-
Neuropharmacology Aug 2020Non-depolarizing neuromuscular blocking agents are used during general anesthesia to facilitate intubation and optimize surgical conditions. When patients leave the... (Review)
Review
Non-depolarizing neuromuscular blocking agents are used during general anesthesia to facilitate intubation and optimize surgical conditions. When patients leave the operating room after surgery, postoperative residual neuromuscular block occurs frequently, increasing vulnerability to respiratory complications such as hypoxemia and unplanned postoperative mechanical ventilation. To restore neuromuscular transmission and skeletal muscle strength, anesthesiologists typically administer peripherally acting acetylcholinesterase inhibitors such as neostigmine. However, neostigmine's desirable effects have a narrow therapeutic range. Even at recommended dose (15-50 μg/kg), neostigmine induces nicotinic (upper airway muscle weakness leading to dysphagia and upper airway obstruction, and decreased maximum inspiratory airflow) and muscarinic (blurred vision, bronchial constriction, abdominal cramping and nausea) side effects. Recent data have questioned as to whether neostigmine reversal of neuromuscular blockade improves relevant patient outcomes such as postoperative respiratory and perioperative cardiovascular complications. A central strategy to avoid side effects of neuromuscular blocking agents is their judicious use based on quantitative monitoring of neuromuscular transmission using repetitive peripheral nerve stimulation (train-of-four ratio). Peripherally acting acetylcholinesterase inhibitors such as neostigmine should then only be administered when indicated and dosed based on results of the train-of-four ratio.
Topics: Anesthesia, General; Cardiovascular System; Cholinesterase Inhibitors; General Surgery; Humans; Morbidity; Neostigmine; Neuromuscular Blockade; Perioperative Care; Postoperative Complications; Respiratory System
PubMed: 32416089
DOI: 10.1016/j.neuropharm.2020.108134 -
Hearing Research Nov 2021Cholinergic axons from the pedunculopontine tegmental nucleus (PPT) innervate the inferior colliculus where they are positioned to modulate both excitatory and...
Cholinergic axons from the pedunculopontine tegmental nucleus (PPT) innervate the inferior colliculus where they are positioned to modulate both excitatory and inhibitory circuits across the central nucleus and adjacent cortical regions. More rostral regions of the auditory midbrain include the nucleus of the brachium of the inferior colliculus (NBIC), the intercollicular tegmentum (ICt) and the rostral pole of the inferior colliculus (ICrp). These regions appear especially important for multisensory integration and contribute to orienting behavior and many aspects of auditory perception. These regions appear to receive cholinergic innervation but little is known about the distribution of cholinergic axons in these regions or the cells that they contact. The present study used immunostaining to examine the distribution of cholinergic axons and then used chemically-specific viral tracing to examine cholinergic projections from the PPT to the intercollicular areas in male and female transgenic rats. Staining with antibodies against vesicular acetylcholine transporter revealed dense cholinergic innervation throughout the NBIC, ICt and ICrp. Deposits of viral vector into the PPT labeled cholinergic axons bilaterally in the NBIC, ICt and ICrp. In each area, the projections were denser on the ipsilateral side. The axons appeared morphologically similar across the three areas. In each area, en passant and terminal boutons from these axons appeared in the neuropil and also in close apposition to cell bodies. Immunostaining with a marker for GABAergic cells suggested that the cholinergic axons likely contact both GABAergic and non-GABAergic cells in the NBIC, ICt and ICrp. Thus, the cholinergic axons could affect multisensory processing by modulating excitatory and inhibitory circuits in the NBIC, ICt and ICrp. The similarity of axons and their targets suggests there may be a common function for cholinergic innervation across the three areas. Given what is known about the PPT, such functions could be associated with arousal, sleep-wake cycle, reward and plasticity.
