scholarly journals Neostigmine Attenuates Proinflammatory Cytokine Expression in Preoptic Area but Not Choroid Plexus during Lipopolysaccharide-Induced Systemic Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Andrzej P. Herman ◽  
Dorota Tomaszewska-Zaremba ◽  
Marta Kowalewska ◽  
Aleksandra Szczepkowska ◽  
Małgorzata Oleszkiewicz ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Proinflammatory Cytokine ◽  
Preoptic Area ◽  
De Novo ◽  
Brain Parenchyma ◽  
Ache Inhibitor ◽  
Ache Inhibitors ◽  
Reproduction Process ◽  
Hypothalamic Structure ◽  
Alpha 7

The study was designed to examine whether the administration of neostigmine (0.5 mg/animal), a peripheral inhibitor of acetylcholinesterase (AChE), during an immune/inflammatory challenge provoked by intravenous injection of bacterial endotoxin—lipopolysaccharide (LPS; 400 ng/kg)—attenuates the synthesis of proinflammatory cytokines in the ovine preoptic area (POA), the hypothalamic structure playing an essential role in the control of the reproduction process, and in the choroid plexus (CP), a multifunctional organ sited at the interface between the blood and cerebrospinal fluid in the ewe. Neostigmine suppressed (p<0.05) LPS-stimulated synthesis of cytokines such as interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF) α in the POA, and this effect was similar to that induced by the treatment with systemic AChE inhibitor—donepezil (2.5 mg/animal). On the other hand, both AChE inhibitors did not influence the gene expression of these cytokines and their corresponding receptors in the CP. It was found that this structure seems to not express the neuronal acetylcholine (ACh) receptor subunit alpha-7, required for anti-inflammatory action of ACh. The mechanism of action involves inhibition of the proinflammatory cytokine synthesis on the periphery as well as inhibition of their de novo synthesis rather in brain microvessels and not in the CP. In conclusion, it is suggested that the AChE inhibitors incapable of reaching brain parenchyma might be used in the treatment of neuroinflammatory processes induced by peripheral inflammation.

scholarly journals Peripheral Inhibitor of AChE, Neostigmine, Prevents the Inflammatory Dependent Suppression of GnRH/LH Secretion during the Follicular Phase of the Estrous Cycle

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Andrzej P. Herman ◽  
Janina Skipor ◽  
Agata Krawczyńska ◽  
Joanna Bochenek ◽  
Karolina Wojtulewicz ◽  
...  
Keyword(s):  
Estrous Cycle ◽  
Inhibitory Effect ◽  
Follicular Phase ◽  
Ache Inhibitor ◽  
Ache Inhibitors ◽  
The Central Nervous System ◽  
Lh Release ◽  
Hypothalamic Structure ◽  
Lh Secretion ◽  
Lps Treatment

The study was designed to test the hypothesis that the inhibition of acetylcholinesterase (AChE) activity at the periphery by Neostigmine (0.5 mg/animal) will be sufficient to prevent inflammatory dependent suppression of the gonadotropin-releasing hormone (GnRH)/luteinising hormone (LH) secretion in ewes in the follicular phase of the estrous cycle, and this effect will be comparable with the systemic AChE inhibitor, Donepezil (2.5 mg/animal). An immune/inflammatory challenge was induced by peripheral administration of lipopolysaccharide (LPS; 400 ng/kg). Peripheral treatment with Donepezil and Neostigmine prevented the LPS-induced decrease (P<0.05) in LHβ gene expression in the anterior pituitary gland (AP) and in LH release. Moreover, Donepezil completely abolished (P<0.05) the suppressory effect of inflammation on GnRH synthesis in the preoptic area, when pretreatment with Neostigmine reduced (P<0.05) the decrease in GnRH content in this hypothalamic structure. Moreover, administration of both AChE inhibitors diminished (P<0.05) the inhibitory effect of LPS treatment on the expression of GnRH receptor in the AP. Our study shows that inflammatory dependent changes in the GnRH/LH secretion may be eliminated or reduced by AChE inhibitors suppressing inflammatory reaction only at the periphery such as Neostigmine, without the need for interfering in the central nervous system.

