-
Molecules (Basel, Switzerland) Apr 2021Epilepsy is a common brain disorder characterized by recurrent epileptic seizures with neuronal hyperexcitability. Apart from the classical imbalance between excitatory... (Review)
Review
Epilepsy is a common brain disorder characterized by recurrent epileptic seizures with neuronal hyperexcitability. Apart from the classical imbalance between excitatory glutamatergic transmission and inhibitory γ-aminobutyric acidergic transmission, cumulative evidence suggest that cholinergic signaling is crucially involved in the modulation of neural excitability and epilepsy. In this review, we briefly describe the distribution of cholinergic neurons, muscarinic, and nicotinic receptors in the central nervous system and their relationship with neural excitability. Then, we summarize the findings from experimental and clinical research on the role of cholinergic signaling in epilepsy. Furthermore, we provide some perspectives on future investigation to reveal the precise role of the cholinergic system in epilepsy.
Topics: Animals; Cholinergic Agents; Epilepsy; Humans; Receptors, Nicotinic
PubMed: 33924731
DOI: 10.3390/molecules26082258 -
Nature Neuroscience Dec 2022Variation in an animal's behavioral state is linked to fluctuations in brain activity and cognitive ability. In the neocortex, state-dependent circuit dynamics may...
Variation in an animal's behavioral state is linked to fluctuations in brain activity and cognitive ability. In the neocortex, state-dependent circuit dynamics may reflect neuromodulatory influences such as that of acetylcholine (ACh). Although early literature suggested that ACh exerts broad, homogeneous control over cortical function, recent evidence indicates potential anatomical and functional segregation of cholinergic signaling. In addition, it is unclear whether states as defined by different behavioral markers reflect heterogeneous cholinergic and cortical network activity. Here, we perform simultaneous, dual-color mesoscopic imaging of both ACh and calcium across the neocortex of awake mice to investigate their relationships with behavioral variables. We find that higher arousal, categorized by different motor behaviors, is associated with spatiotemporally dynamic patterns of cholinergic modulation and enhanced large-scale network correlations. Overall, our findings demonstrate that ACh provides a highly dynamic and spatially heterogeneous signal that links fluctuations in behavior to functional reorganization of cortical networks.
Topics: Animals; Mice; Neocortex; Acetylcholine; Arousal; Calcium; Cholinergic Agents
PubMed: 36443609
DOI: 10.1038/s41593-022-01202-6 -
Brain : a Journal of Neurology Jul 2022Currently, enhancement of cholinergic neurotransmission via cholinesterase inhibitors represents the main available approach to treat cognitive and behavioural symptoms... (Review)
Review
Currently, enhancement of cholinergic neurotransmission via cholinesterase inhibitors represents the main available approach to treat cognitive and behavioural symptoms of the early as well as late stages of Alzheimer's disease. Restoring the cholinergic system has been a primary means of improving cognition in Alzheimer's disease, as four of the six approved therapies are acetylcholinesterase inhibitors. Memantine is an N-methyl-d-aspartate antagonist with a well-documented clinical effect on behavioural symptoms, which is often added to cholinesterase inhibitors to potentiate their effect and aducanumab, targeting the amyloid pathology, has recently been approved. The early, progressive and selective degeneration of the cholinergic system together and its close relation to cognitive deficits supports the use of cholinergic therapy for Alzheimer's disease. This review provides an updated view of the basal forebrain cholinergic system, its relation to cognition and its relevance for therapy of Alzheimer's disease. It deals with the three main aspects that form the basis of the cholinergic-oriented therapy of Alzheimer's disease, its origin, its mechanism of action, its clinical effects, advantages and limits of a cholinergic therapeutic approach. It includes a new and updated overview of the involvement of muscarinic receptors in Alzheimer's disease as well as the recent development of new and highly selective M1 muscarinic receptor agonists with disease-modifying potential. It also addresses the discovery of a novel nerve growth factor metabolic pathway responsible for the trophic maintenance of the basal forebrain system and its deregulation in Alzheimer's disease. It discusses new clinical studies and provides evidence for the long-term efficacy of cholinesterase inhibitor therapy suggesting a disease-modifying effect of these drugs. The classical symptomatic cholinergic therapy based on cholinesterase inhibitors is judiciously discussed for its maximal efficacy and best clinical application. The review proposes new alternatives of cholinergic therapy that should be developed to amplify its clinical effect and supplement the disease-modifying effect of new treatments to slow down or arrest disease progression.
Topics: Acetylcholinesterase; Alzheimer Disease; Cholinergic Agents; Cholinesterase Inhibitors; Humans; Receptor, Muscarinic M1
PubMed: 35289363
DOI: 10.1093/brain/awac096 -
Neuroscience Feb 2021In this review we will discuss the effect of two neuromodulatory transmitters, acetylcholine (ACh) and adenosine, on the synaptic release probability and short-term... (Review)
Review
In this review we will discuss the effect of two neuromodulatory transmitters, acetylcholine (ACh) and adenosine, on the synaptic release probability and short-term synaptic plasticity. ACh and adenosine differ fundamentally in the way they are released into the extracellular space. ACh is released mostly from synaptic terminals and axonal bouton of cholinergic neurons in the basal forebrain (BF). Its mode of action on synaptic release probability is complex because it activate both ligand-gated ion channels, so-called nicotinic ACh receptors and G-protein coupled muscarinic ACh receptors. In contrast, adenosine is released from both neurons and glia via nucleoside transporters or diffusion over the cell membrane in a non-vesicular, non-synaptic fashion; its receptors are exclusively G-protein coupled receptors. We show that ACh and adenosine effects are highly specific for an identified synaptic connection and depend mostly on the presynaptic but also on the postsynaptic receptor type and discuss the functional implications of these differences.
