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American Journal of Physiology. Heart... Jul 2024Activation of the vagus nerve mediates cardioprotection and attenuates myocardial ischemia/reperfusion (I/R) injury. In response to vagal activation, acetylcholine (ACh)...
Activation of the vagus nerve mediates cardioprotection and attenuates myocardial ischemia/reperfusion (I/R) injury. In response to vagal activation, acetylcholine (ACh) is released from the intracardiac nervous system (ICNS) and activates intracellular cardioprotective signaling cascades. Recently, however, a nonneuronal cholinergic cardiac system (NNCCS) in cardiomyocytes has been described as an additional source of ACh. To investigate whether the NNCCS mediates cardioprotection in the absence of vagal and ICNS activation, we used a reductionist approach of isolated adult rat ventricular cardiomyocytes without neuronal cells, using hypoxic preconditioning (HPC) as a protective stimulus. Adult rat ventricular cardiomyocytes were isolated, the absence of neuronal cells was confirmed, and HPC was induced by 10/20 min hypoxia/reoxygenation (H/R) before subjection to 30/5 min H/R to simulate I/R injury. Cardiomyocyte viability was assessed by trypan blue staining at baseline and after HPC+H/R or H/R. Intra- and extracellular ACh was quantified using liquid chromatography-coupled mass spectrometry at baseline, after HPC, after hypoxia, and after reoxygenation, respectively. In a subset of experiments, muscarinic and nicotinic ACh receptor (m- and nAChR) antagonists were added during HPC or during H/R. Cardiomyocyte viability at baseline (69 ± 4%) was reduced by H/R (10 ± 3%). With HPC, cardiomyocyte viability was preserved after H/R (25 ± 6%). Intra- and extracellular ACh increased during hypoxia; HPC further increased both intra- and extracellular ACh (from 0.9 ± 0.7 to 1.5 ± 1.0 nmol/mg; from 0.7 ± 0.6 to 1.1 ± 0.7 nmol/mg, respectively). The addition of mAChR and nAChR antagonists during HPC had no impact on HPC's protection; however, protection was abrogated when antagonists were added during H/R (cardiomyocyte viability after H/R: 23 ± 5%; 13 ± 4%). In conclusion, activation of the NNCCS is involved in cardiomyocyte protection; HPC increases intra- and extracellular ACh during H/R, and m- and nAChRs are causally involved in HPC's cardiomyocyte protection during H/R. The interplay between upstream ICNS activation and NNCCS activation in myocardial cholinergic metabolism and cardioprotection needs to be investigated in future studies. The intracardiac nervous system is considered to be involved in ischemic conditioning's cardioprotection through the release of acetylcholine (ACh). However, we demonstrate that hypoxic preconditioning (HPC) protects from hypoxia/reoxygenation injury and increases intra- and extracellular ACh during hypoxia in isolated adult ventricular rat cardiomyocytes. HPC's protection involves cardiomyocyte muscarinic and nicotinic ACh receptor activation. Thus, besides the intracardiac nervous system, a nonneuronal cholinergic cardiac system may also be causally involved in cardiomyocyte protection by ischemic conditioning.
Topics: Animals; Myocytes, Cardiac; Acetylcholine; Myocardial Reperfusion Injury; Male; Cell Hypoxia; Rats; Non-Neuronal Cholinergic System; Ischemic Preconditioning, Myocardial; Rats, Sprague-Dawley; Cell Survival; Receptors, Muscarinic; Cells, Cultured; Muscarinic Antagonists
PubMed: 38700468
DOI: 10.1152/ajpheart.00211.2024 -
British Journal of Clinical Pharmacology Jul 2024Anticholinergic-induced cognitive impairment may be partially reversible upon cessation. A barrier to deprescribing of anticholinergics is the unknown risk of...
Anticholinergic-induced cognitive impairment may be partially reversible upon cessation. A barrier to deprescribing of anticholinergics is the unknown risk of anticholinergic adverse drug withdrawal events (ADWE), with only limited information available on the incidence, timing and severity of anticholinergic ADWE. We report the case of a 76-year-old woman who experienced significant cognitive improvement following deprescribing long-term use of a strong anticholinergic drug, doxepin, and dose reduction of another possible anticholinergic agent. The patient decided to abruptly stop taking doxepin, despite a planned careful taper with twice weekly monitoring, but did not experience any severe anticholinergic ADWE and subsequently had significantly improved cognitive function. Future research should focus on better understanding the risk of anticholinergic ADWE so that anticholinergic deprescribing decisions, including how often and by how much to taper, can be made confidently and safely.
