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[Display omitted] • Alzheimer's disease (AD), a neurodegenerative disease, can be caused by extracellular accumulation of amyloid plaques and intracellular deposition of neurofibrillary tangles. They also cause other related complications that worsen the condition. • The current study primarily focuses on different properties of targeted and forthcoming drugs for the treatment of Alzheimer's Disease. Targeted drugs are categorized under various classes of phase studies and mechanism-based therapies. • In this review, various physio-pathological causes of dysfunction in Alzheimer's disease are comprehensively discussed i.e. synaptic impairment, receptor or neurotransmitter-based impairment, cholinergic loss, and amyloid-tau-based symptoms. • Additionally, this study focuses on future targets that could lead to treatment of the main symptoms associated with this disease. Targeted new treatments address epigenetic regulation, oxidative stress, vascular dementia, and more. The analytical and experimental investigation of several targets and biomarkers that help in explaining significant cognitive deficits, covering drug development and precision medicine aimed at different chronic neurodegenerative conditions such as Alzheimer's disease (AD), Parkinson's disease, synaptic dysfunction, brain damage from neuronal apoptosis, and other disease pathologies; this served as the foundation for all phase studies. The focus of current therapeutic approaches is on developing humanized antibodies, agonist and antagonist drugs, receptors, signaling molecules, major targeted drug-metabolizing enzymes, and other metabolites to treat neurodegeneration in the AD brain brought on by tau hyperphosphorylation, amyloid plagues, or other cholinergic effects. The five A's—amnesia, agnosia, aphasia, apraxia, and anomia—are the typical symptoms associated with AD. While the main goal of drug therapeutics studies is modified amino acids acting as pro-drugs, pharmacokinetics studies and trends in evaluating drug-drug interactions focus on interactions between drugs and antibodies, drugs and therapeutic biologics like metabolites, herbs, interleukin-based, and gene silencing mechanism-based. Studies on the biotransformation of xenobiotic compounds and the metabolism of exogenous and endogenous substances are conducted under Phase I, Phase II, and Phase III trials because the pivotal pharmacokinetic properties of drugs, such as absorption, distribution, metabolism, and excretion (ADME), aid in understanding variations in the crucial improvement of various target drugs. This review also highlights the developments in soon-to-be genetically created targeted medications that may serve as ground-breaking treatments for cholinergic illnesses in the brains of AD patients and other neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

• The activity of cholinergic circuits is critical for the induction of vagus nerve stimulation (VNS)-mediated plasticity. • Transcutaneous auricular VNS (taVNS) stimulation does not influence short-latency afferent inhibition. • Cholinergic circuits explored by SAI are different from cholinergic circuits engaged by taVNS. The mechanisms of actions of transcutaneous auricular vagus nerve stimulation (taVNS) are still unclear, however the activity of the cholinergic system seems to be critical for the induction of VNS-mediated plasticity. Transcranial Magnetic Stimulation (TMS) is a well-suited, non-invasive tool to investigate cortical microcircuits involving different neurotransmitters. Herein, we evaluated the effect of taVNS on short-latency afferent inhibition (SAI), a TMS paradigm specifically measuring cholinergic neurotransmission. Fifteen healthy subjects participated in this randomized placebo-controlled double-blind study. Each subject underwent two different sessions of 1-hour exposure to taVNS (real and sham) separated by a minimum of 48 h. Real taVNS was administered at left external acoustic meatus, while sham stimulation was performed at left ear lobe. We evaluated SAI bilaterally over the motor cortex before and after exposure to taVNS. No side effects were reported by any of the participants. Statistical analysis did not show any significant effect of taVNS on SAI. Our study demonstrated that cholinergic circuits explored by SAI are different from circuits engaged by taVNS. Since the influence of VNS on cholinergic neurotransmission has been exhaustively demonstrated in animal models, further studies are mandatory to understand the actual impact of VNS on cholinergic circuits in humans. [ABSTRACT FROM AUTHOR]

Previously consolidated memories can become temporarily labile upon reactivation. Reactivation-based memory updating is chiefly studied in young subjects, so we aimed to assess this process across the lifespan. To do this, we developed a behavioural paradigm wherein a reactivated object memory is updated with contextual information; 3-month-old and 6-month-old male C57BL/6 mice displayed object memory updating, but 12-month-old mice did not. We found that M1 muscarinic acetylcholine receptor signaling during reactivation was necessary for object memory updating in the young mice. Next, we targeted this mechanism in an attempt to facilitate object memory updating in aging mice. Remarkably, systemic pharmacological M1 receptor activation reversed the age-related deficit. Quantification of cholinergic system markers within perirhinal cortex revealed subtle cellular changes that may contribute to differential performance across age groups. These findings suggest that natural cholinergic change across the lifespan contributes to inflexible memory in the aging brain. • Memory reactivation can signal an opportunity to update previously stored memory. • Muscarinic receptor activity gates post-reactivation object memory updating in mice. • Healthy and moderately aged mice display an object memory updating impairment. • An M1 muscarinic receptor agonist can reverse age-related memory updating deficits. [ABSTRACT FROM AUTHOR]

Ketamine provides the highest safety profile among sedatives for procedural sedation and analgesia in the pediatric emergency setting. However, it can cause vomiting and recovery agitation. No studies have examined epigenetic factors, such as microRNAs, for predicting the occurrence of these adverse events. Neuronal‐derived extracellular vesicle microRNA profiles were studied to predict the occurrence of ketamine‐induced vomiting and recovery agitation in children. For this aim, a single‐center prospective pharmacoepigenetic study was performed and 50 children who underwent procedural sedation with intravenous ketamine as the only sedative drug were enrolled between October 2019 and November 2022. MiRNA profiling in plasma neural‐derived extracellular vesicles was analyzed through next‐generation sequencing and measured before treatment with ketamine. Twenty‐two patients experienced vomiting or recovery agitation. Among the 16 differentially expressed microRNAs, the upregulated miR‐15a‐5p and miR‐484 targeted genes related to N‐methyl‐D‐aspartate (NMDA) receptor activity, including glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A). Preliminary data confirmed lower GRIN2A levels in patients who developed these events. Downregulated miR‐126‐3p and miR‐24‐3p targeted AMPA receptor‐associated genes. Functional analyses of gene targets revealed the enrichment of glutamatergic and neurotrophins signaling. Recovery agitation was associated with this network. Vomiting was related to dopaminergic and cholinergic systems. Three miRNAs (miR‐18a‐3p, miR‐484, and miR‐548az‐5p) were identified as predictive biomarkers (AUC 0.814; 95% CI: 0.632–0.956) for ketamine‐induced vomiting and recovery agitation. MicroRNA profiles can predict the development of ketamine‐induced vomiting or recovery agitation in children. This study contributes to the understanding of the mechanisms underlying ketamine‐induced adverse events. [ABSTRACT FROM AUTHOR]

Background: Deficits in cholinergic function are assumed to cause cognitive decline. Studies have demonstrated that changes in serum cholinesterase activities are associated with a higher incidence of delirium in critically ill patients. Additionally, basic research indicates that the cholinergic and circadian systems are interconnected, with each system influencing the functionality of the other. This data analysis of a proof-of-concept pilot study investigates whether modification in ICU design, including dynamic light therapy, may influence the circadian oscillation of serum cholinesterase activities. Methods: We enrolled adult critically ill patients who were on mechanical ventilation and had an anticipated ICU stay of at least 48 h. The patients were treated in either modified or standard ICU rooms. The modified rooms received extensive architectural modifications, including a new dynamic lighting system. Serum acetylcholinesterase and butyrylcholinesterase activities were measured every four hours for up to three 24-h assessment periods. Results: We included 64 patients in the data analysis (n = 34 patients in modified rooms, n = 30 in standard rooms). The median values of serum acetylcholinesterase and butyrylcholinesterase activities showed different patterns. Acetylcholinesterase activities differed significantly between the groups during the first assessment period (p = 0.04) and the second assessment period (p = 0.045). The intensity of light, as quantified by the effective circadian irradiance, significantly influenced the activities of acetylcholinesterase and butyrylcholinesterase throughout all assessment periods for patients in both groups (p < 0.001). The analysis showed significant interaction (p < 0.001), indicating that the differences in acetylcholinesterase and butyrylcholinesterase activities between the groups were inconsistent over time but apparent during specific periods of the day. Conclusion: Implementing a comprehensive set of changes to the design of ICU rooms, including a dynamic lighting system, may influence the course of the activity patterns of acetylcholinesterase and butyrylcholinesterase in critically ill patients. Modifications to environmental factors could potentially offer neuroprotective benefits and facilitate the realignment of circadian rhythms within the cholinergic system. Clinical trial registration ClinicalTrials.gov: NCT02143661. Registered May 21, 2014. [ABSTRACT FROM AUTHOR]

ABSTRACT As cholinergic innervation is a major contributor to increased vagal tone and mucus secretion, inhaled long‐acting muscarinic antagonists (LAMA) are a pillar for the treatment of chronic obstructive pulmonary disease and asthma. By blocking the muscarinic receptors expressed in the lung, LAMA improve lung function and reduce exacerbations in asthma patients who remained poorly controlled despite treatment with inhaled corticosteroids and long‐acting β2 agonists. Asthma guidelines recommend LAMA as a third controller to be added on before the initiation of biologicals. In addition to bronchodilation, LAMA also exert anti‐inflammatory and anti‐fibrotic effects by inhibiting muscarinic receptors present in neutrophils, macrophages, fibroblasts and airway smooth muscle cells. Thus, besides bronchodilation, LAMA might provide additional therapeutic effects, thereby supporting an endotype‐driven approach to asthma management. The Position Paper, developed by the Asthma Section of the European Academy of Allergy and Clinical Immunology, discusses the main cholinergic pathways in the lung, reviews the findings of significant clinical trials and real‐life studies on LAMA use in asthma, examines the placement of these drugs in asthma clinical guidelines, and considers the potential for personalised medicine with LAMA in both adult and paediatric asthma patients. [ABSTRACT FROM AUTHOR]

