Search Results (1,630)

Background/Objectives: Ischemia with non-obstructive coronary arteries (INOCA) remains an underdiagnosed and undertreated condition due to the extensive diagnostic testing required and heterogeneous pathophysiology of different endotypes, each of which require tailored treatment. This study aimed to explore the effect of intracoronary physiology testing-based endotype-specific medical therapy on quality of life in patients with INOCA. Methods: Intracoronary physiology testing was performed in patients presenting with cardiac symptoms, evidence of significant ischemia on non-invasive testing, and non-obstructive epicardial coronary arteries. Microvascular angina (MVA) was defined as coronary flow reserve ≤ 2.5 and an index of microvascular resistance ≥ 25. Vasospastic angina (VSA) was defined as a >90% vasoconstriction of an epicardial artery during acetylcholine provocation test in the presence of ischemic electrocardiogram changes and chest pain. Quality of life was evaluated using the Seattle Angina Questionnaire 7 (SAQ-7) before the start of new treatment and at the three months follow-up. Results: The total study population consisted of 35 patients (80% women), of whom MVA was observed in 19 (54.3%), VSA in 9 (25.7%), and the combination of MVA and VSA in 3 (8.6%) cases. Four patients (11.4%) had no pathology on intracoronary physiology testing detected. High rates of dyslipidemia (100%), arterial hypertension (85.7%), diabetes (17.1%), and depression and anxiety (34.3%) were documented. In the isolated MVA and VSA groups, adjustment of medical therapy resulted in an improvement in the SAQ-7 summary score at 3 months (p < 0.001 and p = 0.007, respectively). There was no change of SAQ-7 summary score in the mixed endotype group (p = 0.11). Conclusions: Adjustment of medical therapy according to intracoronary physiology testing-based phenotype resulted in improved quality of life as assessed by the SAQ-7. Our findings highlight the importance of invasive testing in patients with clinically suspected INOCA. Full article

In our previous study, we demonstrated that a standardized ethanol extract of Perilla frutescens var. acuta (PE) alleviates memory deficits in an Alzheimer’s disease mouse model by inhibiting amyloid β (Aβ) aggregation and promoting its disaggregation. However, the extent to which PE exerts additional cognitive benefits independent of Aβ pathology remained unclear. Here, we aimed to evaluate the effects of PE on synaptic plasticity and learning and memory functions. Male ICR mice were used, and cognitive impairment was induced by scopolamine administration. PE was orally administered at doses determined from previous studies, and cognitive performance was assessed using the passive avoidance, Y-maze, and Morris water maze tests. In parallel, hippocampal slices were employed to examine the effects of PE on synaptic plasticity. PE (100 and 300 μg/mL) significantly enhanced long-term potentiation (LTP) in a concentration-dependent manner without altering basal synaptic transmission. This facilitation of LTP was blocked by scopolamine (1 μM), a muscarinic acetylcholine receptor (mAChR) antagonist, and IEM-1460 (50 μM), a calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) inhibitor, indicating the involvement of mAChR and CP-AMPAR pathways. In vivo, PE (100, 250, and 500 mg/kg) treatment improved memory performance across all behavioral tasks and upregulated hippocampal synaptic proteins including GluN2B, PSD-95, and CaMKII. Collectively, these results demonstrate that PE ameliorates scopolamine (1 mg/kg)-induced cognitive impairment by enhancing synaptic plasticity, likely through modulation of mAChR, CP-AMPAR, and NMDA receptor signaling. These findings highlight the therapeutic potential of PE for memory deficits associated with cholinergic dysfunction. Full article

Background/Objectives: The prebiotic effect of resistant potato starch (RPS) has been demonstrated, but the role of this nutrient in choline metabolism and the production of microbially modified choline-derived toxins is unknown. Methods: We performed post hoc analysis comparing changes in choline and related metabolites in serum from baseline to the week 4 time point in a human clinical trial evaluating daily consumption of 3.5 g RPS versus a placebo. Results: Choline levels increased in the RPS consuming group, while levels of trimethylamine decreased and levels of the cardiovascular toxin trimethylamine oxide were unaffected by RPS consumption. Increases in choline were positively correlated with increases in Akkermansia in the gut. Oxidation of choline to betaine was unaffected by RPS, as was acetylcholine metabolism. Levels of various saturated even acyl chain and hydroxylated acyl chain sphingomyelins were increased in RPS consuming participants, and levels of phospholipid degradation products phosphocholine and glycerophosphocholine were decreased. Conclusions: These data suggest that RPS enhances choline absorption without increasing TMAO and stimulates the incorporation of choline into sphingomyelins containing saturated even acyl chains and hydroxylated acyl chains. Future studies assessing the physiological consequences, such as cognitive or neurological benefits, of enhanced choline absorption and sphingomyelin levels in people consuming RPS are warranted. Full article

