RESUMEN
BACKGROUND: Clinical and preclinical research have demonstrated that short-term exposure to nicotine during the initial experimentation stage can lead to early manifestation of withdrawal-like signs, indicating the state of "acute dependence". As drug withdrawal is a major factor driving the progression toward regular drug intake, characterizing and understanding the features of early nicotine withdrawal may be important for the prevention and treatment of drug addiction. In this study, we corroborate the previous studies by showing that withdrawal-like signs can be precipitated after short-term nicotine exposure in mice, providing a potential animal model of acute dependence on nicotine. RESULTS: To model nicotine exposure from light tobacco use during the initial experimentation stage, mice were treated with 0.5 mg/kg (-)-nicotine ditartrate once daily for 3 days. On the following day, the behavioral tests were conducted after implementing spontaneous or mecamylamine-precipitated withdrawal. In the open field test, precipitated nicotine withdrawal reduced locomotor activity and time spent in the center zone. In the elevated plus maze test, the mecamylamine challenge increased the time spent in the closed arm and reduced the number of entries irrespective of nicotine experience. In the examination of the somatic aspect, precipitated nicotine withdrawal enhanced the number of somatic signs. Finally, nicotine withdrawal did not affect cognitive functioning or social behavior in the passive avoidance, spatial object recognition, or social interaction test. CONCLUSIONS: Collectively, our data demonstrate that early nicotine withdrawal-like signs could be precipitated by the nicotinic antagonist mecamylamine in mice, and that early withdrawal from nicotine primarily causes physical symptoms.
Asunto(s)
Nicotina , Síndrome de Abstinencia a Sustancias , Ratones , Animales , Nicotina/efectos adversos , Mecamilamina/farmacología , Mecamilamina/uso terapéutico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/etiología , Síndrome de Abstinencia a Sustancias/psicología , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , AutoestimulaciónRESUMEN
Evidence to date indicates that activation of nicotinic acetylcholine receptors (nAChRs) can reduce cardiac injury from ischemia and subsequent reperfusion. The use of nAChR agonists in various animal models leads to a reduction in reperfusion injury. Earlier this effect was shown for the agonists of α7 nAChR subtype. In this work, we demonstrated the expression of mRNA encoding α4, α6 and ß2 nAChR subunits in the left ventricle of rat heart. In a rat model of myocardial ischemia, we studied the effect of α4ß2 nAChR agonists cytisine and varenicline, medicines used for the treatment of nicotine addiction, and found them to significantly reduce myocardium ischemia-reperfusion injury, varenicline manifesting a higher protection. Dihydro-ß-erythroidine, antagonist of α4ß2 nAChR, as well as methyllycaconitine, antagonist of α7 and α6ß2-containing nAChR, prevented protective effect of varenicline. This together with the presence of α4, α6 and ß2 subunit mRNA in the left ventricule of rat heart raises the possibility that the varenicline effect is mediated by α4ß2 as well as by α7 and/or α6ß2-containing receptors. Our results point to a new way for the use of cytisine and varenicline as cardioprotective agents.
Asunto(s)
Alcaloides , Isquemia Miocárdica , Receptores Nicotínicos , Daño por Reperfusión , Ratas , Animales , Vareniclina/farmacología , Antagonistas Nicotínicos/uso terapéutico , Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/uso terapéutico , Alcaloides/farmacología , Alcaloides/uso terapéutico , Receptores Nicotínicos/genética , Reperfusión , Isquemia Miocárdica/tratamiento farmacológico , Daño por Reperfusión/tratamiento farmacológico , ARN Mensajero/genéticaRESUMEN
Growing evidence suggests that inhibition of the α3ß4 nicotinic acetylcholine receptor (nAChR) represents a promising therapeutic strategy to treat cocaine use disorder. Recently, aristoquinoline (1), an alkaloid from Aristotelia chilensis, was identified as an α3ß4-selective nAChR inhibitor. Here, we prepared 22 derivatives of 1 and evaluated their ability to inhibit the α3ß4 nAChR. These studies revealed structure-activity trends and several compounds with increased potency compared to 1 with few off-target liabilities. Additional mechanistic studies indicated that these compounds inhibit the α3ß4 nAChR noncompetitively, but do not act as channel blockers, suggesting they are negative allosteric modulators. Finally, using a cocaine-primed reinstatement paradigm, we demonstrated that 1 significantly attenuates drug-seeking behavior in an animal model of cocaine relapse. The results from these studies further support a role for the α3ß4 nAChR in the addictive properties of cocaine and highlight the possible utility of aristoquinoline derivatives in treating cocaine use disorder.
