Activation Of Cholinergic System Research Articles

Transcutaneous auricular vagus nerve stimulation enhances short-latency afferent inhibition via central cholinergic system activation

The present study examined the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on short-latency afferent inhibition (SAI), as indirect biomarker of cholinergic system activation. 24 healthy adults underwent intermittent taVNS (30 s on/30 s off, 30 min) or continuous taVNS at a frequency of 25 Hz (15 min) along with earlobe temporary stimulation (15 min or 30 min) were performed in random order. The efficiency with which the motor evoked potential from the abductor pollicis brevis muscle by transcranial magnetic stimulation was attenuated by the preceding median nerve conditioning stimulus was compared before taVNS, immediately after taVNS, and 15 min after taVNS. Continuous taVNS significantly increased SAI at 15 min post-stimulation compared to baseline. A positive correlation (Pearson coefficient = 0.563, p = 0.004) was observed between baseline SAI and changes after continuous taVNS. These results suggest that 15 min of continuous taVNS increases the activity of the cholinergic nervous system, as evidenced by the increase in SAI. In particular, the increase after taVNS was more pronounced in those with lower initial SAI. This study provides fundamental insight into the clinical potential of taVNS for cholinergic dysfunction.

Activation of a non-neuronal cholinergic system in visceral white adipose tissue of obese mice and humans

Background and objectivesSince white adipose tissue (WAT) lacks parasympathetic cholinergic innervation, the source of the acetylcholine (ACh) acting on white adipocyte cholinergic receptors is unknown. This study was designed to identify ACh-producing cells in mouse and human visceral WAT and to determine whether a non-neuronal cholinergic system becomes activated in obese inflamed WAT. MethodsMouse epididymal WAT (eWAT) and human omental fat were studied in normal and obese subjects. The expression of the key molecules involved in cholinergic signaling was evaluated by qRT-PCR and western blotting whereas their tissue distribution and cellular localization were investigated by immunohistochemistry, confocal microscopy and in situ hybridization. ACh levels were measured by liquid chromatography/tandem mass spectrometry. The cellular effects of ACh were assessed in cultured human multipotent adipose-derived stem cell (hMADS) adipocytes. ResultsIn mouse eWAT, diet-induced obesity modulated the expression of key cholinergic molecular components and, especially, raised the expression of choline acetyltransferase (ChAT), the ACh-synthesizing enzyme, which was chiefly detected in interstitial macrophages, in macrophages forming crown-like structures (CLSs), and in multinucleated giant cells (MGCs). The stromal vascular fraction of obese mouse eWAT contained significantly higher ACh and choline levels than that of control mice. ChAT was undetectable in omental fat from healthy subjects, whereas it was expressed in a number of interstitial macrophages, CLSs, and MGCs from some obese individuals. In hMADS adipocytes stressed with tumor necrosis factor α, ACh, alone or combined with rivastigmine, significantly blunted monocyte chemoattractant protein 1 and interleukin 6 expression, it partially but significantly, restored adiponectin and GLUT4 expression, and promoted glucose uptake. ConclusionsIn mouse and human visceral WAT, obesity induces activation of a macrophage-dependent non-neuronal cholinergic system that is capable of exerting anti-inflammatory and insulin-sensitizing effects on white adipocytes.

Profiling Novel Quinuclidine-Based Derivatives as Potential Anticholinesterase Drugs: Enzyme Inhibition and Effects on Cell Viability.