Background: Postural instability and gait disturbances (PIGD) represent a significant cause of disability in Parkinson's disease (PD). Cholinergic system dysfunction has been implicated in falls in PD. The occurrence of falls typically results in fear of falling (FoF) that in turn may lead to poorer balance self-efficacy. Balance self-efficacy refers to one's level of confidence in their ability to balance while completing activities of daily living like getting dressed, bathing, and walking. Lower self-efficacy, or greater FoF during these activities is a function of motor, cognitive, and emotional impairments and may impact quality of life in PD. Unlike known cholinergic reduction, especially in the right lateral geniculate and caudate nuclei, little is known about the role of cholinergic transporters in FoF or mobility self-efficacy in PD. Methods: [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) positron emission tomography (PET) studies were conducted to assess vesicular acetylcholine transporter (VAChT) expression in 126 patients with PD (male (m) = 95, female (f) = 31). Participants had a mean age of 67.3 years (standard deviation (SD) = 7.1) and median Hoehn Yahr stage of 2.5. Patients also completed the Short Falls Efficacy Scale (sFES-I) as a survey measure of concerns about falling. [18F]FEOBV data were processed in Statistical Parametric Mapping (SPM) using a voxel-wise regression model with sFES-I scores as the outcome measure. Results: Reduced [18F]FEOBV binding in tectum, metathalamic (lateral more than medial geniculate nuclei), thalamus proper, bilateral mesiotemporal (hippocampal, parahippocampal, fusiform gyri and fimbriae), and right cerebellar lobule VI significantly associated with higher sFES-I scores (p < 0.05, family-wise error (FWE) correction after Threshold-Free Cluster Enhancement (TFCE)). Conclusions: Unlike the more limited involvement of the brainstem-thalamic complex and caudate nuclei cholinergic topography associated with falls in PD, cholinergic reductions in the extended connectivity between the thalamic complex and the temporal limbic system via the fimbriae associates with FoF. Additional cholinergic changes were seen in the cerebellum. The temporal limbic system plays a role not only in episodic memory but also in spatial navigation, scene and contextual (e.g., emotional) processing. Findings may augur novel therapeutic approaches to treat poor mobility self-efficacy in PD. [ABSTRACT FROM AUTHOR]

Background: Beneficial effects of whole-body vibration (WBV) on brain and musculoskeletal health in mice have been demonstrated, but underlying mechanisms remain relatively unrevealed. WBV improves attention and memory performance in mice, putatively through stimulation of the cholinergic system. Here, we investigated the effects of WBV on the septo-hippocampal cholinergic system. Methods: Young C57BL/6 mice (8 weeks old) were subjected to 10 min WBV/day (mechanical vibration: 30 Hz; ~0.1-µm peak-to-peak displacement), 5X/week for 5 weeks. In Experiment 1, choline acetyltransferase (ChAT)-immunoreactivity in the septum and hippocampus was analyzed either 2 or 24 h after the last WBV session. Pseudo-WBV-treated mice (same handling procedure as WBV, but no vibrations) served as controls. In Experiment 2, the longitudinal profile of ChAT-immunoreactivity was analyzed in the hippocampus after 1, 2, 3, 4, or 5 weeks of WBV. In addition, synaptophysin immunostaining was performed at either 2 and 5 weeks of WBV. Mice housed 1/cage during the entire experiment served as controls. The balance-beam test was used to monitor the functional impact of WBV. In Experiment 3, a Y-maze reference-memory test was performed after 5 weeks of WBV to obtain a functional cognitive outcome measure of WBV. Pseudo-WBV treated mice served as controls. Results: In Experiment 1, ChAT-immunoreactivity was significantly enhanced after the last WBV session of the 5-week period. This was found in the septum, Cornu Ammonis 1 (CA1), CA3, and dentate gyrus, and was dependent on layer and time-point (2 or 24 h). Experiment 2 revealed that, ChAT-immunoreactivity was lower after 2 weeks of WBV, whereas it was significantly higher after 5 weeks (similar to in Experiment 1). Immunostaining for synaptophysin, a marker for synaptic density, was also significantly higher after 5 weeks of WBV, but not significantly lower after 2 weeks, as was ChAT. WBV-treated groups performed significantly better than did controls on the balance beam from week 3 onwards. Experiment 3 showed that WBV-treated mice had better spatial-reference memory performance in the Y-maze test than did pseudo-WBV controls. Conclusions: Our results indicate that WBV stimulates the septo-hippocampal cholinergic system in a gradual and dynamic way that may contribute to improved spatial-memory performance. This finding suggests that WBV, by upregulation of the septo-hippocampal cholinergic system, may be considered a valuable therapeutic strategy to enhance brain functions in aging, neurodegenerative, and other brain diseases. [ABSTRACT FROM AUTHOR]

The study unveils the importance of Spondias mombin leaf extract (S. mombin: 100 mg/kg b.wt.) in mitigating the toxic insult mediated by copper (16 mg/kg) on the cholinergic system via oral gavage. Male mice were weighed and distributed into five groups, six mice per group. Group A represents the basal control group given only distilled water; Group B and C were given 16 mg/kg of copper sulphate and 100 mg/kg of S. mombin methanol leaf extract, respectively, for 31 days; Group D was given 16 mg/kg of copper sulphate for 31 days, followed by treatment with 100 mg/kg of S. mombin methanol leaf extract for 15 days; and Group E was assigned only S. mombin. The copper concentration was evaluated using atomic absorption spectroscopy, while the cognitive abilities were assessed using Morris water maze and elevated plus‐maze. The result showed that S. mombin reversed the disparities in cholinesterase and choline acetyltransferase activities in vivo due to copper neurotoxicity, with a relative (p < 0.05) decrease in brain and blood copper concentration in co‐ and posttreatment groups. Furthermore, S. mombin reported decreased the disparity between pro‐ and antioxidant occurrence caused by copper toxicity by lowering brain lipid peroxidation, raising thiol levels, and increasing the activities of antioxidant enzymes such as glutathione transferase, catalase, and superoxide dismutase. The result showed that the extract had a protective influence on memory deficits (p < 0.05), significantly reduced anxiety levels, and increased the overall number of neurons in the hippocampus subfields. In conclusion, S. mombin ameliorates Cu‐induced neurotoxicity and neurocognitive dysfunctions by virtue of enhancement of cholinergic signalling and antioxidant activities in the brain. [ABSTRACT FROM AUTHOR]

Background: Cognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examine ex vivo electrophysiological evidence for active compensation in Alzheimer's disease (AD) focusing on the cholinergic innervation of layer 6 in prefrontal cortex. Cholinergic pathways are vulnerable to neuropathology in AD and its preclinical models, and their modulation of deep layer prefrontal cortex is essential for attention and executive function. Methods: We functionally interrogated cholinergic modulation of prefrontal layer 6 pyramidal neurons in two preclinical models: a compound transgenic AD mouse model that permits optogenetically-triggered release of endogenous acetylcholine and a transgenic AD rat model that closely recapitulates the human trajectory of AD. We then tested the impact of therapeutic interventions to further amplify the compensated responses and preserve the typical kinetic profile of cholinergic signaling. Results: In two AD models, we found potentially compensatory upregulation of functional cholinergic responses above non-transgenic controls after onset of pathology. To identify the locus of this enhanced cholinergic signal, we dissected key pre- and post-synaptic components with pharmacological strategies. We identified a significant and selective increase in post-synaptic nicotinic receptor signalling on prefrontal cortical neurons. To probe the additional impact of therapeutic intervention on the adapted circuit, we tested cholinergic and nicotinic-selective pro-cognitive treatments. Inhibition of acetylcholinesterase further enhanced endogenous cholinergic responses but greatly distorted their kinetics. Positive allosteric modulation of nicotinic receptors, by contrast, enhanced endogenous cholinergic responses and retained their rapid kinetics. Conclusions: We demonstrate that functional nicotinic upregulation occurs within the prefrontal cortex in two AD models. Promisingly, this nicotinic signal can be further enhanced while preserving its rapid kinetic signature. Taken together, our work suggests that compensatory mechanisms are active within the prefrontal cortex that can be harnessed by nicotinic receptor positive allosteric modulation, highlighting a new direction for cognitive treatment in AD neuropathology. [ABSTRACT FROM AUTHOR]

Aims: The nucleus basalis of Meynert (NBM) is a major source of cholinergic innervation in the central nervous system. We aimed to investigate the characteristics of structural and functional alterations in the NBM and its projections in patients with mild cognitive impairment (MCI) and the effects of computerized cognitive training (CCT). Methods: Forty‐five patients with MCI and 45 cognitively unimpaired controls (CUCs) were recruited. NBM volume, mean diffusivity (MD) of NBM white matter (WM) projections, and functional connectivity (FC) of projections of the NBM were measured with T1‐weighted imaging, diffusion tensor imaging (DTI), and resting‐state functional magnetic resonance imaging (rs‐fMRI). Thirty‐six MCI patients were randomly assigned to receive CCT or control training. The effects of CCT on the neuropsychological measures and MRI properties were analyzed with a linear mixed model (LMM). Results: We detected that compared with the CUCs, the MCI patients had a reduced volume of the NBM and a greater MD of both cholinergic pathways. Increased MD values of both pathways were related to lower scores of global cognition, processing speed and attention in all participants. After CCT intervention, significant group × timepoint effects on score of the Backward Digit Span and the FC between NBM and right putamen were observed in the CCT group compared to the control group. Conclusion: NBM atrophy and WM pathway disruption occurred in MCI patients and were correlated with cognitive impairment. Working memory and the FC between NBM and right putamen could be improved by cognitive training. [ABSTRACT FROM AUTHOR]