Asunto(s)
Alcaloides , Cocaína , Quinolinas , Receptores Nicotínicos , Animales , Alcaloides/farmacología , Alcaloides/uso terapéutico , Comportamiento de Búsqueda de Drogas , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéuticoRESUMEN
In the striatum, presynaptic α6-containig nicotinic receptors are crucially involved in the modulation of dopamine release. CVN417, a novel selective antagonist at this receptor subtype, attenuates motor dysfunction in a Parkinson's disease-relevant animal model, suggesting, for this pathology, a therapeutic strategy that could greatly profit from the restricted localization of α6* nicotinic receptors in the brain.
Asunto(s)
Enfermedad de Parkinson , Receptores Nicotínicos , Animales , Cuerpo Estriado , Receptores Nicotínicos/metabolismo , Dopamina/farmacología , Encéfalo/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéuticoRESUMEN
The pentameric nicotinic acetylcholine receptors (nAChRs) are typically classed as muscle- or neuronal-type, however, the latter has also been reported in non-neuronal cells. Given their broad distribution, nAChRs mediate numerous physiological and pathological processes including synaptic transmission, presynaptic modulation of transmitter release, neuropathic pain, inflammation, and cancer. There are 17 different nAChR subunits and combinations of these subunits produce subtypes with diverse pharmacological properties. The expression and role of some nAChR subtypes have been extensively deciphered with the aid of knock-out models. Many nAChR subtypes expressed in heterologous systems are selectively targeted by the disulfide-rich α-conotoxins. α-Conotoxins are small peptides isolated from the venom of cone snails, and a number of them have potential pharmaceutical value.
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Conotoxinas , Receptores Nicotínicos , Conotoxinas/farmacología , Conotoxinas/química , Conotoxinas/metabolismo , Receptores Nicotínicos/metabolismo , Péptidos/farmacología , Membrana Celular/metabolismo , Neuronas/metabolismo , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéuticoRESUMEN
Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4ß2 nAChRs, MLA and DhßE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4ß2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Región CA3 Hipocampal/efectos de los fármacos , Mecamilamina/farmacología , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Animales , Bicuculina/farmacología , Región CA1 Hipocampal/fisiología , Región CA3 Hipocampal/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas del GABA/farmacología , Técnicas In Vitro , Mecamilamina/uso terapéutico , Antagonistas Nicotínicos/uso terapéutico , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Receptores Nicotínicos/química , Convulsiones/prevención & control , Convulsiones/veterinaria , Transmisión Sináptica/efectos de los fármacosAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/uso terapéutico , Ansiedad/tratamiento farmacológico , Colinérgicos/uso terapéutico , Neuronas Colinérgicas/metabolismo , Cognición/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Ansiedad/metabolismo , Ansiedad/psicología , Colinérgicos/química , Colinérgicos/metabolismo , Neuronas Colinérgicas/efectos de los fármacos , Cognición/fisiología , Humanos , Agonistas Nicotínicos/química , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/uso terapéutico , Antagonistas Nicotínicos/química , Antagonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/uso terapéutico , Estructura Secundaria de Proteína , Receptores Nicotínicos/químicaRESUMEN
Tobacco use is a persistent public health issue. It kills up to half its users and is the cause of nearly 90% of all lung cancers. The main psychoactive component of tobacco is nicotine, primarily responsible for its abuse-related effects. Accordingly, most pharmacotherapies for smoking cessation target nicotinic acetylcholine receptors (nAChRs), nicotine's major site of action in the brain. The goal of the current review is twofold: first, to provide a brief overview of the most commonly used behavioral procedures for evaluating smoking cessation pharmacotherapies and an introduction to pharmacokinetic and pharmacodynamic properties of nicotine important for consideration in the development of new pharmacotherapies; and second, to discuss current and potential future pharmacological interventions aimed at