Topics: Acetylcholine; Cholinergic Agents; Presynaptic Terminals; Receptors, Muscarinic; Receptors, Nicotinic; Synaptic Transmission
PubMed: 32540364
DOI: 10.1016/j.neuroscience.2020.06.006 -
Current Neuropharmacology 2021Acetylcholine in the brain promotes arousal and facilitates cognitive functions. Cholinergic neurons in the mesopontine brainstem and basal forebrain are important for...
Acetylcholine in the brain promotes arousal and facilitates cognitive functions. Cholinergic neurons in the mesopontine brainstem and basal forebrain are important for activation of the cerebral cortex, which is characterized by the suppression of irregular slow waves, an increase in gamma (30- 100 Hz) activity in the electroencephalogram, and the appearance of a hippocampal theta rhythm. During general anesthesia, a decrease in acetylcholine release and cholinergic functions contribute to the desired outcomes of general anesthesia, such as amnesia, loss of awareness and consciousness, and immobility. Animal experiments indicate that inactivation, lesion, or genetic ablation of cholinergic neurons in the basal forebrain potentiated the effects of inhalational and injectable anesthetics, including isoflurane, halothane, propofol, pentobarbital, and in some cases, ketamine. Increased behavioral sensitivity to general anesthesia, faster induction time, and delayed recovery of a loss of righting reflex have been observed in rodents with basal forebrain cholinergic deficits. Cholinergic stimulation in the prefrontal cortex, thalamus, and basal forebrain hastens recovery from general anesthesia. Anticholinesterase accelerates emergence from general anesthesia, but with mixed success, in part depending on the anesthetic used. Cholinergic deficits may contribute to cognitive impairments after anesthesia and operations, which are severe in aged subjects. We propose a cholinergic hypothesis for postoperative cognitive disorder, in line with the cholinergic deficits and cognitive decline in aging and Alzheimer's disease. The current animal literature suggests that brain cholinergic neurons can regulate the immune and inflammatory response after surgical operation and anesthetic exposure, and anticholinesterase and α7-nicotinic cholinergic agonists can alleviate postoperative inflammatory response and cognitive deficits.
Topics: Anesthesia, General; Animals; Cholinergic Agents; Cholinergic Neurons; Isoflurane; Ketamine; Propofol
PubMed: 33882810
DOI: 10.2174/1570159X19666210421095504 -
Reviews in the Neurosciences Dec 2016The cerebellar cholinergic system belongs to the third type of afferent nerve fiber system (after the climbing and mossy fibers), and has important modulatory effects on... (Review)
Review
The cerebellar cholinergic system belongs to the third type of afferent nerve fiber system (after the climbing and mossy fibers), and has important modulatory effects on cerebellar circuits and cerebellar-mediated functions. In this report, we review the cerebellar cholinergic system, including cholinergic origins and innervations, acetylcholine receptor expression and distributions, cholinergic modulations of neuronal firing and synaptic plasticity, the cholinergic role in cerebellar-mediated integral functions, and cholinergic changes during development and aging. Because some motor and mental disorders, such as cerebellar ataxia and autism, are accompanied with cerebellar cholinergic disorders, we also discuss the correlations between cerebellar cholinergic dysfunctions and these disorders. The cerebellar cholinergic input plays an important role in the modulation of cerebellar functions; therefore, cholinergic abnormalities could induce physiological dysfunctions.
Topics: Animals; Cerebellum; Cholinergic Agents; Cholinergic Neurons; Humans; Models, Neurological; Nerve Fibers; Neuronal Plasticity
PubMed: 27559688
DOI: 10.1515/revneuro-2016-0008 -
Preface: Cholinergic mechanisms: This is the Preface for the special issue "Cholinergic Mechanisms".Journal of Neurochemistry Sep 2021This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover...
This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover the broad spectrum of topics and disciplines presented at the XVIth International Symposium on Cholinergic Mechanisms (ISCM-XVI), ranging from the molecular and the cellular to the clinical and the cognitive mechanisms of cholinergic transmission. The authors discuss recent developments in the field, for instance, the association of cholinergic transmission with a number of important neurological and neuromuscular diseases in the central and peripheral nervous systems.
Topics: Acetylcholine; Animals; Brain; Cholinergic Agents; Cholinergic Neurons; Humans; Peripheral Nervous System; Synaptic Transmission
PubMed: 34458988
DOI: 10.1111/jnc.15480 -
Nature Reviews. Neuroscience Apr 2023Acetylcholine plays an essential role in fundamental aspects of cognition. Studies that have mapped the activity and functional connectivity of cholinergic neurons have... (Review)
Review
Acetylcholine plays an essential role in fundamental aspects of cognition. Studies that have mapped the activity and functional connectivity of cholinergic neurons have shown that the axons of basal forebrain cholinergic neurons innervate the pallium with far more topographical and functional organization than was historically appreciated. Together with the results of studies using new probes that allow release of acetylcholine to be detected with high spatial and temporal resolution, these findings have implicated cholinergic networks in 'binding' diverse behaviours that contribute to cognition. Here, we review recent findings on the developmental origins, connectivity and function of cholinergic neurons, and explore the participation of cholinergic signalling in the encoding of cognition-related behaviours.
Topics: Humans; Acetylcholine; Basal Forebrain; Cholinergic Agents; Cognition; Signal Transduction
PubMed: 36823458
DOI: 10.1038/s41583-023-00677-x -
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 -
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