Topics: Humans; Female; Aged; Deprescriptions; Cholinergic Antagonists; Cognition; Substance Withdrawal Syndrome; Cognitive Dysfunction
PubMed: 38697619
DOI: 10.1111/bcp.16078 -
Asian Journal of Anesthesiology Dec 2023Deep neuromuscular blockade (d-NMB) is an essential requirement for carboperitoneum during laparoscopy surgery. However, sustaining d-NMB till the completion of surgery... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Deep neuromuscular blockade (d-NMB) is an essential requirement for carboperitoneum during laparoscopy surgery. However, sustaining d-NMB till the completion of surgery delays the reversal of the residual block. Therefore, there is a merit in exploring the effect of synergistic vecuronium-atracurium combination on the duration-of-action of d-NMB during "laparoscopic" surgery when we compare intubating bolus non-depolarizers (atracurium, vecuronium) administered alone. This study aims to evaluate whether the synergistic effect atracurium-vecuronium combination increases duration-of-action of d-NMB "laparoscopic" surgery settings.
METHODS
Forty-eight patients (18-60 years, American Society of Anesthesiologists physical status- II/III, either sex) undergoing laparoscopic cholecystectomy were randomly allocated to receive vecuronium (vecuronium group, n = 16) or atracurium (atracurium group, n = 16) or vecuroniumatr-acurium combination (vecuronium-atracurium combination group, n = 16) and analyzed for the effects on the duration-of-action (primary objective); onset-of-action, reversibility, and quality of intubating conditions (secondary objectives) profile of neuromuscular blockade in patients undergoing laparoscopic cholecystectomy.
RESULTS
Duration-of-action of neuromuscular blockade was significantly longer in patients who received atracurium-vecuronium combination (53.9 ± 9.7 minutes) versus atracurium-alone (41.1 ± 3.8 minutes) or vecuronium-alone (43.5 ± 9.2 minutes) (P = 0.000). No difference was found for the time to onset-of-action (vecuronium [198.1 ± 34.9 seconds], atracurium [188.5 ± 50.6 seconds], or atracurium-vecuronium combination [196.3 ± 46.3 seconds] [P = 0.829]); time for the reversal of muscle relaxation effect (vecuronium [559.9 ± 216.2 seconds], atracurium [584.7 ± 258.3 seconds], and atracurium-vecuronium combination [555.0 ± 205.4 seconds] [P = 0.925]); and quality-of-intubating conditions (vecuronium group [9.6 ± 1.3]; atracurium group [10.0 ± 0.0]; atracurium-vecuronium group [10.0 ± 0.0] [P = 0.182]).
CONCLUSION
The synergistic effect of the atracurium-vecuronium combination leads to an increased duration-of-action of d-NMB during laparoscopic cholecystectomy without impacting onset-of-action, quality of intubating conditions, and reversal of muscle relaxant effect.
Topics: Humans; Atracurium; Male; Female; Vecuronium Bromide; Adult; Middle Aged; Neuromuscular Nondepolarizing Agents; Neuromuscular Blockade; Laparoscopy; Young Adult; Adolescent; Cholecystectomy, Laparoscopic; Drug Therapy, Combination; Drug Synergism
PubMed: 38695065
DOI: 10.6859/aja.202312_61(4).0001 -
AAPS PharmSciTech May 2024Tolterodine tartrate (TOTA) is associated with adverse effect, high hepatic access, varied bioavailability, slight aqueous solubility, and short half-life after oral...
HSPiP, Computational, and Thermodynamic Model-Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus-Based In Vivo Prediction in Humans: Part I.