decreasing tobacco use. Attention will focus on the potential for allosteric modulators of nAChRs to offer an improvement over currently approved pharmacotherapies. Additionally, given increasing public concern for the potential health consequences of using electronic nicotine delivery systems, which allow users to inhale aerosolized solutions as an alternative to smoking tobacco, an effort will be made throughout this review to address the implications of this relatively new form of nicotine delivery, specifically as it relates to smoking cessation. SIGNIFICANCE STATEMENT: Despite decades of research that have vastly improved our understanding of nicotine and its effects on the body, only a handful of pharmacotherapies have been successfully developed for use in smoking cessation. Thus, investigation of alternative pharmacological strategies for treating tobacco use disorder remains active; allosteric modulators of nicotinic acetylcholine receptors represent one class of compounds currently under development for this purpose.
Asunto(s)
Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Tabaquismo/tratamiento farmacológico , Animales , Ensayos Clínicos Fase III como Asunto , Humanos , Nicotina/farmacocinética , Receptores Nicotínicos/metabolismo , Cese del Hábito de Fumar/métodos , Tabaquismo/metabolismoRESUMEN
Receptors containing α4 and ß2 subunits are a major neuronal nicotinic acetylcholine receptor (nAChR) subtype in the brain. This receptor plays a critical role in nicotine addiction, with potential smoking cessation therapeutics producing modulation of α4ß2 nAChR. In addition, compounds that act as agonists at α4ß2 nAChR may be useful for the treatment of pathological pain. Further, as the α4ß2 nAChR has been implicated in cognition, therapeutics that act as α4ß2 nAChR agonists are also being examined as treatments for cognitive disorders and neurological diseases that impact cognitive function, such as Alzheimer's disease and schizophrenia. This review will cover the molecular in vitro evidence that allosteric modulators of the α4ß2 neuronal nAChR provide several advantages over traditional α4ß2 nAChR orthosteric ligands. Specifically, we explore the concept that nAChR allosteric modulators allow for greater pharmacological selectivity, while minimizing potential deleterious off-target effects. Further, here we discuss the development and preclinical in vivo behavioral assessment of allosteric modulators at the α4ß2 neuronal nAChR as therapeutics for smoking cessation, pathological pain, as well as cognitive disorders and neurological diseases that impact cognitive function. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
Asunto(s)
Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Dolor/metabolismo , Receptores Nicotínicos/metabolismo , Agentes para el Cese del Hábito de Fumar/farmacología , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Animales , Humanos , Agonistas Nicotínicos/uso terapéutico , Antagonistas Nicotínicos/uso terapéutico , Dolor/tratamiento farmacológico , Agentes para el Cese del Hábito de Fumar/uso terapéuticoRESUMEN
Postsynaptic nAChRs in the peripheral nervous system are critical for neuromuscular and autonomic neurotransmission. Pre- and peri-synaptic nAChRs in the brain modulate neurotransmission and are responsible for the addictive effects of nicotine. Subtypes of nAChRs in lymphocytes and non-synaptic locations may modulate inflammation and other cellular functions. All AChRs that function as ligand-gated ion channels are formed from five homologous subunits organized to form a central cation channel whose opening is regulated by ACh bound at extracellular subunit interfaces. nAChR subtype subunit composition can range from α7 homomers to α4ß2α6ß2ß3 heteromers. Subtypes differ in affinities for ACh and other agonists like nicotine and in efficiencies with which their channels are opened and desensitized. Subtypes also differ in affinities for antagonists and for positive and negative allosteric modulators. Some agonists are "silent" with respect to channel opening, and AChRs may be able to signal metabotropic pathways by releasing G-proteins independent of channel opening. Electrophysiological studies that can resolve single-channel openings and molecular genetic approaches have allowed characterization of the structures of ligand binding sites, the cation channel, and the linkages between them, as well as the organization of AChR subunits and their contributions to function. Crystallography and cryo-electron-microscopy are providing increasing insights into the structures and functions of AChRs. However, much remains to be learned about both AChR structure and function, the in vivo functional roles of some AChR subtypes, and the development of better pharmacological tools directed at AChRs to treat addiction, pain, inflammation, and other medically important issues. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
