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Pharmacological Research Nov 2023Nicotinic acetylcholine receptors (nAChRs) belong to a superfamily of cys-loop receptors characterized by the assembly of five subunits into a multi-protein channel... (Review)
Review
Nicotinic acetylcholine receptors (nAChRs) belong to a superfamily of cys-loop receptors characterized by the assembly of five subunits into a multi-protein channel complex. Ligand binding to nAChRs activates rapid allosteric transitions of the receptor leading to channel opening and ion flux in neuronal and non-neuronal cell. Thus, while ionotropic properties of nAChRs are well recognized, less is known about ligand-mediated intracellular metabotropic signaling responses. Studies in neural and non-neural cells confirm ionotropic and metabotropic channel responses following ligand binding. In this review we summarize evidence on the existence of ionotropic and metabotropic signaling responses by homopentameric α7 nAChRs in various cell types. We explore how coordinated calcium entry through the ion channel and calcium release from nearby stores gives rise to signaling important for the modulation of cytoskeletal motility and cell growth. Amino acid residues for intracellular protein binding within the α7 nAChR support engagement in metabotropic responses including signaling through heterotrimeric G proteins in neural and immune cells. Understanding the dual properties of ionotropic and metabotropic nAChR responses is essential in advancing drug development for the treatment of various human disease.
Topics: Humans; Receptors, Nicotinic; Calcium; Ligands; Signal Transduction; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 38032294
DOI: 10.1016/j.phrs.2023.106975 -
Brain : a Journal of Neurology May 2024Most individuals with Parkinson's disease experience cognitive decline. Mounting evidence suggests this is partially caused by cholinergic denervation due to...
Most individuals with Parkinson's disease experience cognitive decline. Mounting evidence suggests this is partially caused by cholinergic denervation due to α-synuclein pathology in the cholinergic basal forebrain. Alpha-synuclein deposition causes inflammation, which can be measured with free water fraction, a diffusion MRI-derived metric of extracellular water. Prior studies have shown an association between basal forebrain integrity and cognition, cholinergic levels and cognition, and basal forebrain volume and acetylcholine, but no study has directly investigated whether basal forebrain physiology mediates the relationship between acetylcholine and cognition in Parkinson's disease. We investigated the relationship between these variables in a cross-sectional analysis of 101 individuals with Parkinson's disease. Cholinergic levels were measured using fluorine-18 fluoroethoxybenzovesamicol (18F-FEOBV) PET imaging. Cholinergic innervation regions of interest included the medial, lateral capsular and lateral perisylvian regions and the hippocampus. Brain volume and free water fraction were quantified using T1 and diffusion MRI, respectively. Cognitive measures included composites of attention/working memory, executive function, immediate memory and delayed memory. Data were entered into parallel mediation analyses with the cholinergic projection areas as predictors, cholinergic basal forebrain volume and free water fraction as mediators and each cognitive domain as outcomes. All mediation analyses controlled for age, years of education, levodopa equivalency dose and systolic blood pressure. The basal forebrain integrity metrics fully mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and attention/working memory, and partially mediated the relationship between medial acetylcholine and attention/working memory. Basal forebrain integrity metrics fully mediated the relationship between medial, lateral capsular and lateral perisylvian acetylcholine and free water fraction. For all mediations in attention/working memory and executive function, the free water mediation was significant, while the volume mediation was not. The basal forebrain integrity metrics fully mediated the relationship between hippocampal acetylcholine and delayed memory and partially mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and delayed memory. The volume mediation was significant for the hippocampal and lateral perisylvian models, while free water fraction was not. Free water fraction in the cholinergic basal forebrain mediated the relationship between acetylcholine and attention/working memory and executive function, while cholinergic basal forebrain volume mediated the relationship between acetylcholine in temporal regions in memory. These findings suggest that these two metrics reflect different stages of neurodegenerative processes and add additional evidence for a relationship between pathology in the basal forebrain, acetylcholine denervation and cognitive decline in Parkinson's disease.
Topics: Humans; Basal Forebrain; Male; Female; Aged; Parkinson Disease; Middle Aged; Cross-Sectional Studies; Cognition; Acetylcholine; Positron-Emission Tomography; Cholinergic Neurons; Neuropsychological Tests
PubMed: 38109781
DOI: 10.1093/brain/awad420 -
Neurochemical Research Oct 2023Astrocytes release numerous factors known to contribute to the process of synaptogenesis, yet knowledge about the signals that control their release is limited. We...