The cholinergic system, relying on the neurotransmitter acetylcholine (ACh), plays a significant role in muscle contraction, cognition, and autonomic nervous system regulation. The enzymes acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, responsible for hydrolyzing ACh, can fine-tune the cholinergic system's activity and are, therefore, excellent pharmacological targets to address a range of medical conditions. We designed, synthesized, and profiled 14 N-alkyl quaternary quinuclidines as inhibitors of human AChE and BChE and analyzed their impact on cell viability to assess their safety in the context of application as potential therapeutics. Our results showed that all of the 14 tested quinuclidines inhibited both AChE and BChE in the micromolar range (Ki = 0.26 - 156.2 μM). The highest inhibition potency was observed for two bisquaternary derivatives, 7 (1,1'-(decano)bis(3-hydroxyquinuclidinium bromide)) and 14 (1,1'-(decano)bis(3-hydroxyiminoquinuclidinium bromide)). The cytotoxic effect within 7-200 μM was observed only for monoquaternary quinuclidine derivatives, especially those with the C12-C16 alkyl chain. Further analysis revealed a time-independent mechanism of action, significant LDH release, and a decrease in the cells' mitochondrial membrane potential. Taking all results into consideration, we can confirm that a quinuclidine core presents a good scaffold for cholinesterase binding and that two bisquaternary quinuclidine derivatives could be considered as candidates worth further investigations as drugs acting in the cholinergic system. On the other hand, specific cell-related effects probably triggered by the free long alkyl chain in monoquaternary quinuclidine derivatives should not be neglected in future N-alkyl quaternary quinuclidine derivative structure refinements. Such an effect and their potential to interact with other specific targets, as indicated by a pharmacophore model, open up a new perspective for future investigations of these compounds' scaffold in the treatment of specific conditions and diseases other than cholinergic system-linked disorders.

Research on the contribution of REM sleep to procedural learning

Many studies have confirmed the contribution of sleep to memory consolidation. However, the benefit of rapid eye movement (REM) sleep on memory consolidation remains debatable due to discrepant findings. This paper reviewed the latest human studies that employed complex cognitive procedural learning tasks and new learning techniques, including metacognition stimulation and targeted memory reaction (TMR), to provide evidence on the correlation between REM sleep and memory consolidation of procedural learning. Next, the main hypotheses aiming to explain its underlying neurobiological mechanisms were summarized, with a discussion about the striatum's role, the cholinergic system's activity, and synaptic plasticity during REM sleep. Finally, the paper discussed potential reasons for data inconsistency and several aspects that should be considered in future sleep and memory research.

Direct Evidence for Using Coriandrum sativum var. microcarpum Essential Oil to Ameliorate Scopolamine-Induced Memory Impairment and Brain Oxidative Stress in the Zebrafish Model.

Essential oil from Coriandrum sativum has been demonstrated to provide various pharmacological properties, such as antioxidant, antimicrobial, antibacterial, antifungal, antidiabetic, anticonvulsive, anxiolytic-antidepressant, and anti-aging properties. This study investigated the mechanism of Coriandrum sativum var. microcarpum essential oil (CSEO, 25, 150, and 300 μL/L) and cognitive impairment and brain oxidative stress in a scopolamine (SCOP, 100 μM) zebrafish model (Danio rerio) of cognitive impairment. Spatial memory, response to novelty, and recognition memory were assessed using the Y-maze test and the novel object recognition test (NOR), while anxiety-like behavior was investigated using the novel tank diving test (NTT). The cholinergic system activity and brain oxidative stress were also evaluated. CSEO was administered to zebrafish once a day for 21 days, while SCOP and galantamine (GAL, 1 mg/L) were delivered 30 min before behavioral testing and euthanasia. Our data revealed that SCOP induced memory dysfunction and anxiety-like behavior, while CSEO improved memory performance, as evidenced by behavioral tasks. Moreover, CSEO attenuated SCOP-induced brain oxidative stress and decreased acetylcholinesterase (AChE) activity. The results demonstrated the potential use of the CSEO in providing beneficial effects by reducing memory deficits and brain oxidative stress involved in the genesis of a dementia state.

