology of DEG-3/DES-2 from C. elegans and highlight the pharmacological differences between non-parasitic and parasitic nematode species. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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Graphical abstract

13 pages, 1854 KiB  
Article
The Mechanisms Mediated by α7 Acetylcholine Nicotinic Receptors May Contribute to Peripheral Nerve Regeneration
by Michael Sebastian Salazar Intriago, Roberta Piovesana, Alessandro Matera, Marilena Taggi, Rita Canipari, Cinzia Fabrizi, Claudio Papotto, Carlo Matera, Marco De Amici, Clelia Dallanoce and Ada Maria Tata
Molecules 2021, 26(24), 7668; https://doi.org/10.3390/molecules26247668 - 18 Dec 2021
Cited by 7 | Viewed by 2478
Abstract
Due to the microenvironment created by Schwann cell (SC) activity, peripheral nerve fibers are able to regenerate. Inflammation is the first response to nerve damage and the removal of cellular and myelin debris is essential in preventing the persistence of the local inflammation [...] Read more.
Due to the microenvironment created by Schwann cell (SC) activity, peripheral nerve fibers are able to regenerate. Inflammation is the first response to nerve damage and the removal of cellular and myelin debris is essential in preventing the persistence of the local inflammation that may negatively affect nerve regeneration. Acetylcholine (ACh) is one of the neurotransmitters involved in the modulation of inflammation through the activity of its receptors, belonging to both the muscarinic and nicotinic classes. In this report, we evaluated the expression of α7 nicotinic acetylcholine receptors (nAChRs) in rat sciatic nerve, particularly in SCs, after peripheral nerve injury. α7 nAChRs are absent in sciatic nerve immediately after dissection, but their expression is significantly enhanced in SCs after 24 h in cultured sciatic nerve segments or in the presence of the proinflammatory neuropeptide Bradykinin (BK). Moreover, we found that activation of α7 nAChRs with the selective partial agonist ICH3 causes a decreased expression of c-Jun and an upregulation of uPA, MMP2 and MMP9 activity. In addition, ICH3 treatment inhibits IL-6 transcript level expression as well as the cytokine release. These results suggest that ACh, probably released from regenerating axons or by SC themselves, may actively promote through α7 nAChRs activation an anti-inflammatory microenvironment that contributes to better improving the peripheral nerve regeneration. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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23 pages, 2277 KiB  
Article
Fractionation of Lycopodiaceae Alkaloids and Evaluation of Their Anticholinesterase and Cytotoxic Activities
by Aleksandra Dymek, Jarosław Widelski, Krzysztof Kamil Wojtanowski, Vladyslav Vivcharenko, Agata Przekora and Tomasz Mroczek
Molecules 2021, 26(21), 6379; https://doi.org/10.3390/molecules26216379 - 22 Oct 2021
Cited by 8 | Viewed by 2509
Abstract
In view of the abundant evidence that Lycopodiaceae alkaloids, including the well-known huperzine A (HupA), are among the potent acetylcholinesterase (AChE) inhibitors, an attempt was made to search for new compounds responsible for this property. For this purpose, three plant species belonging to [...] Read more.
