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Oxidative Medicine and Cellular... 2019Cardiomyocyte apoptosis is critical for the development of coxsackievirus B3- (CVB3-) induced myocarditis, which is a common cardiac disease that may result in heart...
BACKGROUND
Cardiomyocyte apoptosis is critical for the development of coxsackievirus B3- (CVB3-) induced myocarditis, which is a common cardiac disease that may result in heart failure or even sudden death. Previous studies have associated CVB3-induced apoptosis with the downregulation of antiapoptotic proteins. Here, attempts were made to examine whether nicotinic acetylcholine receptors (nAChRs), especially 34-nAChRs, were a novel therapeutic antiapoptotic target via the activation of survivin, a strong antiapoptotic protein, in viral myocarditis (VMC).
METHODS AND RESULTS
In the present study, we demonstrated that nAChRs, 34-nAChR subunits in particular, were present and upregulated in CVB3-infected neonatal rat cardiomyocytes (NRC) and H9c2 cells by RT-qPCR. The function of 34-nAChRs was next examined using its specific blocker -CTX AuIB in vitro. The results of the TUNEL assay and western blot experiments showed that the block of 34-nAChRs abrogated nicotine-mediated protection of NRC from CVB3-induced apoptosis, and this effect displayed a substantial correlation with the protein expressions of pAkt, survivin, and Cleaved Caspase-3. Hence, the involvement of the PI3K/Akt pathway was further verified by LY294002, a selective inhibitor of PI3K. As a result, nicotine-mediated induction of pAkt and survivin was abolished by LY294002; meanwhile, apoptotic NRC were increased accompanied by an increase of Cleaved Caspase-3 expression. Regarding CVB3-infected BALB/c mice, the -CTX AuIB- and LY294002-treated groups had a lower survival rate, deteriorative ventricular systolic function, and more severe inflammation than the nicotine-treated group and the modulation of pAkt, survivin, and Cleaved Caspase-3 protein expressions was similar to that in CVB3-infected NRC. In addition, we found that a nicotinic agonist reduced CVB3 replication in a dose-dependent manner in vitro, which indicates that nAChR activation may serve as a possible protection mechanism of CVB3-induced myocarditis.
CONCLUSIONS
Our study demonstrated that 34-nAChR subunits are essential in the nicotine-mediated antiapoptotic effect of protecting cardiomyocytes from CVB3-induced apoptosis in vivo and in vitro. This protection correlated with the PI3K/Akt pathway and the inducement of the antiapoptotic protein survivin. A combination of these mechanisms serves as a novel protective response to treat viral myocarditis.
Topics: Animals; Apoptosis; Humans; Male; Mice; Myocarditis; Myocytes, Cardiac; Nicotinic Agonists; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Survivin; Up-Regulation
PubMed: 30984342
DOI: 10.1155/2019/9496419 -
Journal of Psychiatry & Neuroscience :... Mar 1998Tobacco dependence is a complex phenomenon that is not fully understood. Nicotine is the main alkaloid in tobacco and the addictive compound of tobacco. It can improve... (Review)
Review
Tobacco dependence is a complex phenomenon that is not fully understood. Nicotine is the main alkaloid in tobacco and the addictive compound of tobacco. It can improve both mood and cognitive functioning; these positive effects are strong reinforcements for smokers and contribute to their addiction. Opposite results also have been reported, however, and the effects of nicotine remain controversial. Recent epidemiological and empirical studies have indicated that smoking or nicotine or both may have protective effects against certain diseases. These findings have suggested that nicotine may be used as a therapeutic agent. However, because a variety of nicotinic cholinergic receptors are present in the brain, new agonist compounds may prove to be more effective than nicotine for therapeutic purposes. Studies are reviewed and the suggestion made that nicotine may prove useful as a tool to help us understand normal and pathological brain functioning.