Astrocytes release numerous factors known to contribute to the process of synaptogenesis, yet knowledge about the signals that control their release is limited. We hypothesized that neuron-derived signals stimulate astrocytes, which respond to neurons through the modulation of astrocyte-released synaptogenic factors. Here we investigate the effect of cholinergic stimulation of astrocytes on synaptogenesis in co-cultured neurons. Using a culture system where primary rat astrocytes and primary rat neurons are first grown separately allowed us to independently manipulate astrocyte cholinergic signaling. Subsequent co-culture of pre-stimulated astrocytes with naïve neurons enabled us to assess how prior stimulation of astrocyte acetylcholine receptors uniquely modulates neuronal synapse formation. Pre-treatment of astrocytes with the acetylcholine receptor agonist carbachol increased the expression of synaptic proteins, the number of pre- and postsynaptic puncta, and the number of functional synapses in hippocampal neurons after 24 h in co-culture. Astrocyte secretion of the synaptogenic protein thrombospondin-1 increased after cholinergic stimulation and inhibition of the receptor for thrombospondins prevented the increase in neuronal synaptic structures. Thus, we identified a novel mechanism of neuron-astrocyte-neuron communication, where neuronal release of acetylcholine stimulates astrocytes to release synaptogenic proteins leading to increased synaptogenesis in neurons. This study provides new insights into the role of neurotransmitter receptors in developing astrocytes and into our understanding of the modulation of astrocyte-induced synaptogenesis.
Topics: Rats; Animals; Astrocytes; Synapses; Neurons; Coculture Techniques; Cholinergic Agents
PubMed: 37402036
DOI: 10.1007/s11064-023-03979-9 -
Respiratory Research Oct 2023The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional...
INTRODUCTION
The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological T2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease.
METHODS
After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function.
RESULTS
Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol.
CONCLUSION
Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the T2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.
Topics: Mice; Rats; Humans; Animals; Guinea Pigs; Bronchoconstriction; Methacholine Chloride; Amitriptyline; Histamine; Bronchodilator Agents; Serotonin; Acetylcholine; Sympathomimetics; 1-Methyl-3-isobutylxanthine; Dilatation; Lung; Asthma; Albuterol; Endothelins; Thromboxanes
PubMed: 37907918
DOI: 10.1186/s12931-023-02580-6 -
Science Advances Aug 2023Host-derived succinate accumulates in the airways during bacterial infection. Here, we show that luminal succinate activates murine tracheal brush (tuft) cells through a...
Host-derived succinate accumulates in the airways during bacterial infection. Here, we show that luminal succinate activates murine tracheal brush (tuft) cells through a signaling cascade involving the succinate receptor 1 (SUCNR1), phospholipase Cβ2, and the cation channel transient receptor potential channel subfamily M member 5 (TRPM5). Stimulated brush cells then trigger a long-range Ca wave spreading radially over the tracheal epithelium through a sequential signaling process. First, brush cells release acetylcholine, which excites nearby cells via muscarinic acetylcholine receptors. From there, the Ca wave propagates through gap junction signaling, reaching also distant ciliated and secretory cells. These effector cells translate activation into enhanced ciliary activity and Cl secretion, which are synergistic in boosting mucociliary clearance, the major innate defense mechanism of the airways. Our data establish tracheal brush cells as a central hub in triggering a global epithelial defense program in response to a danger-associated metabolite.
Topics: Mice; Animals; Trachea; Acetylcholine; Signal Transduction; Succinates; Epithelium
PubMed: 37531421
DOI: 10.1126/sciadv.adg8842 -
Proceedings of the National Academy of... Jul 2023The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural...
The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural populations. The circuit computations underlying cholinergic actions are confounded by recent findings that forebrain cholinergic neurons corelease both acetylcholine (ACh) and GABA. We have identified that corelease of ACh and GABA by cholinergic inputs to the claustrum, a structure implicated in the control of attention, has opposing effects on the electrical activity of claustrum neurons that project to cortical vs. subcortical targets. These actions differentially alter neuronal gain and dynamic range in the two types of neurons. In model networks, the differential effects of ACh and GABA toggle network efficiency and the impact of noise on population dynamics between two different projection subcircuits. Such cholinergic switching between subcircuits provides a potential logic for neurotransmitter corelease in implementing behaviorally relevant computations.