Background/Objectives: Antipsychotic medicines are used to treat several psychological disorders and some symptoms caused by dementia and schizophrenia. Haloperidol (Hal) is a typical antipsychotic usually used to treat psychosis; however, its use causes motor or extrapyramidal symptoms (EPS) such as catalepsy. Hal blocks the function of presynaptic D2 receptors on cholinergic interneurons, leading to the release of acetylcholine (ACh), which is hydrolyzed by the enzyme acetylcholinesterase (AChE). Methods: This study was designed to investigate the Hal-inhibitory effects on AChE activity in regions representative of the cholinergic system of mice and potential associations between cataleptic effects generated by Hal using therapeutic doses and their inhibitory effects on AChE. Results: The distribution of the AChE activity in the different regions of the brain followed the order striatum > hippocampus > (prefrontal cortex/hypothalamus/ cerebellum) > brainstem > septo-hippocampal system. In ex vivo assays, Hal inhibited AChE activity obtained from homogenate tissue of the striatum, hippocampus, and septo-hippocampal system in a concentration-dependent manner. The inhibitory concentration of 50% of enzyme activity (IC50) indicated that the septo-hippocampal system required a higher concentration of Hal (IC50 = 202.5 µmol·L−1) to inhibit AChE activity compared to the striatum (IC50 = 162.5 µmol·L−1) and hippocampus (IC50 = 145 µmol·L−1). In in vivo assays, male Swiss mice treated with concentrations of Hal higher than 0.1 mg·kg−1 induced cataleptic effects. Positive correlations with Spearman's correlation were observed only between the lack of cataleptic effect and the decreased AChE activity of the hippocampus in the mice treated with 0.01 mg·kg−1 of Hal but not in the striatum and septo-hippocampal system. Conclusions: Our results suggest that Hal could increase cholinergic effects via AChE inhibition, in addition to its dopamine antagonist effect, as an alternative approach to the treatment of behavioral disturbances associated with dementia. [ABSTRACT FROM AUTHOR]

Objective: The microencapsulation of Celecoxib (CXB) using different polymers aimed to enhance its solubility and permeability profile for potential neuroprotective applications in neurodegenerative diseases like Alzheimer's disease. Methods: The solvent evaporation method was used for microencapsulation of CXB formulation. Characterization and evaluation of microencapsulation was done by FT-IR, DSC, XRD, SEM, and dissolution methods. Neuroprotective effect was evaluated by Scopolamine induced rat model. Results and Discussion: The solvent evaporation method yielded microencapsulated CXB formulations with high drug loading and improved dissolution profiles. Scanning electron microscopy revealed morphological changes, while differential scanning calorimetry and X-ray diffraction confirmed the conversion of CXB to an amorphous state post-encapsulation. Fourier-transform infrared spectroscopy indicated the formation of hydrogen bonds between CXB and polymers. In behavioral studies, microencapsulated CXB demonstrated superior efficacy in mitigating cognitive impairment induced by scopolamine, suggesting its potential as a neuroprotective agent. This effect may be attributed to the activation of cholinergic pathways. Conclusions: Thus, microencapsulation presents a promising strategy to enhance the therapeutic efficacy of CXB for neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

6-hydroxy-L-nicotine (6HLN) is a nicotine (NIC) derivative with proven therapeutic potential in neurodegenerative disorders. Here, the impact of 6HLN on cell growth, migratory behavior, and inflammatory status of three different cancer cell lines (A549, MCF7, and U87) and two normal cell lines (16HBE14o and MCF10A) was investigated. In silico analyses were conducted to evaluate the binding affinity of 6HLN to nicotinic receptors (nAChRs) containing α9 and α5 subunits. The obtained in silico data revealed that 6HLN might act on the cholinergic system. Interestingly, the in vitro data showed the compound has cancer-stimulatory effects in U87 glioblastoma cells and cancer-inhibitory effects in MCF7 breast cancer cells. In A549 lung cancer cells, no changes were detected upon 6HLN administration. More importantly, 6HLN appears not to be deleterious for normal cells, with the viability of 16HBE14o pulmonary cells and MCF10A mammary cells remaining unchanged. [ABSTRACT FROM AUTHOR]

Emotional arousal is caused by the activity of two parallel ascending systems targeting mostly the subcortical limbic regions and the prefrontal cortex. The aversive, negative arousal system is initiated by the activity of the mesolimbic cholinergic system and the hedonic, appetitive, arousal is initiated by the activity of the mesolimbic dopaminergic system. Both ascending projections have a diffused nature and arise from the rostral, tegmental part of the brain reticular activating system. The mesolimbic cholinergic system originates in the laterodorsal tegmental nucleus and the mesolimbic dopaminergic system in the ventral tegmental area. Cholinergic and dopaminergic arousal systems have converging input to the medial prefrontal cortex. The arousal system can modulate cortical EEG with alpha rhythms, which enhance synaptic strength as shown by an increase in long-term potentiation (LTP), whereas delta frequencies are associated with decreased arousal and a decrease in synaptic strength as shown by an increase in long-term depotentiation (LTD). It is postulated that the medial prefrontal cortex is an adaptable node with decision making capability and may control the switch between positive and negative affect and is responsible for modifying or changing emotional state and its expression. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusion Intestinal ischemia‐reperfusion injury (IIRI) is common in a variety of critical diseases and acute stress, and acupuncture is a promising treatment for IIRI. The aim of this study is to explore the mechanism of electroacupuncture (EA) at Zusanli (ST36) in improving IIRI from the perspective of the cholinergic anti‐inflammatory pathway (CAP) and miRNA 124.Seven groups of mice were performed: Control group, I/R group (IIRI model), EA group (I/R + EA), miRNA mimic group (I/R + EA + miRNA 124 mimic), miRNA inhibitor group (I/R + EA + miRNA 124 inhibitor), PNU group (I/R + EA + α7nAChR agonist), and MLA group (I/R + EA+ α7nAChR antagonist). The expression of intestinal macrophages, α7nAChR, miRNA 124, and related molecules, including p‐STAT3 and IL‐6, as well as histological damage (Chiu's score) and mucosal permeability (serum FD4 concentration), were detected.The serum FD4 concentrations in the EA and PNU groups were significantly lower compared to the I/R group (p < 0.05). The expression of intestinal α7nAChR and miRNA 124 in the EA, miRNA mimic, and PNU groups was higher than that in the I/R group (p < 0.05), while levels of p‐STAT3 and IL‐6 were reduced (p < 0.05). Conversely, in the miRNA inhibitor and MLA groups, miRNA 124 levels were significantly lower than in the EA group (p < 0.05), and IL‐6 levels were increased (p < 0.05).EA at Zusanli may induce miRNA124 through the cholinergic pathway on intestinal macrophages, which may be a key neuro‐immune target of EA in the treatment of IIRI. [ABSTRACT FROM AUTHOR]

Background: The nucleus basalis of Meynert (NBM) is known to play a crucial role in the development and pathogenesis of Alzheimer's Disease (AD), particularly the cholinergic system within the NBM. However, the relationship between synaptic loss in the NBM and the clinical profile of AD remains unclear. Methods: In our study, we included 44 Aβ-negative normal controls (CN) and 76 Aβ-positive participants with cognitive impairment (CI). All participants underwent structural and diffusion magnetic resonance imaging (MRI), as well as positron emission tomography (PET) imaging to measure synaptic vesicle glycoprotein 2 A (SV2A) levels (Trial registration: NCT05623124. Registered 21 November 2022). The SV2A standardized uptake value ratios (SUVR) distribution in the NBM of CN participants was used as the reference norm. We investigated the association between NBM synaptic density and clinical performance, traditional AD biomarkers, and white matter tracts that passed the NBM. Results: Participants with cognitive impairment (CI) who had NBM synaptic density below 1.5 standard deviations (SD) or 0.5 SD of the norm exhibited worse cognitive performance compared to cognitively normal (CN) individuals. Crucially, the extent of deviation in synaptic density from the norm was directly proportional to the severity of cognitive impairment and neurodegeneration biomarkers. Furthermore, among patients with cognitive impairment, synaptic loss in the NBM was associated with potential impairment in the density and organization of neurites within the white matter tracts connected to the NBM. Finally, neurite density index in the medial tracts may play a mediating role in the relationship between NBM synaptic density and MMSE scores. Conclusion: The extent that synaptic density in NBM deviated from the norm suggested the extent of worse cognitive performance and severe neurodegeneration. Furthermore, cognitive impairment associated with synaptic loss in the NBM may be mediated by its pathological impact on NBM white matter tracts. [ABSTRACT FROM AUTHOR]

