Search Results (922)

Background/Objectives: Jangwon-hwan (JH), known as Zhuangyuan-wan in Chinese medicine, has traditionally been used for forgetfulness and poor memory, often accompanied by palpitations and insomnia. However, the pharmacological mechanisms underlying its traditional use for memory-related symptoms remain unclear. This study aimed to evaluate the effects of JH on memory function and to elucidate the underlying mechanisms, thereby providing scientific evidence for its use. Methods: JH (30 or 100 mg/kg) was orally administered for 28 days in normal mice and for 14 days in scopolamine-induced memory-impaired mice. Memory performance was assessed behaviorally, with molecular and histological analyses of brain tissue. Results: JH improved passive avoidance memory and increased hippocampal synaptophysin and postsynaptic density protein 95 in normal mice. JH also enhanced medial septal cholinergic neuronal activation and increased hippocampal acetylcholine levels. It further increased muscarinic acetylcholine receptor M1 and metabotropic glutamate receptor 5 expression, upregulated synaptic plasticity-related genes, and enhanced hippocampal neuronal activation. Consistent with its effects on cholinergic signaling, JH attenuated scopolamine-induced memory impairment and preserved hippocampal phosphorylation of calcium/calmodulin-dependent protein kinase II, extracellular signal-regulated kinase, and cAMP response element-binding protein. Conclusions: Collectively, these findings indicate that the memory-enhancing effects of JH are associated with enhanced cholinergic signaling, synaptic plasticity, and hippocampal neuronal activation, providing molecular evidence supporting its traditional use for forgetfulness and poor memory. Full article

Statins are widely prescribed lipid-lowering agents and remain central to the prevention of atherosclerotic cardiovascular disease. Although generally well tolerated, they have been associated with neuromuscular adverse events, including new-onset or worsening myasthenia gravis (MG). Current evidence supports a primarily temporal association between statin exposure and MG onset or exacerbation; this signal has emerged largely from case reports, pharmacovigilance analyses, and retrospective observational studies, while more recent population-based observational data strengthen the association. Statin-associated MG should be distinguished from other statin-related neuromuscular syndromes, particularly toxic myopathy and immune-mediated necrotizing myopathy. Beyond cholesterol-lowering, statins may influence neuromuscular junction function through multiple converging mechanisms, including perturbation of the mevalonate–dolichol–glycosylation pathway, isoprenoid-dependent immune dysregulation, altered lipid raft integrity and acetylcholine receptor clustering, and coenzyme Q10-linked mitochondrial vulnerability. In this review, we summarize the clinical evidence linking statins to MG, outline key differential diagnostic considerations, and propose an integrated glycosylation–immune–structural–metabolic framework to guide future mechanistic studies and potential risk-stratified clinical management. Full article

Seizures in several epilepsy syndromes cluster within narrow windows of the sleep–wake cycle, even though the underlying molecular defects are present continuously. This narrative review asks how constitutive molecular pathologies give rise to state-dependent seizures. We integrated epilepsy genetics with sleep neurophysiology, drawing on literature retrieved from PubMed/MEDLINE across eleven concept blocks, and organized the evidence around four gene families: nicotinic acetylcholine receptor subunits, KCNT1, the GATOR1–mTOR complex, and thalamocortical calcium and HCN channels. Across these pathways, the genetic evidence ranges from well-established monogenic causation to susceptibility alleles of insufficient effect. We propose, as an integrative working model, that non-rapid eye movement (NREM) sleep converts continuous defects into state-bound seizures by strengthening thalamocortical coupling, withdrawing cholinergic tone and destabilizing arousal, with circadian phase adding a further layer of temporal control. In this model, sleep-state dependence may reflect the interaction between molecular lesions and vigilance states rather than the properties of any single gene. The strength of evidence for this link varies across gene families and is weakest for the GATOR1 pathway; much of the supporting evidence derives from animal, expression, and computational studies, whose extension to human syndromes remains inferential. Full article