Tolterodine tartrate (TOTA) is associated with adverse effect, high hepatic access, varied bioavailability, slight aqueous solubility, and short half-life after oral delivery. Hansen solubility parameters (HSP, HSPiP program), experimental solubility (T = 298.2 to 318.2 K and p = 0.1 MPa), computational (van't Hoff and Apelblat models), and thermodynamic models were used to the select solvent(s). HSPiP predicted PEG400 as the most suitable co-solvent based on HSP values (δ = 17.88, δ = 4.0, and δ = 8.8 of PEG400) and comparable to the drug (δ = 17.6, δ = 2.4, and δ = 4.6 of TOTA). The experimental mole fraction solubility of TOTA was maximum (x = 0.0852) in PEG400 confirming the best fit of the prediction. The observed highest solubility was attributed to the δ and δ interacting forces. The activity coefficient (ϒi) was found to be increased with temperature. The higher values of r (linear regression coefficient) and low RMSD (root mean square deviation) indicated a good correlation between the generated "xe" data for crystalline TOTA and the explored models (modified Apelblat and van't Hoff models). TOTA solubility in "PEG400 + water mixture" was endothermic and entropy-driven. IR (immediate release product) formulation can be tailored using 60% PEG400 in buffer solution for 2 mg of TOTA in 0.25 mL (dosing volume). The isotonic binary solution was associated with a pH of 7.2 suitable for sub-Q delivery. The approach would be a promising alternative with ease of delivery to children and aged patients.
Topics: Solubility; Humans; Tolterodine Tartrate; Solvents; Thermodynamics; Polyethylene Glycols; Biological Availability; Chemistry, Pharmaceutical; Injections, Subcutaneous; Drug Delivery Systems
PubMed: 38693316
DOI: 10.1208/s12249-024-02800-2 -
British Journal of Pharmacology Apr 2024Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal...
BACKGROUND AND PURPOSE
Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M and/or M receptors-the two most abundant muscarinic receptors in the striatum-reduced tic-related behaviours in mouse models of TS.
EXPERIMENTAL APPROACH
Studies were conducted using CIN-d and D1CT-7 mice, two TS models characterized by early-life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M/M receptor agonist, on tic-like and other TS-related responses. Then, we examined whether xanomeline effects were reduced by either M or M antagonists or mimicked by the M/M agonist cevimeline or the M positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M and M receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c-Fos.
KEY RESULTS
Systemic and intrastriatal xanomeline reduced TS-related behaviours in CIN-d and D1CT-7 mice. Most effects were blocked by M, but not M, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline-like ameliorative effects in both models. M, but not M, receptors were down-regulated in the striatum of CIN-d mice. Additionally, VU0467154 reduced striatal c-Fos levels in these animals.
CONCLUSION AND IMPLICATIONS
Activation of striatal M, but not M, receptors reduced tic-like manifestations in mouse models, pointing to xanomeline and M PAMs as novel putative therapeutic strategies for TS.
PubMed: 38689378
DOI: 10.1111/bph.16392 -
Brain and Behavior May 2024Alzheimer's disease (AD) is a neurodegenerative condition characterized by gradual loss of cognitive abilities (dementia) and is a major public health problem. Here, we...
A comprehensive assessment of the cholinergic-supporting and cognitive-enhancing effects of Rosa damascena Mill. (Damask rose) essential oil on scopolamine-induced amnestic rats.
INTRODUCTION
Alzheimer's disease (AD) is a neurodegenerative condition characterized by gradual loss of cognitive abilities (dementia) and is a major public health problem. Here, we aimed at investigating the effects of Rosa damascena essential oil (RDEO) on learning and memory functions in a rat model of amnesia induced by scopolamine, as well as on changes in acetylcholinesterase (AChE) activity, M muscarinic acetylcholine receptor (mAChR) expression, and brain-derived neurotrophic factor (BDNF) levels in the extracted brain tissues.
METHODS
The control, amnesia (scopolamine, 1 mg/kg/i.p.) and treatment (RDEO, 100 μL/kg/p.o. or galantamine, 1.5 mg/kg/i.p.) groups were subjected to Morris water maze and new object recognition tests. AChE activity was assayed by ELISA, and M mAChR and BDNF concentration changes were determined by western blotting. Also, using computational tools, human M mAChR was modeled in an active conformation, and the major components of RDEO were docked onto this receptor.