Topics: Animals; Axons; Cholinergic Agents; Female; Inferior Colliculi; Male; Mesencephalon; Rats; Tegmentum Mesencephali
PubMed: 34564033
DOI: 10.1016/j.heares.2021.108352 -
The European Journal of Neuroscience Apr 2021The critical role of acetylcholine (ACh) in the basal ganglia is evident from the effect of cholinergic agents in patients suffering from several related neurological... (Review)
Review
The critical role of acetylcholine (ACh) in the basal ganglia is evident from the effect of cholinergic agents in patients suffering from several related neurological disorders, such as Parkinson's disease, Tourette syndrome, or dystonia. The striatum possesses the highest density of ACh markers in the basal ganglia underlying the importance of ACh in this structure. Striatal cholinergic interneurons (CINs) are responsible for the bulk of striatal ACh, although extrinsic cholinergic afferents from brainstem structures may also play a role. CINs are tonically active, and synchronized pause in their activity occurs following the presentation of salient stimuli during behavioral conditioning. However, the synaptic mechanisms involved are not fully understood in this physiological response. ACh modulates striatal circuits by acting on muscarinic and nicotinic receptors existing in several combinations both presynaptically and postsynaptically. While the effects of ACh in the striatum through muscarinic receptors have received particular attention, nicotinic receptors function has been less studied. Here, after briefly reviewing relevant results regarding muscarinic receptors expression and function, I will focus on striatal nicotinic receptor expressed presynaptically on glutamatergic and dopaminergic afferents and postsynaptically on diverse striatal interneurons populations. I will also review recent evidence suggesting the involvement of different GABAergic sources in two distinct nicotinic-receptor-mediated striatal circuits: the disynaptic inhibition of striatal projection neurons and the recurrent inhibition among CINs. A better understanding of striatal nicotinic receptors expression and function may help to develop targeted pharmacological interventions to treat brain disorders such as Parkinson's disease, Tourette syndrome, dystonia, or nicotine addiction.
Topics: Acetylcholine; Cholinergic Agents; Cholinergic Neurons; Corpus Striatum; Dopamine; Humans; Interneurons; Receptors, Nicotinic
PubMed: 33529401
DOI: 10.1111/ejn.15135 -
Respiratory Research Nov 2023Airway tuft cells, formerly called brush cells have long been described only morphologically in human airways. More recent RNAseq studies described a chemosensory cell...
BACKGROUND
Airway tuft cells, formerly called brush cells have long been described only morphologically in human airways. More recent RNAseq studies described a chemosensory cell population, which includes tuft cells, by a distinct gene transcription signature. Yet, until which level in the tracheobronchial tree in native human airway epithelium tuft cells occur and if they function as regulators of innate immunity, e.g., by regulating mucociliary clearance, remained largely elusive.
METHODS
We performed immunohistochemistry, RT-PCR and immunoblotting analyses for various tuft cell markers to confirm the presence of this cell type in human tracheal samples. Immunohistochemistry was conducted to study the distribution of tuft cells along the intrapulmonary airways in humans. We assessed the influence of bitter substances and the taste transduction pathway on mucociliary clearance in mouse and human tracheal samples by measuring particle transport speed.
RESULTS
Tuft cells identified by the expression of their well-established marker POU class 2 homeobox 3 (POU2F3) were present from the trachea to the bronchioles. We identified choline acetyltransferase in POU2F3 expressing cells as well as the transient receptor potential melastatin 5 (TRPM5) channel in a small population of tracheal epithelial cells with morphological appearance of tuft cells. Application of bitter substances, such as denatonium, led to an increase in mucociliary clearance in human tracheal preparations. This was dependent on activation of the TRPM5 channel and involved cholinergic and nitric oxide signalling, indicating a functional role for human tuft cells in the regulation of mucociliary clearance.
CONCLUSIONS
We were able to detect tuft cells in the tracheobronchial tree down to the level of the bronchioles. Moreover, taste transduction and cholinergic signalling occur in the same cells and regulate mucociliary clearance. Thus, tuft cells are potentially involved in the regulation of innate immunity in human airways.
Topics: Humans; Mice; Animals; Mucociliary Clearance; Trachea; Signal Transduction; Taste; Cholinergic Agents
PubMed: 37925434
DOI: 10.1186/s12931-023-02570-8 -
Behavioural Brain Research Feb 2023Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events....
Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events. This study assessed the role of these systems in the hippocampus for the extinction memory process by submitting male Wistar rats to fear-motivated step-down inhibitory avoidance (IA). The post-extinction session administration of the nicotinic and muscarinic cholinergic receptor antagonists, mecamylamine and scopolamine, respectively, both at doses of 2 µg/µl/side, and rapamycin, an mTOR inhibitor (0.02 µg/µl/side), into the CA1 region of the dorsal hippocampus, impaired the IA extinction memory. Furthermore, the nicotinic and muscarinic cholinergic receptor agonists, nicotine and muscarine, respectively, had a dose-dependent effect on the IA extinction memory when administered intra-CA1, immediately after the extinction session. Nicotine (0.6 µg/µl/side) and muscarine (0.02 µg/µl/side), respectively, had no effect, while the higher doses (6 and 2 µg/µl/side, respectively) impaired the IA extinction memory. Interestingly, the co-administration of muscarine at the lower dose blocked the impairment that was induced by rapamycin. This effect was not observed when nicotine at the lower dose was co-administered. These results have demonstrated the participation of the cholinergic receptors and mTOR in the hippocampus for IA extinction, and that the cholinergic agonists had a dose-dependent effect on the IA extinction memory. This study provides insights related to the behavioural aspects and the neurobiological properties underlying the early stage of fear-motivated IA extinction memory consolidation and suggests that there is hippocampal muscarinic receptor participation independent of mTOR in this memory process.