In view of the abundant evidence that Lycopodiaceae alkaloids, including the well-known huperzine A (HupA), are among the potent acetylcholinesterase (AChE) inhibitors, an attempt was made to search for new compounds responsible for this property. For this purpose, three plant species belonging to the Lycopodiaceae family, commonly found in the Euro-Asia region, were subjected to the isolation of bioactive compounds, their identification and subsequent evaluation of their anticholinesterase and cytotoxic activities. Methanolic extracts of two Lycopodium and one Hupezia species were obtained via optimized pressurized liquid extraction (PLE) and then pre-purified using innovative gradient vacuum liquid chromatography (gVLC). For the first time, three sorbents of different porosity packed in polypropylene cartridges and mobile phase systems of different polarity were used to elute the target compounds. This technique proved to be a rapid tool for the obtainment of alkaloid fractions and allowed one to select the appropriate process conditions to yield potent AChE inhibitors in each of the species studied. More than 100 collected fractions were analyzed via HPLC/ESI-QTOF-MS, which enabled one to detect more than 50 compounds, including several new ones previously unreported. Some of them were present in high purity fractions (60–90% of the established purity). TLC bioautography assays proved that the analyzed species are rich sources of AChE inhibitors, but H. selago showed the highest anti-AChE activity. Additionally, the modified silanized silica gel sorbent used allowed one to isolate L. clavatum alkaloids more efficiently using an aqueous reversed-phase solvent system. Furthermore, the tested extracts from the three plant extracts were found to be safe, as they did not exhibit cytotoxicity to skin fibroblasts. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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16 pages, 6008 KiB  
Article
Participation of the Cholinergic System in the Development of Polycystic Ovary Syndrome
by Rosa Linares, Xóchitl N. Acuña, Gabriela Rosas, Elizabeth Vieyra, Deyra A. Ramírez, Andrea Chaparro, Julieta A. Espinoza, Roberto Domínguez and Leticia Morales-Ledesma
Molecules 2021, 26(18), 5506; https://doi.org/10.3390/molecules26185506 - 10 Sep 2021
Cited by 8 | Viewed by 2169
Abstract
In rats with polycystic ovary syndrome (PCOS) induced by injection of estradiol valerate (EV), unilateral or bilateral section of the vagus nerve restores ovulatory function in 75% of animals, suggesting that the vagus nerve participates in the development of PCOS. Since the vagus [...] Read more.
In rats with polycystic ovary syndrome (PCOS) induced by injection of estradiol valerate (EV), unilateral or bilateral section of the vagus nerve restores ovulatory function in 75% of animals, suggesting that the vagus nerve participates in the development of PCOS. Since the vagus nerve is a mixed nerve through which mainly cholinergic-type information passes, the objective of the present study was to analyze whether acetylcholine (ACh) is involved in the development of PCOS. Ten-day-old rats were injected with 2.0 mg EV, and at 60 days of age, they were microinjected on the day of diestrus in the bursa of the left or right ovary with 100 or 700 mg/kg of ovarian weight atropine, a blocker of muscarinic receptors, and sacrificed for histopathological examination after the surgery. Animals with PCOS microinjected with 100 mg of atropine showed a lack of ovulation, lower serum concentrations of progesterone and testosterone, and cysts. Histology of the ovaries of animals microinjected with 700 mg of atropine showed corpus luteum and follicles at different stages of development, which was accompanied by a lower concentration of progesterone and testosterone. These results allow us to suggest that in animals with PCOS, ACh, which passes through parasympathetic innervation, is an important component in the persistence and development of the pathophysiology. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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19 pages, 2618 KiB  
Article
Imidazopyridazine Acetylcholinesterase Inhibitors Display Potent Anti-Proliferative Effects in the Human Neuroblastoma Cell-Line, IMR-32
by Rakesh Kumar Sharma, Manisha Singh, Khagendra Ghimeray, Pinky Juneja, Gagan Dev, Sridhar Pulavarthi, Sabbasani Rajasekhara Reddy and Ravi Shankar Akundi
Molecules 2021, 26(17), 5319; https://doi.org/10.3390/molecules26175319 - 1 Sep 2021
Cited by 6 | Viewed by 3012
Abstract
Imidazo[1,2-b]pyridazine compounds are a new class of promising lead molecules to which we have incorporated polar nitro and amino moieties to increase the scope of their biological activity. Two of these substituted 3-nitro-6-amino-imidazo[1,2-b]pyridazine compounds (5c and 5h) showed potent [...] Read more.
