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Yulia V Dobryakova, Olga Y Ivanova, Vladimir A Markevich
Muscarinic acetylcholine receptors (mAChR) are known to be related to learning and memory processes. Inactivation of mAChR by cholinergic antagonists have been shown to produce amnesia in a variety of behavioral tasks. In this study, we investigated the role of M1 and M2 AChR on passive avoidance learning and plasticity of synapses formed by Schaffer collaterals in freely moving rats. Experiments were performed using Wistar male rats. Seven days before testing, a recording electrode was lowered in the CA1 region under chloral hydrate anaesthesia to record the field excitatory postsynaptic potential (fEPSP) in response to Schaffer collateral stimulation...
2018: Acta Neurobiologiae Experimentalis
Yong Beom Kim, Hong-Seuk Yang, Ha Jung Kim, Hey-Ran Choi, Junyong In, Soon-Young Yoon, Young Jin Ro
This in-vivo study tested the hypothesis that the modulation of acetylcholine (ACh) release by the M1 muscarinic receptor (mAChR) in the neuromuscular junction of disused muscles may affect the tensions of the muscles during the neuromuscular monitoring of a rocuronium-induced neuromuscular block and compared the results with those obtained from normal muscles. A total of 20 C57BL/6 (wild-type) and 10 α7 knock out (α7KO) mice were used in this experiment. As a pre-experimental procedure, knee and ankle joints of right hind limbs were fixed by needle pinning at the 90° flexed position...
July 13, 2018: Clinical and Experimental Pharmacology & Physiology
Mélissa Sourioux, Sandrine S Bertrand, Jean-René Cazalets
Here, we investigated intrinsic spinal cord mechanisms underlying the physiological requirement for autonomic and somatic motor system coupling. Using an in vitro spinal cord preparation from newborn rat, we demonstrate that the specific activation of muscarinic cholinergic receptors (mAchRs) (with oxotremorine) triggers a slow burst rhythm in thoracic spinal segments, thereby revealing a rhythmogenic capability in this cord region. Whereas axial motoneurons (MNs) were rhythmically activated during both locomotor activity and oxotremorine-induced bursting, intermediolateral sympathetic preganglionic neurons (IML SPNs) exhibited rhythmicity solely in the presence of oxotremorine...
July 2018: PLoS Biology
Rui Tan, You Mee Ahn, Hye Yoom Kim, Yun Jung Lee, Kyung Woo Cho, Dae Gill Kang, Ho Sub Lee
The change of the secretion of atrial natriuretic peptide (ANP) from the atria is to be defined in hypertension accompanied by ventricular hypertrophy and increased synthesis of ANP. To identify the change of the secretion and mechanisms involved, experiments were performed in isolated perfused beating atria from sham-operated normotensive and renovascular hypertensive rats. Expressions of ANP, natriuretic peptide receptor (NPR)-C, components of the renin-angiotensin system (RAS) and muscarinic signaling pathway were measured in cardiac tissues...
July 6, 2018: American Journal of Physiology. Heart and Circulatory Physiology
Ji Eun Kim, Mi Rim Lee, Jin Ju Park, Jun Young Choi, Bo Ram Song, Hong Joo Son, Young Whan Choi, Kyung Mi Kim, Jin Tae Hong, Dae Youn Hwang
CONTEXT: Quercetin (QCT) has been known as a potential therapeutic strategy for gastrointestinal diseases because it contributes to the stabilization of mast cells, the prevention of histamine release and modulation of CaCC chloride channel. OBJECTIVE: We investigated the laxative effect and action mechanism of QCT in Lop-induced constipation model. MATERIALS AND METHODS: Constipation of SD rats was induced by subcutaneous injection of loperamide (Lop) (4 mg/kg weight) in 0...
December 2018: Pharmaceutical Biology
Toshiaki Ishizuka, Ayako Ozawa, Mieko Katsuura, Sayaka Nomura, Yasushi Satoh
Muscarinic acetylcholine receptors (mAchRs), which are expressed in various embryonic cells, may regulate neuronal differentiation. In the present study, we examined the effects of mAchR stimulation on the differentiation of mouse induced pluripotent stem (iPS) cells into neural progenitor cells (NPCs). Mouse iPS cells were cultured on ultra-low attachment dishes to induce embryoid body (EB) formation. All-trans retinoic acid (ATRA, 3 μmol/L) and/or pilocarpine (10 or 100 μmol/L), a mAchR agonist, were added to EB cultures for 4 days, following which the EBs were cultured on gelatin-coated plates for 7 days...