Asunto(s)
Agonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/metabolismo , Receptores Nicotínicos/metabolismo , Transducción de Señal/fisiología , Animales , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Ligandos , Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/uso terapéutico , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/metabolismo , Estructura Secundaria de Proteína , Receptores Nicotínicos/química , Transducción de Señal/efectos de los fármacosRESUMEN
Racemic 3-quinuclidinyl-α-methoxydiphenylacetate (MB266) was synthesised. Its activity at muscarinic acetylcholine receptors (mAChRs), and muscle and neuronal nicotinic acetylcholine receptors (nAChRs), was compared to that of atropine and racemic 3-quinucidinyl benzilate (QNB) using a functional assay based on agonist-induced elevation of intracellular calcium ion concentration in CN21, Chinese Hamster Ovary (CHO) and SHSY5Y human cell lines. MB266 acted as an antagonist at acetylcholine receptors, displaying 18-fold selectivity for mAChR versus nAChR (compared to the 15,200-fold selectivity observed for QNB). Thus O-methylation of QNB reduced the affinity for mAChR antagonism and increased the relative potency at both muscle and neuronal nAChRs. Despite MB266 having a pharmacological profile potentially useful for the treatment of anticholinesterase poisoning, its administration did not improve the neuromuscular function in a soman-poisoned guinea-pig diaphragm preparation pretreated with the organophosphorus nerve agent soman. Consideration should be given to exploring the potential of MB266 for possible anticonvulsant action in vitro as part of a multi-targeted ligand approach.
Asunto(s)
Antídotos/farmacología , Antídotos/uso terapéutico , Inhibidores de la Colinesterasa/envenenamiento , Antagonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/uso terapéutico , Agentes Nerviosos/envenenamiento , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Animales , Anticonvulsivantes/química , Anticonvulsivantes/uso terapéutico , Antídotos/síntesis química , Células CHO , Línea Celular , Cricetinae , Cricetulus , Diafragma/efectos de los fármacos , Cobayas , Humanos , Técnicas In Vitro , Masculino , Antagonistas Muscarínicos/síntesis química , Músculo Esquelético/efectos de los fármacos , Neuronas/efectos de los fármacos , Antagonistas Nicotínicos/síntesis química , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Soman/envenenamientoRESUMEN
Abstract: α-Conotoxin TxIB is a specific antagonist of α6/α3ß2ß3(α6ß2*) nicotinic acetylcholine receptor (nAChR) with an IC50 of 28 nM. Previous studies have shown that α6ß2* nAChRs are abundantly expressed in midbrain dopaminergic neurons and play an important role in mediating the mechanism of nicotine and other drugs reward effect. It provided important targets for the development of anti-addiction drugs. The present study evaluated the pharmacological activity of TxIB in vivo with conditioned place preference (CPP) model, which were induced by subcutaneous injection (s.c.) of nicotine (NIC, 0.5 mg/kg). α-Conotoxin TxIB inhibited the expression and reinstatement of CPP in mice dose-dependently, but had no significant effect on locomotor activity. The concentrations of dopamine (DA), γ-aminobutyric acid (GABA) and noradrenaline (NE) in different brain regions were measured by enzyme-linked immunosorbent assay (ELISA). We found that TxIB could inhibit the concentrations of DA, GABA and NE in different brain regions (such as nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC)) in NIC-induced mice. The concentrations of DA and NE were decreased in ventral tegmental area (VTA), while GABA had little change. The current work described the inhibition activity of TxIB in NIC-induced CPP, suggesting that α6ß2* nAChR-targeted compound may be a promising drug for nicotine addiction treatment.
