-
Respiratory Medicine 2019Tiotropium is a long-acting muscarinic antagonist approved for maintenance treatment of asthma in children, adolescents, and adults in the United States, and recommended... (Review)
Review
OBJECTIVE
Tiotropium is a long-acting muscarinic antagonist approved for maintenance treatment of asthma in children, adolescents, and adults in the United States, and recommended as add-on treatment for uncontrolled asthma despite treatment with inhaled corticosteroids and/or long-acting beta-2 agonists. This review traces the journey of tiotropium from its historical origins through early preclinical testing to human clinical trials and real-life studies.
DATA SOURCES
A search was performed in PubMed using search terms 'tiotropium' and 'asthma.' Relevant references cited in those articles were reviewed.
STUDY SELECTIONS
English language articles published from December 2008-December 2018 were screened. Articles evaluating the efficacy, cost-effectiveness, real-life evidence, and steroid-sparing effect of tiotropium with inadequately controlled asthma were included.
RESULTS
Anticholinergics have a long history of use in the treatment of obstructive airway diseases. Evidence indicates that tiotropium's mechanism of action consists of bronchodilation and diminished mucus secretion, with preclinical evidence suggesting an anti-inflammatory effect as well. Phase 2 and 3 clinical trials have demonstrated that tiotropium is efficacious and safe, resulting in significant improvements in lung function in adults, adolescents, and children across asthma severities. Emerging evidence suggests that add-on tiotropium might potentially enable reductions in inhaled corticosteroid dose in patients with uncontrolled asthma. Further, tiotropium is a cost-effective treatment option that is also effective in the clinical practice setting.
CONCLUSIONS
An increasing body of evidence indicates that tiotropium can play a significant role in the treatment of patients with uncontrolled asthma.
Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Adult; Asthma; Bronchodilator Agents; Child; Cholinergic Antagonists; Clinical Trials as Topic; Cost-Benefit Analysis; Expectorants; Humans; Muscarinic Antagonists; Prevalence; Tiotropium Bromide; Treatment Outcome; United States; Young Adult
PubMed: 31212121
DOI: 10.1016/j.rmed.2019.06.008 -
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 -
Neuroscience and Biobehavioral Reviews Sep 2023Sensory systems are highly plastic, but the mechanisms of sensory plasticity remain unclear. People with vision or hearing loss demonstrate significant neural network... (Review)
Review
Sensory systems are highly plastic, but the mechanisms of sensory plasticity remain unclear. People with vision or hearing loss demonstrate significant neural network reorganization that promotes adaptive changes in other sensory modalities as well as in their ability to combine information across the different senses (i.e., multisensory integration. Furthermore, sensory network remodeling is necessary for sensory restoration after a period of sensory deprivation. Acetylcholine is a powerful regulator of sensory plasticity, and studies suggest that cholinergic medications may improve visual and auditory abilities by facilitating sensory network plasticity. There are currently no approved therapeutics for sensory loss that target neuroplasticity. This review explores the systems-level effects of cholinergic signaling on human visual and auditory perception, with a focus on functional performance, sensory disorders, and neural activity. Understanding the role of acetylcholine in sensory plasticity will be essential for developing targeted treatments for sensory restoration.
Topics: Humans; Acetylcholine; Deafness; Auditory Perception; Cholinergic Agents; Hearing Loss; Neuronal Plasticity; Visual Perception; Sensory Deprivation
PubMed: 37467908
DOI: 10.1016/j.neubiorev.2023.105323 -
Molecules (Basel, Switzerland) Sep 2022In recent years, an impressive number of research studies have been conducted to improve the understanding of the structure and function of the cholinergic system, and...
In recent years, an impressive number of research studies have been conducted to improve the understanding of the structure and function of the cholinergic system, and significant progress has also been made in elucidating the roles of neuronal and non-neuronal acetylcholine (ACh) in the pathogenesis and treatment of human disease [...].
