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Current Neuropharmacology 2016Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh... (Review)
Review
Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh from acetyl-CoA and choline in the cytoplasm and the vesicular acetylcholine transporter (VAChT) uptakes the neurotransmitter into synaptic vesicles. Following depolarization, ACh undergoes exocytosis reaching the synaptic cleft, where it can bind its receptors, including muscarinic and nicotinic receptors. ACh present at the synaptic cleft is promptly hydrolyzed by the enzyme acetylcholinesterase (AChE), forming acetate and choline, which is recycled into the presynaptic nerve terminal by the high-affinity choline transporter (CHT1). Cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are severely lost in Alzheimer's disease (AD). AD is the most ordinary cause of dementia affecting 25 million people worldwide. The hallmarks of the disease are the accumulation of neurofibrillary tangles and amyloid plaques. However, there is no real correlation between levels of cortical plaques and AD-related cognitive impairment. Nevertheless, synaptic loss is the principal correlate of disease progression and loss of cholinergic neurons contributes to memory and attention deficits. Thus, drugs that act on the cholinergic system represent a promising option to treat AD patients.
Topics: Acetylcholine; Alzheimer Disease; Animals; Cholinergic Agents; Cholinergic Neurons; Cholinesterase Inhibitors; Drug Delivery Systems; Humans; Receptors, Cholinergic
PubMed: 26813123
DOI: 10.2174/1570159x13666150716165726 -
Molecules (Basel, Switzerland) Mar 2022Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer's disease (AD), a... (Review)
Review
Acetylcholine, a neurotransmitter secreted by cholinergic neurons, is involved in signal transduction related to memory and learning ability. Alzheimer's disease (AD), a progressive and commonly diagnosed neurodegenerative disease, is characterized by memory and cognitive decline and behavioral disorders. The pathogenesis of AD is complex and remains unclear, being affected by various factors. The cholinergic hypothesis is the earliest theory about the pathogenesis of AD. Cholinergic atrophy and cognitive decline are accelerated in age-related neurodegenerative diseases such as AD. In addition, abnormal central cholinergic changes can also induce abnormal phosphorylation of ttau protein, nerve cell inflammation, cell apoptosis, and other pathological phenomena, but the exact mechanism of action is still unclear. Due to the complex and unclear pathogenesis, effective methods to prevent and treat AD are unavailable, and research to explore novel therapeutic drugs is various and active in the world. This review summaries the role of cholinergic signaling and the correlation between the cholinergic signaling pathway with other risk factors in AD and provides the latest research about the efficient therapeutic drugs and treatment of AD.
Topics: Acetylcholine; Alzheimer Disease; Cholinergic Agents; Humans; Neurodegenerative Diseases; Signal Transduction
PubMed: 35335180
DOI: 10.3390/molecules27061816 -
Brain : a Journal of Neurology Jul 2018Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that... (Review)
Review
Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Cholinergic Agents; Cholinergic Neurons; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Humans; Neurofibrillary Tangles
PubMed: 29850777
DOI: 10.1093/brain/awy132 -
Neuron Nov 2022Cholinergic neurons in the medial septum (MS) constitute a major source of cholinergic input to the forebrain and modulate diverse functions, including sensory...
Cholinergic neurons in the medial septum (MS) constitute a major source of cholinergic input to the forebrain and modulate diverse functions, including sensory processing, memory, and attention. Most studies to date have treated cholinergic neurons as a single population; as such, the organizational principles underling their functional diversity remain unknown. Here, we identified two subsets (D28K versus D28K) of cholinergic neurons that are topographically segregated in mice, Macaca fascicularis, and humans. These cholinergic subpopulations possess unique electrophysiological signatures, express mutually exclusive marker genes (kcnh1 and aifm3 versus cacna1h and gga3), and make differential connections with physiologically distinct neuronal classes in the hippocampus to form two structurally defined and functionally distinct circuits. Gain- and loss-of-function studies on these circuits revealed their differential roles in modulation of anxiety-like behavior and spatial memory. These results provide a molecular and circuitry-based theory for how cholinergic neurons contribute to their diverse behavioral functions.