Asunto(s)
Condicionamiento Psicológico/efectos de los fármacos , Conotoxinas/farmacología , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Tabaquismo/tratamiento farmacológico , Animales , Técnicas de Observación Conductual , Conducta Animal/efectos de los fármacos , Conotoxinas/uso terapéutico , Modelos Animales de Enfermedad , Dopamina/análisis , Dopamina/metabolismo , Humanos , Inyecciones Subcutáneas , Ligandos , Masculino , Ratones , Nicotina/administración & dosificación , Nicotina/efectos adversos , Antagonistas Nicotínicos/uso terapéutico , Norepinefrina/análisis , Norepinefrina/metabolismo , Recompensa , Área Tegmental Ventral/química , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismo , Ácido gamma-Aminobutírico/análisis , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Identifying novel therapeutics for the treatment of substance use disorder (SUD) is an area of intensive investigation. Prior strategies that have attempted to modify one or a few neurotransmitter receptors have had limited success, and currently there are no FDA-approved medications for the treatment of cocaine, methamphetamine, and marijuana use disorders. Because drugs of abuse are known to alter the expression of numerous genes in reward-related brain regions, epigenetic-based therapies have emerged as intriguing targets for therapeutic innovation. Here, I evaluate potential therapeutic approaches and challenges in targeting epigenetic factors for the treatment of SUD and highlight examples of promising strategies and future directions.
Asunto(s)
Conducta Adictiva/tratamiento farmacológico , Conducta Adictiva/genética , Encéfalo/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Trastornos Relacionados con Sustancias/genética , Animales , Conducta Adictiva/metabolismo , Encéfalo/metabolismo , Epigénesis Genética/fisiología , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Antagonistas de Narcóticos/farmacología , Antagonistas de Narcóticos/uso terapéutico , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Trastornos Relacionados con Sustancias/metabolismoRESUMEN
Alterations in membrane proteins (MPs) and their regulated pathways have been established as cancer hallmarks and extensively targeted in clinical applications. However, the analysis of MP-interacting proteins and downstream pathways across human malignancies remains challenging. Here, we present a systematically integrated method to generate a resource of cancer membrane protein-regulated networks (CaMPNets), containing 63,746 high-confidence protein-protein interactions (PPIs) for 1962 MPs, using expression profiles from 5922 tumors with overall survival outcomes across 15 human cancers. Comprehensive analysis of CaMPNets links MP partner communities and regulated pathways to provide MP-based gene sets for identifying prognostic biomarkers and druggable targets. For example, we identify CHRNA9 with 12 PPIs (e.g., ERBB2) can be a therapeutic target and find its anti-metastasis agent, bupropion, for treatment in nicotine-induced breast cancer. This resource is a study to systematically integrate MP interactions, genomics, and clinical outcomes for helping illuminate cancer-wide atlas and prognostic landscapes in tumor homo/heterogeneity.
Asunto(s)
Biomarcadores de Tumor/genética , Redes Reguladoras de Genes , Neoplasias/genética , Receptores Nicotínicos/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Bupropión/farmacología , Bupropión/uso terapéutico , Línea Celular Tumoral , Conjuntos de Datos como Asunto , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Estimación de Kaplan-Meier , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Pronóstico , Mapeo de Interacción de Proteínas/métodos , Mapas de Interacción de Proteínas/efectos de los fármacos , Mapas de Interacción de Proteínas/genética , Receptores Nicotínicos/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Nicotinic acetylcholine receptors (nAChRs) are associated with various cancers, but the relation between nAChRs and cervical cancer remains unclear. Therefore, this study investigated the differential expression of nAChR subunits in human cervical cancer cell lines (SiHa, HeLa, and CaSki) and in normal ectocervical cell lines (Ect1/E6E7) at mRNA and protein levels. Two specific nAChR subtype blockers, αO-conotoxin GeXIVA and α-conotoxin TxID, were then selected to treat different human cervical cancer cell lines with specific nAChR subtype overexpression. The results showed that α3, α9, α10, and ß4 nAChR subunits were overexpressed in SiHa cells compared with that in normal cells. α9 and α10 nAChR subunits were overexpressed in CaSki cells. α*-conotoxins that targeted either α9α10 or α3ß4 nAChR were able to significantly inhibit cervical cancer cell proliferation. These findings may provide a basis for new targets for cervical cancer targeted therapy.