Imidazo[1,2-b]pyridazine compounds are a new class of promising lead molecules to which we have incorporated polar nitro and amino moieties to increase the scope of their biological activity. Two of these substituted 3-nitro-6-amino-imidazo[1,2-b]pyridazine compounds (5c and 5h) showed potent acetylcholinesterase (AChE) inhibitory activity (IC50 40–50 nM), which we have previously reported. In this study, we wanted to test the biological efficacy of these compounds. Cytotoxicity assays showed that compound 5h mediated greater cell death with over 43% of cells dead at 100 μM and activation of caspase 3-mediated apoptosis. On the other hand, compound 5c mediated a dose-dependent decrease in cell proliferation. Both compounds showed cell cycle arrest in the G0/G1 phase and reduced cellular ATP levels leading to activation of adenosine monophosphate-activated protein kinase (AMPK) and enhanced mitochondrial oxidative stress. It has to be noted that all these effects were observed at doses beyond 10 μM, 200-fold above the IC50 for AChE inhibition. Both compounds also inhibited bacterial lipopolysaccharide-mediated cyclooxygenase-2 and nitric oxide release in primary rat microglial cells. These results suggested that the substituted imidazo (1,2-b) pyridazine compounds, which have potent AChE inhibitory activity, were also capable of antiproliferative, anti-migratory, and anti-inflammatory effects at higher doses. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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19 pages, 17667 KiB  
Article
Synthesis, Biological Evaluation, and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold
by Paptawan Suwanhom, Jirakrit Saetang, Pasarat Khongkow, Teerapat Nualnoi, Varomyalin Tipmanee and Luelak Lomlim
Molecules 2021, 26(16), 4895; https://doi.org/10.3390/molecules26164895 - 12 Aug 2021
Cited by 20 | Viewed by 2994
Abstract
A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC50 values of 0.077 to 50.080 µM, [...] Read more.
A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC50 values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood–brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC50 values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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23 pages, 11490 KiB  
Article
Determinants for α4β2 vs. α3β4 Subtype Selectivity of Pyrrolidine-Based nAChRs Ligands: A Computational Perspective with Focus on Recent cryo-EM Receptor Structures
by Francesco Bavo, Marco Pallavicini, Rebecca Appiani and Cristiano Bolchi
Molecules 2021, 26(12), 3603; https://doi.org/10.3390/molecules26123603 - 12 Jun 2021
Cited by 8 | Viewed by 2076
Abstract
The selectivity of α4β2 nAChR agonists over the α3β4 nicotinic receptor subtype, predominant in ganglia, primarily conditions their therapeutic range and it is still a complex and challenging issue for medicinal chemists and pharmacologists. Here, we investigate the determinants for such subtype selectivity [...] Read more.
The selectivity of α4β2 nAChR agonists over the α3β4 nicotinic receptor subtype, predominant in ganglia, primarily conditions their therapeutic range and it is still a complex and challenging issue for medicinal chemists and pharmacologists. Here, we investigate the determinants for such subtype selectivity in a series of more than forty α4β2 ligands we have previously reported, docking them into the structures of the two human subtypes, recently determined by cryo-electron microscopy. They are all pyrrolidine based analogues of the well-known α4β2 agonist N-methylprolinol pyridyl ether A-84543 and differ in the flexibility and pattern substitution of their aromatic portion. Indeed, the direct or water mediated interaction with hydrophilic residues of the relatively narrower β2 minus side through the elements decorating the aromatic ring and the stabilization of the latter by facing to the not conserved β2-Phe119 result as key distinctive features for the α4β2 affinity. Consistently, these compounds show, despite the structural similarity, very different α4β2 vs. α3β4 selectivities, from modest to very high, which relate to rigidity/extensibility degree of the portion containing the aromatic ring and to substitutions at the latter. Furthermore, the structural rationalization of the rat vs. human differences of α4β2 vs. α3β4 selectivity ratios is here proposed. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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19 pages, 4180 KiB  
Article
The Impact of Dextran Sodium Sulfate-Induced Gastrointestinal Injury on the Pharmacokinetic Parameters of Donepezil and Its Active Metabolite 6-O-desmethyldonepezil, and Gastric Myoelectric Activity in Experimental Pigs
by Jan Bures, Ilja Tacheci, Jaroslav Kvetina, Vera Radochova, Lukas Prchal, Darina Kohoutova, Martin Valis, Martin Novak, Rafael Dolezal, Marcela Kopacova, Stanislav Rejchrt, Vit Sestak, Veronika Knoblochova, Eva Peterova and Jana Zdarova Karasova
Molecules 2021, 26(8), 2160; https://doi.org/10.3390/molecules26082160 - 9 Apr 2021
Cited by 8 | Viewed by 2288
Abstract
Gastrointestinal side effects of donepezil, including dyspepsia, nausea, vomiting or diarrhea, occur in 20–30% of patients. The pathogenesis of these dysmotility associated disorders has not been fully clarified yet. Pharmacokinetic parameters of donepezil and its active metabolite 6-O-desmethyldonepezil were investigated in [...] Read more.
