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https://www.readbyqxmd.com/read/29778241/dual-autonomic-inhibitory-action-of-central-apelin-on-gastric-motor-functions-in-rats
#1
Mehmet Bülbül, Osman Sinen
Centrally administered apelin has been shown to inhibit gastric emptying (GE) in rodents, however, the relevant mechanism has been investigated incompletely. Using male Wistar rats, we investigated the efferent pathways involved in gastroinhibitory action of central apelin. Stereotaxic intracerebroventricular (icv) cannulation, subdiaphragmatic vagotomy (VGX) and/or celiac ganglionectomy (CGX) were performed 7 days prior to the experiments. Apelin-13 was administered (30 nmol, icv) 90 min prior to GE measurement...
July 2018: Autonomic Neuroscience: Basic & Clinical
https://www.readbyqxmd.com/read/29777683/probing-the-binding-site-of-novel-selective-positive-allosteric-modulators-at-the-m-1-machr
#2
Elham Khajehali, Celine Valant, Manuela Jörg, Andrew B Tobin, P Jeffrey Conn, Craig W Lindsley, Patrick M Sexton, Peter J Scammells, Arthur Christopoulos
Subtype-selective allosteric modulation of the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) is an attractive approach for the treatment of numerous disorders, including cognitive deficits. The discovery of benzyl quinolone carboxylic acid, BQCA, a selective M1 mAChR positive allosteric modulator (PAM), spurred the subsequent development of newer generation M1 PAMs representing diverse chemical scaffolds, different pharmacodynamic properties and, in some instances, improved pharmacokinetics. Key exemplar molecules from such efforts include PF-06767832 (N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-5-methyl-4-(4-(thiazol-4-yl)benzyl)pyridine-2-carboxamide), VU6004256 (4,6-difluoro-N-(1S,2S)-2-hydroxycyclohexyl-1-((6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl)methyl)-1H-indole-3-carboxamide) and MIPS1780 (3-(2-hydroxycyclohexyl)-6-(2-((4-(1-methyl-1H-pyrazol-4-yl)-benzyl)oxy)phenyl)pyrimidin-4(3H)-one)...
May 16, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29775722/inflammatory-and-oxidative-mechanisms-potentiate-bifenthrin-induced-neurological-alterations-and-anxiety-like-behavior-in-adult-rats
#3
Brahim Gargouri, Harsharan S Bhatia, Michèle Bouchard, Bernd L Fiebich, Hamadi Fetoui
Bifenthrin (BF) is a synthetic pyrethroid pesticide widely used in several countries to manage insect pests on diverse agricultural crops. Growing evidence indicates that BF exposure is associated with an increased risk of developing neurodegenerative disorders. However, the mechanisms by which BF induces neurological and anxiety alterations in the frontal cortex and striatum are not well known. The present in vivo study was carried out to determine whether reactive oxygen species (ROS)-mediated oxidative stress (OS) and neuroinflammation are involved in such alterations...
May 15, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29775673/gender-dependent-contribution-of-muscarinic-receptors-in-memory-retrieval-under-sub-chronic-stress
#4
Habiba Rashid, Touqeer Ahmed
Stress induces retrograde amnesia in humans and rodents. Muscarinic antagonism under normal physiological conditions causes gender dependent impairment in episodic memory retrieval. We aimed to explore the gender dependent role of muscarinic receptors in memory retrieval under sub-chronic stress condition. Male and female mice were trained for Morris water maze test and contextual fear conditioning, followed by 3 hour restraint stress per day for five days. Stress was either given alone or in combination with a daily subcutaneous injection of scopolamine (1 mg/kg) or donepezil (1 mg/kg)...
May 15, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29774778/an-overview-of-glycopyrrolate-eflow%C3%A2-cs-in-copd
#5
Edward Kerwin, Gary T Ferguson
COPD is highly prevalent in the US and globally, requiring new treatment strategies due to the high disease burden and increase in the aging population. Here, we profile the newly FDA-approved LONHALA MAGNAIR (glycopyrrolate [GLY]/eFlow® Closed System [CS]; 25 mcg twice daily), a nebulized long-acting muscarinic antagonist (LAMA) for the long-term maintenance treatment of COPD, including chronic bronchitis and/or emphysema. Areas covered: An overview of COPD and the treatment landscape, focusing on GLY/eFlow CS, is reported by reviewing the published literature pertinent to the drug/device combination...