Background: An impaired intestinal barrier with the activation of corticotropin‐releasing factor (CRF), Toll‐like receptor 4 (TLR4), and proinflammatory cytokine signaling, resulting in visceral hypersensitivity, is a crucial aspect of irritable bowel syndrome (IBS). The gut exhibits abundant expression of neurotensin; however, its role in the pathophysiology of IBS remains uncertain. This study aimed to clarify the effects of PD149163, a specific agonist for neurotensin receptor 1 (NTR1), on visceral sensation and gut barrier in rat IBS models. Methods: The visceral pain threshold in response to colonic balloon distention was electrophysiologically determined by monitoring abdominal muscle contractions, while colonic permeability was measured by quantifying absorbed Evans blue in colonic tissue in vivo in adult male Sprague–Dawley rats. We employed the rat IBS models, i.e., lipopolysaccharide (LPS)‐ and CRF‐induced visceral hypersensitivity and colonic hyperpermeability, and explored the effects of PD149163. Key Results: Intraperitoneal PD149163 (160, 240, 320 μg kg−1) prevented LPS (1 mg kg−1, subcutaneously)‐induced visceral hypersensitivity and colonic hyperpermeability dose‐dependently. It also prevented the gastrointestinal changes induced by CRF (50 μg kg−1, intraperitoneally). Peripheral atropine, bicuculline (a GABAA receptor antagonist), sulpiride (a dopamine D2 receptor antagonist), astressin2‐B (a CRF receptor subtype 2 [CRF2] antagonist), and intracisternal SB‐334867 (an orexin 1 receptor antagonist) reversed these effects of PD149163 in the LPS model. Conclusions and Inferences: PD149163 demonstrated an improvement in visceral hypersensitivity and colonic hyperpermeability in rat IBS models through the dopamine D2, GABAA, orexin, CRF2, and cholinergic pathways. Activation of NTR1 may modulate these gastrointestinal changes, helping to alleviate IBS symptoms. [ABSTRACT FROM AUTHOR]

Background: Blackcurrant (Ribes nigrum L.) is a berry rich in anthocyanins, bioactive compounds known for their antioxidant and neuroprotective properties that benefit human health. Aims: This study aimed to investigate the effects of blackcurrant and its association with Donepezil on memory impairment, cholinergic neurotransmission, and antioxidant systems in a mouse model of amnesia induced by chronic administration of Scopolamine. Methods: Adult male Swiss mice were given saline, blackcurrant (50 mg/kg, orally), and/or Donepezil (5 mg/kg, orally) and/or Scopolamine (1 mg/kg, intraperitoneally). Results: Behavioral tests revealed that blackcurrant and/or Donepezil prevented the learning and memory deficits induced by Scopolamine. In the cerebral cortex and hippocampus, blackcurrant and/or Donepezil treatments prevented the increase in acetylcholinesterase and butyrylcholinesterase activities induced by Scopolamine. Scopolamine also disrupted the glutathione redox system and increased levels of reactive species; nevertheless, blackcurrant and/or Donepezil treatments were able to prevent oxidative stress. Furthermore, these treatments prevented the increase in gene expression and protein density of acetylcholinesterase and the decrease in gene expression of the choline acetyltransferase enzyme induced by Scopolamine. Conclusions: Findings suggest that blackcurrant and Donepezil, either alone or in combination, have anti-amnesic effects by modulating cholinergic system enzymes and improving the redox profile. Therefore, blackcurrant could be used as a natural supplement for the prevention and treatment of memory impairment in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The highly hazardous chemical ammonia has been proven to be absorbed by nanoparticles, thereby exerting highly toxic effects on aquatic organisms. As a ubiquitous pollutant in aquatic environments, polystyrene nanomicroplastics (PSNPs) have shown strong adsorption capacity due to their large surface area. Therefore, the potential joint effects of ammonia and PSNPs need to be clarified. In this study, zebrafish embryos were exposed to a water solution with ammonia concentrations (0, 0.1, 1, and 10 mg/L) with or without PSNP (100 μg/L) treatment up to 120 hpf. The results showed that combined exposure increased the accumulation of ammonia and obviously reduced the locomotor speed of zebrafish larvae compared with exposure to ammonia alone. Further studies indicated that PSNPs can aggravate ammonia-induced neurotoxicity by altering the cholinergic system, dopaminergic neurons, and the retinal structure in zebrafish larvae. In addition, our results revealed that ammonia caused significant alterations in the expression of genes related to neurodevelopment and retinal development, and PSNPs exacerbated this adverse effect. In conclusion, PSNPs can aggravate ammonia-induced neurotoxicity in the early stage of zebrafish and their associated health risk to aquatic animals should not be underestimated. The main contribution of this article lies in revealing the synergistic neurotoxicity of ammonia and PSNPs in the early stage of zebrafish. Moreover; it emphasizes that the associated health risks to aquatic animals should not be underestimated. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) affects millions of people and has limited treatment options, thus making it a global health concern. Amyloid β (Aβ), a disrupted cholinergic system with high acetylcholinesterase (AChE), oxidative stress (OS), reduced antioxidants, and neuroinflammation are key factors influencing AD progression. Prior research has shown that AChE can interact with Aβ and increase its accumulation and neurotoxicity, so targeting AChEs and Aβ could be a potential therapeutic approach for AD treatment. It has been known that nonsteroidal anti‐inflammatory drugs (NSAIDs) can inhibit Aβ accumulation. Previously, TKM01, a derivative of 4‐anilinoquinazoline, has demonstrated inhibitory effects against GSK‐3β—a regulator in AD progression. The current research included molecular docking studies of NSAIDs and TKM01 with Aβ and AChEs as targets. TKM01 exhibited a higher binding affinity with Aβ among all tested compounds. Molecular dynamic (MD) simulations confirmed the stability of the protein‐TKM01 complexes. TKM01 also exhibited favorable drug‐likeness properties, and no hepatoxicity was visualized in comparison with other compounds. Further, in vitro assay showed an inhibitory action of TKM01 (50–1200 µg/mL) on AChEs. In the in vivo studies on zebrafish larvae brains, we found that TKM01 (120 and 240 µg/mL) reduced the levels of AChEs and lipid peroxidation (LPO) and increased antioxidant superoxide dismutase (SOD) and catalase (CAT) in AlCl3(80 µM)‐induced AD‐like model. Additionally, TKM01 treatment was found to decrease pro‐inflammatory cytokines TNF‐α, IL‐1β, and IL‐6. The current study demonstrates that TKM01 can be used to treat AD. Nonetheless, experimental validation is needed to reveal the cellular, sub‐cellular, and molecular mechanisms and possible implications at a clinical stage. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second‐fastest growing neurodegenerative disease in the world. The major clinical symptoms rigor, tremor, and bradykinesia derive from the degeneration of the nigrostriatal pathway. However, PD is a multi‐system disease, and neurodegeneration extends beyond the degradation of the dopaminergic pathway. Symptoms such as postural instability, freezing of gait, falls, and cognitive decline are predominantly caused by alterations of transmitter systems outside the classical dopaminergic axis. While levodopa and deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus internus effectively address PD primary motor symptoms, they often fall short in mitigating axial symptoms and cognitive impairment. Along these lines, the cholinergic system is increasingly recognized to play a crucial role in governing locomotion, postural stability, and cognitive function. Thus, there is a growing interest in bolstering the cholinergic tone by DBS of cholinergic targets such as the pedunculopontine nucleus (PPN) and nucleus basalis of Meynert (NBM), aiming to alleviate these debilitating symptoms resistant to traditional treatment strategies targeting the dopaminergic network. This review offers a comprehensive overview of the role of cholinergic dysfunction in PD. We discuss the impact of PPN and NBM DBS on the management of symptoms not readily accessible to established DBS targets and pharmacotherapy in PD and seek to provide guidance on patient selection, surgical approach, and stimulation paradigms. [ABSTRACT FROM AUTHOR]

Active dendritic integrative mechanisms such as regenerative dendritic spikes enrich the information processing abilities of neurons and fundamentally contribute to behaviorally relevant computations. Dendritic Ca2+ spikes are generally thought to produce plateau-like dendritic depolarization and somatic complex spike burst (CSB) firing, which can initiate rapid changes in spatial coding properties of hippocampal pyramidal cells (PCs). However, here we reveal that a morpho-topographically distinguishable subpopulation of rat and mouse hippocampal CA3PCs exhibits compound apical dendritic Ca2+ spikes with unusually short duration that do not support the firing of sustained CSBs. These Ca2+ spikes are mediated by L-type Ca2+ channels and their time course is restricted by A-and M-type K+ channels. Cholinergic activation powerfully converts short Ca2+ spikes to long-duration forms, and facilitates and prolongs CSB firing. We propose that cholinergic neuromodulation controls the ability of a CA3PC subtype to generate sustained plateau potentials, providing a state-dependent dendritic mechanism for memory encoding and retrieval. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Recent research linking choline‐containing lipids to degeneration of basal forebrain cholinergic neurons in neuropathological states illustrates the challenge of balancing lipid integrity with optimal acetylcholine levels, essential for memory preservation. The endocannabinoid system influences learning and memory processes regulated by cholinergic neurotransmission. Therefore, we hypothesised that activation of the endocannabinoid system may confer neuroprotection against cholinergic degeneration.We examined the neuroprotective potential of sub‐chronic treatments with the cannabinoid agonist WIN55,212‐2, using ex vivo organotypic tissue cultures including nucleus basalis magnocellularis and cortex and in vivo rat models of specific cholinergic damage induced by 192IgG‐saporin. Levels of lipids, choline and acetylcholine were measured with histochemical and immunofluorescence assays, along with [35S]GTPγS autoradiography of cannabinoid and muscarinic GPCRs and MALDI‐mass spectrometry imaging analysis. Learning and memory were assessed by the Barnes maze and the novel object recognition test in rats and in the 3xTg‐AD mouse model.Degeneration, induced by 192IgG‐saporin, of baso‐cortical cholinergic pathways resulted in memory deficits and decreased cortical levels of lysophosphatidylcholines (LPC). WIN55,212‐2 restored cortical cholinergic transmission and LPC levels via activation of cannabinoid receptors. This activation altered cortical lipid homeostasis mainly by reducing sphingomyelins in lesioned animals. These modifications were crucial for memory recovery.We hypothesise that WIN55,212‐2 facilitates an alternative choline source by breaking down sphingomyelins, leading to elevated cortical acetylcholine levels and LPCs. These results imply that altering choline‐containing lipids via activation of cannabinoid receptors presents a promising therapeutic approach for dementia linked to cholinergic dysfunction. [ABSTRACT FROM AUTHOR]

