keyword
https://read.qxmd.com/read/37955136/advances-in-adrenergic-receptors-for-the-treatment-of-chronic-obstructive-pulmonary-disease-2023-update
#21
REVIEW
Maria Gabriella Matera, Barbara Rinaldi, Luigino Calzetta, Paola Rogliani, Mario Cazzola
INTRODUCTION: Strong scientific evidence and large experience support the use of β2 -agonists for the symptomatic alleviation of COPD. Therefore, there is considerable effort in discovering highly potent and selective β2 -agonists. AREAS COVERED: Recent research on novel β2 -agonists for the treatment of COPD. A detailed literature search was performed in two major databases (PubMed/MEDLINE and Scopus) up to September 2023." EXPERT OPINION: Compounds that preferentially activate a Gs - or β-arrestin-mediated signaling pathway via β- adrenoceptors (ARs) are more innovative...
2023: Expert Opinion on Pharmacotherapy
https://read.qxmd.com/read/37907853/galantamine-ameliorates-experimental-pancreatitis
#22
JOURNAL ARTICLE
Dane A Thompson, Tea Tsaava, Arvind Rishi, Sam J George, Tyler D Hepler, Daniel Hyde, Valentin A Pavlov, Michael Brines, Sangeeta S Chavan, Kevin J Tracey
BACKGROUND: Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4+ T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis. Galantamine is an acetylcholinesterase inhibitor (AChEI) which amplifies the CAP via modulation of central muscarinic ACh receptors (mAChRs)...
October 31, 2023: Molecular Medicine
https://read.qxmd.com/read/37895835/exploring-cholinergic-compounds-for-peripheral-neuropathic-pain-management-a-comprehensive-scoping-review-of-rodent-model-studies
#23
REVIEW
Edouard Montigné, David Balayssac
Neuropathic pain affects about 7-8% of the population, and its management still poses challenges with unmet needs. Over the past decades, researchers have explored the cholinergic system (muscarinic and nicotinic acetylcholine receptors: mAChR and nAChR) and compounds targeting these receptors as potential analgesics for neuropathic pain management. This scoping review aims to provide an overview of studies on peripheral neuropathic pain (PNP) in rodent models, exploring compounds targeting cholinergic neurotransmission...
September 27, 2023: Pharmaceuticals
https://read.qxmd.com/read/37842807/repositioning-vu-0365114-as-a-novel-microtubule-destabilizing-agent-for-treating-cancer-and-overcoming-drug-resistance
#24
JOURNAL ARTICLE
Yao-Yu Hsieh, Jia-Ling Du, Pei-Ming Yang
Microtubule-targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule-targeting agents without such limitations are urgently needed. By employing a gene expression-based drug repositioning strategy, this study identifies VU-0365114, originally synthesized as a positive allosteric modulator of human muscarinic acetylcholine receptor M5 (M5 mAChR), as a novel type of tubulin inhibitor by destabilizing microtubules...
October 16, 2023: Molecular Oncology
https://read.qxmd.com/read/37767557/a-muscarinic-girk-channel-mediated-inhibition-of-inspiratory-related-xii-nerve-motor-output-emerges-in-early-postnatal-development-in-mice
#25
JOURNAL ARTICLE
Samantha L Rudy, Jesse C Wealing, Tatum Banayat, Chody Black, Gregory D Funk, Ann L Revill
In neonatal rhythmic medullary slices, muscarinic acetylcholine receptor (mAChR) activation of hypoglossal (XII) motoneurons that innervate the tongue has a net excitatory effect on XII inspiratory motor output. Conversely, during rapid eye movement sleep in adult rodents, XII motoneurons experience a loss of excitability partly due to activation of mAChRs. This may be mediated by activation of G-protein coupled inwardly rectifying potassium (GIRK) channels. Therefore, this study was designed to evaluate whether muscarinic modulation of XII inspiratory motor output in mouse rhythmic medullary slices includes GIRK channel-mediated inhibition and if so, when this inhibitory mechanism emerges...