Topics: Animals; Humans; Nicotine; Nicotinic Agonists; Smoking
PubMed: 9549250
DOI: No ID Found -
The Journal of Pharmacology and... Feb 2009The specific pharmacological response evoked by a nicotinic acetylcholine receptor (nAChR) agonist is governed by the anatomical distribution and expression of each... (Review)
Review
The specific pharmacological response evoked by a nicotinic acetylcholine receptor (nAChR) agonist is governed by the anatomical distribution and expression of each receptor subtype and by the stoichiometry of subunits comprising each subtype. Contributing to this complexity is the ability of agonists that bind to the orthosteric site of the receptor to alter the affinity state of the receptor and induce desensitization and the observation that, at low doses, some nAChR antagonists evoke agonist-like nicotinic responses. Brain concentrations of nicotine rarely increase to the low-mid micromolar concentrations that have been reported to evoke direct agonist-like responses, such as calcium influx or neurotransmitter release. Low microgram per kilogram doses of nicotine administered to humans or to nonhuman primates to improve cognition and working memory probably result only in low nanomolar brain concentrations--more in line with the ability of nicotine to induce receptor desensitization. Here we review data illustrating that nicotine, its major metabolite cotinine, and two novel analogs of choline, JWB1-84-1 [2-(4-(pyridin-3-ylmethyl)piperazin-1-yl)ethanol] and JAY2-22-33, JWB1-84-1 [2-(methyl(pyridine-3-ylmethyl)amino)-ethanol], improve working memory in macaques. The effectiveness of these four compounds in the task was linearly related to their effectiveness in producing desensitization of the pressor response to ganglionic stimulation evoked by a nAChR agonist in rats. Only nicotine evoked an agonist-like action (increased resting blood pressure). Therefore, it is possible to develop new chemical entities that have the ability to desensitize nAChRs without an antecedent agonist action. Because these "silent desensitizers" are probably acting allosterically, an additional degree of subtype specificity could be attained.
Topics: Allosteric Regulation; Animals; Binding Sites; Choline; Drug Design; Humans; Isoxazoles; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Phenylurea Compounds; Piperazines; Pyridines; Rats; Receptors, Nicotinic
PubMed: 19023041
DOI: 10.1124/jpet.108.145292 -
Psychopharmacology Aug 2020Prolinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian α4β2 nicotinic acetylcholine receptors (nAChRs)....
Behavioural and pharmacological profiles of zebrafish administrated pyrrolidinyl benzodioxanes and prolinol aryl ethers with high affinity for heteromeric nicotinic acetylcholine receptors.
RATIONALE
Prolinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian α4β2 nicotinic acetylcholine receptors (nAChRs). Electrophysiological studies have shown that the former are full agonists and the latter partial agonists or antagonists of human α4β2 receptors, but their in vivo effects are unknown.
OBJECTIVES AND METHODS
As α4β2 nAChRs play an important role in the cognition and the rewarding effects of nicotine, we tested the effects of two full agonists and one antagonist on spatial learning, memory and attention in zebrafish using a T-maze task and virtual object recognition test (VORT). The effect of a partial agonist in reducing nicotine-induced conditioned place preference (CPP) was also investigated.
RESULTS
In comparison with the vehicle alone, the full agonists MCL-11 and MCL-28 induced a significant cognitive enhancement as measured by the reduced running time in the T-maze and increased attention as measured by the increased discrimination index in the VORT. MCL-11 was 882 times more potent than nicotine. The two compounds were characterised by an inverted U-shaped dose-response curve, and their effects were blocked by the co-administration of the antagonist MCL-117, which alone had no effect. The partial agonist MCL-54 induced CPP and had an inverted U-shaped dose-response curve similar to that of nicotine but blocked the reinforcing effect of co-administered nicotine. Binding studies showed that all of the compounds have a higher affinity for heteromeric [H]-epibatidine receptors than [I]-αBungarotoxin receptors. MCL-11 was the most selective of heteromeric receptors.
CONCLUSIONS
These behavioural studies indicate that full agonist prolinol aryl ethers are very active in increasing spatial learning, memory and attention in zebrafish. The benzodioxane partial agonist MCL-54 reduced nicotine-induced CPP, and the benzodioxane antagonist MCL-117 blocked all agonist-induced activities.
Topics: Animals; Dose-Response Relationship, Drug; Ethers; Female; Male; Maze Learning; Morphinans; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Pyrrolidines; Pyrrolidinones; Receptors, Nicotinic; Zebrafish
PubMed: 32382782
DOI: 10.1007/s00213-020-05536-6 -
Nature Communications Oct 2016Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate...
Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma.