Botulinum neurotoxin (BoNT) is one of the most lethal biological substances to humans, which inhibits acetylcholine release by the presynaptic nerve in neuromuscular junctions. Of the existing BoNT serotypes, BoNT serotype A (BoNT/A) is particularly potent, making it the primary focus in neurotoxin research. Its catalytic domain exhibits similar structural features and zinc-dependent activity as thermolysin, a key bacterial enzyme, which provides a foundation for designing antibacterial agents targeting related protease mechanisms. Repurposing of preapproved drugs or existing medications has recently proven an effective strategy to accelerate drug discovery. Accordingly, we employed drug-likeness screening, quantitative estimation of drug-likeness (QED), and molecular docking to screen about 9000 ligands from the FDA-preapproved drug library using the known crystal structures of the toxin’s light chain, and we identified potential inhibitors with the highest binding affinity. We further refined our selection using molecular dynamics simulations to investigate the stability of the receptor–ligand complexes. The binding mode analysis and binding free energies of the receptor–ligand complexes provide crucial information about the mechanism of action of our top-ranked potential inhibitors. Notably, 16 ligands exhibit a binding affinity greater (in magnitude) than that of the hydroxamate inhibitors that are co-crystallized in the X-ray structure. Most of these ligands contain fluorine, carboxylic and phosphate moieties as key functional groups that enhance their interactions with key residues of the BoNT active site. Our results suggest that dinoprost and 15 other clinically investigated ligands may serve as candidate scaffolds for further evaluation as potential BoNT/A LC inhibitors, pending experimental validation. Full article

The tumor microenvironment (TME) is an innervated and neurochemically active setting. To date, its cholinergic and GABAergic signaling have largely been analyzed as separate systems, contributing to inconsistent findings across the literature. We propose a Calcium-Gated Excitability (CAGE) model, in which α7 nicotinic acetylcholine receptor (nAChR), α4β2 nAChR, GABA type A (GABA_A) and type B (GABA_B) receptors, and α2δ-1 converge on a single downstream variable: Ca²⁺ flux. α7 conducts Ca²⁺ directly; α4β2 may redirect cholinergic input toward GABA release; GABA_A and GABA_B set the direction of the calcium response through intracellular chloride-gradient state and opposing intracellular signaling branches; α2δ-1 sets the gain that determines whether depolarization reaches a functional threshold. The resulting calcium-axis configuration, defined by receptor functional state, chloride-gradient status, α2δ-1 gain, and ligand exposure, shapes Ca²⁺ output and constrains downstream biological responses. Under this framework, some divergent findings on acetylcholine, nicotine, and GABA become testable consequences of distinct calcium-regulatory configurations. CAGE yields testable predictions, including nonlinear nAChR dose–response curves, reversal of GABA_A polarity, α2δ-1-dependent signal scaling, and spatially heterogeneous Ca²⁺ states. Studies evaluating nAChR- and GABA-receptor-targeted therapies without prior calcium-axis stratification may not be underpowered; they may be asking the wrong question. Full article

Background: Myasthenia gravis is an autoimmune disorder of the neuromuscular junction characterized by fluctuating skeletal muscle weakness. Late-onset MG (onset ≥ 50 and <65 years) and very late-onset MG (VLOMG; onset ≥ 65 years) are increasingly recognized subgroups, and diagnosis in very elderly patients remains challenging because symptoms frequently overlap with age-related conditions and comorbidities. Case Presentation: An 88-year-old man with very late-onset myasthenia gravis (symptom onset at approximately age 85) was urgently referred because of a several-day history of rapidly worsening dysphagia and dysarthria, superimposed on fluctuating diplopia, dysphagia, dysarthria, and fatigable bulbar symptoms that had progressively worsened over the preceding three years. Initial diagnostic evaluation was challenging because of advanced age, previous lacunar infarctions, and multiple comorbidities, including pulmonary thromboembolism, chronic kidney disease, and permanent pacemaker implantation (which precluded brain MRI). Neurological examination and the characteristic fluctuation of symptoms raised suspicion of myasthenia gravis. Serological testing confirmed markedly elevated acetylcholine receptor antibodies, whereas MuSK antibodies were negative. Repetitive nerve stimulation was not performed given the high antibody titer and unambiguous clinical presentation. Thoracic computed tomography excluded thymoma. Treatment with pyridostigmine, azathioprine (maintenance dose kept lower than standard due to chronic kidney disease stage IIIB), and low-dose prednisone (selected due to age and comorbidity profile) resulted in early, patient-reported clinical improvement (approximately 60% in speech and swallowing) over eight weeks of follow-up; a validated severity scale (MG-ADL) showed a score of six (scoring range 0–24). Conclusions: Myasthenia gravis should remain an important differential diagnosis in very elderly patients presenting with fluctuating ocular and bulbar symptoms, even in the presence of multiple comorbidities that may obscure the diagnosis. In this patient, early recognition, antibody testing, and individualised initiation of therapy were followed by meaningful short-term improvement; a single case with eight weeks of follow-up cannot establish that such therapy prevents disease progression or myasthenic crisis, and longer follow-up and additional cases are needed. Full article