September 28, 2023: Journal of Applied Physiology
https://read.qxmd.com/read/37691124/acetylcholinesterase-inhibition-protects-against-trastuzumab-induced-cardiotoxicity-through-reducing-multiple-programmed-cell-death-pathways
#26
JOURNAL ARTICLE
Thawatchai Khuanjing, Chayodom Maneechote, Benjamin Ongnok, Nanthip Prathumsap, Apiwan Arinno, Titikorn Chunchai, Busarin Arunsak, Siriporn C Chattipakorn, Nipon Chattipakorn
BACKGROUND: Trastuzumab (Trz)-induced cardiotoxicity (TIC) is one of the most common adverse effects of targeted anticancer agents. Although oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and ferroptosis have been identified as potential mechanisms underlying TIC, the roles of pyroptosis and necroptosis under TIC have never been investigated. It has been shown that inhibition of acetylcholinesterase function by using donepezil exerts protective effects in various heart diseases...
September 11, 2023: Molecular Medicine
https://read.qxmd.com/read/37679045/characterization-of-selective-m-5-acetylcholine-muscarinic-receptor-modulators-on-dopamine-signaling-in-the-striatum
#27
JOURNAL ARTICLE
Vivien Zell, Greetje Teuns, Alexandra Stormy Needham, Sruti Mukherjee, Nathaniel Roscoe, Michelle Le, Lawrence Fourgeaud, Grace Woodruff, Anindya Bhattacharya, Mathieu Marella, Pascal Bonaventure, Wayne C Drevets, Bartosz Balana
The type-5 muscarinic acetylcholine receptor (mAChR, M5 ) is almost exclusively expressed in dopamine (DA) neurons of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc); therefore, ideally located to modulate DA signaling and underlying behaviors. However, the role of M5 in shaping DA release is still poorly characterized. In this study, we first quantitatively mapped the expression of M5 in different neurons of the mouse midbrain, then used voltammetry in mouse striatum to evaluate the effect of M5 -selective modulators on DA release...
September 7, 2023: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/37673901/xanomeline-displays-concomitant-orthosteric-and-allosteric-binding-modes-at-the-m-4-machr
#28
JOURNAL ARTICLE
Wessel A C Burger, Vi Pham, Ziva Vuckovic, Alexander S Powers, Jesse I Mobbs, Yianni Laloudakis, Alisa Glukhova, Denise Wootten, Andrew B Tobin, Patrick M Sexton, Steven M Paul, Christian C Felder, Radostin Danev, Ron O Dror, Arthur Christopoulos, Celine Valant, David M Thal
The M4 muscarinic acetylcholine receptor (M4 mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, cognition, and addiction. The mAChR agonist, xanomeline, has provided significant improvement in the Positive and Negative Symptom Scale (PANSS) scores in a Phase II clinical trial for the treatment of patients suffering from schizophrenia. Here we report the active state cryo-EM structure of xanomeline bound to the human M4 mAChR in complex with the heterotrimeric Gi1 transducer protein...
September 6, 2023: Nature Communications
https://read.qxmd.com/read/37660916/the-biased-m3-machr-ligand-pd-102807-mediates-qualitatively-distinct-signaling-to-regulate-airway-smooth-muscle-phenotype
#29
JOURNAL ARTICLE
Eric Tompkins, Bogdana Mimic, Raymond B Penn, Tonio Pera
Airway smooth muscle (ASM) cells attain a hypercontractile phenotype during obstructive airway diseases. We recently identified a biased M3 muscarinic acetylcholine receptor (mAChR) ligand, PD 102807, that induces GRK-/arrestin-dependent AMPK activation to inhibit TGF-β-induced hypercontractile ASM phenotype. Conversely, the balanced mAChR agonist, methacholine (MCh), activates AMPK yet does not regulate ASM phenotype. In the current study, we demonstrate that PD 102807- and MCh-induced AMPK activation both depend on Ca2+ /calmodulin-dependent kinase kinases (CaMKKs)...
September 1, 2023: Journal of Biological Chemistry
https://read.qxmd.com/read/37641543/vagus-nerve-stimulation-induced-stromal-cell-derived-factor-l-alpha-participates-in-angiogenesis-and-repair-of-infarcted-hearts
#30
JOURNAL ARTICLE
Yan Wang, Yun Liu, Xing-Yuan Li, Lu-Yuan Yao, MagdaleenaNaemi Mbadhi, Shao-Juan Chen, Yan-Xia Lv, Xin Bao, Long Chen, Shi-You Chen, Jing-Xuan Zhang, Yan Wu, Jing Lv, Liu-Liu Shi, Jun-Ming Tang
AIMS: We aim to explore the role and mechanism of vagus nerve stimulation (VNS) in coronary endothelial cells and angiogenesis in infarcted hearts. METHODS AND RESULTS: Seven days after rat myocardial infarction (MI) was prepared by ligation of the left anterior descending coronary artery, the left cervical vagus nerve was treated with electrical stimulation 1 h after intraperitoneal administration of the α7-nicotinic acetylcholine inhibitor mecamylamine or the mAChR inhibitor atropine or 3 days after local injection of Ad-shSDF-1α into the infarcted heart...
