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Archives of Medical Research May 2020The production of new neurons continues in the adult mammalian brain because of the sustained proliferation and differentiation of neural stem cells (NSCs) in neurogenic... (Review)
Review
The production of new neurons continues in the adult mammalian brain because of the sustained proliferation and differentiation of neural stem cells (NSCs) in neurogenic regions. The subventricular zone (SVZ), lining the lateral ventricle, and the subgranular zone (SGZ), which is in the dentate gyrus (DG) of the hippocampus, are the central regions of neurogenesis in the brain. Neurogenesis brings great hope for repairing a damaged brain and motivates researchers to detect the controlling signals of this process. Neurogenesis is regulated by intracellular and extracellular mechanisms that are influenced by neurogenic microenvironments. Recent experimental evidence suggests that the cholinergic system and nicotinic acetylcholine receptors (nAChRs) can directly regulate postnatal neurogenesis via specific mechanisms in these regions. In this review, we outline the cholinergic projections to the neurogenic niches and explain how the cholinergic system may regulate the formation of new neurons. We also discuss the intrinsic signaling pathways by which this system affects neurogenesis.
Topics: Cholinergic Agents; Humans; Neurogenesis; Nicotine; Non-Neuronal Cholinergic System; Signal Transduction
PubMed: 32279909
DOI: 10.1016/j.arcmed.2020.03.014 -
Current Alzheimer Research 2017The major components of the cholinergic receptor system of the human brain include projections from the basal forebrain nuclei, and utilize the two types of receptors... (Review)
Review
The major components of the cholinergic receptor system of the human brain include projections from the basal forebrain nuclei, and utilize the two types of receptors that they synapse on, nicotinic and muscarinic acetylcholine receptors. With the widespread cortical and subcortical projections of the basal forebrain, activity of these two receptor systems provide modulation of neurotransmitter activity underlying normal cognitive processes, such as attention, episodic memory, and working memory. Alzheimer's disease (AD) targets and damages cholinergic neurons in the basal forebrain, and as these projections are lost, cognitive performance progressively declines. Currently, the most widely prescribed treatment for AD is acetylcholinesterase inhibitor medications, which work by partially blocking the degradation of acetylcholine in the synapse and enabling more of the neurotransmitter to reach and activate cholinergic receptors. However since these medications have limited effectiveness, alternate treatments that focus on augmenting the activity of the receptors themselves, independent of acetylcholinesterase inhibition, are being explored. This review will discuss: 1) the role of the cholinergic system in modulating cognition, 2) novel cholinergic treatment strategies for AD-related cognitive decline, in particular treatments intended to increase cholinergic system activity by selectively targeting muscarinic and nicotinic acetylcholinergic receptors to improve cognitive performance, 3) risks, and additional considerations for cholinergic cognitive treatments for AD.
Topics: Alzheimer Disease; Animals; Cholinergic Agents; Humans; Neuroprotective Agents; Nootropic Agents
PubMed: 27697062
DOI: 10.2174/1567205013666160930112625 -
Biological & Pharmaceutical Bulletin 2022Immune cells such as T and B cells, monocytes and macrophages all express most of the cholinergic components of the nervous system, including acetylcholine (ACh),...
Immune cells such as T and B cells, monocytes and macrophages all express most of the cholinergic components of the nervous system, including acetylcholine (ACh), choline acetyltransferase (ChAT), high affinity choline transporter, muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively), and acetylcholinesterase (AChE). Because of its efficient cleavage by AChE, ACh synthesized and released from immune cells acts only locally in an autocrine and/or paracrine fashion at mAChRs and nAChRs on themselves and other immune cells located in close proximity, leading to modification of immune function. Immune cells generally express all five mAChR subtypes (M-M) and neuron type nAChR subunits α2-α7, α9, α10, β2-β4. The expression pattern and levels of mAChR subtypes and nAChR subunits vary depending on the tissue involved and its immunological status. Immunological activation of T cells via T-cell receptor-mediated pathways and cell adhesion molecules upregulates ChAT expression, which facilitates the synthesis and release of ACh. At present, α7 nAChRs expressed in macrophages are receiving much attention because they play a central role in anti-inflammatory cholinergic pathways. However, it now appears that through modification of cytokine synthesis, G-coupled mAChRs play a prominent role in regulation of T cell proliferation and differentiation and B cell immunoglobulin class switching. It is anticipated that greater understanding of G-coupled mAChRs on immune cells will provide an opportunity to develop new and effective treatments for immunological disorders.