May 18, 2018: Expert Review of Respiratory Medicine
https://www.readbyqxmd.com/read/29772545/autoantibodies-against-muscarinic-acetylcholine-receptor-m-3-in-sjogren-s-syndrome-and-corresponding-mouse-models
#6
Xinhua Yu, Gabriela Riemekasten, Frank Petersen
Muscarinic acetylcholine receptor M3 (M3R) is a GPCR on exocrine gland cells involved in fluid secretion. In the last two decades, evidence has been accumulated arguing for a role of autoantibodies (aab) against M3R in the development of Sjögren's syndrome (SS). In this review, we provide an updated overview on this issue and critically discuss the relation between autoimmunity to M3R and SS pathogenesis. Clinical data as well as findings from experimental disease were summarized in categories addressing the presence of aab against M3R in SS patients, the function of anti-M3R aab, the association of aab against M3R with SS-related phenotypes, in vivo pathogenicity of transferred aab against M3R in mice, and mouse models induced via immunization with M3R...
June 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/29768179/intestinal-epithelial-wnt-signaling-mediates-acetylcholine-triggered-host-defense-against-infection
#7
Sid Ahmed Labed, Khursheed A Wani, Sakthimala Jagadeesan, Abdul Hakkim, Mehran Najibi, Javier Elbio Irazoqui
Regulated antimicrobial peptide expression in the intestinal epithelium is key to defense against infection and to microbiota homeostasis. Understanding the mechanisms that regulate such expression is necessary for understanding immune homeostasis and inflammatory disease and for developing safe and effective therapies. We used Caenorhabditis elegans in a preclinical approach to discover mechanisms of antimicrobial gene expression control in the intestinal epithelium. We found an unexpected role for the cholinergic nervous system...
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29768168/a-worm-s-gut-feelings-neuronal-muscarinic-and-epithelial-canonical-wnt-pathways-promote-antimicrobial-defense
#8
Romana R Gerner, Manuela Raffatellu
Molecular mechanisms connecting the gut-brain axis to immunity remain elusive. In this issue of Immunity, Labed et al. (2018) demonstrate that two evolutionarily conserved signaling mechanisms, the neuronal muscarinic and the epithelial Wnt pathways, together induce antimicrobial peptide expression that protects Caenorhabditis elegans against intestinal infection.
May 15, 2018: Immunity
https://www.readbyqxmd.com/read/29765331/high-ph-sensitive-store-operated-ca-2-entry-mediated-by-ca-2-release-activated-ca-2-channels-in-rat-odontoblasts
#9
Maki Kimura, Koichi Nishi, Asuka Higashikawa, Sadao Ohyama, Kaoru Sakurai, Masakazu Tazaki, Yoshiyuki Shibukawa
Odontoblasts play a crucial role in dentin formation and sensory transduction following the application of stimuli to the dentin surface. Various exogenous and endogenous stimuli elicit an increase in the intracellular free calcium concentration ([Ca2+ ]i ) in odontoblasts, which is mediated by Ca2+ release from intracellular Ca2+ stores and/or Ca2+ influx from the extracellular medium. In a previous study, we demonstrated that the depletion of Ca2+ stores in odontoblasts activated store-operated Ca2+ entry (SOCE), a Ca2+ influx pathway...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29765214/tiotropium-inhibits-methacholine-induced-extracellular-matrix-production-via-%C3%AE-catenin-signaling-in-human-airway-smooth-muscle-cells
#10
Yating Huo, Lili Guan, Jiawen Xu, Luqian Zhou, Rongchang Chen
Background: Airway remodeling is an important feature of chronic obstructive pulmonary disease (COPD) that is associated with disease severity and irreversible airflow limitation. An extensive alteration of the extracellular matrix (ECM) surrounding the airway smooth muscle (ASM) bundle is one of the pathological manifestations of airway remodeling, which contributes to the decline in lung function. Tiotropium, a long-acting inhaled muscarinic receptor antagonist, has been confirmed to play a role in preventing airway remodeling including ECM deposition beyond bronchodilation in vivo, but the relationship between ASM cell (ASMC) relaxation and ECM production remains unclear...
