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Neurogastroenterology and Motility Aug 2021Esophageal hypercontractility (EHC) is considered a major esophageal motor disorder of unclear etiology. Different mechanisms have been proposed, including an imbalance...
BACKGROUND
Esophageal hypercontractility (EHC) is considered a major esophageal motor disorder of unclear etiology. Different mechanisms have been proposed, including an imbalance in inhibitory and excitatory esophageal innervation. We hypothesized that patients with EHC suffer from cholinergic hyperactivity.
AIM
To interrogate the excitatory and inhibitory neurotransmission in EHC by assessing the esophageal motor response to atropine (ATR) and cholecystokinin (CCK), respectively, in EHC patients.
METHOD
We retrospectively reviewed patients who underwent high-resolution manometry (HRM) with pharmacologic challenge in a tertiary referral center between 2007 and 2017. We identified 49 EHC patients who were categorized based on frequency of hypercontractile peristaltic sequence into "frequent" and "infrequent" and motility diagnosis groups. Deglutitive pressure metrics and esophageal motor responses to ATR (12 mcg/kg iv) and CCK (40 ng/kg iv) were analyzed across groups.
RESULTS
Atropine abolished hypercontractility across all groups studied, converting nearly half of patients to a motor pattern of ineffective esophageal motility. Abnormal CCK responses primarily occurred in the patient groups with concomitant outflow obstruction.
CONCLUSIONS
Hypercontractility is cholinergically mediated in all esophageal motor disorders. Most patients with isolated EHC appear to have excessive cholinergic drive, rather than loss of inhibitory innervation, and might be candidates for treatment with anticholinergic agents.
Topics: Aged; Atropine; Esophageal Motility Disorders; Esophagus; Female; Humans; Male; Manometry; Middle Aged; Muscarinic Antagonists; Muscle Contraction; Peristalsis; Retrospective Studies
PubMed: 33185322
DOI: 10.1111/nmo.14017 -
Food & Function May 2021Brain injury and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are urgent medical problems, which... (Review)
Review
Brain injury and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are urgent medical problems, which severely threaten the life quality of patients and their carers. However, there are currently no effective therapies. Fucoidan is a natural compound found in brown algae and some animals, which has multiple biological and pharmacological activities, such as antioxidant, anti-tumor, anti-coagulant, anti-thrombotic, immunoregulatory, anti-viral, and anti-inflammatory effects. A growing number of studies have shown that fucoidan also exerts a neuroprotective function. Particularly, recent findings have indicated that fucoidan could slow down the neurodegenerative processes and show protective effects against brain injury, which might be of therapeutic value for intervening in brain injury and neurodegenerative diseases. In this review, we have discussed the pharmacokinetics of fucoidan as well as the molecular mechanisms by which fucoidan exerts its neuroprotective effect on some neurological disorders. Along with this, we have also summarized the potential benefits of fucoidan in combination with other drugs in the treatment of neurodegenerative diseases and brain injury. Although the extraction process of fucoidan has been improved well, more efforts should be devoted to the translational research and clinical trials of fucoidan in the near future.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Antiviral Agents; Apoptosis; Brain Injuries; Cholinergic Agents; Drug Therapy, Combination; Humans; Mitochondria; Neurites; Neurodegenerative Diseases; Neuroprotective Agents; Polysaccharides
PubMed: 33861265
DOI: 10.1039/d0fo03153d -
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 -
Journal of Neurochemistry Apr 2024Hermona Soreq holds a Hebrew University Slesinger Chair in Molecular Neuroscience and is among the founding members of the Edmond and Lily Safra Center of Brain Sciences...
Hermona Soreq holds a Hebrew University Slesinger Chair in Molecular Neuroscience and is among the founding members of the Edmond and Lily Safra Center of Brain Sciences (ELSC). Soreq's research (H-impact: 98) focuses on acetylcholine (ACh)-related pathways and combines RNA-sequencing technologies, transgenic engineering, and molecular biology tests with in-depth analysis approaches. Her work addresses microRNAs (miRs) and transfer RNA fragments (tRFs) which have rapidly acquired wide recognition as global controllers of regulatory processes in healthy and diseased brain and body, including anxiety, inflammation, and cognition. Altogether, Soreq's work leads to molecular neuroscience-driven prevention and/or intervention with diseases involving impaired ACh signaling, including schizophrenia, bipolar disorder, Alzheimer's disease, and stress. Hermona led this Special Issue based on the 17th Symposium on Cholinergic Mechanisms (ISCM2022). We interviewed her on the progress in the field, what she wants to achieve as Senior Editor for the Gene Regulation and Genetics category at the Journal of Neurochemistry, key moments, and future directions.