Gastrointestinal side effects of donepezil, including dyspepsia, nausea, vomiting or diarrhea, occur in 20–30% of patients. The pathogenesis of these dysmotility associated disorders has not been fully clarified yet. Pharmacokinetic parameters of donepezil and its active metabolite 6-O-desmethyldonepezil were investigated in experimental pigs with and without small intestinal injury induced by dextran sodium sulfate (DSS). Morphological features of this injury were evaluated by a video capsule endoscopy. The effect of a single and repeated doses of donepezil on gastric myoelectric activity was assessed. Both DSS-induced small intestinal injury and prolonged small intestinal transit time caused higher plasma concentrations of donepezil in experimental pigs. This has an important implication for clinical practice in humans, with a need to reduce doses of the drug if an underlying gastrointestinal disease is present. Donepezil had an undesirable impact on porcine myoelectric activity. This effect was further aggravated by DSS-induced small intestinal injury. These findings can explain donepezil-associated dyspepsia in humans. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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15 pages, 3359 KiB  
Article
Central Activation of Alpha7 Nicotinic Signaling Attenuates LPS-Induced Neuroinflammation and Sickness Behavior in Adult but Not in Aged Animals
by Elisa Navarro, Diana M. Norden, Paige J. Trojanowski, Jonathan P. Godbout and Manuela G. López
Molecules 2021, 26(8), 2107; https://doi.org/10.3390/molecules26082107 - 7 Apr 2021
Cited by 8 | Viewed by 2351
Abstract
We previously reported that lipopolysaccharide (LPS) challenge caused microglial-mediated neuroinflammation and sickness behavior that was amplified in aged mice. As α7 nAChRs are implicated in the “Cholinergic anti-inflammatory pathway”, we aimed to determine how α7 nAChR stimulation modulates microglial phenotype in an LPS-induced [...] Read more.
We previously reported that lipopolysaccharide (LPS) challenge caused microglial-mediated neuroinflammation and sickness behavior that was amplified in aged mice. As α7 nAChRs are implicated in the “Cholinergic anti-inflammatory pathway”, we aimed to determine how α7 nAChR stimulation modulates microglial phenotype in an LPS-induced neuroinflammation model in adult and aged mice. For this, BALB/c mice were injected intraperitoneally with LPS (0.33 mg/kg) and treated with the α7 nAChR agonist PNU282987, using different administration protocols. LPS challenge reduced body weight and induced lethargy and social withdrawal in adult mice. Peripheral (intraperitoneal) co-administration of the α7 nAChR agonist PNU282987 with LPS, attenuated body weight loss and sickness behavior associated with LPS challenge in adult mice, and reduced microglial activation with suppression of IL-1β and TNFα mRNA levels. Furthermore, central (intracerebroventricular) administration of the α7 nAChR agonist, even 2 h after LPS injection, attenuated the decrease in social exploratory behavior and microglial activation induced by peripheral administration of LPS, although this recovery was not achieved if activation of α7 nAChRs was performed peripherally. Finally, we observed that the positive results of central activation of α7 nAChRs were lost in aged mice. In conclusion, we provide evidence that stimulation of α7 nAChR signaling reduces microglial activation in an in vivo LPS-based model, but this cholinergic-dependent regulation seems to be dysfunctional in microglia of aged mice. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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15 pages, 2987 KiB  
Article
Different Classes of Antidepressants Inhibit the Rat α7 Nicotinic Acetylcholine Receptor by Interacting within the Ion Channel: A Functional and Structural Study
by Yorley Duarte, Maximiliano Rojas, Jonathan Canan, Edwin G. Pérez, Fernando González-Nilo and Jesús García-Colunga
Molecules 2021, 26(4), 998; https://doi.org/10.3390/molecules26040998 - 13 Feb 2021
Cited by 8 | Viewed by 2810
Abstract
Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording [...] Read more.
Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, ICh, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). The antidepressants inhibited ICh with the order: norfluoxetine ~ mirtazapine ~ imipramine < bupropion ~ fluoxetine ~ venlafaxine ~ escitalopram. The constructed homology model of the rat α7 nAChR resulted in the extracellular vestibule and the channel pore is highly negatively charged, which facilitates the permeation of cations and the entrance of the protonated form of antidepressants. Molecular docking and molecular dynamics simulations were carried out within the ion−channel of the α7 nAChR, revealing that the antidepressants adopt poses along the receptor channel, with slightly different binding-free energy values. Furthermore, the inhibition of ICh and free energy values for each antidepressant-receptor complex were highly correlated. Thus, the α7 nAChR is negatively modulated by a variety of antidepressants interacting in the ion−channel. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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12 pages, 2419 KiB  
Article
Hydrazones of 4-(Trifluoromethyl)benzohydrazide as New Inhibitors of Acetyl- and Butyrylcholinesterase
by Martin Krátký, Katarína Svrčková, Quynh Anh Vu, Šárka Štěpánková and Jarmila Vinšová
Molecules 2021, 26(4), 989; https://doi.org/10.3390/molecules26040989 - 13 Feb 2021
Cited by 16 | Viewed by 2990
Abstract
Based on the broad spectrum of biological activity of hydrazide–hydrazones, trifluoromethyl compounds, and clinical usage of cholinesterase inhibitors, we investigated hydrazones obtained from 4-(trifluoromethyl)benzohydrazide and various benzaldehydes or aliphatic ketones as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). They were evaluated using [...] Read more.
Based on the broad spectrum of biological activity of hydrazide–hydrazones, trifluoromethyl compounds, and clinical usage of cholinesterase inhibitors, we investigated hydrazones obtained from 4-(trifluoromethyl)benzohydrazide and various benzaldehydes or aliphatic ketones as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). They were evaluated using Ellman’s spectrophotometric method. The hydrazide–hydrazones produced a dual inhibition of both cholinesterase enzymes with IC50 values of 46.8–137.7 µM and 19.1–881.1 µM for AChE and BuChE, respectively. The majority of the compounds were stronger inhibitors of AChE; four of them (2-bromobenzaldehyde, 3-(trifluoromethyl)benzaldehyde, cyclohexanone, and camphor-based 2o, 2p, 3c, and 3d, respectively) produced a balanced inhibition of the enzymes and only 2-chloro/trifluoromethyl benzylidene derivatives 2d and 2q were found to be more potent inhibitors of BuChE. 4-(Trifluoromethyl)-N’-[4-(trifluoromethyl)benzylidene]benzohydrazide 2l produced the strongest inhibition of AChE via mixed-type inhibition determined experimentally. Structure–activity relationships were identified. The compounds fit physicochemical space for targeting central nervous systems with no apparent cytotoxicity for eukaryotic cell line together. The study provides new insights into this CF3-hydrazide–hydrazone scaffold. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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Review

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23 pages, 2101 KiB  
Review
Role of Cholinergic Signaling in Alzheimer’s Disease
by Zhi-Ru Chen, Jia-Bao Huang, Shu-Long Yang and Fen-Fang Hong
Molecules 2022, 27(6), 1816; https://doi.org/10.3390/molecules27061816 - 10 Mar 2022
Cited by 145 | Viewed by 15563
Abstract
Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer’s disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is [...] Read more.
Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer’s disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is complex and remains unclear, being affected by various factors. The cholinergic hypothesis is the earliest theory about the pathogenesis of AD. Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD. In addition, abnormal central cholinergic changes can also induce abnormal phosphorylation of ttau protein, nerve cell inflammation, cell apoptosis, and other pathological phenomena, but the exact mechanism of action is still unclear. Due to the complex and unclear pathogenesis, effective methods to prevent and treat AD are unavailable, and research to explore novel therapeutic drugs is various and active in the world. This review summaries the role of cholinergic signaling and the correlation between the cholinergic signaling pathway with other risk factors in AD and provides the latest research about the efficient therapeutic drugs and treatment of AD. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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19 pages, 4249 KiB  
Review
Striatal Cholinergic Signaling in Time and Space
by Dvyne Nosaka and Jeffery R. Wickens
Molecules 2022, 27(4), 1202; https://doi.org/10.3390/molecules27041202 - 10 Feb 2022
Cited by 7 | Viewed by 2394
Abstract
The cholinergic interneurons of the striatum account for a small fraction of all striatal cell types but due to their extensive axonal arborization give the striatum the highest content of acetylcholine of almost any nucleus in the brain. The prevailing theory of striatal [...] Read more.
