Search Results (92)

Tobacco use disorder remains a leading cause of preventable mortality, with nicotine playing a central role in the development and maintenance of dependence, mainly through its action on α4β2 nicotinic acetylcholine receptors (nAChRs). Smoking cessation treatments must address both physiological withdrawal and the affective disturbances (such as anxiety, irritability, and mood lability) which often facilitate relapses. This review compares two pharmacotherapies used in smoking cessation, varenicline and cytisinicline (cytisine), with particular focus on their impact on emotional regulation, psychological symptoms, and neuropsychiatric safety. Varenicline, a high-affinity partial agonist at α4β2 nAChRs, has demonstrated superior efficacy in maintaining abstinence and is well-supported by robust clinical data, including in psychiatric populations. However, its use may be limited by adverse effects such as nausea and sleep disorders. Cytisinicline, a structurally similar but less potent partial agonist, has recently gained renewed interest due to its lower cost, favorable tolerability profile, and comparable effectiveness in the general population. Although less extensively studied in patients with serious mental illness, preliminary data suggest cytisinicline may offer a better side effect profile, particularly regarding sleep disturbances and emotional reactivity. Both agents appear to ameliorate withdrawal-related affective symptoms without significantly increasing psychiatric risk. Ultimately, pharmacotherapy choice should be guided by individual clinical features, mental health status, treatment tolerability, and resource availability. Further research is needed to establish cytisinicline’s efficacy and safety across diverse clinical contexts, particularly among individuals with severe psychiatric comorbidities. Full article

Background: Acute respiratory distress syndrome (ARDS) is a high-mortality disease strongly associated with an imbalance in the inflammatory response. The ratio of helper T 17 (Th17) cells to regulatory T (Treg) cells is significantly correlated with prognosis and outcomes in ARDS. Vagus nerve stimulation (VNS) alleviates lung injury in ARDS model rats. The objective of this study was to further investigate whether VNS attenuates lipopolysaccharide-induced ARDS by regulating Th17/Treg homeostasis and to explore the underlying mechanisms. Methods: We assessed the degree of lung injury using hematoxylin and eosin staining, the lung wet-to-dry ratio, and total protein and pro-inflammatory cytokine levels in bronchoalveolar lavage fluid. The expression levels of Th17 and Treg cells were determined using flow cytometry, Western blotting, quantitative real-time PCR, and enzyme-linked immunosorbent assays. Results: We found that VNS reduced lung injury in ARDS model rats. Additionally, VNS regulated Th17/Treg homeostasis and reduced the levels of inflammatory factors in both the lungs and spleens. Notably, the effects of VNS were consistent when the afferent or efferent vagus nerve, or both, were stimulated. Further investigation revealed that VNS upregulated splenic α7 nicotinic acetylcholine receptors (α7nAChRs). The administration of an α7nAChR agonist enhanced VNS-mediated regulation of Th17/Treg homeostasis and attenuated lung injury, while these effects were blocked by α7nAChR antagonists. Conclusions: Our study demonstrated that VNS regulates the Th17/Treg balance through α7nAChR activation in the spleen, thereby mitigating lung injury in ARDS. These findings provide new theoretical support for the use of VNS in attenuating ARDS. Full article

The α7 nicotinic acetylcholine receptor (α7-nAChR) is a pivotal regulator of neurotransmission, neuroprotection, and immune modulation in the central nervous system. This review explores its structural and functional attributes, highlighting its therapeutic potential in neurodegenerative disorders, particularly Parkinson’s disease (PD). α7-nAChRs mediate synaptic plasticity, modulate inflammatory responses, and influence dopamine release, positioning them as a promising pharmacological target. Positive allosteric modulators (PAMs) enhance α7-nAChR activity mainly by reducing desensitization, offering a superior therapeutic approach compared with direct agonists. Emerging preclinical studies suggest that α7-nAChR activation mitigates dopaminergic neurodegeneration, improves L-dopa-induced dyskinesia, and reduces neuroinflammation. Despite promising findings, clinical trials have yielded mixed results, necessitating further research into optimizing α7-targeted therapies. This review underscores the significance of α7-nAChRs in PD pathophysiology and highlights future directions for their translational potential in neuroprotection and symptomatic relief. Full article