RESULTS
According to our behavioral tests, RDEO was able to mitigate the learning and memory impairments caused by scopolamine in vivo. Our in vitro assays showed that the observed positive effects correlated well with a decrease in AChE activity and an increase in M mAChR and BDNF levels in amnestic rat brains. We also demonstrated in an in silico setting that the major components of RDEO, specifically -citronellol, geraniol, and nerol, could be accommodated favorably within the allosteric binding pocket of active-state human M mAChR and anchored here chiefly by hydrogen-bonding and alkyl-π interactions.
CONCLUSION
Our findings offer a solid experimental foundation for future RDEO-based medicinal product development for patients suffering from AD.
Topics: Animals; Scopolamine; Rats; Amnesia; Oils, Volatile; Male; Rosa; Brain-Derived Neurotrophic Factor; Acetylcholinesterase; Receptor, Muscarinic M1; Rats, Wistar; Nootropic Agents; Disease Models, Animal; Brain; Cognition; Maze Learning
PubMed: 38688895
DOI: 10.1002/brb3.3507 -
Investigative Ophthalmology & Visual... Apr 2024The lacrimal gland (LG) is the main organ responsible for tear secretion and an important pathogenic site for dry eye disease (DED). This study aimed to comprehensively...
PURPOSE
The lacrimal gland (LG) is the main organ responsible for tear secretion and an important pathogenic site for dry eye disease (DED). This study aimed to comprehensively characterize LG cellular heterogeneity under normal and DED conditions using single-nucleus RNA sequencing (snRNA-seq).
METHODS
Single LG nuclei isolated from mice with or without DED induced by scopolamine (SCOP)/desiccating stress (DS) were subjected to snRNA-seq using the 10x Genomics platform. These cells were clustered and annotated using the t-distributed stochastic neighbor embedding (t-SNE) method and unbiased computational informatic analysis. Cluster identification and functional analysis were performed based on marker gene expression and bioinformatic data mining.
RESULTS
The snRNA-seq analysis of 30,351 nuclei identified eight major cell types, with acinar cells (∼72.6%) being the most abundant cell type in the LG. Subclustering analysis revealed that the LG mainly contained two acinar cell subtypes, two ductal cell subclusters, three myoepithelial cell (MECs) subtypes, and four immunocyte subclusters. In the SCOP-induced DED model, three major LG parenchymal cell types were significantly altered, characterized by a reduced proportion of acinar cells with a lowered secretion potential and an augmented proportion of ductal cells and MECs. LG immunocytes in DED scenarios showed an intensified inflammatory response and dysregulated intercellular communication with three major LG parenchymal cells.
CONCLUSIONS
Overall, this study offers a systemic single-nucleus transcriptomic profile of LGs in both normal and DED conditions and an atlas of the complicated interactions of immunocytes with major LG parenchymal cells. The findings also facilitate understanding the pathogenesis of DED.
Topics: Animals; Dry Eye Syndromes; Mice; Scopolamine; Lacrimal Apparatus; Disease Models, Animal; Mice, Inbred C57BL; Female; Cell Nucleus; Tears; Epithelial Cells
PubMed: 38687491
DOI: 10.1167/iovs.65.4.46 -
Hernia : the Journal of Hernias and... Apr 2024Post-operative urinary retention (POUR) is a known complication of hernia surgery. Minimally invasive inguinal hernia repair (IHR) is typically done under general...
PURPOSE
Post-operative urinary retention (POUR) is a known complication of hernia surgery. Minimally invasive inguinal hernia repair (IHR) is typically done under general anesthesia with neuromuscular blockade (NMB), which is commonly reversed with an anticholinesterase inhibitor paired with an anticholinergic agent. Sugammadex is a unique NMB reversal agent that does not have to be paired with an anticholinergic. We sought to explore the role of sugammadex in reducing the rate of POUR following these procedures.
METHODS
Data were collected retrospectively at a single institution between February 2016 and October 2019. We identified and studied patients who underwent minimally invasive IHR and received either sugammadex or neostigmine/glycopyrrolate for NMB reversal. The primary endpoint was POUR requiring bladder catheterization. Secondary endpoints included post-operative and 30-day readmissions.