Aging, one of the main factors associated with cardiovascular diseases, induces vascular modifications through nitric oxide (NO) release and oxidative stress. Based on the antioxidant properties of the non-enzymatic spirulina extract (non-Enz-Spir-E) and that degrading enzymes enhances the extract bioactivity, the aim of this study was to analyze the in vitro effect of an Alcalase-assisted Enz-Spir-E on the vasodilator function of conduit and resistance arteries (which differently contribute to blood pressure regulation) in aging. Therefore, thoracic aorta (TA) and mesenteric arteries (MA) from male Sprague–Dawley rats (20–22 months-old) were divided into two groups: non-incubated vessels and vessels exposed to Enz-Spir-E (0.1% w/v) for 3 h. The vasodilation to acetylcholine (ACh), sodium nitroprusside (SNP, a NO donor), carbon-monoxide-releasing molecule (CORM), and cromakalim (a potassium channel opener), as well as NO and superoxide anion production, were studied. Enz-Spir-E increased the ACh-, SNP-, and CORM-induced responses in both types of arteries, while the cromalakim-induced relaxation was increased only in MA. Enz-Spir-E increased NO release (TA: 5.69-fold; MA: 1.79-fold), while it reduced superoxide anion formation (TA: 0.52-fold; MA: 0.66-fold). These results indicate that Enz-Spir-E improves aging-associated vasodilation through increasing NO release/bioavailability in both types of arteries and hyperpolarizing mechanisms only in MA. Full article

Autosomal-dominant sleep-related hypermotor epilepsy (ADSHE) was the first distinct genetic epilepsy proven to be caused by mutation of the CHRNA4 gene, originally reported in 1994. In the past three decades, pathomechanisms of ADSHE associated with mutant nicotinic acetylcholine receptors (nAChRs) have been explored via various studies, including in vitro experiments and genetic rodent models. However, findings emphasize that functional abnormalities of ADSHE-mutant nAChRs alone cannot generate ictogenesis; rather, development of abnormalities in various other transmission systems induced by ADSHE-mutant nAChRs during the neurodevelopmental process before the ADSHE onset is involved in development of epileptogenesis/ictogenesis. Intra-thalamic GABAergic disinhibition induced by loss-of-function of S284L-mutant nAChRs (S286L-mutant nAChRs in rat ADSHE models) contributes to enhancing propagation of physiological ripple-burst high-frequency oscillation (HFO) and Erk signaling during sleep, leading to enhancement of the trafficking of pannexin1, connexin43, and P2X7 purinergic receptor to the astroglial plasma membrane. The combination of activation of physiological ripple-HFO and upregulation of astroglial hemichannels under the GABAergic disinhibition plays an important role in generation of epileptogenic fast-ripple-HFO during sleep. Therefore, loss-of-function of the S284L-mutation alone cannot drive ictogenesis but contributes to the development of epileptogenesis as an initial abnormality. Based on these recent findings using genetic rat ADSHE models, harboring the rat S286L-mutant Chrna4 corresponding to the human S284L-mutant CHRNA4, this report proposes hypothetical pathomechanisms of ADSHE. Full article

The central cholinergic system is an important player in the control of motor function, appetite, the reward system, attention, memory and learning. Its participation in neurological diseases (e.g., Alzheimer’s and Parkinson’s disease, epilepsy) and in psychiatric diseases (e.g., schizophrenia, depression) makes it a preferred study subject for drug development. The present review summarizes salient features of the central cholinergic synapses that will guide future studies. Cholinergic synapses are defined by the presence of choline acetyltransferase (ChAT), the vesicular ACh transporter (VAChT), the high-affinity choline transporter CHT-1 and the presence of PRiMA-coupled acetylcholinesterase (AChE). The firing frequency of cholinergic fibers is reflected in high-affinity choline uptake activity, which also responds to variations in ChAT, VAChT and AChE activities conferring considerable plasticity to cholinergic responses. The availability of glucose and choline can limit ACh synthesis and release under conditions of high ACh turnover. Future studies will focus on rapid methods to measure ACh release and a deeper understanding of cholinergic plasticity during development, aging and dementia. Full article