2018: International Journal of Chronic Obstructive Pulmonary Disease
https://www.readbyqxmd.com/read/29763411/characteristics-and-health-care-resource-use-of-subjects-with-copd-in-the-year-before-initiating-lama-monotherapy-or-lama-laba-combination-therapy-a-u-s-database-study
#11
Saurabh Nagar, Jeetvan Patel, Richard H Stanford
PURPOSE: To characterize subjects with chronic obstructive pulmonary disease (COPD) newly initiated on long-acting muscarinic antagonists (LAMA) or dual LAMA/long-acting β2-adrenergic agonist (LABA) therapy. DESIGN: This pilot/preliminary analysis was a retrospective crosssectional study of subjects with COPD from the Optum Impact National Managed Care Benchmark Database. METHODOLOGY: Subjects with at least one LAMA prescription in the index period (July 2008-June 2009) were included and stratified by treatment...
May 2018: Managed Care
https://www.readbyqxmd.com/read/29761601/postnatal-development-of-cholinergic-input-to-the-thalamic-reticular-nucleus-of-the-mouse
#12
Guela Sokhadze, Peter Whitney Campbell, William Guido
The thalamic reticular nucleus (TRN), a shell-like structure comprised of GABAergic neurons, gates signal transmission between thalamus and cortex. While TRN is innervated by axon collaterals of thalamocortical and corticothalamic neurons, other ascending projections modulate activity during different behavioral states such as attention, arousal, and sleep-wake cycles. One of the largest arise from cholinergic neurons of the basal forebrain and brainstem. Despite its integral role, little is known about how or when cholinergic innervation and synapse formation occurs...
May 14, 2018: European Journal of Neuroscience
https://www.readbyqxmd.com/read/29757584/effects-of-nerve-growth-factor-shrna-inhibition-on-asthma-phenotypes-in-a-mouse-model-of-asthma
#13
Jinhong Wu, Bing Chen, Wenxian Li, Yanan Xiao
Nerve growth factor (NGF) plays an important role in airway hyper-responsiveness (AHR). In this study, we aimed at investigating the effect of NGF inhibition on AHR and other asthma phenotypes in a mouse model of asthma. 12 mice in each group were injected with lentiviral vectors expressing non-targeting shRNA (sham shRNA), targeting NGF (shRNA-1 and shRNA-2), or normal saline for control before the asthma models were established. Peak inspiratory pressure (PIP), NGF levels in bronchoalveolar lavage fluid (BALF), and bronchoconstriction in response to acetylcholine (ACh) were measured...
April 2018: Iranian Journal of Allergy, Asthma, and Immunology
https://www.readbyqxmd.com/read/29751997/modulation-of-nesfatin-1-induced-cardiovascular-effects-by-the-central-cholinergic-system
#14
Begum Aydin, Gokcen Guvenc, Burcin Altinbas, Nasir Niaz, Murat Yalcin
Nesfatin-1, a peptide whose receptor is yet to be identified, has been shown to be involved in the modulation of feeding, stress, and metabolic responses. Recently, increasing evidence has supported a modulatory role of nesfatin-1 in cardiovascular activity. We have previously reported that nesfatin-1 causes an increase in blood pressure in normotensive and hypotensive rats by increasing plasma catecholamine, vasopressin, and renin levels. Recent reports suggest that nesfatin-1 may activate the central cholinergic system...