Topics: Acetylcholine; Acetylcholinesterase; Choline O-Acetyltransferase; Cholinergic Agents; Immunity; Receptors, Muscarinic
PubMed: 35650095
DOI: 10.1248/bpb.b21-01005 -
Toxicon : Official Journal of the... Oct 2022Pseudosperma species are widely distributed worldwide. Many of them cause poisoning incidents every year, and the toxin responsible for poisoning is muscarine, which...
Pseudosperma species are widely distributed worldwide. Many of them cause poisoning incidents every year, and the toxin responsible for poisoning is muscarine, which could stimulate the parasympathetic nervous system. This study established a method using multiwalled carbon nanotube purification and liquid chromatography-tandem mass spectrometry for the targeted screening of mushroom toxins (muscarine, isoxazole derivatives, tryptamine alkaloids, three amatoxins and three phallotoxins) from Pseudosperma umbrinellum, a common poisonous mushroom distributed in north and northwestern China. Surprisingly, in addition to muscarine, phalloidin was also detected in P. umbrinellum, and the contents were 3022.2 ± 604.4 to 4002.3 ± 804.6 mg/kg (k = 2; p = 95%) muscarine and 5.9 ± 1.2 to 9.3 ± 1.8 mg/kg (k = 2; p = 95%) phalloidin.
Topics: Agaricales; Amanitins; Muscarine; Mushroom Poisoning; Phalloidine
PubMed: 35998714
DOI: 10.1016/j.toxicon.2022.08.005 -
Neuroscience Oct 2023While the functional and behavioral role of the medial habenula (MHb) is still emerging, recent data indicate an involvement of this nuclei in regulating mood, aversion,...
While the functional and behavioral role of the medial habenula (MHb) is still emerging, recent data indicate an involvement of this nuclei in regulating mood, aversion, and addiction. Unique to the MHb is a large cluster of cholinergic neurons that project to the interpeduncular nucleus and densely express acetylcholine receptors (AChRs) suggesting that the activity of these cholinergic neurons may be regulated by ACh itself. Whether endogenous ACh from within the habenula regulates cholinergic neuron activity has not been demonstrated. Supporting a role for ACh in modulating MHb activity, acetylcholinesterase inhibitors increased the firing rate of MHb cholinergic neurons in mouse habenula slices, an effect blocked by AChR antagonists and mediated by ACh which was detected via expressing fluorescent ACh sensors in MHb in vivo. To test if cholinergic afferents innervate MHb cholinergic neurons, we used anterograde and retrograde viral tracing to identify cholinergic inputs. Surprisingly, tracing experiments failed to detect cholinergic inputs into the MHb, including from the septum, suggesting that MHb cholinergic neurons may release ACh within the MHb to drive cholinergic activity. To test this hypothesis, we expressed channelrhodopsin in a portion of MHb cholinergic neurons while recording from non-opsin-expressing neurons. Light pulses progressively increased activity of MHb cholinergic neurons indicating feed-forward activation driven by MHb ACh release. These data indicate MHb cholinergic neurons may utilize a unique feed-forward mechanism to synchronize and increase activity by releasing local ACh.
Topics: Mice; Animals; Acetylcholine; Habenula; Acetylcholinesterase; Cholinergic Neurons; Cholinergic Agents
PubMed: 37572877
DOI: 10.1016/j.neuroscience.2023.07.030 -
Clinical Toxicology (Philadelphia, Pa.) Jul 2022The U.S. National Library of Medicine and Department of Homeland Security assembled subject matter experts (SMEs) for the Toxic Chemical Syndrome Definitions and...
