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Neuroscience Bulletin Dec 2023Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP)...
Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP) in the affected limb. NP is insensitive to the existing treatments, which makes it a challenge to researchers and clinicians. Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction, which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP. However, the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear. In this study, through using a novel BPA C7 root avulsion mouse model, we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased, and the markers of sympathetic nervous system activity including α1 and α2 adrenergic receptors (α1-AR and α2-AR) also increased after BPA. The phenomenon of superexcitation of the sympathetic nervous system, including hypothermia and edema of the affected extremity, was also observed in BPA mice by using CatWalk gait analysis, an infrared thermometer, and an edema evaluation. Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice. Further, intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice. In another branch experiment, we also found the elevated expression of BDNF, TrκB, TH, α1-AR, and α2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry. Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP. This study also opens a novel analgesic target (BDNF) in the treatment of this pain with fewer complications, which has great potential for clinical transformation.
Topics: Humans; Mice; Animals; Hyperalgesia; Brain-Derived Neurotrophic Factor; Hypothermia; Neuralgia; Brachial Plexus; Edema
PubMed: 37335428
DOI: 10.1007/s12264-023-01075-0 -
Journal of Aerosol Medicine and... Aug 2023The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed... (Review)
Review
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. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.
Topics: Humans; Muscarinic Antagonists; Tiotropium Bromide; Glycopyrrolate; Administration, Inhalation; Asthma; Cholinergic Antagonists; Adrenal Cortex Hormones; Inflammation; Bronchodilator Agents; Adrenergic beta-2 Receptor Agonists; Pulmonary Disease, Chronic Obstructive
PubMed: 37428619
DOI: 10.1089/jamp.2022.0059 -
Fundamental & Clinical Pharmacology Feb 2024Catecholamines and β-adrenergic receptors (β-ARs) play an important role in the regulation of cardiac tolerance to the impact of ischemia and reperfusion. This... (Review)
Review
The role of β-adrenergic receptors in the regulation of cardiac tolerance to ischemia/reperfusion. Why do β-adrenergic receptor agonists and antagonists protect the heart?
BACKGROUND
Catecholamines and β-adrenergic receptors (β-ARs) play an important role in the regulation of cardiac tolerance to the impact of ischemia and reperfusion. This systematic review analyzed the molecular mechanisms of the cardioprotective activity of β-AR ligands.
METHODS
We performed an electronic search of topical articles using PubMed databases from 1966 to 2023. We cited original in vitro and in vivo studies and review articles that documented the cardioprotective properties of β-AR agonists and antagonists.
RESULTS
The infarct-reducing effect of β-AR antagonists did not depend on a decrease in the heart rate. The target for β-blockers is not only cardiomyocytes but also neutrophils. β1-blockers (metoprolol, propranolol, timolol) and the selective β2-AR agonist arformoterol have an infarct-reducing effect in coronary artery occlusion (CAO) in animals. Antagonists of β1- and β2-АR (metoprolol, propranolol, nadolol, carvedilol, bisoprolol, esmolol) are able to prevent reperfusion cardiac injury. All β-AR ligands that reduced infarct size are the selective or nonselective β1-blockers. It was hypothesized that β1-AR blocking promotes an increase in cardiac tolerance to I/R. The activation of β1-AR, β2-AR, and β3-AR can increase cardiac tolerance to I/R. The cardioprotective effect of β-AR agonists is mediated via the activation of kinases and reactive oxygen species production.
CONCLUSIONS
It is unclear why β-blockers with the similar receptor selectivity have the infarct-sparing effect while other β-blockers with the same selectivity do not affect infarct size. What is the molecular mechanism of the infarct-reducing effect of β-blockers in reperfusion? Why did in early studies β-blockers decrease the mortality rate in patients with acute myocardial infarction (AMI) and without reperfusion and in more recent studies β-blockers had no effect on the mortality rate in patients with AMI and reperfusion? The creation of more effective β-AR ligands depends on the answers to these questions.
PubMed: 38423796
DOI: 10.1111/fcp.12988 -
The Journal of Biological Chemistry Jun 2024Beta-adrenergic receptors (βARs) are G protein-coupled receptors (GPCRs) that mediate catecholamine hormone-induced stress responses, such as elevation of heart rate....