May 4, 2018: Neuropeptides
https://www.readbyqxmd.com/read/29751234/pyridinyl-and-pyridazinyl-3-6-diazabicyclo-3-1-1-heptane-anilines-novel-selective-ligands-with-subnanomolar-affinity-for-%C3%AE-4-%C3%AE-2-nach-receptors
#15
Francesco Deligia, Gabriele Murineddu, Cecilia Gotti, Giulio Ragusa, Francesca Fasoli, Miriam Sciaccaluga, Simona Plutino, Sergio Fucile, Giovanni Loriga, Battistina Asproni, Gerard A Pinna
The cholinergic pathways in the central nervous system (CNS) of animals and humans are important for cognitive and behavioural functions. Until a few years ago, it was thought that the key molecules transducing the cholinergic message were the metabotropic muscarinic receptors, but it is now known that ionotropic neuronal nicotinic receptors (nAChRs) are also involved. Based on recent studies, we prepared a small library of novel 3-substituted-3,6-diazabicyclo [3.1.1]heptanes, whose binding activity and functionality have been assayed...
April 17, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29750142/single-inhaler-triple-therapy-in-symptomatic-copd-patients-fulfil-subgroup-analyses
#16
David M G Halpin, Ruby Birk, Noushin Brealey, Gerard J Criner, Mark T Dransfield, Emma Hilton, David A Lomas, Chang-Qing Zhu, David A Lipson
Triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β2 -agonist (LABA) therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD) and at risk of exacerbations. However, the benefits versus side-effects of triple inhaled therapy for COPD, based on distinct patient clinical profiles, are unclear. FULFIL, a phase III, randomised, double-blind study, compared 24 weeks of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62...
April 2018: ERJ Open Research
https://www.readbyqxmd.com/read/29742799/hippocampal-place-cell-dysfunction-and-the-effects-of-muscarinic-m-1-receptor-agonism-in-a-rat-model-of-alzheimer-s-disease
#17
Claire R Galloway, Kaushik Ravipati, Suyashi Singh, Evan P Lebois, Robert M Cohen, Allan I Levey, Joseph R Manns
Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory and the hippocampus. However, it is unclear how AD pathology influences the activity of surviving neurons in the hippocampus to contribute to the memory symptoms in AD. One well-understood connection between spatial memory and neuronal activity in healthy brains is the activity of place cells, neurons in the hippocampus that fire preferentially in a specific location of a given environment (the place field of the place cell)...
May 9, 2018: Hippocampus
https://www.readbyqxmd.com/read/29741535/amanita-muscaria-fly-agaric-from-a-shamanistic-hallucinogen-to-the-search-for-acetylcholine
#18
M R Lee, E Dukan, I Milne
The mushroom Amanita muscaria (fly agaric) is widely distributed throughout continental Europe and the UK. Its common name suggests that it had been used to kill flies, until superseded by arsenic. The bioactive compounds occurring in the mushroom remained a mystery for long periods of time, but eventually four hallucinogens were isolated from the fungus: muscarine, muscimol, muscazone and ibotenic acid. The shamans of Eastern Siberia used the mushroom as an inebriant and a hallucinogen. In 1912, Henry Dale suggested that muscarine (or a closely related substance) was the transmitter at the parasympathetic nerve endings, where it would produce lacrimation, salivation, sweating, bronchoconstriction and increased intestinal motility...
March 2018: Journal of the Royal College of Physicians of Edinburgh
https://www.readbyqxmd.com/read/29741108/the-safety-of-indacaterol-for-the-treatment-of-copd
#19
Evgenios I Metaxas, Evangelos Balis
Bronchodilators, namely long-acting inhaled β2-agonists and long-acting muscarinic antagonists, are the first-line medications for chronic obstructive pulmonary disease (COPD). The safety of these medicines is of great concern since COPD patients usually have other co-morbidities such as cardio- and cerebrovascular diseases. Areas covered: In this review we present information about the safety and the use of indacaterol in COPD. Indacaterol is the first once-daily, long-acting inhaled β2-agonist approved for COPD...
May 9, 2018: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/29740282/muscarinic-m4-receptors-on-cholinergic-and-dopamine-d1-receptor-expressing-neurons-have-opposing-functionality-for-positive-reinforcement-and-influence-impulsivity
#20
Anna M Klawonn, Daniel B Wilhelms, Sarah H Lindström, Anand Kumar Singh, Maarit Jaarola, Jürgen Wess, Michael Fritz, David Engblom
The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice...
2018: Frontiers in Molecular Neuroscience
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