Derivatives of squaric acid are valuable building blocks with promising applications in the investigation of various bioactivities. In this study, we focus on squaramides functionalized with the (−)-cytisine moiety, an alkaloid known for its bioactivity as a nicotinic acetylcholine receptor agonist and its application in nicotine addiction treatment. Reactions of cytisine-monosquarate with several amines, such as ammonia, propargylamine, and morpholine, led to the formation of novel conjugates of cytisine-squaramides. Additionally, squaramide containing two cytisine moieties was synthesized via the reaction of diethyl squarate with cytisine at a 1:2 molar ratio. All obtained squaramides were thoroughly characterized by MS, FT-IR, and NMR methods and by single-crystal X-ray diffraction analysis. To gain deeper insights into their structural properties and intermolecular interactions, geometry optimizations were performed using DFT calculations, complemented with 3D molecular electrostatic potential maps. Full article

We recorded transmembrane currents through single nicotinic acetylcholine receptors (nAChRs) in cell-attached patches at high temporal resolutions from cultured and transiently transfected HEK 293 cells. Receptor activation was elicited by acetylcholine (ACh) or epibatidine (Ebd) at concentrations ranging from 0.01 to 100 µM, binding to one (R_αδ or R_αε) or both extracellular ligand binding sites (R_αδ+αε). Agonist binding to R_αδ resulted in very short openings with mean durations of (τ_o1 < 5 µs), while the binding to R_αε produced short (τ_o2 = 37 µs) and intermediate openings (τ_o3 = 187 µs). Binding at both sites (R_αδ+αε) generated long openings (τ_o4 = 752 µs). All durations are noted in brackets since missed closures could shorten the results. Mono-liganded bursts were elicited at 0.01 µM ACh or Ebd, lasted less than a millisecond, displayed the typical current amplitude, and were interrupted by frequent microsecond-scale closures (µBs) that often did not reach the zero current. In contrast, bi-liganded bursts exhibited classical full amplitudes and long open states lasting up to several milliseconds, interspersed with rare µB closures of a similar duration to those observed in mono-liganded bursts. Full article

Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematologic parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h or at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated. Full article

Studying the involvement of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in neuropsychiatric brain disorders such as autism spectrum disorder (ASD) has gained a growing interest. The flavonoid apigenin (APG) has been confirmed in its pharmacological action as a positive allosteric modulator of α7-nAChRs. However, there is no research describing the pharmacological potential of APG in ASD. The aim of this study was to evaluate the effects of the subchronic systemic treatment of APG (10–30 mg/kg) on ASD-like repetitive and compulsive-like behaviors and oxidative stress status in the hippocampus and cerebellum in BTBR mice, utilizing the reference drug aripiprazole (ARP, 1 mg/kg, i.p.). BTBR mice pretreated with APG (20 mg/kg) or ARP (1 mg/g, i.p.) displayed significant improvements in the marble-burying test (MBT), cotton-shredding test (CST), and self-grooming test (SGT) (all p < 0.05). However, a lower dose of APG (10 mg/kg, i.p.) failed to modulate behaviors in the MBT or SGT, but significantly attenuated the increased shredding behaviors in the CST of tested mice. Moreover, APG (10–30 mg/kg, i.p.) and ARP (1 mg/kg) moderated the disturbed levels of oxidative stress by mitigating the levels of catalase (CAT) and superoxide dismutase (SOD) in the hippocampus and cerebellum of treated BTBR mice. In patch clamp studies in hippocampal slices, the potency of choline (a selective agonist of α7-nAChRs) in activating fast inward currents was significantly potentiated following incubation with APG. Moreover, APG markedly potentiated the choline-induced enhancement of spontaneous inhibitory postsynaptic currents. The observed results propose the potential therapeutic use of APG in the management of ASD. However, further preclinical investigations in additional models and different rodent species are still needed to confirm the potential relevance of the therapeutic use of APG in ASD. Full article

Currently, insecticides that target nicotinic acetylcholine receptors (nAChR) are widely used. Studies on the sublethal effects of insecticides have found that they can affect the amount of virus in insects. The mechanism by which insecticides affect insect virus load remain unclear. Here, we show that nAChR targeting insecticide can affect viral replication through the immune deficiency (IMD) pathway. We demonstrate that a low dose of spinosad (6.8 ng/mL), acting as an antagonist to Drosophila melanogaster nicotinic acetylcholine receptor α6 (Dα6), significantly elevates Drosophila melanogaster sigmavirus (DMelSV) virus titers in adults of Drosophila melanogaster. Conversely, a high dose of spinosad (50 ng/mL), acting as an agonist to Dα6, substantially decreases viral load. This bidirectional regulation of virus levels is absent in Dα6-knockout flies, signifying the specificity of spinosad’s action through Dα6. Furthermore, the knockdown of Dα6 results in decreased expression of genes in the IMD pathway, including dredd, imd, relish, and downstream antimicrobial peptide genes AttA and AttB, indicating a reduced innate immune response. Subsequent investigations reveal no significant difference in viral titers between relish mutant flies and Dα6-relish double mutants, suggesting that the IMD pathway’s role in antiviral defense is dependent on Dα6. Collectively, our findings shed light on the intricate interplay between nAChR signaling and the IMD pathway in mediating antiviral immunity, highlighting the potential for nAChR-targeting compounds to inadvertently influence viral dynamics in insect hosts. This knowledge may inform the development of integrated pest management strategies that consider the broader ecological impact of insecticide use. Full article

Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer, with a poor prognosis. GBM cells, which develop in the environment of neural tissue, often exploit neurotransmitters and their receptors to promote their own growth and invasion. Nicotinic acetylcholine receptors (nAChRs), which play a crucial role in central nervous system signal transmission, are widely represented in the brain, and GBM cells express several subtypes of nAChRs that are suggested to transmit signals from neurons, promoting tumor invasion and growth. Analysis of published GBM transcriptomes revealed spatial heterogeneity in nAChR subtype expression, and functional nAChRs of α1*, α7, and α9 subtypes are demonstrated in our work on several patient-derived GBM microsphere cultures and on the U87MG GBM cell line using subtype-selective neurotoxins and fluorescent calcium mobilization assay. The U87MG cell line shows reactions to nicotinic agonists similar to those of GBM patient-derived culture. Selective α1*, α7, and α9 nAChR neurotoxins stimulated cell growth in the presence of nicotinic agonists. Several cultivating conditions with varying growth factor content have been proposed and tested. The use of selective neurotoxins confirmed that cell cultures obtained from patients are representative GBM models, but the use of media containing fetal bovine serum can lead to alterations in nAChR expression and functioning. Full article

Acetylcholine signaling is attenuated in early Alzheimer’s disease (AD) and other dementias. A significant reduction in the expression of nicotinic acetylcholine receptors (nAChRs) in the brain of AD patients has also been reported in several molecular biological and in situ labeling studies. The modulation of the functional deficit of the cholinergic system as a pharmacological target could therefore have a clinical benefit, which is not to be neglected. This systematic review was conducted to identify clinical trials, which evaluated the safety and efficacy of nicotinic acetylcholine receptor agonists using Clinicaltrial (CT) and EudraCT databases. Structured searches identified 39 trials, which used 15 different drugs designed to increase the function of the nAChRs. Most of the identified clinical trials were phase II trials, with some of them classified as ongoing for several years. The systematic screening of the literature led to the selection of 14 studies out of the 8261 bibliographic records retrieved. Six trials reported detailed data on adverse events associated with the intervention, while twelve trials reported data on efficacy measures, such as attention, behavior and cognition. Overall, smost of the physical side effects of cholinergic agonists were reported to be well tolerated. Some trials also reported improvements in attention. However, the efficacy of these drugs in other cognitive and behavioral outcomes remains highly controversial. Full article

Neonicotinoids, including imidacloprid, are pesticides that resemble nicotine and undergo slight chemical alterations through metabolic changes in the environment. However, the effects of these metabolites on organisms remain unknown. In this study, we assessed the developmental processes of medaka embryos exposed to neonicotinoid metabolites. The target compounds were imidacloprid metabolites: 2-chloro-5-pyridine carbaldehyde (CPC) and 6-chloronicotinic acid (6-CNA). Medaka embryos within 6 h of fertilization were exposed to the compounds, and their developmental processes were observed under a stereomicroscope. Medaka embryos exposed to 5 mg/L CPC showed no abnormalities compared to the controls. Contrastingly, medaka embryos exposed to 10, 15, and 20 mg/L CPC showed abnormalities such as thrombus formation, asymmetry, disorganized development of the eyeballs, and low blood flow. This trend was more pronounced at higher CPC concentrations. On the other hand, embryos exposed to 80 and 160 mg/L 6-CNA showed no abnormalities until day 7 of exposure. However, on day 8 of exposure, sudden embryo death was observed. Both compounds may have bound to acetylcholine receptors as agonists; however, their effects were different. CPC caused abnormal development and 6-CNA caused inhibition of hatching gland development and/or synthesis of the hatching enzyme. Full article