Asunto(s)
Caracol Conus , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Conotoxinas/farmacología , Conotoxinas/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Antagonistas Nicotínicos/uso terapéutico , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: The morbidity and mortality associated with tobacco smoking is well established. Nicotine is the addictive component of tobacco. Nicotine, through the non-neuronal α7nicotinic receptor, induces cell proliferation, neo-angiogenesis, epithelial to mesenchymal transition, and inhibits drug-induced apoptosis. OBJECTIVE: To understand the genetic, molecular and cellular biology of addiction, chronic obstructive pulmonary disease and lung cancer. METHODS: The search for papers to be included in the review was performed during the months of July- September 2018 in the following databases: PubMed (http://www.ncbi.nlm.nih.gov), Scopus (http://www.scopus.com), EMBASE (http://www.elsevier.com/online-tools/embase), and ISI Web of Knowledge (http://apps.webofknowledge.com/). The following searching terms: "nicotine", "nicotinic receptor", and "addiction" or "COPD" or "lung cancer" were used. Patents were retrieved in clinicaltrials.gov (https://clinicaltrials.gov/). All papers written in English were evaluated. The reference list of retrieved articles was also reviewed to identify other eligible studies that were not indexed by the above-mentioned databases. New experimental data on the ability of nicotine to promote transformation of human bronchial epithelial cells, exposed for one hour to Benzo[a]pyrene-7,8-diol-9-10-epoxide, are reported. RESULTS: Nicotinic receptors variants and nicotinic receptors upregulation are involved in addiction, chronic obstructive pulmonary disease and/or lung cancer. Nicotine through α7nicotinic receptor upregulation induces complete bronchial epithelial cells transformation. CONCLUSION: Genetic studies highlight the involvement of nicotinic receptors variants in addiction, chronic obstructive pulmonary disease and/or lung cancer. A future important step will be to translate these genetic findings to clinical practice. Interventions able to help smoking cessation in nicotine dependence subjects, under patent, are reported.
Asunto(s)
Neoplasias Pulmonares/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Agentes para el Cese del Hábito de Fumar/metabolismo , Fumar Tabaco/metabolismo , Tabaquismo/metabolismo , Animales , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Antagonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Patentes como Asunto , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores Nicotínicos/metabolismo , Factores de Riesgo , Cese del Hábito de Fumar/métodos , Agentes para el Cese del Hábito de Fumar/farmacología , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Fumar Tabaco/tratamiento farmacológico , Tabaquismo/tratamiento farmacológicoRESUMEN
INTRODUCTION: Green tobacco sickness occurs from transdermal absorption of chemicals from freshly harvested, green tobacco leaves. Signs and symptoms include nausea, vomiting, headache, and abdominal cramps. Prevalence has shifted from the United States and Europe to China, India, and Brazil. Worldwide 8 million individuals are afflicted, including women and children. Areas covered: Mecamylamine (Inversine®, Vecamyl®), a nicotinic acetylcholine receptor (nAChR) antagonist, should be tested as a remedy for green tobacco sickness. Mecamylamine is approved as an oral tablet for the treatment of hypertension, is safe, and is off-patent. Mecamylamine attenuates many of the effects of nicotine and tobacco including seizures, thereby supporting its use as an effective pharmacotherapy for tobacco dependence. Varenicline (Chantix®) and cytisine (Tabex®) are low efficacy (i.e. intrinsic activity) nAChR agonists, are used as smoking cessation aids, and are viable options to test as remedies against green tobacco sickness. Nicotine immunization strategies may provide further options for future testing. Expert commentary: Efforts to demonstrate reversal and/or prevention of green tobacco sickness by mecamylamine will underscore the importance of nicotine in this illness and highlight a new medication for effective treatment of tobacco poisoning.