Topics: Animals; Asthma; Cells, Cultured; Cytokines; Disease Models, Animal; Humans; Lymphocytes; Mice, Inbred BALB C; Mice, Knockout; Nicotinic Agonists; Respiratory Hypersensitivity; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 27752043
DOI: 10.1038/ncomms13202 -
Journal of Pharmacological Sciences 2011Several lines of evidence suggest that cholinergic deficits may contribute to the pathophysiology of psychiatric disorders as well as Alzheimer's disease. There is... (Review)
Review
Several lines of evidence suggest that cholinergic deficits may contribute to the pathophysiology of psychiatric disorders as well as Alzheimer's disease. There is growing clinical evidence that galantamine, currently used for the treatment of Alzheimer's disease, may improve cognitive dysfunction and psychiatric illness in schizophrenia, major depression, bipolar disorder, and alcohol abuse. Since galantamine is a rather weak acetylcholinesterase inhibitor, but has additional allosteric potentiating effects at nicotinic receptors, it affects not only cholinergic transmission but also other neurotransmitter systems such as monoamines, glutamate, and γ-aminobutyric acid (GABA) through its allosteric mechanism. It is likely that these effects may result in more beneficial effects. To understand the underlying mechanism for the clinical effectiveness of galantamine, neuropharmacological studies have been performed in animal models of several psychiatric disorders. These studies suggest that not only the nicotinic receptor-modulating properties but also the muscarinic receptor activation contribute to the antipsychotic effect and improvement of cognitive dysfunction by galantamine. This review summaries the current status on the pharmacology of galantamine, focusing on its effect on neurotransmitter release and pharmacological studies in animal models of psychiatric disorders.
Topics: Allosteric Regulation; Animals; Cholinesterase Inhibitors; Galantamine; Humans; Mental Disorders; Muscarinic Agonists; Nicotinic Agonists; Psychotropic Drugs
PubMed: 21498956
DOI: 10.1254/jphs.11r01cr -
Life Sciences May 2007Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and... (Review)
Review
Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) whereas NNN bound with high affinity to epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) bound to both receptors but with lower affinity. High levels of the alpha7nAChR were expressed in human small cell lung cancer (SCLC) cell lines and in hamster pulmonary neuroendocrine cells (PNECs), which serve as a model for the cell of origin of human SCLC. Exposure of SCLC or PNECs to NNK or nicotine increased expression of the alpha7nAChR and caused influx of Ca(2+), activation of PKC, Raf-1, ERK1/2, and c-myc, resulting in the stimulation of cell proliferation. Signaling via the alpha7nAChR was enhanced when cells were maintained in an environment of 10-15% CO(2) similar to that in the diseased lung. Hamsters with hyperoxia-induced pulmonary fibrosis developed neuroendocrine lung carcinomas similar to human SCLC when treated with NNK, DEN, or nicotine. The development of the NNK-induced tumors was prevented by green tea or theophylline. The beta-adrenergic receptor agonist, isoproterenol or theophylline blocked NNK-induced cell proliferation in vitro. NNK and nicotine-induced hyperactivity of the alpha7nAChR/RAF/ERK1/2 pathway thus appears to play a crucial role in the development of SCLC in smokers and could be targeted for cancer prevention.
Topics: Animals; Binding, Competitive; Humans; Molecular Structure; Nicotinic Agonists; Nitrosamines; Receptors, Nicotinic
PubMed: 17459420
DOI: 10.1016/j.lfs.2007.03.006 -
Neuroscience and Biobehavioral Reviews Jan 2018Late-life depression is characterized by both lower mood and poor cognitive performance, symptoms that often do not fully respond to current antidepressant medications.... (Review)
Review
Late-life depression is characterized by both lower mood and poor cognitive performance, symptoms that often do not fully respond to current antidepressant medications. Nicotinic acetylcholine receptor (nAChR) agonists such as nicotine may serve as a novel therapeutic approach for this population. Both preclinical and preliminary clinical studies suggest that nAChR agonists can improve depressive behavior in animal models and improve mood in depressed individuals. Substantial literature also supports that nAChR agonists benefit cognitive performance, particularly in older populations. These potential benefits may be mediated by the effects of nAChR stimulation on neural network function and connectivity. Functional neuroimaging studies detail effects of nAChR agonists on the default mode network, central-executive network, and salience network that may oppose or reverse network changes seen in depression. We propose that, given the existent literature and the clinical presentation of late-life depression, nicotine or other nAChR agonists may have unique therapeutic benefits in this population and that clinical trials examining nicotine effects on mood, cognition, and network dynamics in late-life depression are justified.