RETRACTED: Non-neuronal cholinergic system delays cardiac remodelling in type 1 diabetes

AimsType 1 diabetes mellitus (T1DM) is associated with increased risk of cardiovascular disease (CVD) and mortality. The underlying mechanisms for T1DM-induced heart disease still remains unclear. In this study, we aimed to investigate the effects of cardiac non-neuronal cholinergic system (cNNCS) activation on T1DM-induced cardiac remodelling. MethodsT1DM was induced in C57Bl6 mice using low-dose streptozotocin. Western blot analysis was used to measure the expression of cNNCS components at different time points (4, 8, 12, and 16 weeks after T1DM induction). To assess the potential benefits of cNNCS activation, T1DM was induced in mice with cardiomyocyte-specific overexpression of choline acetyltransferase (ChAT), the enzyme required for acetylcholine (Ac) synthesis. We evaluated the effects of ChAT overexpression on cNNCS components, vascular and cardiac remodelling, and cardiac function. Key findingsWestern blot analysis revealed dysregulation of cNNCS components in hearts of T1DM mice. Intracardiac ACh levels were also reduced in T1DM. Activation of ChAT significantly increased intracardiac ACh levels and prevented diabetes-induced dysregulation of cNNCS components. This was associated with preserved microvessel density, reduced apoptosis and fibrosis, and improved cardiac function. SignificanceOur study suggests that cNNCS dysregulation may contribute to T1DM-induced cardiac remodelling, and that increasing ACh levels may be a potential therapeutic strategy to prevent or delay T1DM-induced heart disease.

Sub-pocket-focused designing of tacrine derivatives as potential acetylcholinesterase inhibitors

Human acetylcholinesterase (hAChE) has a potential role in the management of acetylcholine, one of the neurotransmitters that modulate the overall activity of cholinergic system, AChE inhibitors have a greater impact in the therapeutics. Though the atomic structure of hAChE has been extensively studied, the precise active site geometry upon binding to different ligands are yet to be explored. In the present study, an extensive structural analysis of our recently reported hAChE-tacrine complex has carried out and revealed the presence of two prominent sub-pockets located at the vicinity of the hAChE active site. Structural bioinformatics assisted studies designed 132 putative sub-pockets focused tacrine derivatives (SPFTDs), their molecular docking, free energy estimations revealed that they are stronger than tacrine in terms of binding affinity. Our in vitro studies also supported the in silico findings, all these SPFTDs are having better potencies than tacrine. Cytotoxic nature of these SPFTDs on HepG2 and Neuro-2a cell lines, diminishes the possibilities for future in vivo studies. However, the identification of these sub pockets and the SPFTDs paved a new way to the future drug discovery especially since AChE is one of the promising and approved drug targets in treatment of AD drug discovery.

Promnesic, Anxiolytic and Antioxidant Effects of Glaucosciadium cordifolium (Boiss.) Burtt & Davis Essential Oil in a Zebrafish Model of Cognitive Impairment.

The purpose of this study was to investigate the effect of Glaucosciadium cordifolium essential oil (GCEO, 25 and 150 µL/L) on anxiety and learning and memory impairment induced by scopolamine (SCOP) in zebrafish. The chemical composition was analyzed by GC-MS, and the results showed that the highest content was limonene followed by α- and β-pinene, p-cymene and α-phellandrene. The dementia model was induced by SCOP (100 µM), whereas GCEO and galantamine (GAL, 1 mg/L) were delivered to the SCOP-induced model. It was found that GCEO significantly improved memory impairment and anxiety-like response induced by SCOP through the Y-maze, novel object recognition (NOR) test, and novel tank diving tests (NTT). Biochemical analyses showed that GCEO reduced SCOP-induced oxidative damage. Additionally, the cholinergic system activity was improved in the SCOP-induced model by decreasing the acetylcholinesterase (AChE) activity following the exposure to GCEO. It was clear that as a mixture, GCEO displays positive action in improving memory impairment through restoring cholinergic dysfunction and brain antioxidant status.

TaVNS Alleviates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats Via Activating Basal Forebrain Cholinergic Neurons.