Alzheimer’s disease (AD) is a progressive neurological condition with limited effective pharmaceutical treatments, often accompanied by side effects. This has increased interest in plant-based alternatives. This study examined the cognitive effects of a Natural Polyherbal Extract (NPX) on scopolamine-induced memory deficits in mice. Male C57BL/6 mice (10 weeks old, n = 36) were divided into four groups: control (saline), scopolamine (1 mg/kg, i.p.), tacrine (10 mg/kg, oral), and NPX (1000 mg/kg, oral). NPX and tacrine were administered daily by oral gavage for two weeks. Cognitive function was assessed weekly using the Y-maze task. Brain tissues were collected for biochemical analysis, including AChE activity and immunohistochemical detection of neurodegeneration-related markers. Results: Mice treated with NPX demonstrated improved spontaneous alternation behavior compared to the scopolamine group. NPX also significantly reduced acetylcholinesterase activity. Immunohistochemistry revealed decreased expression of amyloid-beta (Aβ) and caspase-3, with enhanced choline acetyltransferase levels. These outcomes were comparable to those observed in the tacrine-treated group. Conclusions: NPX alleviated scopolamine-induced memory impairment through enhancement of cholinergic signaling and mitigation of neurodegenerative markers. The findings suggest that NPX may serve as a promising plant-derived candidate for managing memory-related disorders, including AD. Full article

Cytisine, a naturally occurring alkaloid and partial agonist of nicotinic acetylcholine receptors (nAChRs), has long been used as a smoking cessation aid and serves as the pharmacophore for varenicline. Recent research has expanded its therapeutic scope to neurodegenerative and neurological disorders, motivating the development of new cytisine derivatives. Among these, N-propargylcytisine combines the biological activity of the parent compound with the synthetic versatility of the terminal alkyne group. Herein, we report the synthesis and characterization of N-propargylcytisine, and its symmetrical dimer linked through 1,3-diyne moiety obtained via a copper-mediated Glaser–Hay oxidative coupling. The products were analyzed by NMR, FT-IR, and mass spectrometry, confirming the introduction of the propargyl moiety and the formation of the diyne bridge. Solvatochromic study of both compounds were performed using UV-VIS absorption spectroscopy in solvents of varying polarity, including protic solvents capable of hydrogen bonding. The 1,3-diyne motif, commonly found in bioactive natural products, endows the resulting dimer with potential for further derivatization and biological evaluation. This study demonstrates the utility of the Glaser–Hay reaction in the functionalization of alkaloid scaffolds and highlights the prospects of N-propargylcytisine derivatives in drug discovery targeting the central nervous system. Full article

Hydroethanolic Cucurbita pepo seed extracts are traditionally used for alleviating lower urinary tract symptoms (LUTS), yet their mechanisms remain unclear. Adenosine, a purine nucleoside involved in neuromodulation and smooth muscle relaxation, was recently identified in C. pepo seeds. Since A₁ adenosine receptors (A₁AR) suppress parasympathetic bladder overactivity by inhibiting acetylcholine (ACh) release, we investigated to which extent purines from pumpkin seed extracts contribute to A₁AR activation. Complementary antioxidant capacity was assessed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Three hydrophilic seed extracts containing different adenosine levels (0.60–1.18 mg/g dw) were evaluated for agonist activity using a cAMP inhibition assay. The most active extract showed an EC₅₀ of 40.22 µg/mL. Selective removal of adenosine shifted the dose–response curve rightward, while further elimination of an adenosine derivative increased the EC₅₀ to 212.10 µg/mL, confirming adenosine as the principal active compound. Guanosine and inosine did not exhibit A₁AR agonist or allosteric effects. All samples exhibited measurable but weak antioxidant activity (IC₅₀ = 1.02–4.19 mg/mL), consistent with their low total phenolic content. These findings underscore the importance of accounting for naturally occurring agonists in plant extracts to avoid overestimating receptor-mediated effects in vitro which are not translatable in vivo. Full article

Marine sources contain compounds that act on a wide variety of systems, including ligand-gated ion channels. This review will focus on the effectors of nicotinic acetylcholine receptors (nAChRs), for which the diversity of ligands and modulators from marine sources is determined mainly by neurotoxic peptides (α-conotoxins) from mollusks of the Conus genus. These are very selective compounds that allow the study of the role of different nAChR subtypes in the cancer cells. They have analgesic or anti-inflammatory activities associated with cholinergic transmission and have shown analgesic effect in case of chemotherapy-induced neuropathic pain. Another class of marine compounds targeting nAChRs for which cytotoxicity for cancer cells was shown is represented by low molecular organic substances found mostly in dinoflagellates and marine sponges. Some of the compounds discussed in this review show promise for developing drugs that suppress cancer growth. Full article