June 19, 2018: Clinical and Experimental Pharmacology & Physiology
Samuel T Kissinger, Alexandr Pak, Yu Tang, Sotiris C Masmanidis, Alexander A Chubykin
Familiarity of the environment changes the way we perceive and encode incoming information. However, the neural substrates underlying this phenomenon are poorly understood. Here we describe a new form of experience-dependent low-frequency oscillations in the primary visual cortex (V1) of awake adult male mice. The oscillations emerged in visually evoked potentials and single-unit activity following repeated visual stimulation. The oscillations were sensitive to the spatial frequency content of a visual stimulus and required the mAChRs for their induction and expression...
July 4, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Brittany J Carr, Koichiro Mihara, Rithwik Ramachandran, Mahmoud Saifeddine, Neil M Nathanson, William K Stell, Morley D Hollenberg
Purpose: Myopia is a refractive disorder that degrades vision. It can be treated with atropine, a muscarinic acetylcholine receptor (mAChR) antagonist, but the mechanism is unknown. Atropine may block α-adrenoceptors at concentrations ≥0.1 mM, and another potent myopia-inhibiting ligand, mamba toxin-3 (MT3), binds equally well to human mAChR M4 and α1A- and α2A-adrenoceptors. We hypothesized that mAChR antagonists could inhibit myopia via α2A-adrenoceptors, rather than mAChR M4...
June 1, 2018: Investigative Ophthalmology & Visual Science
Chelsea T Tiernan, Stephen D Ginsberg, Bin He, Sarah M Ward, Angela L Guillozet-Bongaarts, Nicholas M Kanaan, Elliott J Mufson, Scott E Counts
Cholinergic basal forebrain neurons of the nucleus basalis of Meynert (nbM) regulate attentional and memory function and are exquisitely prone to tau pathology and neurofibrillary tangle (NFT) formation during the progression of Alzheimer's disease (AD). nbM neurons require the neurotrophin nerve growth factor (NGF), its cognate receptor TrkA, and the pan-neurotrophin receptor p75NTR for their maintenance and survival. Additionally, nbM neuronal activity and cholinergic tone are regulated by the expression of nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors as well as receptors modulating glutamatergic and catecholaminergic afferent signaling...
September 2018: Neurobiology of Disease
Yesim A Tahirovic, Valarie M Truax, Robert J Wilson, Edgars Jecs, Huy H Nguyen, Eric J Miller, Michelle B Kim, Katie M Kuo, Tao Wang, Chi S Sum, Mary E Cvijic, Gretchen M Schroeder, Lawrence J Wilson, Dennis C Liotta
A novel series of CXCR4 antagonists with piperidinyl and piperazinyl alkylamine side chains designed as butyl amine replacements are described. Several of these compounds showed similar activity to the parent compound TIQ-15 ( 5 ) in a SDF-1 induced calcium flux assay. Preliminary structure-activity relationship investigations led us to identify a series containing N -propyl piperazine side chain analogs exemplified by 16 with improved off-target effects as measured in a muscarinic acetylcholine receptor (mAChR) calcium flux assay and in a limited drug safety panel screen...
May 10, 2018: ACS Medicinal Chemistry Letters
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)...
August 2018: Biochemical Pharmacology
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...
September 15, 2018: Toxicology Letters
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
Josep Tomàs, Neus Garcia, Maria A Lanuza, Manel M Santafé, Marta Tomàs, Laura Nadal, Erica Hurtado, Anna Simó-Ollé, Víctor Cilleros-Mañé, Laia Just-Borràs
In the last few years, we have studied the presence and involvement in synaptogenesis and mature transmitter release of the adenosine autoreceptors (AR) in the mammalian neuromuscular junction (NMJ). Here, we review and bring together the previously published data to emphasize the relevance of these receptors for developmental axonal competition, synaptic loss and mature NMJ functional modulation. However, in addition to AR, activity-dependent mediators originating from any of the three cells that make the synapse (nerve, muscle, and glial cells) cross the extracellular cleft to generate signals in target metabotropic receptors...