Walnut oil (WO), known for abundant polyunsaturated fatty acids and an array of bioactive substances such as tocopherols, phytosterols, squalene, melatonin, and polyphenols, which is endowed with numerous health advantages. The primary objective of this research was to ascertain the impact of WO on cognitive deficits in learning and memory impairment mice caused by scopolamine (SCOP). The Morris water maze and the step-down avoidance test were utilized to assess the memory and learning capabilities. WO notably counteracted the detrimental effects of SCOP on learning and memory in the Morris water maze, as indicated by a reduction in escape latency and swimming distance. Likewise, WO administration led to a notably reduced number of errors in training trial and an increased latency in testing trial when compared to the SCOP group in the step-down avoidance test. Moreover, WO activated the cholinergic system of the brain by upregulating choline acetyltransferase activity and reducing acetylcholinesterase activity. These results suggest that WO has the potential to protect against memory decline in mice, offering a promising strategy for the prevention of memory-related disorders. [ABSTRACT FROM AUTHOR]

Introduction: Tissue injury results in the release of inflammatory mediators, including a cascade of algogenic substances, which contribute to the development of hyperalgesia. During this process, endogenous analgesic substances are peripherally released to counterbalance hyperalgesia. The present study aimed to investigate whether inflammatory mediators TNF-α, IL-1β, CXCL1, norepinephrine (NE), and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the cholinergic system. Methods: Male Swiss mice were subjected to paw withdrawal test. All the substances were injected via the intraplantar route. Results: The main findings of this study were as follows: (1) carrageenan (Cg), TNF-α, CXCL-1, IL1-β, NE, and PGE2 induced hyperalgesia; (2) the acetylcholinesterase enzyme inhibitor, neostigmine, reversed the hyperalgesia observed after Cg, TNF-α, CXCL-1, and IL1-β injection; (3) the non-selective muscarinic receptor antagonist, atropine, and the selective muscarinic type 1 receptor (m1AChr) antagonist, telenzepine, potentiated the hyperalgesia induced by Cg and CXCL-1; (4) mecamylamine, a non-selective nicotinic receptor antagonist, potentiated the hyperalgesia induced by Cg, TNF-α, CXCL-1, and IL1-β; (5) Cg, CXCL-1, and PGE2 increased the expression of the m1AChr and nicotinic receptor subunit α4protein. Conclusion: These results suggest that the cholinergic system may modulate the inflammatory pain induced by Cg, PGE2, TNF-α, CXCL-1, and IL1-β. [ABSTRACT FROM AUTHOR]

Background: Several studies have reported the protective effects of mesenchymal stem cell-derived exosomes (MSC-Exos) in reducing inflammation and decreasing conjunctival goblet cell (CGC) loss in dry eye disease. However, whether MSC-Exos provide anti-inflammatory profiles in macrophages, thus contributing to CGC protection, has remained elusive. Methods: Macrophages were incubated with PKH26‐labeled periodontal ligament mesenchymal stem cell-derived exosomes (PDLSC-Exos) for 12 h, and uptake of PDLSC-Exos by macrophages was observed by a confocal fluorescence microscope. The mRNA expression of TNF-α, IL-10, and Arg1 was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of TNF-α and IL-10 were quantified using western blotting. Then, CGCs were exposed to different macrophage supernatants and qRT-PCR was used to detect the Muc5ac mRNA expression of CGCs in response to or absence of cholinergic stimulation. ELISA was used to determine the Muc5ac secretion of CGCs in response to cholinergic stimulation. Results: The uptake of PDLSC-Exos by M1 macrophages facilitates M2 macrophage polarization with the elevated expressions of IL-10 and Arg1. In macrophage supernatant-treated CGCs systems, PDLSC-Exo-treated M1 macrophage supernatant significantly enhanced the Muc5ac expression of CGCs in response to, or in the absence of, cholinergic stimulation, while the addition of PDLSC-Exos to the control macrophage supernatant did not generate a change in Muc5ac expression. Conversely, the addition of PDLSC-Exos to the diluted control macrophage supernatant induced a significant increase in Muc5ac expression. Conclusion: PDLSC-Exos could protect CGCs against M1 macrophage-mediated inflammation, and the protective effects of PDLSC-Exos are partly attributable to their effects on M1 macrophages. [ABSTRACT FROM AUTHOR]

Introduction: Antipsychotic psychopharmacotherapy is associated with the risk of drug-induced liver injury (DILI). However, understanding specific risk factors remains challenging due to limited data. This study investigates the relationship between receptor binding affinities and occupancies of antipsychotics and their associated hepatotoxic risks. Methods: A disproportionality analysis with calculation of the Reporting Odds Ratio (ROR) and the Information Component (IC) was conducted using data from the FDA Adverse Event Reporting System (FAERS) to identify signals related to the Standardised MedDRA Query "drug-related hepatic disorders", which served as a proxy for drug-induced hepatotoxicity. This was followed by a pharmacoepidemiologic-pharmacodynamic approach to investigate the relationship between the ROR and substance-related receptor binding affinities and occupancy, which was estimated based on in vitro receptor-binding profiles. Results: Significant signals were identified for several antipsychotics, including chlorpromazine, loxapine, olanzapine, and quetiapine, with chlorpromazine and loxapine showing the highest RORs for DILI. Gender-specific analysis revealed a higher frequency of signals in female patients. Statistically significant negative correlations were identified between the ROR for drug-related hepatic disorders and the affinity for serotonin receptor 5-HT1A (r (17) = -0.68, p = 0.0012), while a positive correlation was observed for cholinergic receptors (r (17) = 0.46, p = 0.048). No significant correlations were found related to other receptors or drug properties. Conclusion: Our findings suggest that the serotonin and probably the cholinergic system may play a role in the development of DILI related to antipsychotic medications. The identification of antipsychotics with a higher association with DILI, such as chlorpromazine, underscores the need for careful monitoring in clinical practice. However, our findings need further longitudinal studies to confirm causality. A better understanding of the associations may inform clinical decision-making, particularly in patients with an increased susceptibility to liver damage. [ABSTRACT FROM AUTHOR]

Adolescent intermittent ethanol (AIE) exposure, which models heavy binge ethanol intake in adolescence, leads to a variety of deficits that persist into adulthood—including suppression of the cholinergic neuron phenotype within the basal forebrain. This is accompanied by a reduction in acetylcholine (ACh) tone in the medial prefrontal cortex (mPFC). Voluntary wheel running exercise (VEx) has been shown to rescue AIE-induced suppression of the cholinergic phenotype. Therefore, the goal of the current study is to determine if VEx will also rescue ACh efflux in the mPFC during spontaneous alternation, attention set shifting performance, and epigenetic silencing of the cholinergic phenotype following AIE. Male and female rats were subjected to 16 intragastric gavages of 20% ethanol or tap water on a two-day on/two-day off schedule from postnatal day (PD) 25–54, before being assigned to either VEx or stationary control groups. In Experiment 1, rats were tested on a four-arm spontaneous alternation maze with concurrent in vivo microdialysis for ACh in the mPFC. An operant attention set-shifting task was used to measure changes in cognitive and behavioral flexibility. In Experiment 2, a ChIP analysis of choline acetyltransferase (ChAT) genes was performed on basal forebrain tissue. It was found that VEx increased ACh efflux in the mPFC in both AIE and control male and female rats, as well as rescued the AIE-induced epigenetic methylation changes selectively at the Chat promoter CpG island across sexes. Overall, these data support the restorative effects of exercise on damage to the cholinergic projections to the mPFC and demonstrate the plasticity of cholinergic system for recovery after alcohol induced brain damage. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (AgNPs) are ubiquitous in the aquatic environment and have attracted extensive attention to their toxic effects on aquatic species. However, responses of the nervous system to AgNPs are little known, especially co-existing with the ubiquitous natural organic matter (NOM), which is critical for the ability to act in aquatic species. Here, this study investigated the neurotoxicology of environmentally relevant AgNPs with or without bovine serum albumin (BSA; a classical NOM) to zebrafish (Danio rerio) using visualized transgenic zebrafish. Exposure to AgNPs reduced the locomotor behavior of zebrafish by 28%-45%, including swimming distance and velocity, exhibiting obvious behavioral inhibition. The visualized transgenic zebrafish treated with AgNPs showed developmental retardation in the early development of the heart, central nervous, and motor nerve, as well as the related neurodevelopment genes, which may be responsible for the lowered locomotor behavior. In addition, AgNPs can specifically interfere with the cholinergic system and affect neuronal signaling, ultimately leading to behavioral abnormalities. However, the coexisting BSA alleviated the neurotoxicity of AgNPs in zebrafish, which may partially be attributed to the increased size and electronegativity of AgNPs caused by BSA, thus reducing the direct interaction of AgNPs with cells. The interaction between BSA and the released Ag+ from AgNPs may also be responsible for the alleviation of the neurodevelopment dysfunction in zebrafish. These findings provide valuable insights into the toxicity and risks of AgNPs in natural aquatic environments. [ABSTRACT FROM AUTHOR]