Topics: Humans; Mice; Animals; Cholinergic Neurons; Cholinergic Agents; Prosencephalon; Hippocampus
PubMed: 36130594
DOI: 10.1016/j.neuron.2022.08.025 -
The New England Journal of Medicine Feb 2021The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown.
METHODS
In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2.
RESULTS
A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups.
CONCLUSIONS
In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).
Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzilates; Cholinergic Antagonists; Double-Blind Method; Drug Combinations; Female; Humans; Least-Squares Analysis; Male; Middle Aged; Muscarinic Agonists; Nortropanes; Pyridines; Schizophrenia; Thiadiazoles
PubMed: 33626254
DOI: 10.1056/NEJMoa2017015 -
Biological Psychiatry Dec 2022In the neurogenic niches of the adult hippocampus, new functional neurons are continuously generated throughout life, and generation of these neurons has been implicated...
BACKGROUND
In the neurogenic niches of the adult hippocampus, new functional neurons are continuously generated throughout life, and generation of these neurons has been implicated in learning and memory. Astrocytes, as components of the neurogenic niches, are critical in the regulation of adult hippocampal neurogenesis (AHN). However, little is known about how astrocytes receive and respond to extrinsic cues to regulate AHN.
METHODS
By using a transgenic strategy to conditionally delete astrocytic CRHM1 in mice and AAV (adeno-associated virus)-mediated overexpression of astrocytic CHRM1 specifically in the hippocampal dentate gyrus, we systematically investigated the role of astrocytic CHRM1 in the regulation of AHN and the underlying mechanisms using the combined approaches of immunohistochemistry, retrovirus labeling, electrophysiology, primary astrocyte cultures, immunoblotting, and behavioral assays.
RESULTS
We report that genetic ablation of CHRM1 in astrocytes led to defects in neural stem cell survival, neuronal differentiation, and maturation and integration of newborn neurons in the dentate gyrus. Astrocytic CHRM1-mediated modulation of AHN was mediated by BDNF (brain-derived neurotrophic factor) signaling. Furthermore, CHRM1 ablation in astrocytes impaired contextual fear memory. These impairments in both AHN and memory were rescued by overexpression of astrocytic CHRM1 in the dentate gyrus.
CONCLUSIONS
Our findings reveal a critical role for astrocytes in mediating cholinergic regulation of AHN and memory through CHRM1.
Topics: Mice; Animals; Astrocytes; Neurogenesis; Hippocampus; Receptors, Muscarinic; Cholinergic Agents; Dentate Gyrus
PubMed: 35787318
DOI: 10.1016/j.biopsych.2022.04.019 -
Neuron Nov 2023Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility...
Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility and efficacy. To investigate alternate pain control mechanisms, we explored cholinergic signaling in the ventrolateral periaqueductal gray (vlPAG), a critical nexus for descending pain modulation. Biosensor assays revealed that pain states decreased acetylcholine release in vlPAG. Activation of cholinergic projections from the pedunculopontine tegmentum to vlPAG relieved pain, even in opioid-tolerant conditions, through ⍺7 nicotinic acetylcholine receptors (nAChRs). Activating ⍺7 nAChRs with agonists or stimulating endogenous acetylcholine inhibited vlPAG neuronal activity through Ca and peroxisome proliferator-activated receptor α (PPAR⍺)-dependent signaling. In vivo 2-photon imaging revealed that chronic pain induces aberrant excitability of vlPAG neuronal ensembles and that ⍺7 nAChR-mediated inhibition of these cells relieves pain, even after opioid tolerance. Finally, pain relief through these cholinergic mechanisms was not associated with tolerance, reward, or withdrawal symptoms, highlighting its potential clinical relevance.