BACKGROUND
The U.S. National Library of Medicine and Department of Homeland Security assembled subject matter experts (SMEs) for the Toxic Chemical Syndrome Definitions and Nomenclature Workshop. The SMEs at this meeting identified a lack of research evaluating the effectiveness of field recognition of toxidromes to guide treatment. They suggested that mnemonics may be helpful for remembering and recognizing toxidromes and further, that rapid toxidrome recognition, through use of a mnemonic or otherwise, leads to rapid action and urgent intervention.
OBJECTIVES
(1) Determine if published studies demonstrate HPs can learn and recall hazardous materials (hazmat) toxidromes. (2) Determine if Healthcare Professionals (HPs) can learn mnemonics for muscarinic and nicotinic toxidromes during the Advanced Hazmat Life Support (AHLS) Provider Course (PC) and recall these cholinergic mnemonics when retested years later. Our hypothesis is HPs can learn these mnemonics and recall them up to four years later.
METHODS
We analyzed results of HPs who completed AHLS PC pre-tests and post-tests during their initial AHLS PC between March 1, 2007 and March 1, 2010, and then, within four years, took either an online retest or a pre-test for a second AHLS PC. We compared pre- and post-test answers for questions regarding muscarinic and nicotinic mnemonics to assess if HPs can learn these mnemonics during an initial AHLS PC and then recall these mnemonics later, during retesting. We compared the percentage of HPs who correctly identified each cholinergic mnemonic on the pre-test, post-test, and retest using McNemar's test for paired, nominal data. We searched six literature databases to see if there were any previous similar studies.
RESULTS
Our literature search found no similar published studies. The mean time to re-testing was 3.6 years (SD 0.8 year). The percentage of respondents correctly answering the question for the muscarinic toxidrome was 53% on the pre-test, 100% on the post-test, and 75% on the retest. The percentage of respondents correctly answering the nicotinic toxidrome question was 52% on the pre-test, 100% on the post-test, and 77% on the retest.
CONCLUSION
All studied healthcare professionals learned the cholinergic toxidrome mnemonics during their initial AHLS PC. Mnemonic recall declined somewhat on retesting; however, recall was evident in 75-77% of retest takers compared to their pre-test results up to four years earlier, a statistically significant difference ( < .001) for both mnemonics. This supports our study hypothesis that HPs can learn these mnemonics and recall them up to 4 years later.
Topics: Cholinergic Agents; Delivery of Health Care; Health Personnel; Humans; Learning; Mental Recall
PubMed: 35225116
DOI: 10.1080/15563650.2022.2042551 -
Hypertension (Dallas, Tex. : 1979) Sep 2018
Topics: Cholinergic Agents; Humans; Hypertension; Receptor, Muscarinic M3; Receptors, Muscarinic; Sodium Chloride, Dietary
PubMed: 30354773
DOI: 10.1161/HYPERTENSIONAHA.118.11494 -
Postgraduate Medicine Jun 2017Evidence-based guidelines recommend inhaled long-acting anti-muscarinic agents (LAMAs) as first-line maintenance therapy for symptomatic patients with COPD. Several... (Review)
Review
Evidence-based guidelines recommend inhaled long-acting anti-muscarinic agents (LAMAs) as first-line maintenance therapy for symptomatic patients with COPD. Several LAMAs are now available for use either as monotherapy or in combination with other COPD medications, including long-acting β-agonists (LABAs) or inhaled corticosteroids (ICS). The efficacy and long-term safety of these medications have been evaluated in multiple clinical trials and real-life studies. This review evaluates the evidence available on the safety of existing LAMAs alone or in combination with LABAs and ICS in patients with COPD.
Topics: Administration, Inhalation; Humans; Muscarinic Antagonists; Patient Safety; Pulmonary Disease, Chronic Obstructive
PubMed: 28395575
DOI: 10.1080/00325481.2017.1317575 -
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