Endocannabinoid receptors of the CB1 subtype are the most abundant G-protein-coupled receptors in the central nervous system, where they strongly regulate neurotransmitter release. The effects of the activation of these receptors by exogenously applied agonists have also been described in the peripheral nervous system, particularly at neuromuscular junctions (NMJs). However, the physiological role of these receptors at NMJs has not been demonstrated. We have shown that blockade of CB1 receptors at the NMJs of newborn or young mice increases the quantal content of end-plate potentials, as well as their decay time constant. Neither effect of CB1 receptor blockade is observed if postsynaptic muscle acetylcholine receptors are partially blocked. Thus, CB1 receptors may be involved in maintaining synaptic homeostasis. Importantly, the effect of CB1 receptor blockade on quantal content is potentiated by blockade of the enzyme butyrylcholinesterase. Therefore, butyrylcholinesterase may be considered a component of the extracellular degradation system for endocannabinoids. Full article

Background/Objectives: Myasthenia gravis (MG) is an immune-mediated neuromuscular disorder for which antibody-based assays have limited sensitivity, particularly in double-seronegative MG (dsNMG), highlighting the need for complementary biomarkers. Given their roles in immune regulation, membrane integrity, and metabolic stress responses, lipids represent promising candidates for biomarker discovery. Methods: We designed a prospective case–control study and systematically stratified 68 patients with myasthenia gravis (MG) according to clinical classification and autoantibody status. Using LC–MS/MS, we quantified 824 lipids in 136 serum samples collected from these patients and 68 healthy controls. The analyzed subtypes included ocular MG (OMG), generalized MG (GMG), acetylcholine receptor antibody-positive MG (AChR-MG), and dsNMG. Differential lipid analysis, correlation network construction, KEGG pathway enrichment, and multivariable logistic regression were performed. Diagnostic and subtype prediction models were developed using LASSO with 10 × 10 repeated cross-validation and interpreted using Shapley Additive exPlanations (SHAP) analysis. A longitudinal follow-up analysis was conducted to assess dynamic associations between lipid signatures and disease activity. Results: In total, 240 lipids were significantly altered in MG compared with controls. Lipids distinguishing GMG from OMG were enriched in ether lipid metabolism, necroptosis, and sphingolipid signaling pathways. AChR-MG and dsNMG shared lipid networks related to membrane remodeling and signaling regulation, whereas dsNMG exhibited marked elevations in acylcarnitines and bile acid-related metabolites, potentially reflecting a distinct phenotype characterized by altered energy metabolism. The lipid-based model achieved an AUC of 0.917 for distinguishing MG from controls, and AUCs of 0.77 and 0.71 for differentiating AChR-MG from dsNMG and GMG from OMG, respectively. Longitudinal analyses showed that SM(d18:1/23:0) and Cer(d24:1/18:0(2OH)) displayed dynamic changes consistent with disease activity. Conclusions: Serum lipidomics revealed subtype-specific metabolic features of MG, with stable disease-associated remodeling and dynamic sphingolipid changes potentially reflecting disease activity. By integrating systematic clinical and antibody-based subtype stratification with longitudinal follow-up, this study supports lipidomics as a complementary tool for precision diagnosis and disease stratification, particularly in antibody-negative dsNMG. Full article

Tobacco use remains one of the leading preventable causes of morbidity and mortality worldwide, contributing to more than 7 million deaths annually and imposing a substantial economic burden on healthcare systems and global productivity. The addictive properties of tobacco are primarily mediated by nicotine, which exerts its effects through neuronal nicotinic acetylcholine receptors (nAChRs) within brain reward circuits. Among these receptor subtypes, α4β2-containing nAChRs play a central role in nicotine dependence by regulating dopaminergic signaling associated with reinforcement, craving, withdrawal, and relapse. Repeated nicotine exposure induces neuroadaptive changes in receptor expression and neural circuitry, contributing to the chronic and relapsing nature of addiction. Advances in addiction neuroscience and receptor pharmacology have enhanced the understanding of nicotine-mediated signaling and facilitated the development of evidence-based smoking cessation therapies. Current treatment approaches include nicotine replacement therapies, antidepressant-based interventions, and partial nAChR agonists such as varenicline and cytisine. Emerging strategies encompass subtype-selective ligands, allosteric modulators, immunotherapeutics, neuromodulation techniques, and digital health technologies aimed at improving cessation outcomes. This review summarizes the neuropharmacological mechanisms underlying nicotine addiction and critically examines current and emerging therapeutic strategies, highlighting their mechanisms of action, clinical efficacy, limitations, and future potential for tobacco cessation. Full article