August 29, 2023: ESC Heart Failure
https://read.qxmd.com/read/37591961/nucleus-accumbens-core-acetylcholine-receptors-modulate-the-balance-of-flexible-and-inflexible-cue-directed-motivation
#31
JOURNAL ARTICLE
Erica S Townsend, Kenneth A Amaya, Elizabeth B Smedley, Kyle S Smith
Sign-tracking is a conditioned response where animals interact with reward-predictive cues due to the cues having motivational value, or incentive salience. The nucleus accumbens core (NAc) has been implicated in mediating the sign-tracking response. Additionally, acetylcholine (ACh) transmission throughout the striatum has been attributed to both incentive motivation and behavioral flexibility. Here, we demonstrate a role for NAc ACh receptors in the flexibility of sign-tracking. Sign-tracking animals were exposed to an omission contingency, in which vigorous sign-tracking was punished by reward omission...
August 17, 2023: Scientific Reports
https://read.qxmd.com/read/37577578/elucidating-the-role-of-muscarinic-acetylcholine-receptor-machr-signaling-in-efferent-mediated-responses-of-vestibular-afferents-in-mammals
#32
Anjali K Sinha, Choongheon Lee, Joseph C Holt
The peripheral vestibular system detects head position and movement through activation of vestibular hair cells (HCs) in vestibular end organs. HCs transmit this information to the CNS by way of primary vestibular afferent neurons. The CNS, in turn, modulates HCs and afferents via the efferent vestibular system (EVS) through activation of cholinergic signaling mechanisms. In mice, we previously demonstrated that activation of muscarinic acetylcholine receptors (mAChRs), during EVS stimulation, gives rise to a slow excitation that takes seconds to peak and tens of seconds to decay back to baseline...
August 6, 2023: bioRxiv
https://read.qxmd.com/read/37552895/targeting-the-actions-of-muscarinic-receptors-on-dopamine-systems-new-strategies-for-treating-neuropsychiatric-disorders
#33
REVIEW
Eric J Nunes, Nii A Addy, P Jeffrey Conn, Daniel J Foster
Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes...
August 8, 2023: Annual Review of Pharmacology and Toxicology
https://read.qxmd.com/read/37549771/-r-s-trihexyphenidyl-acting-via-a-muscarinic-receptor-independent-mechanism-inhibits-hippocampal-glutamatergic-and-gabaergic-synaptic-transmissions-potential-relevance-for-treatment-of-organophosphorus-intoxication
#34
JOURNAL ARTICLE
Yasco Aracava, Edson X Albuquerque, Edna F R Pereira
Preclinical studies have reported that, compared to the muscarinic receptor (mAChR) antagonist atropine, (R,S)-trihexyphenidyl (THP) more effectively counters the cholinergic crisis, seizures, and neuropathology triggered by organophosphorus (OP)-induced acetylcholinesterase (AChE) inhibition. The greater effectiveness of THP was attributed to its ability to block mAChRs and N-methyl-d-aspartate-type glutamatergic receptors (NMDARs) in the brain. However, THP also inhibits α7 nicotinic receptors (nAChRs)...
August 5, 2023: Neuropharmacology
https://read.qxmd.com/read/37509081/molecular-basis-of-transglutaminase-2-and-muscarinic-cholinergic-receptors-in-experimental-myopia-a-target-for-myopia-treatment
#35
JOURNAL ARTICLE
Veluchamy Amutha Barathi, Candice E H Ho, Louis Tong
Myopia, a prevalent refractive error disorder worldwide, is characterized by the elongation of the eye, leading to visual abnormalities. Understanding the genetic factors involved in myopia is crucial for developing therapeutic and preventive measures. Unfortunately, only a limited number of genes with well-defined functionality have been associated with myopia. In this study, we found that the homozygous TGM2-deleted gene in mice protected against the development of myopia by slowing down the elongation of the eye...