Analysis of Changes in Signal Intensity of Choroid Plexus in MRI Using FLAIR-DW-EPI Pulse Sequence

2020 ◽  
Vol 3 (1) ◽  
pp. 9-15
Author(s):  
Jingyu Kim ◽  
◽  
Sang-Jin Im ◽  
Keyword(s):  
Choroid Plexus ◽  
Signal Intensity ◽  
Pulse Sequence ◽  
Signal Strength ◽  
Brain Parenchyma ◽  
Weighted Image ◽  
Diffusion Weighted ◽  
Water Signal ◽  
The Brain ◽  
Functional Problems

In this study, the signal intensity of choroid plexus, which is producing cerebrospinal fluid, is analyzed according to the FLAIR diffusion-weighted imaging technique. In the T2*-DW-EPI diffusion-weighted image, the FLAIR-DW-EPI technique, which suppressed the water signal, was additionally examined for subjects with high choroid plexus signals and compared and analyzed the signal intensity. As a result of the experiment, it was confirmed that the FLAIR-DW-EPI technique showed a signal strength equal to or lower than that of the brain parenchyma, and there was a difference in signal strength between the two techniques. As a result of this study, if the choroidal plexus signal is high in the T2 * -DW-EPI diffusionweighted image, additional examination of the FLAIR-DW-EPI technique is thought to be useful in distinguishing functional problems of the choroid plexus. In conclusion, if the choroidal plexus signal is high on the T2*-DW-EPI diffuse weighted image, it is thought that further examination of the FLAIR-DW-EPI technique will be useful in distinguishing functional problems of the choroidal plexus.

scholarly journals Senescent Accelerated Prone 8 (SAMP8) Mice as A Model of Age Dependent Neuroinflammation

2020 ◽  
Author(s):  
Andrés Fernández ◽  
Elena Quintana ◽  
Patricia Velasco ◽  
Belén de Andrés ◽  
Maria Luisa Gaspar ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Inflammatory Cytokines ◽  
Hippocampal Formation ◽  
Morphological Changes ◽  
Interleukin 1 ◽  
Brain Parenchyma ◽  
Age Related ◽  
Inflammatory Changes ◽  
Samp8 Mice ◽  
The Brain

Abstract Background: Aging and age related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). The need of animal models that will allow us to understand and modulate this process is required for the scientific community. Methods: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their resistant to senescence control (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and analyzed Iba1+ clustered cells with aging. To analyse specific constant brain areas we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch), and analyzed their response to systemic LPS- driven inflammation.Results: Aged 10 month old SAMP8 mice presents many of the hallmarks of aging-dependent neuroinflammation when compared with their senescence resistant control (SAMR1); ie, increase of protein aggregates, presence of Iba1+ clusters, but not increase in the number of Iba1+ cells. We have further observed and increased of main inflammatory mediator IL-1β, and augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch) have been analyzed showing that there is not significant increase of CD45+ from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL1β) transcription is mainly enhanced in CD45+BP cells. Furthermore, we are showing that LPS-driven systemic inflammation produces inflammatory cytokines mainly in the border bMyC, sensed to a lesser extent by the BP bMyC, and is enhanced in aged SAMP8 compared to control SAMR1.Conclusion: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of main pro inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

scholarly journals Acetylcholinesterase Inhibition, Molecular Docking and ADME Prediction Studies of New Dihydrofuran-Piperazine Hybrid Compounds

2021 ◽  
Author(s):  
Sait SARI ◽  
Mehmet YILMAZ
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Molecular Docking ◽  
Magnetic Resonance ◽  
High Resolution Mass Spectrometry ◽  
Proton Nuclear Magnetic Resonance ◽  
Acetylcholinesterase Inhibition ◽  
Ache Inhibitor ◽  
Ache Inhibitors ◽  
Melting Point Analysis ◽  
Nuclear Magnetic