Topics: Acetylcholine; Cholinergic Agents; Humans; Neurons; Signal Transduction
PubMed: 36144707
DOI: 10.3390/molecules27185971 -
International Journal of Molecular... Feb 2021Mushroom poisoning has always been a threat to human health. There are a large number of reports about ingestion of poisonous mushrooms every year around the world. It... (Review)
Review
Mushroom poisoning has always been a threat to human health. There are a large number of reports about ingestion of poisonous mushrooms every year around the world. It attracts the attention of researchers, especially in the aspects of toxin composition, toxic mechanism and toxin application in poisonous mushroom. is a large genus of mushrooms and contains toxic substances including muscarine, psilocybin, psilocin, aeruginascin, lectins and baeocystin. In order to prevent and remedy mushroom poisoning, it is significant to clarify the toxic effects and mechanisms of these bioactive substances. In this review article, we summarize the chemistry, most known toxic effects and mechanisms of major toxic substances in mushrooms, especially muscarine, psilocybin and psilocin. Their available toxicity data (different species, different administration routes) published formerly are also summarized. In addition, the treatment and medical application of these toxic substances in mushrooms are also discussed. We hope that this review will help understanding of the chemistry and toxicology of mushrooms as well as the potential clinical application of its bioactive substances to benefit human beings.
Topics: Agaricales; Animals; Humans; Lectins; Muscarine; Mushroom Poisoning; Organophosphorus Compounds; Psilocybin; Tryptamines
PubMed: 33672330
DOI: 10.3390/ijms22042218 -
World Journal of Gastroenterology Jul 2022Cholinergic nerves are widely distributed throughout the human body and participate in various physiological activities, including sensory, motor, and visceral... (Review)
Review
Cholinergic nerves are widely distributed throughout the human body and participate in various physiological activities, including sensory, motor, and visceral activities, through cholinergic signaling. Cholinergic signaling plays an important role in pancreatic exocrine secretion. A large number of studies have found that cholinergic signaling overstimulates pancreatic acinar cells through muscarinic receptors, participates in the onset of pancreatic diseases such as acute pancreatitis and chronic pancreatitis, and can also inhibit the progression of pancreatic cancer. However, cholinergic signaling plays a role in reducing pain and inflammation through nicotinic receptors, but enhances the proliferation and invasion of pancreatic tumor cells. This review focuses on the progression of cholinergic signaling and pancreatic diseases in recent years and reveals the role of cholinergic signaling in pancreatic diseases.
Topics: Acute Disease; Cholinergic Agents; Humans; Pancreas; Pancreatitis; Receptors, Muscarinic
PubMed: 35978870
DOI: 10.3748/wjg.v28.i25.2910 -
Acta Physiologica (Oxford, England) Nov 2022Cardiac autonomic nervous system (ANS) dysregulation is a hallmark of several cardiovascular diseases. Adrenergic signaling enhanced cardiomyocyte cohesion via...
AIM
Cardiac autonomic nervous system (ANS) dysregulation is a hallmark of several cardiovascular diseases. Adrenergic signaling enhanced cardiomyocyte cohesion via PKA-mediated plakoglobin phosphorylation at serine 665, referred to as positive adhesiotropy. This study investigated cholinergic regulation of cardiomyocyte cohesion using muscarinic receptor agonist carbachol (CCH).
METHODS
Dissociation assays, Western blot analysis, immunostaining, atomic force microscopy (AFM), immunoprecipitation, transmission electron microscopy (TEM), triton assays, and siRNA knockdown of genes were performed in either HL-1 cells or plakoglobin (PG) wild type (Jup ) and knockout (Jup ) mice, which served as a model for arrhythmogenic cardiomyopathy.