RESULTS
274 patients were included in this study (143 received neostigmine and glycopyrrolate, 131 sugammadex). The sugammadex patients were on average 5 years older than the neostigmine/ glycopyrrolate patients (63.2 vs 58.2, p = 0.003), and received less median intravenous fluids (IVF) (900 ml vs 1000 ml; p = 0.015). There was a significant difference in the rate of POUR between the sugammadex and neostigmine/glycopyrrolate patients (0.0% vs 8.4%, p ≤ 0.001). The difference remained significant after controlling for age and IVF. The odds of POUR for those who received neostigmine/glycopyrrolate were 25 × higher than the odds of those who received sugammadex.
CONCLUSION
The results of this study reflect the protective role of sugammadex against POUR in minimally invasive IHR cases.
PubMed: 38683482
DOI: 10.1007/s10029-024-03038-4 -
Marine Drugs Mar 2024Macrocyclic imine phycotoxins are an emerging class of chemical compounds associated with harmful algal blooms and shellfish toxicity. Earlier binding and...
Macrocyclic imine phycotoxins are an emerging class of chemical compounds associated with harmful algal blooms and shellfish toxicity. Earlier binding and electrophysiology experiments on nAChR subtypes and their soluble AChBP surrogates evidenced common trends for substantial antagonism, binding affinities, and receptor-subtype selectivity. Earlier, complementary crystal structures of AChBP complexes showed that common determinants within the binding nest at each subunit interface confer high-affinity toxin binding, while distinctive determinants from the flexible loop C, and either capping the nest or extending toward peripheral subsites, dictate broad versus narrow receptor subtype selectivity. From these data, small spiroimine enantiomers mimicking the functional core motif of phycotoxins were chemically synthesized and characterized. Voltage-clamp analyses involving three nAChR subtypes revealed preserved antagonism for both enantiomers, despite lower subtype specificity and binding affinities associated with faster reversibility compared with their macrocyclic relatives. Binding and structural analyses involving two AChBPs pointed to modest affinities and positional variability of the spiroimines, along with a range of AChBP loop-C conformations denoting a prevalence of antagonistic properties. These data highlight the major contribution of the spiroimine core to binding within the nAChR nest and confirm the need for an extended interaction network as established by the macrocyclic toxins to define high affinities and marked subtype specificity. This study identifies a minimal set of functional pharmacophores and binding determinants as templates for designing new antagonists targeting disease-associated nAChR subtypes.
Topics: Marine Toxins; Imines; Nicotinic Antagonists; Receptors, Nicotinic; Animals; Macrocyclic Compounds; Structure-Activity Relationship
PubMed: 38667766
DOI: 10.3390/md22040149 -
Marine Drugs Mar 2024Nicotine binds to nicotinic acetylcholine receptors (nAChRs) that are overexpressed in different cancer cells, promoting tumor growth and resistance to chemotherapy. In...
Nicotine binds to nicotinic acetylcholine receptors (nAChRs) that are overexpressed in different cancer cells, promoting tumor growth and resistance to chemotherapy. In this study, we aimed to investigate the potential of APS7-2 and APS8-2, synthetic analogs of a marine sponge toxin, to inhibit nicotine-mediated effects on A549 human lung cancer cells. Our electrophysiological measurements confirmed that APS7-2 and APS8-2 act as α7 nAChR antagonists. APS8-2 showed no cytotoxicity in A549 cells, while APS7-2 showed concentration-dependent cytotoxicity in A549 cells. The different cytotoxic responses of APS7-2 and APS8-2 emphasize the importance of the chemical structure in determining their cytotoxicity on cancer cells. Nicotine-mediated effects include increased cell viability and proliferation, elevated intracellular calcium levels, and reduced cisplatin-induced cytotoxicity and reactive oxygen species production (ROS) in A549 cells. These effects of nicotine were effectively attenuated by APS8-2, whereas APS7-2 was less effective. Our results suggest that APS8-2 is a promising new therapeutic agent in the chemotherapy of lung cancer.
Topics: Humans; alpha7 Nicotinic Acetylcholine Receptor; A549 Cells; Nicotine; Lung Neoplasms; Reactive Oxygen Species; Antineoplastic Agents; Cell Survival; Animals; Nicotinic Antagonists; Cell Proliferation; Cisplatin; Calcium; Porifera
PubMed: 38667764
DOI: 10.3390/md22040147