Abstract Novel acrylamide and methacryloyl carrying piperazine-dihydrofuran derivatives ( 3a-p ) were designed and obtained from radical cyclizations of unsaturated piperazine derivatives ( 1a-f ) with 1,3-dicarbonyl compounds ( 2a-c ) mediated by Mn(OAc) 3 . Structures of obtained compounds were confirmed with 1 H NMR (proton nuclear magnetic resonance), 13 C NMR (Carbon-13 nuclear magnetic resonance), HRMS (High resolution mass spectrometry), FTIR (Fourier-transform infrared spectroscopy and melting point analysis. Inhibitory activites of all piperazine-dihydrofuran compounds were evaluated against AChE (Acetylcholinesterase) by Ellman method and test results showed that 3a , 3c , 3j and 3l are most active AChEI’s (AChE inhibitors) of our work with IC 50 (half-maximal inhibitory concentration) values of 2.62, 5.29, 1.17 and 3.90 µM, respectively. Furthermore, ligand-protein interactions and inhibitory activity mechanisms of 3a and 3j were investigated by molecular docking. Finally, in silico molecular property and ADME (absorption, distribution, metabolism and excretion) of potential AChEI’s (AChE inhibitor) were predicted by PreADMET and Molinspiration webservers. It can be concluded that the lead compound 3j show excellent inhibiton and satisfactory druglike characteristics.

scholarly journals Novel cholinesterase paralogs of Schistosoma mansoni have perceived roles in cholinergic signaling, glucose scavenging and drug detoxification and are essential for parasite survival

2019 ◽  
Author(s):  
Bemnet Tedla ◽  
Javier Sotillo ◽  
Darren Pickering ◽  
Ramon M. Eichenberger ◽  
Luke Becker ◽  
...  
Keyword(s):  
Developmental Expression ◽  
Laboratory Animals ◽  
Parasite Development ◽  
Ache Inhibitor ◽  
Ache Inhibitors ◽  
Cholinergic Signaling ◽  
Parasite Survival ◽  
Drug Detoxification

AbstractCholinesterase (ChE) function in schistosomes is essential for orchestration of parasite neurotransmission but has been poorly defined with respect to the molecules responsible. Interrogation of the S. mansoni genome has revealed the presence of three ChE domain-containing genes (Smche)s, which we have shown to encode two functional acetylcholinesterases (AChE)s (Smache1 – smp_154600 and Smache3 – smp_136690) and a butyrylcholinesterase (BChE) (Smbche1 – smp_125350). Antibodies to recombinant forms of each SmChE localized the proteins to the tegument and neuromusculature of adults and schistosomula and developmental expression profiling differed among the three molecules, suggestive of functions extending beyond traditional cholinergic signaling. For the first time in schistosomes, we identified ChE enzymatic activity in fluke excretory/secretory (ES) products and, using proteomic approaches, attributed this activity to the presence of SmAChE1 and SmBChE1. To address the hypothesis that tegumental AChE mediates exogenous glucose scavenging by the parasite, we show that RNAi-mediated knockdown of smache1 and smache3, but not smbche1, significantly reduces glucose uptake by schistosomes. Parasite survival in vitro and in vivo was significantly impaired by silencing of each smche, either individually or in combination, attesting to the essential roles of these molecules. Lastly, in the first characterization study of a BChE from helminths, evidence is provided that SmBChE1 may act as a bio-scavenger of AChE inhibitors as the addition of recombinant SmBChE1 to parasite cultures mitigated the effect of the anti-schistosome AChE inhibitor DDVP (DDVP), whereas smbche1-silenced parasites displayed increased sensitivity to DDVP.Author summaryCholinesterases - aceytlcholinesterases (AChE)s and butyrylcholinesterases (BChE)s - are multi-functional enzymes that play a pivotal role in the nervous system of parasites by regulating neurotransmission through acetylcholine hydrolysis. Herein, we provide a detailed characterization of schistosome cholinesterases using molecular, enzymatic and gene-silencing approaches and show evidence for these molecules having roles in glucose scavenging and drug detoxification, in addition to their neuronal function. Further, we demonstrate the importance of these proteins to parasite development and survival through gene knockdown experiments in laboratory animals, providing evidence for the use of these proteins in the development of novel intervention strategies against schistosomiasis.