Background: Ocular myasthenia gravis (OMG) can remain restricted to ocular symptoms or progress to generalized myasthenia gravis (GMG). However, the rate of generalization and its predictors may vary across populations, and data on South Korean patients remain inadequate. This study investigated the conversion rate from OMG to GMG and identified clinical, serologic, electrophysiologic, and thymic predictors of this generalization in a South Korean cohort. Methods: This retrospective cohort study included 89 patients who initially presented with OMG and were followed up for at least 2 years. The primary outcome was conversion to GMG during follow-up. The investigated predictors included demographic variables, initial ocular manifestations, acetylcholine receptor antibody (AChR-Ab) status and titer, repetitive nerve stimulation test (RNST) findings, thymic abnormalities, and immunosuppressive treatment. Kaplan–Meier analyses and Cox proportional-hazards models were used to evaluate the GMG-free survival rate and risk factors for conversion. Results: During follow-up, 10 patients (11.2%) progressed to GMG, with this conversion occurring within 2 years in 8 patients (9.0%). All converters were AChR-Ab positive. AChR-Ab positivity, RNST positivity, thymic abnormality, and thymoma were associated with GMG conversion in univariable analyses. RNST positivity in any tested muscle (hazard ratio [HR] = 12.66, 95% confidence interval [CI] = 2.68–59.76, p = 0.001) and thymoma (HR = 10.67, 95% CI = 3.06–37.27, p < 0.001) was associated with generalization. These associations persisted in the restricted multivariable Cox model. Conclusions: The rate of GMG conversion was relatively low in this South Korean OMG cohort, and most conversions occurred within 2 years. The presence of AChR-Ab positivity, RNST abnormality, or thymoma may characterize high-risk patients who require closer monitoring during the early disease course. Full article

Background/Objectives: Understanding the unique properties of human neurons is crucial for advancing knowledge of brain function and facilitating clinical translation. This study explores the use of photopharmacology, specifically a photoswitchable ligand, Phthalimide-Azo-Iperoxo (PAI), to modulate cortical activity in human brain slices. Methods: Human cortical tissue was obtained from patients undergoing resective neurosurgery for pharmacoresistant epilepsy. The inactive cis isomer of PAI (200 nM) was bath-applied to brain slices exhibiting slow-oscillatory activity, producing no effect on the ongoing network activity. Subsequent illumination of the slices with white light induced photoconversion to trans-PAI, the active form of the compound. Results: Photoactivation of PAI selectively activated M₂ muscarinic acetylcholine receptors, resulting in a significant increase in oscillatory frequency accompanied by reductions in both Up-state and Down-state durations. Conclusions: In this proof-of-concept study, our findings provide preliminary evidence that photopharmacology can selectively modulate slow oscillations in human cortical circuits, highlighting its potential as a tool for investigating human cortical dynamics. By extending observations previously made in animal models to human tissue, this work establishes the feasibility of photopharmacological modulation in human cortical tissue and provides a foundation for future translational research. Full article

Hereditary neuromuscular disorders in dogs can be difficult to classify since variants in different genes can result in similar clinical signs or variable phenotypes can be associated with the same DNA sequence variant. A disorder known for many years as Dancing Doberman Disease, suspected to be neuropathy or neuromyopathy, is characterized by repeated lifting and shifting of the pelvic limbs while standing and frequent sitting. More recently, Doberman Pinschers have been identified with a different and more severe phenotype characterized by a crouched stance and bunny hopping gait in the pelvic limbs that is termed duck walking. Dogs with both phenotypes show pelvic limb weakness, muscle atrophy, and fatigue, and clinical signs can progress to involve the thoracic limbs. These distinct phenotypes were evaluated clinically, histologically, and by whole-genome sequencing and genotyping a large cohort of affected and unaffected Doberman Pinschers. The same homozygous missense variant in AGRN (Dog 10K Boxer Tasha chr5:56,346,611,G>A; p.R1710H, XP 038377340.1) was associated with both disorders. AGRN encodes Agrin, an essential synaptic protein, that mediates clustering of acetylcholine receptors on the post-synaptic membrane at the neuromuscular junction. Variants in AGRN are associated with a congenital myasthenic syndrome (CMS) in humans. This is the first report of a CMS in dogs associated with an AGRN variant and expands the spectrum of known CMS genetic risk factors in this species. This study also highlights the importance of whole-genome sequencing (WGS) to accurately classify neuromuscular diseases as forms of CMS, which is not possible based on clinical presentation alone. Full article