The cholinergic interneurons of the striatum account for a small fraction of all striatal cell types but due to their extensive axonal arborization give the striatum the highest content of acetylcholine of almost any nucleus in the brain. The prevailing theory of striatal cholinergic interneuron signaling is that the numerous varicosities on the axon produce an extrasynaptic, volume-transmitted signal rather than mediating rapid point-to-point synaptic transmission. We review the evidence for this theory and use a mathematical model to integrate the measurements reported in the literature, from which we estimate the temporospatial distribution of acetylcholine after release from a synaptic vesicle and from multiple vesicles during tonic firing and pauses. Our calculations, together with recent data from genetically encoded sensors, indicate that the temporospatial distribution of acetylcholine is both short-range and short-lived, and dominated by diffusion. These considerations suggest that acetylcholine signaling by cholinergic interneurons is consistent with point-to-point transmission within a steep concentration gradient, marked by transient peaks of acetylcholine concentration adjacent to release sites, with potential for faithful transmission of spike timing, both bursts and pauses, to the postsynaptic cell. Release from multiple sites at greater distance contributes to the ambient concentration without interference with the short-range signaling. We indicate several missing pieces of evidence that are needed for a better understanding of the nature of synaptic transmission by the cholinergic interneurons of the striatum. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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23 pages, 1278 KiB  
Review
Venom-Derived Neurotoxins Targeting Nicotinic Acetylcholine Receptors
by Ayaulym Bekbossynova, Albina Zharylgap and Olena Filchakova
Molecules 2021, 26(11), 3373; https://doi.org/10.3390/molecules26113373 - 3 Jun 2021
Cited by 11 | Viewed by 4606
Abstract
Acetylcholine was the first neurotransmitter described. The receptors targeted by acetylcholine are found within organisms spanning different phyla and position themselves as very attractive targets for predation, as well as for defense. Venoms of snakes within the Elapidae family, as well as those [...] Read more.
Acetylcholine was the first neurotransmitter described. The receptors targeted by acetylcholine are found within organisms spanning different phyla and position themselves as very attractive targets for predation, as well as for defense. Venoms of snakes within the Elapidae family, as well as those of marine snails within the Conus genus, are particularly rich in proteins and peptides that target nicotinic acetylcholine receptors (nAChRs). Such compounds are invaluable tools for research seeking to understand the structure and function of the cholinergic system. Proteins and peptides of venomous origin targeting nAChR demonstrate high affinity and good selectivity. This review aims at providing an overview of the toxins targeting nAChRs found within venoms of different animals, as well as their activities and the structural determinants important for receptor binding. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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14 pages, 1222 KiB  
Review
Cholinergic Signaling, Neural Excitability, and Epilepsy
by Yu Wang, Bei Tan, Yi Wang and Zhong Chen
Molecules 2021, 26(8), 2258; https://doi.org/10.3390/molecules26082258 - 13 Apr 2021
Cited by 24 | Viewed by 4583
Abstract
Epilepsy is a common brain disorder characterized by recurrent epileptic seizures with neuronal hyperexcitability. Apart from the classical imbalance between excitatory glutamatergic transmission and inhibitory γ-aminobutyric acidergic transmission, cumulative evidence suggest that cholinergic signaling is crucially involved in the modulation of neural excitability [...] Read more.
Epilepsy is a common brain disorder characterized by recurrent epileptic seizures with neuronal hyperexcitability. Apart from the classical imbalance between excitatory glutamatergic transmission and inhibitory γ-aminobutyric acidergic transmission, cumulative evidence suggest that cholinergic signaling is crucially involved in the modulation of neural excitability and epilepsy. In this review, we briefly describe the distribution of cholinergic neurons, muscarinic, and nicotinic receptors in the central nervous system and their relationship with neural excitability. Then, we summarize the findings from experimental and clinical research on the role of cholinergic signaling in epilepsy. Furthermore, we provide some perspectives on future investigation to reveal the precise role of the cholinergic system in epilepsy. Full article
(This article belongs to the Special Issue Recent Advances in the Modulation of Cholinergic Signaling)
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