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CNS Neuroscience & Therapeutics Jun 2024Alzheimer's disease (AD) is a devastating dementia characterized by extracellular amyloid-β (Aβ) protein aggregates and intracellular tau protein deposition....
AIMS
Alzheimer's disease (AD) is a devastating dementia characterized by extracellular amyloid-β (Aβ) protein aggregates and intracellular tau protein deposition. Clinically available drugs mainly target acetylcholinesterase (AChE) and indirectly sustain cholinergic neuronal tonus. Butyrylcholinesterase (BChE) also controls acetylcholine (ACh) turnover and is involved in the formation of Aß aggregates and senile plaques. UW-MD-95 is a novel carbamate-based compound acting as a potent pseudo-irreversible BChE inhibitor, with high selectivity versus AChE, and showing promising protective potentials in AD.
METHODS
We characterized the neuroprotective activity of UW-MD-95 in mice treated intracerebroventricularly with oligomerized Aβ peptide using behavioral, biochemical, and immunohistochemical approaches.
RESULTS
When injected acutely 30 min before the behavioral tests (spontaneous alternation in the Y-maze, object recognition, or passive avoidance), UW-MD-95 (0.3-3 mg/kg) showed anti-amnesic effects in Aβ-treated mice. When injected once a day over 7 days, it prevented Aβ-induced memory deficits. This effect was lost in BChE knockout mice. Moreover, the compound prevented Aβ-induced oxidative stress (assessed by lipid peroxidation or cytochrome c release), neuroinflammation (IL-6 and TNFα levels or GFAP and IBA1 immunoreactivity) in the hippocampus and cortex, and apoptosis (Bax level). Moreover, UW-MD-95 significantly reduced the increase in soluble Aβ level in the hippocampus induced by Aβ.
CONCLUSION
UW-MD-95 appeared as a potent neuroprotective compound in the Aβ model of AD, with potentially an impact on Aβ accumulation that could suggest a novel mechanism of neuroprotection.
Topics: Animals; Neuroprotective Agents; Alzheimer Disease; Amyloid beta-Peptides; Mice; Peptide Fragments; Disease Models, Animal; Male; Cholinesterase Inhibitors; Butyrylcholinesterase; Mice, Inbred C57BL; Maze Learning; Dose-Response Relationship, Drug; Oxidative Stress
PubMed: 38887858
DOI: 10.1111/cns.14814 -
Clinical Case Reports Jun 2024The case highlights an unusual presentation where sleep issues preceded psychotic symptoms, implying link between disrupted sleep and psychosis onset. Earlier symptoms...
KEY CLINICAL MESSAGE
The case highlights an unusual presentation where sleep issues preceded psychotic symptoms, implying link between disrupted sleep and psychosis onset. Earlier symptoms were viewed as depression but may have signaled psychosis exacerbated by insomnia.
ABSTRACT
Sleep disorders, prevalent yet frequently overlooked in individuals with psychotic disorders, have significant associations with the onset and severity of psychosis. Here we describe the case of a patient who first presented with insomnia, but whose condition improved with the use of risperidone and was diagnosed with first-episode psychosis. Multiple studies emphasize the critical relationship between sleep disturbances and psychosis, particularly in the lead-up to first-episode psychosis. Structural abnormalities in the brain, notably the thalamus, combined with neurotransmitter imbalances involving dopamine and acetylcholine, seem pivotal in this interrelation. The connection between dopamine, sleep disturbances, and psychosis, specifically the role of D2 dopamine receptors, highlights a potential pathway bridging sleep irregularities with psychosis. The study underscores the need for further research to delineate the relationship between sleep disturbances and psychosis and to assess the efficacy of various therapeutic interventions targeting both conditions.