The melon fly, Zeugodacus cucurbitae (Coquillett), is a destructive tephritid pest of cucurbit crops, and neonicotinoids remain important tools for its management. Although neonicotinoids primarily target nicotinic acetylcholine receptors (nAChRs), their possible effects on acetylcholinesterase (AChE)-mediated cholinergic homeostasis in Z. cucurbitae remain poorly understood. In this study, we molecularly characterized the Z. cucurbitae Ache gene and evaluated its expression and functional contribution under dinotefuran, acetamiprid, and thiamethoxam stress. Bioinformatics analyses confirmed conserved cholinesterase features, including the FGESAG catalytic motif, catalytic triad, choline-binding site, oxyanion hole, and conserved disulfide-bond residues. Temporal and tissue-specific expression profiling showed high Ache transcript abundance in eggs, third-instar larvae, and adult heads. Larval exposure to LC₅, LC₂₀, and LC₅₀ concentrations of the three neonicotinoids caused dose- and time-dependent mortality and significantly induced Ache expression, with dinotefuran producing the strongest transcriptional response. Parental exposure also impaired F₁ fecundity, hatchability, larval survival, and adult emergence, with acetamiprid and thiamethoxam causing stronger transgenerational effects than dinotefuran. Oral RNAi significantly increased larval susceptibility upon re-exposure to neonicotinoids after 72 h. These findings indicate that Ache contributes to cholinergic stress response and susceptibility modulation in Z. cucurbitae, supporting its possible potential as an RNAi target for integrated pest management (IPM). However, practical utility at the field level requires further evaluation. Full article

Background: Current treatments for myasthenia gravis (MG), while improving outcomes, are often associated with adverse effects, and a proportion of patients remain refractory to standard therapies. Eculizumab, a humanized monoclonal antibody targeting complement protein C5, is approved for refractory anti-acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). Aim of the present study is to explore the rapidity of onset of eculizumab efficacy in a single-center cohort of MG patients. Methods: This retrospective, observational, single-center study evaluated the real-world effectiveness and rapidity of response to eculizumab in patients with AChR-Ab+ gMG. Patients received eculizumab according to the approved regimen and were assessed at baseline (T0), 5 weeks (T1), and 3 months (T2) using the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Quantitative Myasthenia Gravis (QMG) score, and Myasthenia Gravis Foundation of America (MGFA) classification. Results: Eight patients were eligible for the study with a mean age of 73.1 years. A rapid clinical improvement was observed after treatment initiation. Mean MG-ADL scores decreased from 8.38 at T0 to 2.13 at T1 (p < 0.001; Cohen’s d = 2.075), while QMG scores declined from 13.75 to 5.63 (p = 0.001; Cohen’s d = 1.824). Improvements were maintained at T2. Mean percentage reductions from T0 to T1 were 73.5% for MG-ADL and 60.6% for QMG. Eculizumab was well tolerated. Conclusions: These real-world findings confirm a rapid and clinically meaningful response to eculizumab in elderly patients with refractory gMG. These findings highlight its potential role in achieving early symptom control and reducing disease burden in this clinically vulnerable population. Full article

Molecular docking in silico techniques were used to assess the interactions between several drugs used in the treatment of Alzheimer’s disease (AlzD) with neuronal receptors and with tryptophan and glycolytic pathway enzymes. AlzD drugs believed to act by inhibiting acetylcholinesterase (AChE) docked to that enzyme, whereas other drugs did not. No docking was observed to the nicotinic acetylcholine receptor (α-7-nAChR). All the drugs tested docked to the kainic acid receptor for glutamate, whereas donepezil, galantamine, tropisetron and N-acetylcysteine docked to the glutamate-NMDA receptor, but none docked to the glutamate-AMPA receptor. Two compounds docked to GABA receptors. Since the kynurenine pathway of tryptophan metabolism has been linked to AlzD, docking was examined with its various enzymes. Docking to tryptophan-2,3-dioxygenase (TDO2), indoleamine-2,3-dioxygenase-1 (IDO1) and 2-amino-3-carboxymuconic acid-6-semialdehyde decarboxylase was seen with most of the AlzD drugs. Donepezil docked to kynurenine monooxygenase, while rivastigmine, memantine and tropisetron docked to kynurenine aminotransferase-2. There was limited docking to the aryl hydrocarbon receptor and glycolytic enzymes, whereas most drugs docked to phosphoenolpyruvate carboxykinase (PEPCK). Despite their strong docking ability to IDO1 and TDO, none of the compounds tested inhibited their enzyme activity in an assay of kynurenine production. This pilot study highlights the varied pharmacological profile of drugs used in AlzD and suggests that a detailed examination of their functional effects should be considered to assist understanding of their different profiles at on- and off- target sites in human treatment. Full article