Topics: Affect; Animals; Brain; Brain Mapping; Cognition; Depression; Humans; Neural Pathways; Nicotine; Nicotinic Agonists
PubMed: 28859996
DOI: 10.1016/j.neubiorev.2017.08.018 -
Expert Opinion on Pharmacotherapy Aug 2011This review examines the postmarketing experience with varenicline, including case reports, newer clinical trials and secondary analyses of large clinical datasets. (Comparative Study)
Comparative Study Review
INTRODUCTION
This review examines the postmarketing experience with varenicline, including case reports, newer clinical trials and secondary analyses of large clinical datasets.
AREAS COVERED
Varenicline has been shown to be an effective treatment in a broad range of tobacco users with medical, behavioral and diverse demographic characteristics. Recent studies finding excellent safety and efficacy in groups of smokers with diseases including chronic obstructive pulmonary disease are particularly encouraging and call for increased use of this medication for smoking cessation. Despite case reports of serious neuropsychiatric symptoms in patients taking varenicline, including changes in behavior and mood, causality has not been established. Recent analyses of large datasets from clinical trials have not demonstrated that varenicline is associated with more depression or suicidality than other treatments for smoking cessation.
EXPERT OPINION
Now that additional clinical trials in specific populations and observational studies on treatment-seeking smokers outside of clinical trials have been published, we can be confident that varenicline remains the most efficacious monotherapy for smoking cessation and that its side-effect profile remains good. The risk-to-benefit ratio of receiving varenicline to quit smoking must include the increased chances of quitting smoking and avoiding the sizeable risks of smoked-caused disease and death that remain if tobacco addiction is not properly treated.
Topics: Animals; Benzazepines; Humans; Nicotine; Nicotinic Agonists; Quinoxalines; Smoking Cessation; Tobacco Use Cessation; Tobacco Use Disorder; Tobacco, Smokeless; Varenicline
PubMed: 21644843
DOI: 10.1517/14656566.2011.587121 -
The Journal of Biological Chemistry Jan 2016Two α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) isoforms exist with (α4)2(β2)3 and (α4)3(β2)2 subunit stoichiometries and high versus low agonist...
Two α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) isoforms exist with (α4)2(β2)3 and (α4)3(β2)2 subunit stoichiometries and high versus low agonist sensitivities (HS and LS), respectively. Both isoforms contain a pair of α4(+)/(-)β2 agonist-binding sites. The LS isoform also contains a unique α4(+)/(-)α4 site with lower agonist affinity than the α4(+)/(-)β2 sites. However, the relative roles of the conserved α4(+)/(-)β2 agonist-binding sites in and between the isoforms have not been studied. We used a fully linked subunit concatemeric nAChR approach to express pure populations of HS or LS isoform α4β2*-nAChR. This approach also allowed us to mutate individual subunit interfaces, or combinations thereof, on each isoform background. We used this approach to systematically mutate a triplet of β2 subunit (-)-face E-loop residues to their non-conserved α4 subunit counterparts or vice versa (β2HQT and α4VFL, respectively). Mutant-nAChR constructs (and unmodified controls) were expressed in Xenopus oocytes. Acetylcholine concentration-response curves and maximum function were measured using two-electrode voltage clamp electrophysiology. Surface expression was measured with (125)I-mAb 295 binding and was used to define function/nAChR. If the α4(+)/(-)β2 sites contribute equally to function, making identical β2HQT substitutions at either site should produce similar functional outcomes. Instead, highly differential outcomes within the HS isoform, and between the two isoforms, were observed. In contrast, α4VFL mutation effects were very similar in all positions of both isoforms. Our results indicate that the identity of subunits neighboring the otherwise equivalent α4(+)/(-)β2 agonist sites modifies their contributions to nAChR activation and that E-loop residues are an important contributor to this neighbor effect.
Topics: Acetylcholine; Allosteric Site; Animals; Azetidines; Binding Sites; DNA, Complementary; Electrophysiology; Gene Expression Regulation; Humans; Mutagenesis, Site-Directed; Mutation; Nicotine; Nicotinic Agonists; Oocytes; Patch-Clamp Techniques; Protein Binding; Protein Isoforms; RNA; Receptors, Nicotinic; Xenopus laevis
PubMed: 26644472
DOI: 10.1074/jbc.M115.684373