2018: Frontiers in Pharmacology
Rajan Dasgupta, Frederik Seibt, Michael Beierlein
Cholinergic afferents from the basal forebrain (BF) can influence cortical activity on rapid time scales, enabling sensory information processing and exploratory behavior. However, our understanding of how synaptically released acetylcholine (ACh) influences cellular targets in distinct cortical layers remains incomplete. Previous studies have shown that rapid changes in cortical dynamics induced by phasic BF activity can be mediated by the activation of nicotinic ACh receptors (nAChRs) expressed in distinct types of GABAergic interneurons...
June 6, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Sharath S Hegde, M Teresa Pulido-Rios, Mark A Luttmann, James J Foley, Gerald E Hunsberger, Tod Steinfeld, TaeWeon Lee, Yuhua Ji, Mathai M Mammen, Jeffrey R Jasper
Revefenacin (TD-4208) is a novel, long-acting, and lung-selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pKI  = 8.2-9.8) and behaved as a competitive antagonist (pKI, apparent = 9...
June 2018: Pharmacology Research & Perspectives
Sophie J Bradley, Colin Molloy, Christoffer Bundgaard, Adrian J Mogg, Karen J Thompson, Louis Dwomoh, Helen E Sanger, Michael D Crabtree, Simon M Brooke, Patrick M Sexton, Christian C Felder, Arthur Christopoulos, Lisa M Broad, Andrew B Tobin, Christopher J Langmead
The realization of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702 (7-fluoro-5-methyl-3-[1-(oxan-4-yl)piperidin-4-yl]-1 H -benzimidazol-2-one), described previously as a potent M1 receptor allosteric agonist, which showed procognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side effects...
June 2018: Molecular Pharmacology
Hui-Juan Jia, Xin Wang, Xin Fu, Xiao-Feng DU, Wei-Wei Zheng, Feng Luo
Cholinergic receptor activation and intracellular current injection lead to the persistent activity (PA), which may be involved in inducing neural plasticity. Our previous study showed that PA is closely related to the activation of muscarinic acetylcholine receptors (mAChRs) in pyramidal neurons of mouse primary auditory cortex (AI). However, the subtypes of mAChRs involved in PA remain unclear. Thus, using whole-cell patch-clamp recording and pharmacological methods, we investigated the role of different mAChR subtypes in inducing PA in AI layer V pyramidal neurons of young mice...
April 25, 2018: Sheng Li Xue Bao: [Acta Physiologica Sinica]
Emma T van der Westhuizen, Arthur Spathis, Elham Khajehali, Manuela Jörg, Shailesh N Mistry, Ben Capuano, Andrew B Tobin, Patrick M Sexton, Peter J Scammells, Celine Valant, Arthur Christopoulos
Positive allosteric modulators (PAMs) that target the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) are potential treatments for cognitive deficits in conditions such as Alzheimer disease and schizophrenia. We recently reported novel 4-phenylpyridine-2-one and 6-phenylpyrimidin-4-one M1 mAChR PAMs with the potential to display different modes of positive allosteric modulation and/or agonism but whose molecular mechanisms of action remain undetermined. The current study compared the pharmacology of three such novel PAMs with the prototypical first-generation PAM, benzyl quinolone carboxylic acid (BQCA), in a recombinant Chinese hamster ovary (CHO) cell line stably expressing the human M1 mAChR...
July 2018: Molecular Pharmacology
Alice E Berizzi, Aaron M Bender, Craig W Lindsley, P Jeffrey Conn, Patrick M Sexton, Christopher J Langmead, Arthur Christopoulos
Recent years have seen a large increase in the discovery of allosteric ligands targeting muscarinic acetylcholine receptors (mAChRs). One of the challenges in screening such compounds is to understand their mechanisms of action and define appropriate parameter estimates for affinity, cooperativity and efficacy. Herein we describe the mechanisms of action and structure-activity relationships for a series of "pan-Gq -coupled" muscarinic acetylcholine (ACh) receptor (mAChR) positive allosteric modulators (PAMs)...
July 18, 2018: ACS Chemical Neuroscience
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