Postoperative cognitive dysfunction (POCD) is a common complication of central nervous system after anesthesia or surgery. Sevoflurane, an inhalation anesthetic, may inhibit cholinergic pathway that induce neuronal death and neuroinflammation, ultimately leading to POCD. Transauricular vagus nerve stimulation (taVNS) has neuroprotective effects in POCD rats, but the mechanisms related to cholinergic system have not been revealed. Sprague-Dawley rats were anesthetized with sevoflurane to construct the POCD model. The immunotoxin 192-IgG-saporin (192-sap) selectively lesioned cholinergic neurons in the basal forebrain, which is the major source of cholinergic projections to hippocampus. After lesion, rats received 5 days of taVNS treatment (30min per day) starting 24h before anesthesia. Open field test and Morris water maze were used to test the cognitive function. In this study, rats exposed to sevoflurane exhibited cognitive impairment that was attenuated by taVNS. In addition, taVNS treatment activated cholinergic system in the basal forebrain and hippocampus, and downregulated the expression of apoptosis- and necroptosis-related proteins, such as cleaved Caspase-3 and p-MLKL, in the hippocampus. Meanwhile, the activation of Iba1+ microglial by sevoflurane was reduced by taVNS. 192-sap blocked the cholinergic system activation in the basal forebrain and hippocampus and inhibited taVNS-mediated neuroprotection and anti-inflammation effects in the hippocampus. Generally, our study indicated that taVNS might alleviate sevoflurane-induced hippocampal neuronal apoptosis, necroptosis and microglial activation though activating cholinergic system in the basal forebrain.

In vivo cholinergic system integrity and cognition using [18F]‐FEOBV PET in healthy postmenopausal women: a pilot study

AbstractBackgroundWomen are at a higher risk of developing Alzheimer’s disease (AD), and a possible reason for this may be the effects of estrogen depletion and cholinergic system activity following menopause. The investigational radiotracer [18F]‐fluoroethoxybenzovesamicol (FEOBV) can assess in vivo cholinergic integrity, as the tracer binds to the vesicular cholinergic transporter at the synapse. FEOBV has previously shown cholinergic system decline in AD patients. The present study is an investigation of cholinergic system integrity in a sample of cognitively normal postmenopausal women, aged 50‐70 years that were part of a larger study examining cholinergic compensation following menopause. We predicted that higher FEOBV standardized uptake value ratios (SUVR) would be associated with larger basal forebrain cholinergic volumes, lower levels of amyloid SUVR, and better cognitive performance as measured by the RBANS.MethodsTen postmenopausal women (mean age: 57.3 ± 5.1 years) completed an FEOBV PET scan (6.5 mCi dose), MRI and cognitive assessments. The FEOBV PET images were co‐registered to the participant’s structural MRI data. FEOBV SUVR was normalized in reference to the supraventricular white matter to avoid partial volume effects from ventricular tissue. Preliminary analyses focused on associations between FEOBV SUVR and the key outcome variables.ResultsPreliminary analyses showed a positive relationship between FEOBV SUVR and the gray‐matter volume of the cholinergic basal forebrain of both hemispheres (L: r=0.51, R: r=0.65). Two participants were amyloid positive, and their FEOBV SUVR values were lower compared to the amyloid negative participants. A positive relationship was also seen between FEOBV SUVR and the RBANS total score, with higher SUVR associated with better cognitive performance (r=0.43).ConclusionsIn a small sample of cognitively normal postmenopausal women, greater FEOBV uptake was positively associated with both basal forebrain volume and cognitive performance. The results of this pilot sample show the importance of cholinergic system integrity in cognitive performance following menopause, supporting the idea that cholinergic integrity may be linearly related to performance and amyloid aggregation. Deterioration of cholinergic integrity post‐menopause may increase the risk of future cognitive decline and development of AD.