Evidence of possible cerebellar involvement in spatial processing, place learning and other types of higher order functions comes mainly from clinical observations, as well as from mutant mice and lesion studies. The latter, in particular, have reported deficits in spatial learning and memory following surgical or neurotoxic cerebellar ablation. However, the low specificity of such manipulations has often made it difficult to precisely dissect the cognitive components of the observed behaviors. Likewise, due to conflicting data coming from lesion studies, it has not been possible so far to conclusively address whether a cerebellar dysfunction is sufficient per se to induce learning deficits, or whether concurrent damage to other regulatory structure(s) is necessary to significantly interfere with cognitive processing. In the present study, the immunotoxin 192 IgG-saporin, selectively targeting cholinergic neurons in the basal forebrain and a subpopulation of cerebellar Purkinje cells, was administered to adult rats bilaterally into the basal forebrain nuclei, the cerebellar cortices or both areas combined. Additional animals underwent injections of the toxin into the lateral ventricles. Starting from two–three weeks post-lesion, the animals were tested on paradigms of motor ability as well as spatial learning and memory and then sacrificed for post-mortem morphological analyses. All lesioned rats showed no signs of ataxia and no motor deficits that could impair their performance in the water maze task. The rats with discrete cerebellar lesions exhibited fairly normal performance and did not differ from controls in any aspect of the task. By contrast, animals with double lesions, as well as those with 192 IgG-saporin given intraventricularly did manifest severe impairments in both reference and working memory. Histo- and immunohistochemical analyses confirmed the effects of the toxin conjugate on target neurons and fairly similar patterns of Purkinje cell loss in the animals with cerebellar lesion only, basal forebrain-cerebellar double lesions and bilateral intraventricular injections of the toxin. No such loss was by contrast seen in the basal forebrain-lesioned animals, whose Purkinje cells were largely spared and exhibited a normal distribution pattern. The results suggest important functional interactions between the ascending regulatory inputs from the cerebellum and those arising in the basal forebrain nuclei that would act together to modulate the complex sensory–motor and cognitive processes required to control whole body movement in space. Full article

Mechanistically, OPs inhibit acetylcholinesterase (AChE), an enzyme that terminates cholinergic transmission, triggering a sustained activation of acetylcholine receptors. A component of the treatment for OP intoxication is oximes as AChE reactivators. However, oximes may not be efficacious and could worsen OP effects. Further, dealkylation of the AChE-OP adducts prevents oxime reactivation. Therefore, other approaches are needed to rescue AChE activity. We propose that replacing aged extracellular AChE with active intracellular enzymes may be an effective approach. Thus, molecular screening was used to identify small molecules that could displace aged AChE. C2C12 myoblasts were treated with 20 μM of diisopropylfluorophosphate (DFP) for one hour, followed by a drug panel. AChE activity and surface abundance were measured after 6 h. From the chemical screen, a promising hit, Pz-1 (a tyrosine kinase inhibitor), was identified, which decreased surface AChE on DFP-exposed C2C12 myoblasts in a dose-dependent manner without impacting viability. Additionally, AChE presence and activity were recovered after washing and supplementing the media with 100 nM of acetylcholine. Biochemically, Pz-1 inhibits muscle-specific protein kinase (MuSK), a kinase that interacts with AChE. These results suggest that altering MuSK activity may disrupt protein–protein interactions, destabilizing AChE, which may lead to the discovery of new countermeasures for OP exposures. Full article

Diverse neuronal nicotinic acetylcholine receptor (nAChR) subtypes are expressed in hippocampal interneurons. Single-cell analysis of mRNA expression previously revealed prominent co-expression of the α3 and β2 subunits within rat interneurons in the CA1 region. Although the α3 subunit (traditionally expressed together with β4) is usually associated with the peripheral nervous system, its significant co-expression with the β2 subunit in hippocampal interneurons suggests a distinct, potentially novel central nervous system nAChR subtype. We demonstrate that the human α3 and β2 subunits injected into Xenopus laevis oocytes can assemble into at least two functionally distinct subtypes of nAChRs based on different subunit stoichiometries. These subtypes exhibit similar reversal potentials but differ significantly in their desensitization kinetics and acetylcholine (ACh) affinities. The response obtained from a 1:5 α3:β2 mRNA injection ratio shows a higher affinity for ACh and significantly greater desensitization during prolonged ACh application compared to the response obtained from a 5:1 α3:β2 mRNA injection ratio. The identification of distinct functional α3β2 subtypes, characterized by differential desensitization kinetics and ACh affinity, could represent novel targets for the potential development of highly selective cognitive therapeutics for conditions such as Alzheimer’s disease, autism spectrum disorder, and attention deficit hyperactivity disorder, where hippocampal nAChRs are implicated. Full article