Topics: Cholinergic Agents; Acetylcholine; Prosencephalon; Cholinergic Neurons; gamma-Aminobutyric Acid; Logic
PubMed: 37399414
DOI: 10.1073/pnas.2218830120 -
Behavioural Brain Research Feb 2024About 280 million people suffer from depression as the most common neurological disorder and the most common cause of death worldwide. Exercise with serotonin released... (Review)
Review
About 280 million people suffer from depression as the most common neurological disorder and the most common cause of death worldwide. Exercise with serotonin released in the brain by the 5-HT3-IGF-1 mechanism can lead to antidepressant effects. Swimming exercise has antidepressant effects by increasing the sensitivity of serotonin 5-HT2 receptors and postsynaptic 5-HT1A receptors, increasing 5-HT and 5HIAA levels, increasing TPH and serotonin, and decreasing inflammatory levels of IFN-γ and TNF-α. Anaerobic and aerobic exercises increase beta-endorphin, enkephalin, and dynorphin and have antidepressant effects. Exercise by increasing dopamine, D1R, and D2R leads to the expression of BDNF and activation of TrkB and has antidepressant behavior. Exercise leads to a significant increase in GABAAR (γ2 and α2 subunits) and reduces neurodegenerative disorders caused by GABA imbalance through anti-inflammatory pathways. By increasing glutamate and PGC1α and reducing glutamatergic neurotoxicity, exercise enhances neurogenesis and synaptogenesis and prevents neurodegeneration and the onset of depression. Irisin release during exercise shows an important role in depression by increasing dopamine, BDNF, NGF, and IGF-1 and decreasing inflammatory mediators such as IL-6 and IL-1β. In addition, exercise-induced orexin and NPY can increase hippocampal neurogenesis and relieve depression. After exercise, the tryptophan to large neutral amino acids (TRP/LNAA) ratio and the tryptophan to branched-chain amino acids (BCAA) ratio increase, which may have antidepressant effects. The expression of M5 receptor and nAChR α7 increases after exercise and significantly increases dopamine and acetylcholine and ameliorates depression. It appears that during exercise, muscarinic receptors can reduce depression through dopamine in the absence of acetylcholine. Therefore, exercise can be used to reduce depression by affecting neurotransmitters, neuromodulators, cytokines, and/or neurotrophins.
Topics: Humans; Depression; Tryptophan; Insulin-Like Growth Factor I; Serotonin; Dopamine; Brain-Derived Neurotrophic Factor; Acetylcholine; Antidepressive Agents; Swimming; Neurotransmitter Agents; Exercise Therapy
PubMed: 38048912
DOI: 10.1016/j.bbr.2023.114791 -
BMC Musculoskeletal Disorders Aug 2023Myofascial Pain Syndrome (MPS) is a common pain disorder. Diagnostic criteria include physical findings which are often unreliable or not universally accepted. A precise...
BACKGROUND
Myofascial Pain Syndrome (MPS) is a common pain disorder. Diagnostic criteria include physical findings which are often unreliable or not universally accepted. A precise biosignature may improve diagnosis and treatment effectiveness. The purpose of this study was to assess whether microanalytic assays significantly correlate with characteristic clinical findings in people with MPS.
METHODS
This descriptive, prospective study included 38 participants (25 women) with greater than 3 months of myofascial pain in the upper trapezius. Assessments were performed at a university laboratory. The main outcome measures were the Beighton Index, shoulder range of motion, strength asymmetries and microanalytes: DHEA, Kynurenine, VEGF, interleukins (IL-1b, IL-2, IL-4, IL-5, IL-7, IL-8, IL-13), growth factors (IGF-1, IGF2, G-CSF, GM-CSF), MCP-1, MIP-1b, BDNF, Dopamine, Noradrenaline, NPY, and Acetylcholine. Mann-Whitney test and Spearman's multivariate correlation were applied for all variables. The Spearman's analysis results were used to generate a standard correlation matrix and heat map matrix.