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Enfermedades de los Trabajadores Agrícolas/tratamiento farmacológico , Mecamilamina/uso terapéutico , Nicotiana/envenenamiento , Enfermedades de los Trabajadores Agrícolas/epidemiología , Enfermedades de los Trabajadores Agrícolas/fisiopatología , Humanos , Mecamilamina/farmacología , Nicotina/administración & dosificación , Nicotina/inmunología , Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/uso terapéutico , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Hojas de la Planta , Vacunas/administración & dosificación , Vacunas/inmunología , Vareniclina/uso terapéuticoRESUMEN
Recently, the muscle-type nicotinic acetylcholine receptors (nAChRs) have been pursued as a potential target of several diseases, including myogenic disorders, muscle dystrophies and myasthenia gravis, etc. α-conotoxin GI isolated from Conus geographus selectively and potently inhibited the muscle-type nAChRs which can be developed as a tool to study them. Herein, alanine scanning mutagenesis was used to reveal the structureâ»activity relationship (SAR) between GI and mouse α1ß1δε nAChRs. The Pro5, Gly8, Arg8, and Tyr11 were proved to be the critical residues for receptor inhibiting as the alanine (Ala) replacement led to a significant potency loss on mouse α1ß1δε nAChR. On the contrary, substituting Asn4, His10 and Ser12 with Ala respectively did not affect its activity. Interestingly, the [E1A] GI analogue exhibited a three-fold potency for mouse α1ß1δε nAChR, whereas it obviously decreased potency at rat α9α10 nAChR compared to wildtype GI. Molecular dynamic simulations also suggest that loop2 of GI significantly affects the interaction with α1ß1δε nAChR, and Tyr11 of GI is a critical residue binding with three hydrophobic amino acids of the δ subunit, including Leu93, Tyr95 and Leu103. Our research elucidates the interaction of GI and mouse α1ß1δε nAChR in detail that will help to develop the novel analogues of GI.
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Alanina/genética , Conotoxinas/química , Caracol Conus , Antagonistas Nicotínicos/química , Receptores Nicotínicos/metabolismo , Secuencia de Aminoácidos/genética , Animales , Conotoxinas/farmacología , Conotoxinas/uso terapéutico , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Músculo Esquelético/metabolismo , Mutagénesis , Enfermedades Neuromusculares/tratamiento farmacológico , Unión Neuromuscular/metabolismo , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Oocitos , Técnicas de Placa-Clamp , Receptores Nicotínicos/química , Relación Estructura-Actividad , Transmisión Sináptica/efectos de los fármacos , Xenopus laevisRESUMEN
Alpha-asarone is one of the bioactive phytochemicals present in the rhizomes of Acorus species and demonstrated its anticonvulsant activity in rodents. Alpha-asarone protected mice from the gamma-aminobutyric acid (GABA) type A receptor antagonist or N-methyl-d-aspartate (NMDA) receptor agonist-induced seizures. In our recent study, α-asarone attenuated the nicotine withdrawal-induced depression-like behavior in mice. The seizures induced by nicotine is mediated through the activation of nicotinic acetylcholine receptors (nAChRs) and stimulation of NMDA receptors. Therefore, we hypothesized that α-asarone might be effective against nicotine-induced seizures. Also, the interaction of α-asarone with nAChRs is unknown. In this study, we investigated the effect of α-asarone on the locomotor activity and body temperature in mice. In addition, we studied the effect of α-asarone on nicotine-induced seizures in mice. Finally, we assessed in vivo pharmacodynamic interaction of α-asarone with nAChRs using nicotine-induced hypomotility and hypothermia tests in mice. The results of this study showed that the α-asarone (50-200 mg/kg, i.p.) and diazepam (5 mg/kg, i.p.) treatment significantly decreased the locomotor activity and body temperature in mice. Furthermore, α-asarone (50-200 mg/kg, i.p.) and diazepam (5 mg/kg, i.p.) pretreatment significantly prolonged the onset time of nicotine-induced seizures in mice. However, α-asarone (30 and 50 mg/kg, i.p.) pretreatment did not inhibit the nicotine-induced hypomotility or hypothermia in mice. Conversely, mecamylamine (1 mg/kg, s.c.) pretreatment completely blocked the nicotine-induced seizures and significantly prevents the nicotine-induced hypomotility and hypothermia in mice. Overall, these results suggest that the protective effect of α-asarone against nicotine-induced seizures did not mediate through the antagonism of nAChRs. We also postulated that the GABAergic and glutamatergic activities of α-asarone could be involved in its protective effect against nicotine-induced seizures and based on this aspect further studies are required.