Topics: Animals; Male; Rats; Avoidance Learning; Fear; Hippocampus; Muscarine; Muscarinic Antagonists; Nicotine; Rats, Wistar; Receptors, Cholinergic; Sirolimus; TOR Serine-Threonine Kinases; Extinction, Psychological; Memory
PubMed: 36179804
DOI: 10.1016/j.bbr.2022.114129 -
Molecular Metabolism Jan 2024Since white adipose tissue (WAT) lacks parasympathetic cholinergic innervation, the source of the acetylcholine (ACh) acting on white adipocyte cholinergic receptors is...
BACKGROUND AND OBJECTIVES
Since white adipose tissue (WAT) lacks parasympathetic cholinergic innervation, the source of the acetylcholine (ACh) acting on white adipocyte cholinergic receptors is unknown. This study was designed to identify ACh-producing cells in mouse and human visceral WAT and to determine whether a non-neuronal cholinergic system becomes activated in obese inflamed WAT.
METHODS
Mouse epididymal WAT (eWAT) and human omental fat were studied in normal and obese subjects. The expression of the key molecules involved in cholinergic signaling was evaluated by qRT-PCR and western blotting whereas their tissue distribution and cellular localization were investigated by immunohistochemistry, confocal microscopy and in situ hybridization. ACh levels were measured by liquid chromatography/tandem mass spectrometry. The cellular effects of ACh were assessed in cultured human multipotent adipose-derived stem cell (hMADS) adipocytes.
RESULTS
In mouse eWAT, diet-induced obesity modulated the expression of key cholinergic molecular components and, especially, raised the expression of choline acetyltransferase (ChAT), the ACh-synthesizing enzyme, which was chiefly detected in interstitial macrophages, in macrophages forming crown-like structures (CLSs), and in multinucleated giant cells (MGCs). The stromal vascular fraction of obese mouse eWAT contained significantly higher ACh and choline levels than that of control mice. ChAT was undetectable in omental fat from healthy subjects, whereas it was expressed in a number of interstitial macrophages, CLSs, and MGCs from some obese individuals. In hMADS adipocytes stressed with tumor necrosis factor α, ACh, alone or combined with rivastigmine, significantly blunted monocyte chemoattractant protein 1 and interleukin 6 expression, it partially but significantly, restored adiponectin and GLUT4 expression, and promoted glucose uptake.
CONCLUSIONS
In mouse and human visceral WAT, obesity induces activation of a macrophage-dependent non-neuronal cholinergic system that is capable of exerting anti-inflammatory and insulin-sensitizing effects on white adipocytes.
Topics: Humans; Mice; Animals; Mice, Obese; Non-Neuronal Cholinergic System; Adipose Tissue, White; Obesity; Cholinergic Agents
PubMed: 38141849
DOI: 10.1016/j.molmet.2023.101862 -
Translational Psychiatry Mar 2023Cognitive impairment is a predictor of disability across different neuropsychiatric conditions, and cognitive abilities are also strongly related to educational... (Review)
Review
Cognitive impairment is a predictor of disability across different neuropsychiatric conditions, and cognitive abilities are also strongly related to educational attainment and indices of life success in the general population. Previous attempts at drug development for cognitive enhancement have commonly attempted to remedy defects in transmitters systems putatively associated with the conditions of interest such as the glutamate system in schizophrenia. Recent studies of the genomics of cognitive performance have suggested influences that are common in the general population and in different neuropsychiatric conditions. Thus, it seems possible that transmitter systems that are implicated for cognition across neuropsychiatric conditions and the general population would be a viable treatment target. We review the scientific data on cognition and the muscarinic cholinergic receptor system (M1 and M4) across different diagnoses, in aging, and in the general population. We suggest that there is evidence suggesting potential beneficial impacts of stimulation of critical muscarinic receptors for the enhancement of cognition in a broad manner, as well as the treatment of psychotic symptoms. Recent developments make stimulation of the M1 receptor more tolerable, and we identify the potential benefits of M1 and M4 receptor stimulation as a trans-diagnostic treatment model.