RESULTS
Mean age of participants was 32 years (20-61). Eight (21%) had widespread pain (Widespread Pain Index ≥ 7). Thirteen (34%) had MPS for 1-3 years, 14 (37%) 3-10 years, and 11 (29%) for > 10 years. The following showed strong correlations: IL1b,2,4,5,7,8; GM-CSF and IL 2,4,5,7; between DHEA and BDNF and between BDNF and Kynurenine, NPY and acetylcholine. The heat map analysis demonstrated strong correlations between the Beighton Index and IL 5,7, GM-CSF, DHEA. Asymmetries of shoulder and cervical spine motion and strength associated with select microanalytes.
CONCLUSION
Cytokine levels significantly correlate with selected clinical assessments. This indirectly suggests possible biological relevance for understanding MPS. Correlations among some cytokine clusters; and DHEA, BDNF kynurenine, NPY, and acetylcholine may act together in MPS. These findings should be further investigated for confirmation that link these microanalytes with select clinical findings in people with MPS.
Topics: Humans; Female; Young Adult; Adult; Middle Aged; Granulocyte-Macrophage Colony-Stimulating Factor; Prospective Studies; Acetylcholine; Brain-Derived Neurotrophic Factor; Kynurenine; Myofascial Pain Syndromes; Fibromyalgia; Cytokines; Pain; Dehydroepiandrosterone
PubMed: 37528404
DOI: 10.1186/s12891-023-06744-9 -
International Journal of Molecular... Jul 2023Trichlorfon is an organophosphorus pesticide widely used in aquaculture and has potential neurotoxicity, but the underlying mechanism remains unclear. In the present...
Trichlorfon is an organophosphorus pesticide widely used in aquaculture and has potential neurotoxicity, but the underlying mechanism remains unclear. In the present study, zebrafish embryos were exposed to trichlorfon at concentrations (0, 0.1, 2 and 5 mg/L) used in aquaculture from 2 to 144 h post fertilization. Trichlorfon exposure reduced the survival rate, hatching rate, heartbeat and body length and increased the malformation rate of zebrafish larvae. The locomotor activity of larvae was significantly reduced. The results of molecular docking revealed that trichlorfon could bind to acetylcholinesterase (AChE). Furthermore, trichlorfon significantly inhibited AChE activity, accompanied by decreased acetylcholine, dopamine and serotonin content in larvae. The transcription patterns of genes related to acetylcholine (e.g., , , , and ), dopamine (e.g., and ) and serotonin systems (e.g., , , , , , and ) were consistent with the changes in acetylcholine, dopamine, serotonin content and AChE activity. The genes related to the central nervous system (CNS) (e.g., , , , and ) were downregulated. Our results indicate that the developmental neurotoxicity of trichlorfon might be attributed to disorders of cholinergic, dopaminergic and serotonergic signaling and the development of the CNS.
Topics: Animals; Zebrafish; Trichlorfon; Organophosphorus Compounds; Acetylcholinesterase; Larva; Acetylcholine; Dopamine; Molecular Docking Simulation; Serotonin; Pesticides; Embryo, Nonmammalian; Water Pollutants, Chemical
PubMed: 37446277
DOI: 10.3390/ijms241311099 -
Biological Psychiatry Mar 2024Achieving optimal treatment outcomes for individuals living with schizophrenia remains challenging, despite 70 years of drug development efforts. Many chemically... (Review)
Review
Achieving optimal treatment outcomes for individuals living with schizophrenia remains challenging, despite 70 years of drug development efforts. Many chemically distinct antipsychotics have been developed over the past 7 decades with improved safety and tolerability but with only slight variation in efficacy. All antipsychotics currently approved for the treatment of schizophrenia act as antagonists or partial agonists at the dopamine D receptor. With only a few possible exceptions, antipsychotic drugs have similar and modest efficacy for treating positive symptoms and are relatively ineffective in addressing the negative and cognitive symptoms of the disease. The development of novel treatments focused on targeting muscarinic acetylcholine receptors (mAChRs) has been of interest for more than 25 years following reports that treatment with a dual M/M-preferring mAChR agonist resulted in antipsychotic-like effects and procognitive properties in individuals living with Alzheimer's disease and schizophrenia; more recent clinical trials have confirmed these findings. In addition, advances in our understanding of the receptor binding and activation properties of xanomeline at specific mAChRs have the potential to inform future drug design targeting mAChRs.
PubMed: 38537670
DOI: 10.1016/j.biopsych.2024.03.014