The pivotal roles of acetylcholine (ACh) in physiological processes encompass both the nervous and non‐neuronal cholinergic systems (NNCS). This review delineates the synthesis, release, receptor interactions, and degradation of ACh within the nervous system, and explores the NNCS in depth within skin cells including keratinocytes, endothelial cells, fibroblasts, macrophages, and other immune cells. We highlight the NNCS's essential functions in maintaining epidermal barrier integrity, promoting wound healing, regulating microcirculation, and modulating inflammatory responses. The potential of the NNCS as a therapeutic target for localized ACh regulation in the skin is discussed, though the translation of these findings into clinical practice remains uncertain due to the complexity of cholinergic signalling and the lack of comprehensive human studies. The review progresses to therapeutic modulation strategies of the NNCS, including AChE inhibitors, nicotinic and muscarinic receptor agonists and antagonists, choline uptake enhancers, and botulinum toxin, highlighting their relevance in dermatology. We highlight the impact of the NNCS on prevalent skin diseases such as psoriasis, atopic dermatitis, rosacea, acne, bullous diseases, hyperhidrosis and hypohidrosis, illustrating its significance in disease pathogenesis and therapy. This comprehensive overview aims to enhance understanding of the NNCS's role in skin health and disease, offering a foundation for future research and therapeutic innovation. [ABSTRACT FROM AUTHOR]

Background/Objectives: The Trypanosoma cruzi infection promotes an intense inflammatory process that affects several tissues. The cholinergic system may exert a regulatory immune response and control the inflammatory process. This study aimed to evaluate the comparative effect of free and nanoencapsulated benznidazole in acute T. cruzi infection to assess hematological, biochemical, and oxidative status triggered by the cholinergic system. Methods: For this, fifty female Swiss mice were distributed in eight groups, i.e., uninfected and infected animals under four treatment protocols: untreated (control—CT); vehicle treatment (Eudragit L 100—EL-100); benznidazole treatment (BNZ); and nanoencapsulated benznidazole treatment (NBNZ). After eight treatment days, the animals were euthanized for sample collection. Results: The peak of parasitemia was at day 7 p.i., and the BNZ and NBNZ controlled and reduced the parasite rate but showed no efficacy in terms of total elimination of parasites analyzed by RT-PCR in both infected groups. The infection promotes significant anemia, leukopenia, and thrombocytopenia, which the BNZ improves. There was an increase in AChE activity during infection, leading to a pro-inflammatory response and an increase in M1 and M2 mACh receptors in the BNZ group, showing that the treatment interacted with the cholinergic pathway. In addition, a pro-oxidative response was characterized in the infection and mainly in the infected BNZ and NBNZ groups. The histopathological analysis showed significative splenomegaly and inflammatory infiltrate in the heart, liver, and spleen. Conclusions: The administration of the BNZ or NBNZ reverses hematological, hepatic, and renal alterations through cholinergic signaling and stimulates a pro-inflammatory response during acute T. cruzi infection. [ABSTRACT FROM AUTHOR]

Background: Plants have long been recognized for their potential to influence neurological health, with both neuroprotective and neurotoxic properties. This review explores the dual nature of plant-derived compounds and their impact on the human brain. Discussion: Numerous studies have highlighted the neuroprotective effects of various phytoconstituents, such as those found in Ginkgo biloba, Centella asiatica, Panax ginseng, Withania somnifera, and Curcuma longa. The neuroprotective compounds have demonstrated antioxidant, anti-inflammatory, and cognitive-enhancing properties, making them promising candidates for combating neurodegenerative diseases and improving brain function. Polyphenolic compounds, triterpenic acids, and specific phytocompounds like the ones from EGb 761 extract have shown interactions with key enzymes and receptors in the brain, leading to neuroprotective outcomes. However, this review also acknowledges the neurotoxic potential of certain plants, such as the Veratrum species, which contains steroidal alkaloids that can cause DNA damage and disrupt neurological function, or Atropa belladonna, which interfere with the normal functioning of the cholinergic system in the body, leading to a range of symptoms associated with anticholinergic toxicity. Conslusions: This review also emphasizes the need for further research to elucidate the complex mechanisms underlying the neuroprotective and neurotoxic effects of plant-derived compounds, as well as to identify novel phytoconstituents with therapeutic potential. Understanding the complex relationship between plants and the human brain is crucial for harnessing the benefits of neuroprotective compounds while mitigating the risks associated with neurotoxic substances. This review provides a comprehensive overview of the knowledge on the neurological properties of plants and highlights the importance of continued research in this field for the development of novel therapeutic strategies targeting brain health and neurological disorders. [ABSTRACT FROM AUTHOR]

Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer's disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and benzothiazole, employed as pharmacophores, could act as multitarget drugs. AD is a multifactorial disease in which several pharmacological targets have been identified—some are involved with amyloid beta (Aβ) production, such as beta secretase (BACE1) and beta amyloid aggregation, while others are involved with the cholinergic system as acetylcholinesterase (AChE) and butirylcholinesterase (BChE) and nicotinic and muscarinic receptors, as well as the hyperphosphorylation of microtubule-associated protein (tau). In this review, we describe the in silico and in vitro evaluation of benzazoles on three important targets in AD: AChE, BACE1, and Aβ. Benzothiazoles and benzimidazoles could be the best benzazoles to act as multitarget drugs for AD because they have been widely evaluated as AChE inhibitors, forming π–π interactions with W286, W86, Y72, and F338, as well as in the AChE gorge and catalytic site. In addition, the sulfur atom from benzothiazol interacts with S286 and the aromatic ring from W84, with these compounds having an IC50 value in the μM range. Also, benzimidazoles and benzothiazoles can inhibit Aβ aggregation. However, even though benzazoles have not been widely evaluated on BACE1, benzimidazoles evaluated in vitro showed an IC50 value in the nM range. Therefore, important chemical modifications could be considered to improve multitarget benzazoles' activity, such as substitutions in the aromatic ring with electron withdrawal at position five, or a linker 3 or 4 carbons in length, which would allow for better interaction with targets. [ABSTRACT FROM AUTHOR]

Cognitive impairment (CI) is a type of mental health disorder that mainly affects cognitive abilities, such as learning, memory, perception, and problem-solving. Currently, in clinical practice, the treatment of cognitive impairment mainly focuses on the application of cholinesterase inhibitors and NMDA receptor antagonists; however, there is no specific and effective drug yet. Procatechuic acid (PCA) possesses various functions, including antibacterial, antiasthmatic, and expectorant effects. In recent years, it has received growing attention in the cognitive domain. Therefore, by summarizing the mechanisms of action of procatechuic acid in the treatment of cognitive impairment in this paper, it is found that procatechuic acid has multiple effects, such as regulating the expression of neuroprotective factors, inhibiting cell apoptosis, promoting the autophagy-lysosome pathway, suppressing oxidative stress damage, inhibiting inflammatory responses, improving synaptic plasticity dysfunction, inhibiting Aβ deposition, reducing APP hydrolysis, enhancing the cholinergic system, and inhibiting the excitotoxicity of neuronal cells. The involved signaling pathways include activating Pi3K-akt-mTor and inhibiting JNK, P38 MAPK, P38-ERK-JNK, SIRT1, and NF-κB/p53, etc. This paper aims to present the latest progress in research on procatechuic acid, including aspects such as its chemical properties, sources, pharmacokinetics, mechanisms for treating neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Recent research has indicated that parental use of central nervous system-targeting medications during periconceptional periods may affect offspring across various developmental and behavioral domains. The present study sought to investigate the potential influence of paternal use of donepezil, a specific reversible central acetylcholinesterase inhibitor that activates the cholinergic system to promote cognition, on offspring. Results: In this study, male rats were bred after 21 days of oral donepezil administration at a dose of 4 mg/kg to generate F1 offspring. Both male and female F₁ offspring displayed enhanced performance in learning and short-term memory tests, including novel object recognition, Y maze, and operant learning. Transcriptomic analysis revealed notable alterations in genes associated with the extracellular matrix in the hippocampal tissue of the F1 generation. Integration with genes related to intelligence identified potential core genes that may be involved in the observed behavioral enhancements. Conclusions: These findings indicate that prolonged paternal exposure to donepezil may enhance the learning and memory abilities of offspring, possibly by targeting nonneural, extracellular regions. Further research is required to fully elucidate any potential transgenerational effects. [ABSTRACT FROM AUTHOR]

Attention and reward are functions that are critical for the control of behavior, and massive multi-region neural systems have evolved to support the discrete computations associated with each. Previous research has also identified that attention and reward interact, though our understanding of the neural mechanisms that mediate this interplay is incomplete. Here, we review the basic neuroanatomy of attention, reward, and cholinergic systems. We then examine specific contexts in which attention and reward computations interact. Building on this work, we propose two discrete neural circuits whereby acetylcholine, released from cell groups located in different parts of the brain, mediates the impact of stimulus-reward associations as well as motivation on attentional control. We conclude by examining these circuits as a potential shared loci of dysfunction across diseases states associated with deficits in attention and reward. [ABSTRACT FROM AUTHOR]