June 27, 2023: Biomolecules
https://read.qxmd.com/read/37482212/acetylcholine-receptor-agonists-effectively-attenuated-multiple-program-cell-death-pathways-and-improved-left-ventricular-function-in-trastuzumab-induced-cardiotoxicity-in-rats
#36
JOURNAL ARTICLE
Nanthip Prathumsap, Benjamin Ongnok, Thawatchai Khuanjing, Apiwan Arinno, Chayodom Maneechote, Titikorn Chunchai, Busarin Arunsak, Sasiwan Kerdphoo, Siriporn C Chattipakorn, Nipon Chattipakorn
AIMS: Cardiotoxicity is a seriously debilitating complication of trastuzumab (TRZ) therapy in patients with cancer as a consequence of overexpression of the human epidermal growth factor receptor 2. Although most TRZ-induced cardiotoxicity (TIC) cases are reversible, some patients experience chronic cardiac dysfunction, and these irreversible concepts may be associated with cardiomyocyte death. Acetylcholine receptor (AChR) activation has been shown to exert cardioprotection in several heart diseases, but the effects of AChR agonists against TIC have not been investigated...
July 22, 2023: Life Sciences
https://read.qxmd.com/read/37428619/the-role-of-long-acting-antimuscarinic-agents-in-the-treatment-of-asthma
#37
REVIEW
Bahar Arslan, Gülden Paçacı Çetin, İnsu Yilmaz
The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma...
July 11, 2023: Journal of Aerosol Medicine and Pulmonary Drug Delivery
https://read.qxmd.com/read/37423123/design-synthesis-and-evaluation-of-novel-2-phenyl-3-1h-pyrazol-4-yl-pyridine-positive-allosteric-modulators-for-the-m-4-machr
#38
JOURNAL ARTICLE
Manuela Jörg, Emma T van der Westhuizen, Yao Lu, K H Christopher Choy, David M Shackleford, Elham Khajehali, Andrew B Tobin, David M Thal, Ben Capuano, Arthur Christopoulos, Celine Valant, Peter J Scammells
Translation of muscarinic acetylcholine receptor (mAChR) agonists into clinically used therapeutic agents has been difficult due to their poor subtype selectivity. M4 mAChR subtype-selective positive allosteric modulators (PAMs) may provide better therapeutic outcomes, hence investigating their detailed pharmacological properties is crucial to advancing them into the clinic. Herein, we report the synthesis and comprehensive pharmacological evaluation of M4 mAChR PAMs structurally related to 1e, Me-C-c, [11 C]MK-6884 and [18 F]12...
July 1, 2023: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/37401396/the-m1-muscarinic-acetylcholine-receptor-subtype-may-play-a-role-in-learning-and-memory-performance-in-the-hippocampus-of-neonatal-monosodium-glutamate-obese-rats
#39
JOURNAL ARTICLE
Marcelo Florencio Passos Silva, Christian Pereira Rafael, Jeferson Rubens Mamona Silva, Tiago Guardia de Souza E Silva, Rafaela Fadoni Alponti, Patricia Lucio Alves, Maria Regina Lopes Sandoval, Fernando Maurício Francis Abdalla
Here, we investigate the effects of obesity induced by monosodium glutamate (MSG) on cognitive impairment and whether this model induces any alteration in the affinity, density, and subtypes of muscarinic acetylcholine receptors (mAChRs) in rat hippocampus. Healthy rats were used as controls, and MSG-obese rats were selected via the Lee index > 0.300. The effects of MSG-induced obesity on hippocampal spatial learning and memory processes were evaluated by using the working memory versions of the Morris' water maze task and the evaluation of mAChRs by binding assay and their subtypes by immunoprecipitation assays...
June 26, 2023: Behavioural Pharmacology
https://read.qxmd.com/read/37398379/polygenic-adaptation-to-overnutrition-reveals-a-role-for-cholinergic-signaling-in-longevity
#40
Thomas B Rundell, Melina Brunelli, Azva Alvi, Gabrielle Safian, Christina Capobianco, Wangshu Tu, Sanjeena Subedi, Anthony Fiumera, Laura Palanker Musselman
Overnutrition by high-sugar (HS) feeding reduces both the lifespan and healthspan across taxa. Pressuring organisms to adapt to overnutrition can highlight genes and pathways important for the healthspan in stressful environments. We used an experimental evolution approach to adapt four replicate, outbred population pairs of Drosophila melanogaster to a HS or control diet. Sexes were separated and aged on either diet until mid-life, then mated to produce the next generation, allowing enrichment for protective alleles over time...
June 14, 2023: bioRxiv
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