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Anisoles/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Nicotina/toxicidad , Receptores Nicotínicos/fisiología , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Derivados de Alilbenceno , Animales , Anisoles/farmacología , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Relación Dosis-Respuesta a Droga , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Ratones Endogámicos ICR , Fármacos Neuroprotectores/farmacología , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Convulsiones/metabolismoRESUMEN
RATIONALE AND OBJECTIVE: Two mechanisms underlie smoking cessation efficacies of α4ß2* nicotinic acetylcholine receptor (nAChR) agonists: a "nicotine-like" agonist activity reduces craving by substituting for nicotine during a quit attempt, and a "nicotine-blocking" antagonist activity attenuates reinforcement by competing with inhaled nicotine during a relapse. To evaluate the contribution of each mechanism to clinical efficacy, we estimated the degree of agonist and antagonist activities of nicotine replacement therapy (NRT), varenicline, cytisine, and the discontinued nAChR agonists dianicline, ABT-418, ABT-089, CP-601927, and CP-601932, relative to the functional effects of nicotine from smoking. METHODS: Functional activities that occur in vivo with clinical doses were predicted from literature data on binding and functional potencies at the target α4ß2 nAChR, as well as at α6ß2* nAChRs, and from estimates of free drug exposures in human brain. Agonist activity is comprised of nAChR activation and desensitization, which were expressed as percentages of desensitization and activation by nicotine from smoking. Antagonist activity was expressed as the reduction in nAChR occupancy by nicotine during smoking in the presence of an agonist. RESULTS: Comparisons with odds ratios at end of treatment suggest that extensive α4ß2 and α6ß2* nAChR desensitization combined with α6ß2* nAChR activation at similar levels as nicotine from smoking is associated with clinical efficacy (NRT, varenicline, cytisine, ABT-418). Effective competition with inhaled nicotine for α4ß2 and α6ß2* nAChRs further improves clinical efficacy (varenicline). Other discontinued nAChR agonists have lower agonist and antagonist activities at α4ß2 nAChRs and are inactive or less efficacious than NRT (dianicline, ABT-089, CP-601927, CP-601932). CONCLUSION: Three pharmacological effects appear to be key factors underlying smoking cessation efficacy: the degree of activation of α6ß2* nAChRs, desensitization of α4ß2 and α6ß2* nAChRs (agonist activity), and the reduction of nicotine occupancy at α4ß2 and α6ß2* nAChRs (antagonist activity). No single activity is dominant, and the level of smoking cessation efficacy depends on the profile of these activities achieved at clinical doses. While adequate agonist activity alone seems sufficient for a clinical effect (e.g., NRT, cytisine), clinical efficacy is improved with substantial competitive antagonism of α4ß2 nAChRs, i.e., if the drug has a dual agonist-antagonist mechanism of action (e.g., varenicline).