Acute organophosphorus compound (OP) poisoning induces symptoms of the cholinergic crises with the occurrence of severe epileptic seizures. Seizures are induced by hyperstimulation of the cholinergic system, but are enhanced by hyperactivation of the glutamatergic system. Overstimulation of muscarinic cholinergic receptors by the elevated acetylcholine causes glutamatergic hyperexcitation and an increased influx of Ca2+ into neurons through a type of ionotropic glutamate receptors, N‐methyl‐d‐aspartate (NMDA) receptors (NMDAR). These excitotoxic signaling processes generate reactive oxygen species, oxidative stress, and activation of the neuroinflammatory response, which can lead to recurrent epileptic seizures, neuronal cell death, and long‐term neurological damage. In this review, we illustrate the NMDAR structure, complexity of subunit composition, and the various receptor properties that change accordingly. Although NMDARs are in normal physiological conditions important for controlling synaptic plasticity and mediating learning and memory functions, we elaborate the detrimental role NMDARs play in neurotoxicity of OPs and focus on the central role NMDAR inhibition plays in suppressing neurotoxicity and modulating the inflammatory response. The limited efficacy of current medical therapies for OP poisoning concerning the development of pharmacoresistance and mitigating proinflammatory response highlights the importance of NMDAR inhibitors in preventing neurotoxic processes and points to new avenues for exploring therapeutics for OP poisoning. [ABSTRACT FROM AUTHOR]

Agastache rugosa, a traditional Asian herbal medicine, is primarily used for digestive problems; yet, its cognitive benefits remain unexplored. This study evaluated the anti-amnesic effects of A. rugosa extract (ARE) on scopolamine (SCO)-induced memory impairment in mice. Mice received 100 or 200 mg/kg ARE orally for 5 days, followed by SCO injection. The ARE demonstrated significant antioxidant (DPPH IC50: 75.3 µg/mL) and anti-inflammatory effects (NO reduction). Furthermore, the ARE significantly improved memory performance in the passive avoidance test (escape latency: 157.2 s vs. 536.9 s), the novel object recognition test (novel object preference: 47.6% vs. 66.3%) and the Morris water maze (time spent in the target quadrant: 30.0% vs. 45.1%). The ARE reduced hippocampal acetylcholinesterase activity (1.8-fold vs. 1.1-fold) while increasing choline acetyltransferase (0.4-fold vs. 1.0-fold) and muscarinic acetylcholine receptor subtype I (0.3-fold vs. 1.6-fold) expression. The ARE improved hippocampal neurogenesis via doublecortin- (0.4-fold vs. 1.1-fold) and KI-67-positive (6.3 vs. 12.0) cells. Therefore, the ARE exerts protective effects against cognitive decline through cholinergic system modulation and antioxidant activity, supporting its potential use as a cognitive enhancer. [ABSTRACT FROM AUTHOR]

Olfactory oscillations may enhance cognitive processing through coupling with beta (β, 15–30 Hz) and gamma (γ, 30–160 Hz) activity in the hippocampus (HPC). We hypothesize that coupling between olfactory bulb (OB) and HPC oscillations is increased by cholinergic activation in control rats and is reduced in kainic‐acid‐treated epileptic rats, a model of temporal lobe epilepsy. OB γ2 (63–100 Hz) power was higher during walking and immobility‐awake (IMM) compared to sleep, while γ1 (30–57 Hz) power was higher during grooming than other behavioral states. Muscarinic cholinergic agonist pilocarpine (25 mg/kg ip) with peripheral muscarinic blockade increased OB power and OB‐HPC coherence at β and γ1 frequency bands. A similar effect was found after physostigmine (0.5 mg/kg ip) but not scopolamine (10 mg/kg ip). Pilocarpine increased bicoherence and cross‐frequency coherence (CFC) between OB slow waves (SW, 1–5 Hz) and hippocampal β, γ1 and γ2 waves, with stronger coherence at CA1 alveus and CA3c than CA1 stratum radiatum. Bicoherence further revealed a nonlinear interaction of β waves in OB with β waves at the CA1‐alveus. Beta and γ1 waves in OB or HPC were segregated at one phase of the OB‐SW, opposite to the phase of γ2 and γ3 (100–160 Hz) waves, suggesting independent temporal processing of β/γ1 versus γ2/γ3 waves. At CA1 radiatum, kainic‐acid‐treated epileptic rats compared to control rats showed decreased theta power, theta‐β and theta‐γ2 CFC during baseline walking, decreased CFC of HPC SW with γ2 and γ3 waves during baseline IMM, and decreased coupling of OB SW with β and γ2 waves at CA1 alveus after pilocarpine. It is concluded that β and γ waves in the OB and HPC are modulated by a slow respiratory rhythm, in a cholinergic and behavior‐dependent manner, and OB‐HPC functional connectivity at β and γ frequencies may enhance cognitive functions. [ABSTRACT FROM AUTHOR]

Despite longstanding interest in the central cholinergic system in schizophrenia (SCZ), cholinergic imaging studies with patients have been limited to receptors. Here, we conducted a proof-of-concept positron emission tomography study using [18F]-VAT, a new radiotracer that targets the vesicular acetylcholine transporter as a proxy measure of acetylcholine transmission capacity, in patients with SCZ and explored relationships of vesicular acetylcholine transporter with clinical symptoms and cognition. A total of 18 adult patients with SCZ or schizoaffective disorder (the SCZ group) and 14 healthy control participants underwent a positron emission tomography scan with [18F]-VAT. Distribution volume (V T) for [18F]-VAT was derived for each region of interest, and group differences in V T were assessed with 2-sample t tests. Functional significance was explored through correlations between V T and scores on the Positive and Negative Syndrome Scale and a computerized neurocognitive battery (PennCNB). No group differences in [18F]-VAT V T were observed. However, within the SCZ group, psychosis symptom severity was positively associated with V T in multiple regions of interest, with the strongest effects in the hippocampus, thalamus, midbrain, cerebellum, and cortex. In addition, in the SCZ group, working memory performance was negatively associated with V T in the substantia innominata and several cortical regions of interest including the dorsolateral prefrontal cortex. In this initial study, the severity of 2 important features of SCZ—psychosis and working memory deficit—was strongly associated with [18F]-VAT V T in several cortical and subcortical regions. These correlations provide preliminary evidence of cholinergic activity involvement in SCZ and, if replicated in larger samples, could lead to a more complete mechanistic understanding of psychosis and cognitive deficits in SCZ and the development of therapeutic targets. [ABSTRACT FROM AUTHOR]

Antifoulants such as copper pyrithione (CuPT) and zinc pyrithione (ZnPT) are widespread and hazardous pollutants in aquatic environments. The presence of microplastics (MPs) introduces significant uncertainty regarding the toxicity of CuPT and ZnPT, as their effects can be influenced by MPs. There is a limited understanding of the toxic potential of CuPT and ZnPT when they coexist with MPs. Here, the marine mysid Neomysis awatchensis was treated using no observed effect concentration (NOEC) values of CuPT and ZnPT premixed with MPs (1 µm; 1–100 particles mL−1). The presence of MPs increased the toxicity of the antifoulants in juvenile and adult mysids over 96 h. The additive effect of the MPs varied by chemical; feeding was only reduced by CuPT with MPs, whereas no fluctuation in feeding was observed in response to ZnPT with MPs. Co-exposure to antifoulants and MPs increased malonaldehyde levels, but the response of antioxidant components varied by chemical. In mysids co-exposed to CuPT and MPs, the activity levels of catalase and superoxide dismutase were decreased, whereas their enzymatic activity levels were elevated by co-exposure to ZnPT and MPs. Similarly, depletion of glutathione (GSH) was observed in mysids co-exposed to CuPT and MPs, with significant reductions in GSH reductase (GR) and peroxidase (GPx). However, the GSH level was increased by co-exposure to ZnPT and MPs, with elevations in GR and GPx activity levels. Significant inhibition of acetylcholinesterase activity was only observed in response to CuPT and MPs. These results suggest that MPs can increase toxicity via additive and/or synergistic effects through oxidative imbalance, but these effects of MPs can vary with different chemicals. [ABSTRACT FROM AUTHOR]