Katsuo extract derived from dried bonito plays a role in systemic anti-inflammation and consolidation of the blood-brain barrier to regulate higher brain functions

Objects: Recently, a non-neuronal cardiac cholinergic system, in which cardiomyocytes are equipped with components to synthesize acetylcholine, is considered to be important for maintaining physiological homeostasis in the heart, according to its anti-ischemia and hypoxia effects and angiogenesis-enhancing effects to salvage myocardium. Furthermore, it influences sustaining blood brain barrier functions. However, it remains to be fully elucidated whether any substance plays a role in activating the system.Methods: Using Katsuo extract derived from dried bonito, called Katsuobushi in Japanese, we performed in vitro and in vivo studies whether Katsuo extract activates the non-neuronal cardiac cholinergic system and influences the associated physiological responses, specifically focusing on anti-inflammatory property and potentiation of blood brain barrier functions.Results: Katsuo extract potently activates the non-neuronal cardiac cholinergic system and the parasympathetic nervous system. In vitro and in vivo murine models clearly showed that Katsuo extract also exerted anti-inflammatory action by suppressing cytokine production and microglial activation against pathogenic and non-pathogenic factors. Furthermore, it upregulated blood brain barrier components, such as claudin-5 and occludin, strengthened the function and prevented disruption in a brain injury model, and finally influenced murine higher brain functions by activating resiliency against depressive or anxiety-like behaviors.Conclusion: Therefore, the novel findings of this study indicate that Katsuo extract possesses characteristic anti-inflammatory and blood brain barrier consolidation effects, and the non-neuronal cardiac cholinergic system activation. The intake might be effective in influencing pathophysiology of neuroinflammation-related diseases.

Sweroside Ameliorated Memory Deficits in Scopolamine-Induced Zebrafish (Danio rerio) Model: Involvement of Cholinergic System and Brain Oxidative Stress.

Sweroside is a secoiridoid glycoside and belongs to a large group of naturally occurring monoterpenes with glucose sugar attached to C-1 in the pyran ring. Sweroside can promote different biological activities such as antifungal, antibacterial, hepatoprotective, gastroprotective, sedative and antitumor, antioxidant, and neuroprotective activities. Zebrafish were given sweroside (12.79, 8.35, and 13.95 nM) by immersion once daily for 8 days, along with scopolamine (Sco, 100 μM) 30 min before the initiation of the behavioral testing to cause anxiety and memory loss. Employing the novel tank diving test (NTT), the Y-maze, and the novel object recognition test (NOR), anxiety-like reactions and memory-related behaviors were assessed. The following seven groups (n = 10 animals per group) were used: control, Sco (100 μM), sweroside treatment (2.79, 8.35, and 13.95 nM), galantamine (GAL, 2.71 μM as the positive control in Y-maze and NOR tests), and imipramine (IMP, 63.11 μM as the positive control in NTT test). Acetylcholinesterase activity (AChE) and the antioxidant condition of the brains were also evaluated. The structure of sweroside isolated from Schenkia spicata was identified. Treatment with sweroside significantly improved the Sco-induced decrease of the cholinergic system activity and brain oxidative stress. These results suggest that sweroside exerts a significant effect on anxiety and cognitive impairment, driven in part by the modulation of the cholinergic system activity and brain antioxidant action.

DE-71 affected the cholinergic system and locomotor activity via disrupting calcium homeostasis in zebrafish larvae.

Polybrominated diphenyl ethers (PBDEs) can induce neurotoxicity, but the mechanism of their toxicity on the cholinergic system and locomotion behavior remains unclear. In this paper, zebrafish embryos were exposed to DE-71 (0, 1, 3, 10, 30, and 100µg/L) until 120h post fertilization, and its effects on the behavior and cholinergic system of zebrafish larvae and its possible mechanism were investigated. Results indicated a general locomotor activity impairment in the light-dark transition stimulation without affecting the secondary motoneurons. However, with the extension of test time in the dark or light, the decreased locomotor activity was diminished, a significant decrease only observed in the 100µg/L DE-71 exposure groups in the last 10min. Furthermore, whole-body acetylcholine (ACh) contents decreased after DE-71 exposure, whereas no changes in NO contents and inducible nitric oxide synthase activity were found. The expression of certain genes encoding calcium homeostasis proteins (e.g., grin1a, camk2a, and crebbpb) and the concentrations of calcium in zebrafish larvae were significantly decreased after DE-71 exposure. After co-exposure with calcium channel agonist (±)-BAY K8644, calcium concentrations, ACh contents, and locomotor activity in the light-dark transition stimulation was significantly increased compared with the same concentrations of DE-71 exposure alone, whereas no significant difference was observed compared with the control, indicating that calcium homeostasis is involved in the impairment of cholinergic neurotransmission and locomotor activity. Overall, our results suggested that DE-71 can impair the cholinergic system and locomotor activity by impairing calcium homeostasis. Our paper provides a better understanding of the neurotoxicity of PBDEs.