RESULTS
In HL-1 cells grown in norepinephrine (NE)-containing medium for baseline adrenergic stimulation, and murine cardiac slice cultures from Jup and Jup mice CCH treatment impaired cardiomyocyte cohesion. Immunostainings and AFM experiments revealed that CCH reduced desmoglein 2 (DSG2) localization and binding at cell borders. Furthermore, CCH reduced intercalated disc plaque thickness in both Jup and Jup mice, evidenced by TEM analysis. Immunoprecipitation experiments in HL-1 cells revealed no changes in DSG2 interaction with desmoplakin (DP), plakophilin 2 (PKP2), PG, and desmin (DES) after CCH treatment. However, knockdown of any of the above proteins abolished CCH-mediated loss of cardiomyocyte cohesion. Furthermore, in HL-1 cells, CCH inhibited adrenergic-stimulated ERK phosphorylation but not PG phosphorylation at serine 665. In addition, CCH activated the AKT/GSK-3β axis in the presence of NE.
CONCLUSION
Our results demonstrate that cholinergic signaling antagonizes the positive effect of adrenergic signaling on cardiomyocyte cohesion and thus causes negative adhesiotropy independent of PG phosphorylation.
Topics: Mice; Animals; Myocytes, Cardiac; Desmoglein 2; gamma Catenin; Glycogen Synthase Kinase 3 beta; Desmoplakins; Carbachol; Proto-Oncogene Proteins c-akt; Plakophilins; RNA, Small Interfering; Desmin; Cholinergic Agents; Receptors, Muscarinic; Adrenergic Agents; Norepinephrine; Serine
PubMed: 36039679
DOI: 10.1111/apha.13881 -
Inflammopharmacology Aug 2021Connective tissue diseases (CTDs) consist of an extensive range of heterogeneous medical conditions, which are caused by immune-mediated chronic inflammation and... (Review)
Review
Connective tissue diseases (CTDs) consist of an extensive range of heterogeneous medical conditions, which are caused by immune-mediated chronic inflammation and influences the various connective tissues of the body. They include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, Sjögren's syndrome, Behcet's disease, and many other autoimmune CTDs. To date, several anti-inflammatory approaches have been developed to reduce the severity of inflammation or its subsequent organ manifestations. As a logical mechanism to harnesses the undesired inflammation, some studies investigated the role of the intrinsic cholinergic anti-inflammatory pathway (CAP) in the modulation of chronic inflammation. Many different experimental and clinical models have been developed to evaluate the therapeutic significance of the CAP in CTDs. On the other hand, an issue that is less emphasized in this regard is the presence of autonomic neuropathy in CTDs, which influences the efficiency of CAP in such clinical settings. This condition occurs during CTDs and is a well-known complication of patients suffering from them. The advantages and limitations of CAP in the control of inflammatory responses and its possible therapeutic benefits in the treatment of CTDs are the main subjects of the current study. Therefore, this narrative review article is provided based on the recent findings of the complicated role of CAP in CTDs which were retrieved by searching Science Direct, PubMed, Google Scholar, and Web of Science. It seems that delineating the complex influences of CAP would be of great interest in designing novel surgical or pharmacological therapeutic strategies for CTDs therapy.
Topics: Animals; Cholinergic Agents; Connective Tissue Diseases; Humans; Implantable Neurostimulators; Inflammation Mediators; Neuroimmunomodulation; Receptors, Nicotinic; Signal Transduction; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 34125373
DOI: 10.1007/s10787-021-00812-z -
Current Pharmaceutical Design 2023Alzheimer's disease (AD) has been identified as a progressive brain disorder associated with memory dysfunction and the accumulation of β-amyloid plaques and... (Review)
Review
AIM
Alzheimer's disease (AD) has been identified as a progressive brain disorder associated with memory dysfunction and the accumulation of β-amyloid plaques and neurofibrillary tangles of τ protein. Mitochondria is crucial in maintaining cell survival, cell death, calcium regulation, and ATP synthesis. Mitochondrial dysfunction and linked calcium overload have been involved in the pathogenesis of AD. CRM2 (Collapsin response mediator protein-2) is involved in endosomal lysosomal trafficking as well as autophagy, and their reduced level is also a primary culprit in the progression of AD. In addition, Cholinergic neurotransmission and neuroinflammation are two other mechanisms implicated in AD onset and might be protective targets to attenuate disease progression. The microbiota-gut-brain axis (MGBA) is another crucial target for AD treatment. Crosstalk between gut microbiota and brain mutually benefitted each other, dysbiosis in gut microbiota affects the brain functions and leads to AD progression with increased AD-causing biomarkers. Despite the complexity of AD, treatment is only limited to symptomatic management. Therefore, there is an urgent demand for novel therapeutics that target associated pathways responsible for AD pathology. This review explores the role of different mechanisms involved in AD and possible therapeutic targets to protect against disease progression.