Topics: Humans; Female; MicroRNAs; Alzheimer Disease; Brain; Signal Transduction; Cholinergic Agents
PubMed: 38491750
DOI: 10.1111/jnc.16096 -
Naunyn-Schmiedeberg's Archives of... Mar 2023A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus... (Review)
Review
A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus disease 2019 (COVID-19). The binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) induces a series of inflammatory cellular events with cytopathic effects leading to cell injury and hyperinflammation. Severe SARS-CoV-2 infection may lead to dysautonomia and sympathetic storm due to dysfunction of the autonomic nervous system (ANS). Therefore, this review aimed to elucidate the critical role of the cholinergic system (CS) in SARS-CoV-2 infection. The CS forms a multi-faceted network performing diverse functions in the body due to its distribution in the neuronal and non-neuronal cells. Acetylcholine (ACh) acts on two main types of receptors which are nicotinic receptors (NRs) and muscarinic receptors (MRs). NRs induce T cell anergy with impairment of antigen-mediated signal transduction. Nicotine through activation of T cell NRs inhibits the expression and release of the pro-inflammatory cytokines. NRs play important anti-inflammatory effects while MRs promote inflammation by inducing the release of pro-inflammatory cytokines. SARS-CoV-2 infection can affect the morphological and functional stability of CS through the disruption of cholinergic receptors. SARS-CoV-2 spike protein is similar to neurotoxins, which can bind to nicotinic acetylcholine receptors (nAChR) in the ANS and brain. Therefore, cholinergic receptors mainly nAChR and related cholinergic agonists may affect the pathogenesis of SARS-CoV-2 infection. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. In addition, nAChR activators may mitigate endothelial dysfunction (ED), oxidative stress (OS), and associated coagulopathy in COVID-19. Similarly, nAChR activators may improve OS, inflammatory changes, and cytokine storm in COVID-19. Therefore, nAChR activators like varenicline in virtue of its anti-inflammatory and anti-oxidant effects with direct anti-SARS-CoV-2 effect could be effective in the management of COVID-19.
Topics: Humans; COVID-19; SARS-CoV-2; Receptors, Nicotinic; Cholinergic Agents; Cytokines
PubMed: 36460816
DOI: 10.1007/s00210-022-02346-9 -
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 -
CNS Drugs Jul 2023Even though language is essential in human communication, research on pharmacological therapies for language deficits in highly prevalent neurodegenerative and vascular... (Review)
Review
Even though language is essential in human communication, research on pharmacological therapies for language deficits in highly prevalent neurodegenerative and vascular brain diseases has received little attention. Emerging scientific evidence suggests that disruption of the cholinergic system may play an essential role in language deficits associated with Alzheimer's disease and vascular cognitive impairment, including post-stroke aphasia. Therefore, current models of cognitive processing are beginning to appraise the implications of the brain modulator acetylcholine in human language functions. Future work should be directed further to analyze the interplay between the cholinergic system and language, focusing on identifying brain regions receiving cholinergic innervation susceptible to modulation with pharmacotherapy to improve affected language domains. The evaluation of language deficits in pharmacological cholinergic trials for Alzheimer's disease and vascular cognitive impairment has thus far been limited to coarse-grained methods. More precise, fine-grained language testing is needed to refine patient selection for pharmacotherapy to detect subtle deficits in the initial phases of cognitive decline. Additionally, noninvasive biomarkers can help identify cholinergic depletion. However, despite the investigation of cholinergic treatment for language deficits in Alzheimer's disease and vascular cognitive impairment, data on its effectiveness are insufficient and controversial. In the case of post-stroke aphasia, cholinergic agents are showing promise, particularly when combined with speech-language therapy to promote trained-dependent neural plasticity. Future research should explore the potential benefits of cholinergic pharmacotherapy in language deficits and investigate optimal strategies for combining these agents with other therapeutic approaches.
Topics: Humans; Alzheimer Disease; Cholinergic Agents; Brain; Aphasia; Acetylcholine
PubMed: 37341896
DOI: 10.1007/s40263-023-01017-4 -
FASEB Journal : Official Publication of... Jan 2024Purinergic signaling plays an important role in regulating bladder contractility and voiding. Abnormal purinergic signaling is associated with lower urinary tract...
Purinergic signaling plays an important role in regulating bladder contractility and voiding. Abnormal purinergic signaling is associated with lower urinary tract symptoms (LUTS). Ecto-5'-nucleotidase (NT5E) catalyzes dephosphorylation of extracellular AMP to adenosine, which in turn promotes adenosine-A2b receptor signaling to relax bladder smooth muscle (BSM). The functional importance of this mechanism was investigated using Nt5e knockout (Nt5eKO) mice. Increased voiding frequency of small voids revealed by voiding spot assay was corroborated by urodynamic studies showing shortened voiding intervals and decreased bladder compliance. Myography indicated reduced contractility of Nt5eKO BSM. These data support a role for NT5E in regulating bladder function through modulation of BSM contraction and relaxation. However, the abnormal bladder phenotype of Nt5eKO mice is much milder than we previously reported in A2b receptor knockout (A2bKO) mice, suggesting compensatory response(s) in Nt5eKO mouse bladder. To better understand this compensatory mechanism, we analyzed changes in purinergic and other receptors controlling BSM contraction and relaxation in the Nt5eKO bladder. We found that the relative abundance of muscarinic CHRM3 (cholinergic receptor muscarinic 3), purinergic P2X1, and A2b receptors was unchanged, whereas P2Y12 receptor was significantly downregulated, suggesting a negative feedback response to elevated ADP signaling. Further studies of additional ecto-nucleotidases indicated significant upregulation of the nonspecific urothelial alkaline phosphatase ALPL, which might mitigate the degree of voiding dysfunction by compensating for Nt5e deletion. These data suggest a mechanistic complexity of the purinergic signaling network in bladder and imply a paracrine mechanism in which urothelium-released ATP and its rapidly produced metabolites coordinately regulate BSM contraction and relaxation.
Topics: Animals; Mice; 5'-Nucleotidase; Adenosine; Alkaline Phosphatase; Cholinergic Agents; Mice, Knockout; Urinary Bladder
PubMed: 38198186
DOI: 10.1096/fj.202301393R -
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