scholarly journals Biomonitoring of Acetylcholinesterase (AChE) Inhibitor and the Association with Hypertension among Farmers in Bandung, Indonesia

2020 ◽  
Vol 12 (4) ◽  
pp. 325-332
Author(s):  
Mulyana Mulyana ◽  
Iwan Sugiarta ◽  
Lim Jen Fuk ◽  
Vani Nur Pratami ◽  
Dewi Yunia Fitriani ◽  
...  
Keyword(s):  
Risk Factors ◽  
Biological Sample ◽  
Ache Activity ◽  
Descriptive Analysis ◽  
Ache Inhibitor ◽  
Medical Team ◽  
Ache Inhibitors ◽  
Activity Frequency ◽  
History Of ◽  
Independent Risk Factors

BACKGROUND: The use of acetylcholinesterase (AChE) insecticides is still widely used by farmers in flower and agricultural centers. However, biological monitoring of farmers is still very rare in Indonesia. AChE inhibitors are reported to have toxic effects on various organs.METHODS: This study involved 120 subjects in Cihideung, Cikole and Pangalengan areas. All subjects have been interviewed, physically examined and biological sample taken by medical team. Descriptive analysis was performed to assess general conditions of the subjects and AChE erythrocyte activity enzyme at pseudo-baseline and the next 3 months from pseudo-baseline. Statistical analysis have been performed of the pseudo-baseline AChE erythrocyte activity with hypertension and history of exposures.RESULTS: The median value of pseudo-baseline AChE erythrocyte activity was 8.10 (1.3-14.25) U/g hematocrit. In the comparison between pseudo-baseline and 3 month from pseudo-baseline AChE activity, 7 respondents from 19 respondents (36.84%) had lower enzyme activity than 70% and the others subjects have higher activity value. AChE erythrocyte activity is associate with frequency of insecticide exposures. AChE erythrocyte activity (p=0.04; Exp (B)=2.937 CI 95%=1.049-8.224) and age (p=0.025; Exp (B)=3.872 CI 95%=1.180-12.703) are independent risk factors for hypertension in farmworker.CONCLUSION: AChE erythrocyte activity associated with frequency of insecticide exposures and hypertension among farmworkers.KEYWORDS: AChE erythrocyte activity, frequency of insecticide expsoures, hypertension

scholarly journals Computer-Aided Discovery of Pentapeptide AEYTR as a Potent Acetylcholinesterase Inhibitor

2020 ◽  
Vol 21 (1) ◽  
pp. 243
Author(s):  
Enade Perdana Istyastono ◽  
Vivitri Dewi Prasasty
Keyword(s):  
Acetylcholinesterase Inhibitor ◽  
Md Simulations ◽  
Structure Characterization ◽  
Ache Inhibitor ◽  
Ache Inhibitors ◽  
Ic50 Value ◽  
Computer Aided ◽  
Acetylcholinesterase Enzyme ◽  
In Vitro Examination

One of the key targets in the drug development for potential Alzheimer’s disease (AD) therapeutics is the search for acetylcholinesterase enzyme (AChE) inhibitors. Very recently, a pentapeptide AEYTR was reported as a potential inhibitor for AChE. The peptide was identified in a retrospectively validated virtual screening campaign, which was subsequently followed by 10 ns molecular dynamics (MD) simulations. The study aimed to characterize the structure and identify in vitro of AEYTR peptide as a potent acetylcholinesterase inhibitor. This article presents the structure characterization and the in vitro examination of the peptide as an AChE inhibitor, followed by MD simulations for 100 ns. The results show that the pentapeptide is a potent AChE inhibitor with an IC50 value in the picomolar range and stabilizes the enzyme during MD simulations.