Prostate stem cell antigen (PSCA) is a Ly6/uPAR protein that targets neuronal nicotinic acetylcholine receptors (nAChRs). It exists in membrane-tethered and soluble forms, with the latter upregulated in Alzheimer’s disease. We hypothesize that PSCA may be linked to a wider spectrum of neurological diseases and could induce neuroinflammation. Indeed, PSCA expression is significantly upregulated in the brain of patients with multiple sclerosis, Huntington’s disease, Down syndrome, bipolar disorder, and HIV-associated dementia. To investigate PSCA’s structure, pharmacology, and inflammatory function, we produced a correctly folded water-soluble recombinant analog (ws-PSCA). In primary hippocampal neurons and astrocytes, ws-PSCA differently regulates secretion of inflammatory factors and adhesion molecules and induces pro-inflammatory responses by increasing TNFβ secretion. Heteronuclear NMR and ¹⁵N relaxation measurements reveal a classical β-structural three-finger fold with conformationally disordered loops II and III. Positive charge clustering on the molecular surface suggests the functional importance of ionic interactions by these loops. Electrophysiological studies in Xenopus oocytes point on ws-PSCA inhibition of α3β2-, high-, and low-sensitive variants of α4β2- (IC₅₀ ~50, 27, and 15 μM, respectively) but not α4β4-nAChRs, suggesting targeting of the β2 subunit. Ensemble docking and molecular dynamics simulations predict PSCA binding to high-sensitive α4β2-nAChR at α4/β2 and β2/β2 interfaces. Complexes are stabilized by ionic and hydrogen bonds between PSCA’s loops II and III and the primary and complementary receptor subunits, including glycosyl groups. This study gives new structural and functional insights into PSCA’s interaction with molecular targets and provides clues to understand its role in the brain function and mental disorders. Full article

Mamba (Dendroaspis species) snakebites are critical medical emergencies across sub-Saharan Africa. Envenomings can result in the rapid onset of complex neurotoxic symptoms, often leading to high rates of mortality without timely intervention with antivenom. The ancestral state of mambas is the green coloured, forest dwelling type, with the tan/grey coloured, savannah dwelling D. polylepis (Black Mamba) representing a derived state both ecologically and morphologically. However, it has not been tested whether these changes are paralleled by changes in venom biochemistry or if there are differential molecular evolutionary patterns. To fill these knowledge gaps, this study evaluated the neurotoxic effects of all Dendroaspis species venoms using the chick biventer cervicis nerve-muscle preparation, assessed the neutralizing efficacy of three antivenoms commercially available in Africa, and reconstructed the molecular evolutionary history of the toxin types to ascertain whether some were unique to particular species. All Dendroaspis venoms demonstrated potent flaccid-paralysis due to postsynaptic neurotoxicity. The only exception was D. angusticeps venom, which conversely exhibited spastic-paralysis due to presynaptic/synaptic neurotoxicity characterised by potentiation of acetylcholine presynaptic release and sustained synaptic activity of this neurotransmitter. Antivenom efficacy varied significantly. All three antivenoms neutralized to some degree the flaccid-paralysis postsynaptic effects for all species, with D. viridis venom being the best neutralized, and this pattern extended to all the antivenoms. However, neutralisation of flaccid-paralysis postsynaptic effects unmasked spastic-paralysis presynaptic/synaptic neurotoxicity within non-angusticeps venoms. Spastic-paralysis presynaptic effects were poorly neutralized for all species by all antivenoms, consistent with prior clinical reports of poor neutralisation of spastic-paralytic effects. Geographic variation in D. polylepis venom was evident for the relative neutralisation of both spastic-paralysis presynaptic/synaptic and flaccid-paralysis postsynaptic/synaptic neurotoxic pathophysiological effects, with differential neutralization capabilities noted between the Kenyan and South African populations studied. Molecular phylogenetic analyses confirmed spastic-paralysis and flaccid- paralysis toxins to be a trait that emerged in the Dendroaspis last common ancestor, with all species sharing all toxin types. Therefore, differences in venoms’ pathophysiological actions between species are due to differential expression of toxin isoforms rather than the evolution of species-specific novel toxins. Our findings highlight the synergistic nature of flaccid-paralysis postsynaptic and spastic-paralysis presynaptic/synaptic toxins, while contributing significant clinical and evolutionary knowledge of Dendroaspis venoms. These data are crucial for the continued development of more effective therapeutic interventions to improve clinical outcomes and for evidence-based design of clinical management strategies for the envenomed patient. Full article