PubMed: 38887308
DOI: 10.1002/ccr3.9108 -
Scientific Reports Jun 2024Myasthenia gravis (MG) is an autoimmune disease characterized by muscle fatigability due to acetylcholine receptor (AChR) autoantibodies. To better characterize juvenile... (Comparative Study)
Comparative Study
Myasthenia gravis (MG) is an autoimmune disease characterized by muscle fatigability due to acetylcholine receptor (AChR) autoantibodies. To better characterize juvenile MG (JMG), we analyzed 85 pre- and 132 post-pubescent JMG (with a cutoff age of 13) compared to 721 adult MG patients under 40 years old using a French database. Clinical data, anti-AChR antibody titers, thymectomy, and thymic histology were analyzed. The proportion of females was higher in each subgroup. No significant difference in the anti-AChR titers was observed. Interestingly, the proportion of AChR MG patients was notably lower among adult MG patients aged between 30 and 40 years, at 69.7%, compared to over 82.4% in the other subgroups. Thymic histological data were examined in patients who underwent thymectomy during the year of MG onset. Notably, in pre-JMG, the percentage of thymectomized patients was significantly lower (32.9% compared to more than 42.5% in other subgroups), and the delay to thymectomy was twice as long. We found a positive correlation between anti-AChR antibodies and germinal center grade across patient categories. Additionally, only females, particularly post-JMG patients, exhibited the highest rates of lymphofollicular hyperplasia (95% of cases) and germinal center grade. These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty.
Topics: Humans; Myasthenia Gravis; Female; Male; Adult; France; Thymus Gland; Thymectomy; Adolescent; Autoantibodies; Receptors, Cholinergic; Young Adult; Child; Cohort Studies; Germinal Center
PubMed: 38886398
DOI: 10.1038/s41598-024-63162-0 -
Trends in Psychiatry and Psychotherapy Jun 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has been linked to the dysregulation in the cholinergic and endocannabinoid (EC) system. This study...
INTRODUCTION
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has been linked to the dysregulation in the cholinergic and endocannabinoid (EC) system. This study systematically reviews the present literature on treatment strategies aimed at enhancing the activity of both systems in ASD models.
METHOD
We performed a systematic evaluation of literatures that investigated the effects of different therapeutic interventions on the components of the cholinergic and EC systems in ASD models, following the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Four databases were searched: Google Scholar, Web of science, EMBASE and MEDLINE/PubMed, between August 2012 and February 2023. The selected research papers' references were also examined. Twelve papers (five for cholinergic system, six for EC system and one for the two systems) were reviewed in this study of prior relevant treatment strategies that impact both systems. There were 77 studies cited in total.
RESULTS
The majority of research revealed that different therapeutic interventions down-regulated cannabinoid 1 (CB1) receptors, and the systems hydrolyzing enzymes and up-regulated EC, Alpha7 nicotinic acetylcholine receptor (α7 nAChR), and acetylcholine signaling molecules. The regulation of the components of the cholinergic and EC systems by the therapeutics generally enhanced behaviors in ASD models.
CONCLUSION
It is possible that there are therapeutic interventions assessed in one of the systems that may be effective in treating the core ASD-associated phenotype. The benefits of the reviewed therapeutic interventions in this study need to be further investigated in randomized, blind, placebo-controlled clinical trials.
PubMed: 38885129
DOI: 10.47626/2237-6089-2024-0791 -
Frontiers in Pharmacology 2024Myasthenia gravis (MG) is an antibody-mediated autoimmune disease with a prevalence of 150-250 cases per million individuals. Autoantibodies include long-lived... (Review)
Review
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease with a prevalence of 150-250 cases per million individuals. Autoantibodies include long-lived antibodies against the acetylcholine receptor (AChR), mainly of the IgG1 subclass, and IgG4, produced almost exclusively by short-lived plasmablasts, which are prevalent in muscle-specific tyrosine kinase (MuSK) myasthenia gravis. Numerous investigations have demonstrated that MG patients receiving conventional medication today still do not possess satisfactory symptom control, indicating a substantial disease burden. Subsequently, based on the type of the autoantibody and the pathogenesis, we synthesized the published material to date and reached a conclusion regarding the literature related to personalized targeted therapy for MG. Novel agents for AChR MG have shown their efficacy in clinical research, such as complement inhibitors, FcRn receptor antagonists, and B-cell activating factor (BAFF) inhibitors. Rituximab, a representative drug of anti-CD20 therapy, has demonstrated benefits in treatment of MuSK MG patients. Due to the existence of low-affinity antibodies or unidentified antibodies that are inaccessible by existing methods, the treatment for seronegative MG remains complicated; thus, special testing and therapy considerations are necessary. It may be advantageous to initiate the application of novel biologicals at an early stage of the disease. Currently, therapies can also be combined and individualized according to different types of antibodies. With such a wide range of drugs, how to tailor treatment strategies to patients with various conditions and find the most suitable solution for each MG profile are our necessary and urgent aims.