Beta-adrenergic receptors (βARs) are G protein-coupled receptors (GPCRs) that mediate catecholamine hormone-induced stress responses, such as elevation of heart rate. Besides those that are plasma membrane-bound, endomembrane βARs are also signaling competent. Dysregulation of βAR pathways underlies severe pathological conditions. Emerging evidence indicates pathological molecular signatures in deeper endomembrane βARs signaling, likely contributing to conditions such as cardiomyocyte hypertrophy and apoptosis. However, the lack of approaches to control endomembrane β1ARs has impeded linking signaling with pathology. Informed by the β1AR-catecholamine interactions, we engineered an efficient photo-labile pro-ligand (OptoIso) to trigger βAR signaling exclusively in endomembrane regions using blue light stimulation. Not only does OptoIso undergo blue light deprotection in seconds, but also efficiently enters cells and allows examination of G protein heterotrimer activation exclusively at endomembranes. OptoIso also allows optical activation of plasma membrane βAR signaling in selected single cells with native fidelity, which can be reversed by terminating blue light. Thus, OptoIso will be a valuable experimental tool to elicit spatial and temporal control of βAR signaling in user-defined endomembrane or plasma membrane regions in unmodified cells with native fidelity.
PubMed: 38901558
DOI: 10.1016/j.jbc.2024.107481 -
JCI Insight Aug 2023We investigated the extent, biologic characterization, phenotypic specificity, and possible regulation of a β1-adrenergic receptor-linked (β1-AR-linked) gene signaling...
We investigated the extent, biologic characterization, phenotypic specificity, and possible regulation of a β1-adrenergic receptor-linked (β1-AR-linked) gene signaling network (β1-GSN) involved in left ventricular (LV) eccentric pathologic remodeling. A 430-member β1-GSN was identified by mRNA expression in transgenic mice overexpressing human β1-ARs or from literature curation, which exhibited opposite directional behavior in interventricular septum endomyocardial biopsies taken from patients with beta-blocker-treated, reverse remodeled dilated cardiomyopathies. With reverse remodeling, the major biologic categories and percentage of the dominant directional change were as follows: metabolic (19.3%, 81% upregulated); gene regulation (14.9%, 78% upregulated); extracellular matrix/fibrosis (9.1%, 92% downregulated); and cell homeostasis (13.3%, 60% upregulated). Regarding the comparison of β1-GSN categories with expression from 19,243 nonnetwork genes, phenotypic selection for major β1-GSN categories was exhibited for LV end systolic volume (contractility measure), ejection fraction (remodeling index), and pulmonary wedge pressure (wall tension surrogate), beginning at 3 months and persisting to study completion at 12 months. In addition, 121 lncRNAs were identified as possibly involved in cis-acting regulation of β1-GSN members. We conclude that an extensive 430-member gene network downstream from the β1-AR is involved in pathologic ventricular remodeling, with metabolic genes as the most prevalent category.
Topics: Animals; Mice; Humans; Cardiomyopathy, Dilated; Gene Regulatory Networks; Signal Transduction; Mice, Transgenic; Receptors, Adrenergic; Biological Products
PubMed: 37606047
DOI: 10.1172/jci.insight.169720 -
Circulation. Arrhythmia and... Nov 2023β-AR (β-adrenergic receptor) stimulation regulates atrial electrophysiology and Ca homeostasis via cAMP-dependent mechanisms; however, enhanced β-AR signaling can...
BACKGROUND
β-AR (β-adrenergic receptor) stimulation regulates atrial electrophysiology and Ca homeostasis via cAMP-dependent mechanisms; however, enhanced β-AR signaling can promote atrial fibrillation (AF). CNP (C-type natriuretic peptide) can also regulate atrial electrophysiology through the activation of NPR-B (natriuretic peptide receptor B) and cGMP-dependent signaling. Nevertheless, the role of NPR-B in regulating atrial electrophysiology, Ca homeostasis, and atrial arrhythmogenesis is incompletely understood.
METHODS
Studies were performed using atrial samples from human patients with AF or sinus rhythm and in wild-type and NPR-B-deficient (NPR-B) mice. Studies were conducted in anesthetized mice by intracardiac electrophysiology, in isolated mouse atrial preparations using high-resolution optical mapping, in isolated mouse and human atrial myocytes using patch-clamping and Ca imaging, and in mouse and human atrial tissues using molecular biology.
RESULTS
Atrial NPR-B protein levels were reduced in patients with AF, and NPR-B mice were more susceptible to AF. Atrial cGMP levels and PDE2 (phosphodiesterase 2) activity were reduced in NPR-B mice leading to larger increases in atrial cAMP in the presence of the β-AR agonist isoproterenol. NPR-B mice displayed larger increases in action potential duration and L-type Ca current in the presence of isoproterenol. This resulted in the occurrence of spontaneous sarcoplasmic reticulum Ca release events and delayed afterdepolarizations in NPR-B atrial myocytes. Phosphorylation of the RyR2 (ryanodine receptor) and phospholamban was increased in NPR-B atria in the presence of isoproterenol compared with the wildtypes. C-type natriuretic peptide inhibited isoproterenol-stimulated L-type Ca current through PDE2 in mouse and human atrial myocytes.