Topics: Rats; Animals; Humans; Analgesics, Opioid; Chronic Pain; Acetylcholine; Rats, Sprague-Dawley; Pain Measurement; Drug Tolerance; Periaqueductal Gray; Cholinergic Agents; Receptors, Nicotinic
PubMed: 37734381
DOI: 10.1016/j.neuron.2023.08.017 -
Neuron Sep 2022Vagus nerve stimulation (VNS) is a neuromodulation therapy for a broad and expanding set of neurologic conditions. However, the mechanism through which VNS influences...
Vagus nerve stimulation (VNS) is a neuromodulation therapy for a broad and expanding set of neurologic conditions. However, the mechanism through which VNS influences central nervous system circuitry is not well described, limiting therapeutic optimization. VNS leads to widespread brain activation, but the effects on behavior are remarkably specific, indicating plasticity unique to behaviorally engaged neural circuits. To understand how VNS can lead to specific circuit modulation, we leveraged genetic tools including optogenetics and in vivo calcium imaging in mice learning a skilled reach task. We find that VNS enhances skilled motor learning in healthy animals via a cholinergic reinforcement mechanism, producing a rapid consolidation of an expert reach trajectory. In primary motor cortex (M1), VNS drives precise temporal modulation of neurons that respond to behavioral outcome. This suggests that VNS may accelerate motor refinement in M1 via cholinergic signaling, opening new avenues for optimizing VNS to target specific disease-relevant circuitry.
Topics: Animals; Brain; Cholinergic Agents; Mice; Nervous System Diseases; Neuronal Plasticity; Vagus Nerve Stimulation
PubMed: 35858623
DOI: 10.1016/j.neuron.2022.06.017 -
Glia May 2017There is a long history of research on acetylcholine (ACh) function in myelinating glia, but a resurgence of interest recently as a result of the therapeutic potential... (Review)
Review
There is a long history of research on acetylcholine (ACh) function in myelinating glia, but a resurgence of interest recently as a result of the therapeutic potential of manipulating ACh signaling to promote remyelination, and the broader interest in neurotransmitter signaling in activity-dependent myelination. Myelinating glia express all the major types of muscarinic and nicotinic ACh receptors at different stages of development, and acetylcholinesterase and butyrylcholinesterase are highly expressed in white matter. This review traces the history of research on ACh signaling in Schwann cells, oligodendrocytes, and in the myelin sheath, and summarizes current knowledge on the intracellular signaling and functional consequences of ACh signaling in myelinating glia. Implications of ACh in diseases, such as Alzheimer's disease, multiple sclerosis, and white matter toxicity caused by pesticides are considered, together with an outline of major questions for future research. GLIA 2017;65:687-698.
Topics: Animals; Cholinergic Agents; Humans; Myelin Sheath; Neurodegenerative Diseases; Neurons; Oligodendroglia; Schwann Cells
PubMed: 28101995
DOI: 10.1002/glia.23101 -
Natural Product Reports Oct 2016Covering: July 2012 to June 2015. Previous review: Nat. Prod. Rep., 2013, 30, 869-915The structurally diverse imidazole-, oxazole-, and thiazole-containing secondary... (Review)
Review
Covering: July 2012 to June 2015. Previous review: Nat. Prod. Rep., 2013, 30, 869-915The structurally diverse imidazole-, oxazole-, and thiazole-containing secondary metabolites are widely distributed in terrestrial and marine environments, and exhibit extensive pharmacological activities. In this review the latest progress involving the isolation, biological activities, and chemical and biogenetic synthesis studies on these natural products has been summarized.
Topics: Alkaloids; Animals; Bacteria; Biological Products; Imidazoles; Marine Biology; Molecular Structure; Muscarine; Oxazoles; Peptides, Cyclic; Porifera
PubMed: 27714029
DOI: 10.1039/c6np00067c