PubMed: 38881870
DOI: 10.3389/fphar.2024.1370411 -
Mediastinum (Hong Kong, China) 2024Thymectomy with median sternotomy is the gold standard for thymoma and myasthenia gravis, although minimally invasive procedures such as robot-assisted surgery have... (Review)
Review
BACKGROUND AND OBJECTIVE
Thymectomy with median sternotomy is the gold standard for thymoma and myasthenia gravis, although minimally invasive procedures such as robot-assisted surgery have recently become more common. However, the superiority of these approaches has not been established, and they are infrequently recommended for localized lesions. The International Thymic Malignancies Interest Group warned that despite the perceived reduction in length of hospital stay and pain, the benefits of these approaches compared to the open approach have not been fully substantiated and that prospective collaborative data collection is critical in defining the value of these techniques. Whether thymectomy is necessary for stage I thymomas in the absence of myasthenia gravis or anti-acetylcholine receptor antibodies is also unclear. This study reviews and discusses the literature on this subject.
METHODS
A narrative review was conducted using PubMed and Scopus databases. Original research articles comparing robotic to video-assisted thoracic surgery or to open thymectomy for thymomas were included. A comparison of partial resection and total thymectomy (thymothymectomy) for thymomas was also conducted.
KEY CONTENT AND FINDINGS
Perioperative outcomes such as blood loss, operative duration, complications, and length of hospital stay were better for robot-assisted resection of early-stage thymomas than for open thymoma surgery. It would be premature to consider partial resection as an appropriate treatment option for thymomas.
CONCLUSIONS
Robotic thymothymectomy is safe with effective and promising long-term results and oncological and surgical outcomes in patients with thymoma. Robotic thymectomy can become the standard procedure in patients with early-stage thymomas.
PubMed: 38881811
DOI: 10.21037/med-23-37 -
Neurophotonics Jul 2024Widefield microscopy of the entire dorsal part of mouse cerebral cortex enables large-scale ("mesoscopic") imaging of different aspects of neuronal activity with...
SIGNIFICANCE
Widefield microscopy of the entire dorsal part of mouse cerebral cortex enables large-scale ("mesoscopic") imaging of different aspects of neuronal activity with spectrally compatible fluorescent indicators as well as hemodynamics via oxy- and deoxyhemoglobin absorption. Versatile and cost-effective imaging systems are needed for large-scale, color-multiplexed imaging of multiple fluorescent and intrinsic contrasts.
AIM
We aim to develop a system for mesoscopic imaging of two fluorescent and two reflectance channels.
APPROACH
Excitation of red and green fluorescence is achieved through epi-illumination. Hemoglobin absorption imaging is achieved using 525- and 625-nm light-emitting diodes positioned around the objective lens. An aluminum hemisphere placed between objective and cranial window provides diffuse illumination of the brain. Signals are recorded sequentially by a single sCMOS detector.
RESULTS
We demonstrate the performance of our imaging system by recording large-scale spontaneous and stimulus-evoked neuronal, cholinergic, and hemodynamic activity in awake, head-fixed mice with a curved "crystal skull" window expressing the red calcium indicator jRGECO1a and the green acetylcholine sensor . Shielding of illumination light through the aluminum hemisphere enables concurrent recording of pupil diameter changes.
CONCLUSIONS
Our widefield microscope design with a single camera can be used to acquire multiple aspects of brain physiology and is compatible with behavioral readouts of pupil diameter.
PubMed: 38881627
DOI: 10.1117/1.NPh.11.3.034310 -
Therapeutic Advances in Drug Safety 2024Numerous studies report that anticholinergic burden (ACB) has been linked with several health consequences, including increased hospital admissions, prolonged...
BACKGROUND
Numerous studies report that anticholinergic burden (ACB) has been linked with several health consequences, including increased hospital admissions, prolonged hospitalization, and physical and cognitive impairment. However, low- and middle-income settings, as well as younger individuals, are underrepresented.
OBJECTIVES
To assess the prevalence and determinants of ACB, and to assess the impact of ACB on in-hospital mortality among adult in-patients at University of Gondar Comprehensive Specialized Hospital (UOGCSH).
DESIGN
A cross-sectional study was conducted from June to August 2022 at UOGCSH among adult in-patients.