CONCLUSIONS
NPR-B protects against AF by preventing enhanced atrial responses to β-adrenergic receptor agonists.
Topics: Humans; Mice; Animals; Atrial Fibrillation; Isoproterenol; Natriuretic Peptide, C-Type; Heart Atria; Myocytes, Cardiac
PubMed: 37933567
DOI: 10.1161/CIRCEP.123.012199 -
Advances in Experimental Medicine and... 2024Cholesterol is a key molecule for synaptic transmission, and both central and peripheral synapses are cholesterol rich. During intense neuronal activity, a substantial...
Cholesterol is a key molecule for synaptic transmission, and both central and peripheral synapses are cholesterol rich. During intense neuronal activity, a substantial portion of synaptic cholesterol can be oxidized by either enzymatic or non-enzymatic pathways to form oxysterols, which in turn modulate the activities of neurotransmitter receptors (e.g., NMDA and adrenergic receptors), signaling molecules (nitric oxide synthases, protein kinase C, liver X receptors), and synaptic vesicle cycling involved in neurotransmitters release. 24-Hydroxycholesterol, produced by neurons in the brain, could directly affect neighboring synapses and change neurotransmission. 27-Hydroxycholesterol, which can cross the blood-brain barrier, can alter both synaptogenesis and synaptic plasticity. Increased generation of 25-hydroxycholesterol by activated microglia and macrophages could link inflammatory processes to learning and neuronal regulation. Amyloids and oxidative stress can lead to an increase in the levels of ring-oxidized sterols and some of these oxysterols (4-cholesten-3-one, 5α-cholestan-3-one, 7β-hydroxycholesterol, 7-ketocholesterol) have a high potency to disturb or modulate neurotransmission at both the presynaptic and postsynaptic levels. Overall, oxysterols could be used as "molecular prototypes" for therapeutic approaches. Analogs of 24-hydroxycholesterol (SGE-301, SGE-550, SAGE718) can be used for correction of NMDA receptor hypofunction-related states, whereas inhibitors of cholesterol 24-hydroxylase, cholestane-3β,5α,6β-triol, and cholest-4-en-3-one oxime (olesoxime) can be utilized as potential anti-epileptic drugs and (or) protectors from excitotoxicity.
Topics: Oxysterols; Sterols; Synaptic Transmission; Signal Transduction; Nitric Oxide Synthase
PubMed: 38036877
DOI: 10.1007/978-3-031-43883-7_6 -
Journal of Neurotrauma Apr 2024Trauma is a serious public health issue, and remains a major cause of mortality and disability worldwide. The notion that genetic factors contribute to an individual's... (Review)
Review
Trauma is a serious public health issue, and remains a major cause of mortality and disability worldwide. The notion that genetic factors contribute to an individual's response to traumatic injury has advanced significantly. Genetic variations in severely injured patients have been linked to mortality, morbidity, and psychological outcomes. We conducted a comprehensive review of beta-adrenergic receptor polymorphisms and their impact on the pathogenetics of traumatic injuries, which could pave the way for a transformational frontier of personalized medicine in neurotrauma. It remains unclear why some individuals are vulnerable to worse outcomes, whereas others are resilient. Although genetic factors may be significant, the intricate interplay between environmental and genetic factors may be responsible for variations in the presentation and outcome after injury. Recent advancements in genetic analysis and molecular physiology have helped to shed light on the causes of such variability. Although exposure to trauma can initiate a cascade of stress-related responses, these responses alone are insufficient to explain etiopathogenesis. Therefore, gaining insights into how trauma and genetic predispositions to adrenergic variations interact at the molecular level to affect an individual's susceptibility and recuperation could provide an essential understanding of the molecular pathogenesis of traumatic injuries. Therefore, it is imperative to identify potential genetic and physiological markers to guide early management and prognosis of trauma. Such knowledge could pave the way for the discovery of novel biomarkers that can identify a transdiagnostic subgroup that is at high risk and requires early intervention. This could lead to the adoption of personalized medical approaches in neurotrauma care.
Topics: Humans; Precision Medicine; Receptors, Adrenergic, beta; Polymorphism, Genetic; Prognosis; Genetic Predisposition to Disease; Biomarkers
PubMed: 38117124
DOI: 10.1089/neu.2023.0432 -
Cardiovascular Research Dec 2023The sympathetic nervous system increases HR by activating β-adrenergic receptors (β-ARs) and increasing cAMP in sinoatrial node (SAN) myocytes while phosphodiesterases...