Topics: Humans; Receptor, Muscarinic M4; Cognition; Psychotic Disorders; Receptor, Muscarinic M1; Cholinergic Agents
PubMed: 36973270
DOI: 10.1038/s41398-023-02400-x -
Current Molecular Medicine 2023Alzheimer's disease (AD) is a psychological, biological, or developmental disorder that affects basic mental functioning. AD is generally affiliated with marked... (Review)
Review
Alzheimer's disease (AD) is a psychological, biological, or developmental disorder that affects basic mental functioning. AD is generally affiliated with marked discomfort and impaired social, professional, or other crucial aspects of life. AD is predominant worldwide, but a disparity in prevalence is observed amongst nations. Around 3/4 of people with Alzheimer's disease are from underdeveloped nations, which receive only 1/10th of global mental health resources. Residents of each community and age category share their presence in the overall load of AD. AD is a multifactorial disease impacted by numerous environmental, genetic, and endogenous elements. Heteromorphic interactive downstream cascades, networks, and molecular mechanisms (inflammation and immune network, cholinergic deficit, lipid transit, endocytosis, excitotoxicity, oxidative stress, amyloid and tau pathology, energy metabolism, neuron and synapse loss, and cell death) have been isolated, imparting a non-dissociative contribution in pathogenesis of AD. In the CNS, the structural organization of cholinergic neurons can give a novel insight into the mechanism of new learning. The alleviation of central cholinergic transposal following destruction in the basal forebrain cholinergic neurons precipitates a decline in neurocognitive symptoms visible in AD patients. The brain of patients suffering from AD exhibits plaques of aggregated amyloid-β and neurofibrillary tangles containing hyperphosphorylated tau protein. Amyloid-β triggers cholinergic loss by modulation of calcium and generation of cell-damaging molecules such as nitric oxide and reactive oxygen species intermediates. The present review focuses on the pathogenic mechanisms related to stages, diagnosis, and therapeutic approaches involved in AD.
Topics: Humans; Alzheimer Disease; tau Proteins; Amyloid beta-Peptides; Brain; Neurofibrillary Tangles; Cholinergic Agents
PubMed: 35379149
DOI: 10.2174/1566524022666220404112843 -
International Journal of Molecular... Sep 2020A review of the data on the modulatory action of adenosine 5'-triphosphate (ATP), the main co-transmitter with acetylcholine, and adenosine, the final ATP metabolite in... (Review)
Review
A review of the data on the modulatory action of adenosine 5'-triphosphate (ATP), the main co-transmitter with acetylcholine, and adenosine, the final ATP metabolite in the synaptic cleft, on neuromuscular transmission is presented. The effects of these endogenous modulators on pre- and post-synaptic processes are discussed. The contribution of purines to the processes of quantal and non-quantal secretion of acetylcholine into the synaptic cleft, as well as the influence of the postsynaptic effects of ATP and adenosine on the functioning of cholinergic receptors, are evaluated. As usual, the P2-receptor-mediated influence is minimal under physiological conditions, but it becomes very important in some pathophysiological situations such as hypothermia, stress, or ischemia. There are some data demonstrating the same in neuromuscular transmission. It is suggested that the role of endogenous purines is primarily to provide a safety factor for the efficiency of cholinergic neuromuscular transmission.
Topics: Adenosine; Adenosine Triphosphate; Animals; Cholinergic Agents; Humans; Neuromuscular Junction; Synaptic Transmission
PubMed: 32899290
DOI: 10.3390/ijms21176423 -
Zhonghua Shao Shang Za Zhi = Zhonghua... Sep 2021The vagus nerve plays an important role in regulating the homeostasis of inflammation. Inflammation signals in the body are passed to the vagus nerve efferent fibers via... (Review)
Review
The vagus nerve plays an important role in regulating the homeostasis of inflammation. Inflammation signals in the body are passed to the vagus nerve efferent fibers via nerve reflexes, and the signals generated by efferent fibers will play an anti-inflammatory role in various inflammatory diseases through immune cells such as T cells that express choline acetyltransferase and macrophages. However, the resolution of inflammation is not only the interaction between pro-inflammatory and anti-inflammatory cytokines, but also an active process of biosynthesis, including the synthesis of various pro-resolving mediators and their physiological utility process. Moreover, the cholinergic inflammation reflex also plays a crucial role in inflammation resolution. This review reviews and summarizes the cholinergic inflammatory reflex and its key role in the process of inflammation resolution.
Topics: Cholinergic Agents; Cytokines; Humans; Inflammation; Reflex; Vagus Nerve
PubMed: 34645156
DOI: 10.3760/cma.j.cn501120-20200609-00299