Variations in Pupil Size Related to Memory for Recently Presented Words and Event Related Potentials.

Pupillometry has been found to be correlated with activity of cholinergic and noradrenergic neuromodulator systems. These systems regulate the level of cortical arousal and therefore perception, attention, and memory. Here, we tested how different types of pupil size variance (prestimulus baseline and prestimulus hippus power) may correlate with behavioral and event-related potentials (ERPs). We recorded pupil size and ERPs while participants were presented with a series of words and then asked whether the words had been in the initial list when they were later presented intermixed with unpresented words. We found that a smaller prestimulus baseline pupil size during the study phase was associated with better memory performance. Study items also evoked a larger P3 response at presentation and a greater old/new memory ERP effect at test when prestimulus pupil size was small rather than large. Prestimulus hippus power was found to be a between-subjects factor affecting the robustness of memory encoding with less power being associated with a greater old/new memory ERP effect. These results provide evidence relating memory and ERPs to variables defined on pupil size that are thought to reflect varying states of parasympathetic and sympathetic arousal.

Neuroprotective and antioxidant effects of pitaya fruit on Cu‐induced stress in adult zebrafish

The harmful effects of heavy metals on organisms have not been fully described. At present, there is a close relationship between neurodegenerative diseases and copper toxicity. In addition, the copper effect on the central nervous system is followed by high levels of free radicals in different body tissues. An increase in free radical levels leads to aging-related diseases, resulting in the appearance of senile comorbidities. An increase in the consumption of natural compounds that could help to reduce this dangerous effect on organisms was observed. Pitaya (Hylocereus undatus) is a tropical fruit with great antioxidant potential and can help the organism with oxidative damage. This study evaluated the effect of H. undatus on zebrafish organisms in front of copper-induced toxicity. Therefore, the behavior, cholinergic system, antioxidant enzymes, and ALAD activity were evaluated as biomarkers. Our results highlight the great potential of Pitaya's pulp to reduce the levels of anxiety and aggressivity in fish and reduce cortisol levels. It could mediate the normal response of the cholinergic nervous system, antioxidant enzymes, and ALAD activity. Therefore, our data suggest that pitaya might improve the senile aging. PRACTICAL APPLICATIONS: The potential practical application of this study is related to the neuroprotective effect of the Hylocereus undatus microencapsulated pulp extract against metal-induced impairments. The results have shown that this extract is able to reduce the copper-induced damage modulating the antioxidant system and the cholinergic nervous system. One of the implicated potentials of use for this extract is the food supplementation to its fortification.

Bee Venom Activates the Nrf2/HO-1 and TrkB/CREB/BDNF Pathways in Neuronal Cell Responses against Oxidative Stress Induced by Aβ1-42.