BACKGROUND
Amidst various age-related diseases, AD is the most deleterious neurodegenerative disorder that affects more than 24 million people globally. Every year, approximately 7.7 million new cases of dementia have been reported. However, to date, no novel disease-modifying therapies are available to treat AD.
OBJECTIVE
The aim of writing this review is to highlight the role of key biomarker proteins and possible therapeutic interventions that could play a crucial role in mitigating the ongoing prognosis of Alzheimer's disease.
MATERIALS AND METHODS
The available information about the disease was collected through multiple search engines, including PubMed, Science Direct, Clinical Trials, and Google Scholar.
RESULTS
Accumulated pieces of evidence reveal that extracellular aggregation of β-amyloid plaques and intracellular tangles of τ protein are peculiar features of perpetuated Alzheimer's disease (AD). Further, the significant role of mitochondria, calcium, and cholinergic pathways in the pathogenesis of AD makes the respiratory cell organelle a crucial therapeutic target in this neurodegenerative disease. All currently available drugs either delay the clinical damage to cells or temporarily attenuate some symptoms of Alzheimer's disease.
CONCLUSION
The pathological features of AD are extracellular deposition of β-amyloid, acetylcholinesterase deregulation, and intracellular tangles of τ protein. The multifactorial heterogeneity of disease demands more research work in this field to find new therapeutic biological targets.
Topics: Humans; Alzheimer Disease; tau Proteins; Neurodegenerative Diseases; Plaque, Amyloid; Acetylcholinesterase; Calcium; Amyloid beta-Peptides; Disease Progression; Cholinergic Agents
PubMed: 38038007
DOI: 10.2174/0113816128264355231121064704 -
Frontiers in Immunology 2021Neurological and immunological signals constitute an extensive regulatory network in our body that maintains physiology and homeostasis. The cholinergic system plays a... (Review)
Review
Neurological and immunological signals constitute an extensive regulatory network in our body that maintains physiology and homeostasis. The cholinergic system plays a significant role in neuroimmune communication, transmitting information regarding the peripheral immune status to the central nervous system (CNS) and vice versa. The cholinergic system includes the neurotransmitter\ molecule, acetylcholine (ACh), cholinergic receptors (AChRs), choline acetyltransferase (ChAT) enzyme, and acetylcholinesterase (AChE) enzyme. These molecules are involved in regulating immune response and playing a crucial role in maintaining homeostasis. Most innate and adaptive immune cells respond to neuronal inputs by releasing or expressing these molecules on their surfaces. Dysregulation of this neuroimmune communication may lead to several inflammatory and autoimmune diseases. Several agonists, antagonists, and inhibitors have been developed to target the cholinergic system to control inflammation in different tissues. This review discusses how various molecules of the neuronal and non-neuronal cholinergic system (NNCS) interact with the immune cells. What are the agonists and antagonists that alter the cholinergic system, and how are these molecules modulate inflammation and immunity. Understanding the various functions of pharmacological molecules could help in designing better strategies to control inflammation and autoimmunity.
Topics: Animals; Autoimmunity; Cholinergic Agents; Humans; Inflammation; Mice; Neurons; Receptors, Cholinergic; Signal Transduction
PubMed: 33936095
DOI: 10.3389/fimmu.2021.660342