METHODS
A pre-tested questionnaire was utilized to collect data from patients and their corresponding medical charts. A consecutive sampling technique was used to select the participants. Descriptive statistics were used to summarize socio-demographic and clinical characteristics. Chi-squared, Fisher's exact, and Wilcoxon rank sum tests, as appropriate, were used to determine associations between independent variables and ACB. Kaplan-Meier survival curve and Cox proportional hazards regression test were used to assess the impact of ACB on in-hospital mortality.
RESULTS
A total of 420 adult in-patients, median (interquartile range) age of 38 (26, 55) years, participated in this study. Over half (58.3%) were exposed to anticholinergic medicines, with a high ACB (⩾3) seen in 11.2% of participants. High ACB was associated with higher median number of medicines per patient ( = 0.003) higher median hospital length of stay ( = 0.033), and having mental and behavioral disorders ( < 0.001). No significant association was found between ACB and in-hospital mortality (log-rank test = 0.26, Cox regression adjusted hazard ratio: 1.47, 95% CI: 0.335-6.453, = 0.61).
CONCLUSION
Among adult in-patients, a significant majority (58.3%) were subjected to medications possessing anticholinergic properties, with a noteworthy 11.2% of the study subjects exhibiting a high ACB. Participants with higher median length of hospital stay were more likely to have high ACB even in this relatively younger adult patient population.
PubMed: 38881539
DOI: 10.1177/20420986241259624 -
Neurotherapeutics : the Journal of the... Jun 2024Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the X chromosome-linked gene Methyl-CpG Binding Protein 2 (MECP2). Restoring MeCP2...
Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the X chromosome-linked gene Methyl-CpG Binding Protein 2 (MECP2). Restoring MeCP2 expression after disease onset in a mouse model of RTT reverses phenotypes, providing hope for development of treatments for RTT. Translatable biomarkers of improvement and treatment responses have the potential to accelerate both preclinical and clinical evaluation of targeted therapies in RTT. Studies in people with and mouse models of RTT have identified neurophysiological features, such as auditory event-related potentials, that correlate with disease severity, suggesting that they could be useful as biomarkers of disease improvement or early treatment response. We recently demonstrated that treatment of RTT mice with a positive allosteric modulator (PAM) of muscarinic acetylcholine subtype 1 receptor (M) improved phenotypes, suggesting that modulation of M activity is a potential therapy in RTT. To evaluate whether neurophysiological features could be useful biomarkers to assess the effects of M PAM treatment, we acutely administered the M PAM VU0486846 (VU846) at doses of 1, 3, 10 and 30 mg/kg in wildtype and RTT mice. This resulted in an inverted U-shaped dose response with maximal improvement of AEP features at 3 mg/kg but with no marked effect on basal EEG power or epileptiform discharges in RTT mice and no significant changes in wildtype mice. These findings suggest that M potentiation can improve neural circuit synchrony to auditory stimuli in RTT mice and that neurophysiological features have potential as pharmacodynamic or treatment-responsive biomarkers for preclinical and clinical evaluation of putative therapies in RTT.
PubMed: 38880672
DOI: 10.1016/j.neurot.2024.e00384 -
Journal of Pharmacological Sciences Aug 2024We examined the inhibitory effects of α-linolenic acid (ALA) on the contractions of pig coronary arteries. ALA concentration-dependently inhibited the contractions...
We examined the inhibitory effects of α-linolenic acid (ALA) on the contractions of pig coronary arteries. ALA concentration-dependently inhibited the contractions elicited by U46619 and prostaglandin F without affecting those elicited by 80 mM KCl, histamine, acetylcholine, and serotonin. ALA rightward shifted the concentration-response curve of U46619, and Schild plot analysis revealed that ALA competitively antagonized U46619. Furthermore, ALA inhibited the increase in intracellular Ca concentration caused by TP receptor stimulation but not that caused by FP receptor stimulation. These results suggest that ALA behaves as a selective antagonist of TP receptors in coronary arteries.
Topics: Animals; Coronary Vessels; alpha-Linolenic Acid; Swine; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Calcium; Receptors, Thromboxane; Dose-Response Relationship, Drug; Male; Dinoprost; Muscle Contraction
PubMed: 38880549
DOI: 10.1016/j.jphs.2024.06.001