Macrophages serve as vital defenders, protecting the body by exhibiting remarkable cellular adaptability in response to invading pathogens and various stimuli. These cells express nicotinic acetylcholine receptors, with the α7-nAChR being extensively studied due to its involvement in activating the cholinergic anti-inflammatory pathway. Activation of this pathway plays a crucial role in suppressing macrophages’ production of proinflammatory cytokines, thus mitigating excessive inflammation and maintaining host homeostasis. Macrophage polarization, which occurs in response to specific pathogens or insults, is a process that has received limited attention concerning the activation of the cholinergic anti-inflammatory pathway and the contributions of the α7-nAChR in this context. This review aims to present evidence highlighting how the cholinergic constituents in macrophages, led by the α7-nAChR, facilitate the polarization of macrophages towards anti-inflammatory phenotypes. Additionally, we explore the influence of viral infections on macrophage inflammatory phenotypes, taking into account cholinergic mechanisms. We also review the current understanding of macrophage polarization in response to these infections. Finally, we provide insights into the relatively unexplored partial duplication of the α7-nAChR, known as dup α7, which is emerging as a significant factor in macrophage polarization and inflammation scenarios. Full article

Neuropathic pain affects about 7–8% of the population, and its management still poses challenges with unmet needs. Over the past decades, researchers have explored the cholinergic system (muscarinic and nicotinic acetylcholine receptors: mAChR and nAChR) and compounds targeting these receptors as potential analgesics for neuropathic pain management. This scoping review aims to provide an overview of studies on peripheral neuropathic pain (PNP) in rodent models, exploring compounds targeting cholinergic neurotransmission. The inclusion criteria were original articles on PNP in rodent models that explored the use of compounds directly targeting cholinergic neurotransmission and reported results of nociceptive behavioral assays. The literature search was performed in the PubMed and Web of Science databases (1 January 2000–22 April 2023). The selection process yielded 82 publications, encompassing 62 compounds. The most studied compounds were agonists of α4β2 nAChR and α7 nAChR, and antagonists of α9/α10 nAChR, along with those increasing acetylcholine and targeting mAChRs. Studies mainly reported antinociceptive effects in traumatic PNP models, and to a lesser extent, chemotherapy-induced neuropathy or diabetic models. These preclinical studies underscore the considerable potential of cholinergic compounds in the management of PNP, warranting the initiation of clinical trials. Full article

Neonicotinoid pesticides were initially designed in order to achieve species selectivity on insect nicotinic acetylcholine receptors (nAChRs). However, concerns arose when agonistic effects were also detected in human cells expressing nAChRs. In the context of next-generation risk assessments (NGRAs), new approach methods (NAMs) should replace animal testing where appropriate. Herein, we present a combination of in silico and in vitro methodologies that are used to investigate the potentially toxic effects of neonicotinoids and nicotinoid metabolites on human neurons. First, an ensemble docking study was conducted on the nAChR isoforms α7 and α3β4 to assess potential crucial molecular initiating event (MIE) interactions. Representative docking poses were further refined using molecular dynamics (MD) simulations and binding energy calculations using implicit solvent models. Finally, calcium imaging on LUHMES neurons confirmed a key event (KE) downstream of the MIE. This method was also used to confirm the predicted agonistic effect of the metabolite descyano-thiacloprid (DCNT). Full article

Immune cells such as T cells and macrophages express α7 nicotinic acetylcholine receptors (α7 nAChRs), which contribute to the regulation of immune and inflammatory responses. Earlier findings suggest α7 nAChR activation promotes the development of regulatory T cells (Tregs) in mice. Using human CD4⁺ T cells, we investigated the mRNA expression of the α7 subunit and the human-specific dupα7 nAChR subunit, which functions as a dominant-negative regulator of ion channel function, under resting conditions and T cell receptor (TCR)-activation. We then explored the effects of the selective α7 nAChR agonist GTS-21 on proliferation of TCR-activated T cells and Treg development. Varied levels of mRNA for both the α7 and dupα7 nAChR subunits were detected in resting human CD4⁺ T cells. mRNA expression of the α7 nAChR subunit was profoundly suppressed on days 4 and 7 of TCR-activation as compared to day 1, whereas mRNA expression of the dupα7 nAChR subunit remained nearly constant. GTS-21 did not alter CD4⁺ T cell proliferation but significantly promoted Treg development. These results suggest the potential ex vivo utility of GTS-21 for preparing Tregs for adoptive immunotherapy, even with high expression of the dupα7 subunit. Full article