Translational value of choroid plexus imaging for tracking neuroinflammation in mice and humans

2021 ◽  
Vol 118 (36) ◽  
pp. e2025000118
Author(s):  
Vinzenz Fleischer ◽  
Gabriel Gonzalez-Escamilla ◽  
Dumitru Ciolac ◽  
Philipp Albrecht ◽  
Patrick Küry ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Choroid Plexus ◽  
Mouse Models ◽  
Functional Impairment ◽  
Brain Parenchyma ◽  
Autoimmune Encephalomyelitis ◽  
Inflammatory Conditions ◽  
Brain Responses ◽  
Experimental Mouse ◽  
Multiple Sclerosis Patients

Neuroinflammation is a pathophysiological hallmark of multiple sclerosis and has a close mechanistic link to neurodegeneration. Although this link is potentially targetable, robust translatable models to reliably quantify and track neuroinflammation in both mice and humans are lacking. The choroid plexus (ChP) plays a pivotal role in regulating the trafficking of immune cells from the brain parenchyma into the cerebrospinal fluid (CSF) and has recently attracted attention as a key structure in the initiation of inflammatory brain responses. In a translational framework, we here address the integrity and multidimensional characteristics of the ChP under inflammatory conditions and question whether ChP volumes could act as an interspecies marker of neuroinflammation that closely interrelates with functional impairment. Therefore, we explore ChP characteristics in neuroinflammation in patients with multiple sclerosis and in two experimental mouse models, cuprizone diet-related demyelination and experimental autoimmune encephalomyelitis. We demonstrate that ChP enlargement—reconstructed from MRI—is highly associated with acute disease activity, both in the studied mouse models and in humans. A close dependency of ChP integrity and molecular signatures of neuroinflammation is shown in the performed transcriptomic analyses. Moreover, pharmacological modulation of the blood–CSF barrier with natalizumab prevents an increase of the ChP volume. ChP enlargement is strongly linked to emerging functional impairment as depicted in the mouse models and in multiple sclerosis patients. Our findings identify ChP characteristics as robust and translatable hallmarks of acute and ongoing neuroinflammatory activity in mice and humans that could serve as a promising interspecies marker for translational and reverse-translational approaches.

scholarly journals The Role of the Choroid Plexus in Neutrophil Invasion after Traumatic Brain Injury

2009 ◽  
Vol 29 (9) ◽  
pp. 1503-1516 ◽  
Author(s):  
Joanna Szmydynger-Chodobska ◽  
Nathalie Strazielle ◽  
Brian J Zink ◽  
Jean-François Ghersi-Egea ◽  
Adam Chodobski
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Choroid Plexus ◽  
Neutrophil Migration ◽  
Inflammatory Cells ◽  
Brain Parenchyma ◽  
Electron Microscopic ◽  
Epithelial Barriers

Traumatic brain injury (TBI) frequently results in neuroinflammation, which includes the invasion of neutrophils. After TBI, neutrophils infiltrate the choroid plexus (CP), a site of the blood—cerebrospinal fluid (CSF) barrier (BCSFB), and accumulate in the CSF space near the injury, from where these inflammatory cells may migrate to brain parenchyma. We have hypothesized that the CP functions as an entry point for neutrophils to invade the injured brain. Using the controlled cortical impact model of TBI in rats and an in vitro model of the BCSFB, we show that the CP produces CXC chemokines, such as cytokine-induced neutrophil chemoattractant (CINC)-1 or CXCL1, CINC-2α or CXCL3, and CINC-3 or CXCL2. These chemokines are secreted both apically and basolaterally from the choroidal epithelium, a prerequisite for neutrophil migration across epithelial barriers. Consistent with these findings, we also provide electron microscopic evidence that neutrophils infiltrate the choroidal stroma and subsequently reach the intercellular space between choroidal epithelial cells. This is the first detailed analysis of the BCSFB function related to neutrophil trafficking. Our observations support the role of this barrier in posttraumatic neutrophil invasion.

Sign in / Sign up

Export Citation Format

Share Document