AIMS
The sympathetic nervous system increases HR by activating β-adrenergic receptors (β-ARs) and increasing cAMP in sinoatrial node (SAN) myocytes while phosphodiesterases (PDEs) degrade cAMP. Chronotropic incompetence, the inability to regulate heart rate (HR) in response to sympathetic nervous system activation, is common in hypertensive heart disease; however, the basis for this is poorly understood. The objective of this study was to determine the mechanisms leading to chronotropic incompetence in mice with angiotensin II (AngII)-induced hypertensive heart disease.
METHODS AND RESULTS
C57BL/6 mice were infused with saline or AngII (2.5 mg/kg/day for 3 weeks) to induce hypertensive heart disease. HR and SAN function in response to the β-AR agonist isoproterenol (ISO) were studied in vivo using telemetry and electrocardiography, in isolated atrial preparations using optical mapping, in isolated SAN myocytes using patch-clamping, and using molecular biology. AngII-infused mice had smaller increases in HR in response to physical activity and during acute ISO injection. Optical mapping of the SAN in AngII-infused mice demonstrated impaired increases in conduction velocity and altered conduction patterns in response to ISO. Spontaneous AP firing responses to ISO in isolated SAN myocytes from AngII-infused mice were impaired due to smaller increases in diastolic depolarization (DD) slope, hyperpolarization-activated current (If), and L-type Ca2+ current (ICa,L). These changes were due to increased localization of PDE4D surrounding β1- and β2-ARs in the SAN, increased SAN PDE4 activity, and reduced cAMP generation in response to ISO. Knockdown of PDE4D using a virus-delivered shRNA or inhibition of PDE4 with rolipram normalized SAN sensitivity to β-AR stimulation in AngII-infused mice.
CONCLUSIONS
AngII-induced hypertensive heart disease results in impaired HR responses to β-AR stimulation due to up-regulation of PDE4D and reduced effects of cAMP on spontaneous AP firing in SAN myocytes.
Topics: Animals; Mice; Arrhythmias, Cardiac; Isoproterenol; Mice, Inbred C57BL; Myocytes, Cardiac; Receptors, Adrenergic, beta; Signal Transduction; Sinoatrial Node; Hypertension; Cyclic Nucleotide Phosphodiesterases, Type 4
PubMed: 37643895
DOI: 10.1093/cvr/cvad138 -
Psychosomatic MedicinePsychosocial stress is transduced into disease risk through energy-dependent release of hormones from the hypothalamic-pituitary-adrenal and...
OBJECTIVE
Psychosocial stress is transduced into disease risk through energy-dependent release of hormones from the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes. The levels of glucocorticoid and adrenergic hormones, together with the sensitivity of tissues to their signaling, define stress responses. To understand existing pathways responsible for the psychobiological transduction of stressful experiences, we provide a quantitative whole-body map of glucocorticoid and adrenergic receptor (AR) expression.
METHODS
We systematically examined gene expression levels for the glucocorticoid receptor (GR), α- and β-ARs (AR-α1B, AR-α2B AR-β2, and AR-β3), across 55 different organs using the Human Protein Atlas and Human Proteome Map datasets. Given that mitochondria produce the energy required to respond to stress, we leveraged the Human Protein Atlas and MitoCarta3.0 data to examine the link between stress hormone receptor density and mitochondrial gene expression. Finally, we tested the functional interplay between GR activation and AR expression in human fibroblast cells.
RESULTS
The GR was expressed ubiquitously across all investigated organ systems, whereas AR subtypes showed lower and more localized expression patterns. Receptor co-regulation, meaning the correlated gene expression of multiple stress hormone receptors, was found between GR and AR-α1B, as well as between AR-α1B and AR-α2B. In cultured human fibroblasts, activating the GR selectively increased AR-β2 and AR-α1B expression. Consistent with the known energetic cost of stress responses, GR and AR expressions were positively associated with the expression of specific mitochondrial pathways.
CONCLUSIONS
Our results provide a cartography of GR and AR expression across the human body. Because stress-induced GR and AR signaling triggers energetically expensive cellular pathways involving energy-transforming mitochondria, the tissue-specific expression and co-expression patterns of hormone receptor subtypes may in part determine the resilience or vulnerability of different organ systems.
Topics: Humans; Glucocorticoids; Receptors, Adrenergic; Signal Transduction; Receptors, Glucocorticoid
PubMed: 38193786
DOI: 10.1097/PSY.0000000000001275