Honeybee venom has recently been considered an anti-neurodegenerative agent, primarily due to its anti-inflammatory effects. The natural accumulation of amyloid-beta (Aβ) in the brain is reported to be the natural cause of aging neural ability downfall, and oxidative stress is the main route by which Aβ ignites its neural toxicity. Anti-neural oxidative stress is considered an effective approach for neurodegenerative therapy. To date, it is unclear how bee venom ameliorates neuronal cells in oxidative stress induced by Aβ. Here, we evaluated the neuroprotective effect of bee venom on Aβ-induced neural oxidative stress in both HT22 cells and an animal model. Our results indicate that bee venom protected HT22 cells against apoptosis induced by Aβ1–42. This protective effect was explained by the increased nuclear translocation of nuclear factor erythroid 2-like 2 (Nrf2), consequently upregulating the production of heme oxygenase-1 (HO-1), a critical cellular instinct antioxidant enzyme that neutralizes excessive oxidative stress. Furthermore, bee venom treatment activated the tropomyosin-related kinase receptor B (TrkB)/cAMP response element-binding (CREB)/brain-derived neurotrophic factor (BDNF), which is closely related to the promotion of cellular antioxidant defense and neuronal functions. A mouse model with cognitive deficits induced by Aβ1–42 intracerebroventricular (ICV) injections was also used. Bee venom enhanced animal cognitive ability and enhanced neural cell genesis in the hippocampal dentate gyrus region in a dose-dependent manner. Further analysis of animal brain tissue and serum confirmed that bee venom reduced oxidative stress, cholinergic system activity, and intercellular neurotrophic factor regulation, which were all adversely affected by Aβ1–42. Our study demonstrates that bee venom exerts antioxidant and neuroprotective actions against neural oxidative stress caused by Aβ1–42, thereby promoting its use as a therapeutic agent for neurodegenerative disorders.

Cognitive Health After MenoPause (CHAMP) Study: A study of the health of the cholinergic system and risk factors for future cognitive decline in postmenopausal women aged 50‐70

AbstractBackgroundMenopause is associated with changes in hormone balances, and also to cognition in some women. These changes have been proposed to lead to an increased risk of developing Alzheimer’s disease (AD). However, there is not a clear understanding of how these changes are linked to neurodegeneration. One theory of what may be driving cognitive changes may be linked to how estrogen depletion affects cholinergic system activity. Preclinical studies have shown that estrogen is necessary for normal cholinergic functioning and its withdrawal leads to cholinergic dysfunction and cognitive impairment. And previous studies in postmenopausal women have shown that anticholinergic blockade is effective at modulating activity when performing working memory tasks.MethodThe CHAMP study will determine whether menopause‐related cognitive changes correlate with both cholinergic functional integrity and established AD biomarkers in a sample of 120 healthy postmenopausal women aged 50‐70 years. Using an anticholinergic challenge model, this study will examine cognitive performance on memory tasks using fMRI. The present study will collect established AD biomarkers of amyloid and tau levels in both blood and CSF samples, as well as through amyloid PET imaging, and markers of neurodegeneration including medial temporal lobe volume through structure MRI. In addition, the study will also collect genomic markers of impairment, such as APOE and COMT genotypes.ResultWe predict that women with poor compensation following menopause will be more sensitive to anticholinergic blockade, and will show decreased working memory performance, reduced brain activation, and decreased basal forebrain cholinergic system volume.ConclusionIn addition, we predict that these cholinergic markers will also be related to menopausal factors associated with poor cognition and biomarkers that are related to AD.

Origanum vulgare ssp. hirtum (Lamiaceae) Essential Oil Prevents Behavioral and Oxidative Stress Changes in the Scopolamine Zebrafish Model.

Origanum vulgare ssp. hirtum has been used as medicinal herbs promoting antioxidant, anti-inflammatory, antimicrobial, and neuroprotective activities. We investigated the protective effects and the mechanism of O. vulgare ssp. hirtum essential oil (OEO) on cognitive impairment and brain oxidative stress in a scopolamine (Sco)-induced zebrafish (Danio rerio) model of cognitive impairment. Our results show that exposure to Sco (100 µM) leads to anxiety, spatial memory, and response to novelty dysfunctions, whereas the administration of OEO (25, 150, and 300 µL/L, once daily for 13 days) reduced anxiety-like behavior and improved cognitive ability, which was confirmed by behavioral tests, such as the novel tank-diving test (NTT), Y-maze test, and novel object recognition test (NOR) in zebrafish. Additionally, Sco-induced brain oxidative stress and increasing of acetylcholinesterase (AChE) activity were attenuated by the administration of OEO. The gas chromatography–mass spectrometry (GC-MS) analyses were used to elucidate the OEO composition, comprising thymol (38.82%), p-cymene (20.28%), and γ-terpinene (19.58%) as the main identified components. These findings suggest the ability of OEO to revert the Sco-induced cognitive deficits by restoring the cholinergic system activity and brain antioxidant status. Thus, OEO could be used as perspective sources of bioactive compounds, displaying valuable biological activities, with potential pharmaceutical applications.