Introduction: Women are at a higher risk of developing Alzheimer's disease (AD), and the decline in estrogens post-menopause is thought of as a factor increasing this risk. Estradiol (E2) is important in supporting cholinergic neuronal integrity, and cholinergic functioning may be negatively impacted following the loss of E2 post-menopause. The use of exogenous E2 has been observed to enhance cholinergically mediated cognitive performance in healthy post-menopausal women, which indicates a potentially protective mechanism. However, E2 is often co-administered with progestin or progesterone to prevent endometrial proliferation. Progesterone/progestins have previously been shown to have a detrimental effect on E2-mediated biological and cognitive effects mediated by cholinergic systems in preclinical models, therefore the present study aimed to assess whether progesterone would modify the effect of E2 to influence cognition during cholinergic blockade. Methods: Twenty participants completed 3-months of oral E2 treatment with micronized progesterone (mPRO) or with placebo (PLC) in a repeated measures within-subjects crossover design, in which they also completed five anticholinergic challenge days per hormone treatment condition. During the challenge participants were administered low or high doses of the nicotinic cholinergic antagonist mecamylamine, the muscarinic cholinergic antagonist scopolamine, or placebo. Following drug administration participants performed cognitive tests sensitive to cholinergic tone, assessing attention, episodic memory, and working memory. Results: Significant decrements were found on some tasks when participants were taking E2+mPRO compared to E2 alone. Specifically, under more challenging task conditions and larger anticholinergic doses, participants showed poorer performance on the Critical Flicker Fusion task and the Stroop test and responded more conservatively on the N-back working memory task. Other tasks showed no differences between treatments under cholinergic blockade. Discussion: The findings show that mPRO when taken in concert with E2, was detrimental to effortful cognitive performance, in the presence of cholinergic blockade. These results are important for assessing the impact of combined postmenopausal hormone treatment on cognitive performance that is dependent on cholinergic functioning after menopause. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease and threatens the health of the aged population worldwide. In the present study, we investigated cognitive improvement by aloe emodin in aluminum‐induced AD rats. We orally administered aluminum chloride (150 mg/kg) to Sprague–Dawley rats for 8 weeks to induce AD. In the 5th to the 8th week, the rats were injected intraperitoneally with AE (5, 10, and 15 mg/kg). Behavioral, histopathological, and biochemical assessments were performed. The results showed that AE alleviated cognitive impairment in aluminum‐induced AD rats and inhibited aluminum‐induced hippocampal neuronal damage. Furthermore, aloe emodin relieved the aluminum burden in the brain of aluminum‐induced AD rats, attenuated the aluminum‐induced increase in Aβ42 level and acetylcholinesterase activity, and reduced the levels of tumor necrosis factor‐α, interleukin‐6, interleukin‐1α, and interleukin‐1β. These effects suggest that the mechanism by which AE alleviates AD‐related cognitive impairment is by removal of excess aluminum, decreasing Aβ42 deposition, regulating the cholinergic system, and reducing neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: The cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer's disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood. Methods: We enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson's dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores. Results: A total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [βstd] = -0.25, P = 0.01), female (βstd = 0.20, P = 0.04), and diabetes mellitus (βstd = -0.22, P < 0.01) showed a significant association with the BF volume. Sensitivity analyses showed a negative correlation between CHIPS score and normalized BF volume, regardless of WMH severity. Conclusions: We identified a significant correlation between strategic WMH burden in the cholinergic pathway and BF atrophy independently of amyloid positivity and WMH severity. These results suggest a mechanism of cholinergic neuronal loss through the dying-back phenomenon and provide a rationale that strategic WMH assessment may help identify target groups that may benefit from acetylcholinesterase inhibitor treatment. [ABSTRACT FROM AUTHOR]

Cholinesterase (ChE) inhibitors are crucial therapeutic agents for the symptomatic treatment of certain chronic neurodegenerative diseases linked to functional disorders of the cholinergic system. Significant research efforts have been made to develop novel derivatives of classical ChE inhibitors and ChE inhibitors with novel scaffolds. Over the past decade, ruthenium complexes have emerged as promising novel therapeutic alternatives for the treatment of neurodegenerative diseases. Our research group has investigated a number of newly synthesized organoruthenium(II) complexes for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Three complexes (C1a, C1-C, and C1) inhibit ChE in a pharmacologically relevant range. C1a reversibly inhibits AChE and BChE without undesirable peripheral effects, making it a promising candidate for the treatment of Alzheimer's disease. C1-Cl complex reversibly and competitively inhibits ChEs, particularly AChE. It inhibits nerve-evoked skeletal muscle twitch and tetanic contraction in a concentration-dependent manner with no effect on directly elicited twitch and tetanic contraction and is promising for further preclinical studies as a competitive neuromuscular blocking agent. C1 is a selective, competitive, and reversible inhibitor of BChE that inhibits horse serum BChE (hsBChE) without significant effect on the peripheral neuromuscular system and is a highly species-specific inhibitor of hsBChE that could serve as a species-specific drug target. This research contributes to the expanding knowledge of ChE inhibitors based on ruthenium complexes and highlights their potential as promising therapeutic candidates for chronic neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

TRPM4 is a calcium activated non-selective cation channel, impermeable to Ca2+, in neurons it has been implicated in the regulation of the excitability and in the persistent firing. Cholinergic stimulation is also implicated in changes in excitability that leads neurons to an increased firing frequency, however it is not clear whether TRPM4 is involved in the cholinergic-induced increase in firing frequency. Here using a combination of patch clamp electrophysiology, Ca2+ imaging, immunofluorescence, fluorescence recovery after photobleaching (FRAP) and pharmacological approach, we demonstrate that carbachol (Cch) increases firing frequency, intracellular Ca2+ and that TRPM4 inhibition using 9-Ph and CBA reduces firing frequency and decreases the peak in intracellular Ca2+ induced by Cch in cortical pyramidal neurons in culture. Moreover, we determined that cholinergic stimulation reduces TRPM4 recycling and stabilizes TRPM4 in the plasma membrane. Together our results indicate that cholinergic stimulation increases firing in a TRPM4 dependent manner, and also increases the TRPM4 stability in the membrane, suggesting that TRPM4 is locked in microdomains in the membrane, possibly signaling or cytoskeleton proteins complexes. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes that belong to the neuromuscular cholinergic system, their main function is to hydrolyze the neurotransmitter acetylcholine (ACh), through their hydrolysis these enzymes regulate the neuronal and neuromuscular cholinergic system. They have recently attracted considerable attention due to the discovery of new enzymatic and nonenzymatic functions. These discoveries have aroused the interest of numerous scientists, consolidating the relevance of this group of enzymes. Recent investigations have revealed a positive correlation between several risk factors for metabolic syndrome (MetS) and the expression of cholinesterases (ChE's), which underscore the impact of high ChE's activity on the pro‐inflammatory state associated with MetS. In addition, the excessive hydrolysis of ACh and other choline esters (succinylcholine, propionylcholine, butyrylcholine, etc.) by both ChE's results in the overproduction of fatty acid precursor metabolites, which facilitate the synthesis of very low‐density lipoproteins and triacylglycerols. Participation in these processes may represent the link between ChE's and metabolic disorders. However, further scientific research is required to fully elucidate the involvement of ChE's in metabolic diseases. This review aims to collect recent research studies that contribute to understanding the association between the cholinergic system and metabolic diseases. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid 1 (TRPV1) is a calcium‐permeable ion channel that is gated by the pungent constituent of red chili pepper, capsaicin, and by related chemicals from the group of vanilloids, in addition to noxious heat. It is expressed mostly in sensory neurons to act as a detector of painful stimuli produced by pungent chemicals and high temperatures. Although TRPV1 is also found outside the sensory nervous system, its expression and function in the bladder detrusor smooth muscle (DSM) remain controversial. Here, by using Ca2+ imaging and patch clamp on isolated rat DSM cells, in addition to tensiometry on multicellular DSM strips, we show that TRPV1 is expressed functionally in only a fraction of DSM cells, in which it acts as an endoplasmic reticulum Ca2+‐release channel responsible for the capsaicin‐activated [Ca2+]i rise. Carbachol‐stimulated contractions of multicellular DSM strips contain a TRPV1‐dependent component, which is negligible in the circular DSM but reaches ≤50% in the longitudinal DSM. Activation of TRPV1 in rat DSM during muscarinic cholinergic stimulation is ensured by phospholipase A2‐catalysed derivation of arachidonic acid and its conversion by lipoxygenases to eicosanoids, which act as endogenous TRPV1 agonists. Immunofluorescence detection of TRPV1 protein in bladder sections and isolated DSM cells confirmed both its preferential expression in the longitudinal DSM sublayer and its targeting to the endoplasmic reticulum. We conclude that TRPV1 is an essential contributor to the cholinergic contraction of bladder longitudinal DSM, which might be important for producing spatial and/or temporal anisotropy of bladder wall deformation in different regions during parasympathetic stimulation. Key points: The transient receptor potential vanilloid 1 (TRPV1) heat/capsaicin receptor/channel is localized in the endoplasmic reticulum membrane of detrusor smooth muscle (DSM) cells of the rat bladder, operating as a calcium‐release channel.Isolated DSM cells are separated into two nearly equal groups, within which the cells either show or do not show TRPV1‐dependent [Ca2+]i rise.Carbachol‐stimulated, muscarinic ACh receptor‐mediated contractions of multicellular DSM strips contain a TRPV1‐dependent component.This component is negligible in the circular DSM but reaches ≤50% in longitudinal DSM.Activation of TRPV1 in rat DSM during cholinergic stimulation involves phospholipase A2‐catalysed derivation of arachidonic acid and its conversion by lipoxygenases to eicosanoids, which act as endogenous TRPV1 agonists. [ABSTRACT FROM AUTHOR]

Cholinergic signaling in the retina is mediated by acetylcholine (ACh) released from starburst amacrine cells (SACs), which are key neurons for motion detection. SACs comprise ON and OFF subtypes, which morphologically show mirror symmetry to each other. Although many physiological studies on SACs have targeted ON cells only, the synaptic computation of ON and OFF SACs is assumed to be similar. Recent studies demonstrated that gene expression patterns and receptor types differed between ON and OFF SACs, suggesting differences in their functions. Here, we compared cholinergic signaling pathways between ON and OFF SACs in the mouse retina using the patch clamp technique. The application of ACh increased GABAergic feedback, observed as postsynaptic currents to SACs, in both ON and OFF SACs; however, the mode of GABAergic feedback differed. Nicotinic receptors mediated GABAergic feedback in both ON and OFF SACs, while muscarinic receptors mediated GABAergic feedback in ON SACs only in adults. Neither tetrodotoxin, which blocked action potentials, nor LY354740, which blocked neurotransmitter release from SACs, eliminated ACh-induced GABAergic feedback in SACs. These results suggest that ACh-induced GABAergic feedback in ON and OFF SACs is regulated by different feedback mechanisms in adults and mediated by non-spiking amacrine cells other than SACs. [ABSTRACT FROM AUTHOR]