Neuroprotective Activity of Melittin-The Main Component of Bee Venom-Against Oxidative Stress Induced by Aβ25-35 in In Vitro and In Vivo Models.

Melittin, a 26-amino acid peptide, is the main component of the venom of four honeybee species and exhibits neuroprotective actions. However, it is unclear how melittin ameliorates neuronal cells in oxidative stress and how it affects memory impairment in an in vivo model. We evaluated the neuroprotective effect of melittin on Aβ25–35-induced neuro-oxidative stress in both in vitro HT22 cells and in vivo animal model. Melittin effectively protected against HT22 cell viability and significantly deregulated the Aβ25–35-induced overproduction of intracellular reactive oxygen species. Western blot analysis showed that melittin suppressed cell apoptosis and regulated Bax/Bcl-2 ratio, as well as the expression of proapoptotic related factors: Apoptosis-inducing factor (AIF), Calpain, Cytochrome c (CytoC), Cleaved caspase-3 (Cleacas3). Additionally, melittin enhanced the antioxidant defense pathway by regulating the nuclear translocation of nuclear factor erythroid 2-like 2 (Nrf2) thus upregulated the production of the heme oxygenase-1 (HO-1), a major cellular antioxidant enzyme combating neuronal oxidative stress. Furthermore, melittin treatment activated the Tropomyosin-related kinase receptor B (TrkB)/cAMP Response Element-Binding (CREB)/Brain-derived neurotrophic factor (BDNF), contributing to neuronal neurogenesis, and regulating the normal function of synapses in the brain. In our in vivo experiment, melittin was shown to enhance the depleted learning and memory ability, a novel finding. A mouse model with cognitive deficits induced by Aβ25–35 intracerebroventricular injection was used. Melittin had dose-dependently enhanced neural-disrupted animal behavior and enhanced neurogenesis in the dentate gyrus hippocampal region. Further analysis of mouse brain tissue and serum confirmed that melittin enhanced oxidant–antioxidant balance, cholinergic system activity, and intercellular neurotrophic factors regulation, which were all negatively altered by Aβ25–35. Our study shows that melittin exerts antioxidant and neuroprotective actions against neural oxidative stress. Melittin can be a potential therapeutic agent for neurodegenerative disorders.

Antagonism of Cerebral High Mobility Group Box 1 Ameliorates Dendritic Cell Dysfunction in Sepsis.

Sepsis has emerged as a global health issue, and accounts for millions of deaths in intensive care units. Dysregulation of the immune response reportedly contributes to the pathogenesis and progression of this lethal condition, which involves both the dysfunction of immune cells and incompetent immunomodulatory mechanisms. High mobility group box 1 (HMGB1) is known as a later inflammatory mediator and is critically involved in the severity and prognosis of sepsis by inducing intractable inflammation and dysfunction of various immune cells. In the present study, we found that intracerebroventricular (ICV) injection of Box A, a specific antagonist of HMGB1, restored the dysregulated response of splenic dendritic cells (DCs) in septic mice by enhancing the expression of surface molecules, including CD80, CD86, and MHC-II, as well as improving DC priming of T lymphocytes. Cerebral HMGB1 was also confirmed to have potent inhibitory effects on DC functions when administrated by ICV injection in normal mice. The brain cholinergic system was found to mediate the immunomodulatory effects of central HMGB1, as it exhibited enhanced activity with persistent HMGB1 exposure. Furthermore, the inhibitory effects of cerebral HMGB1 on the response of peripheral DCs were also blocked by α7nAchR gene knockout. These findings provide novel insight into the relationship between cerebral HMGB1 and splenic DC dysfunction during sepsis, which is, at least in part, dependent on cholinergic system activity.