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ACS Chemical Neuroscience

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https://www.readbyqxmd.com/read/29787674/single-quantum-dot-tracking-reveals-serotonin-transporter-diffusion-dynamics-are-correlated-with-cholesterol-sensitive-threonine-276-phosphorylation-status-in-primary-midbrain-neurons
#1
Danielle M Bailey, Mackenzie A Catron, Oleg Kovtun, Robert L Macdonald, Qi Zhang, Sandra J Rosenthal
Serotonin transporter (SERT) terminates serotonin signaling in the brain by enabling rapid clearance of the neurotransmitter. SERT dysfunction has been associated with a variety of psychiatric disorders, including depression, anxiety, and autism. Visualizing SERT behavior at the single molecule level in endogenous systems remains a challenge. In this study, we utilize quantum dot (QD) single particle tracking (SPT) to capture SERT dynamics in primary rat midbrain neurons. Membrane microenvironment, specifically membrane cholesterol, plays a key role in SERT regulation and has been found to affect SERT conformational state...
May 24, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29791132/ptml-model-of-chembl-data-for-dopamine-targets-docking-synthesis-and-assay-of-new-plg-peptidomimetics
#2
Joana Ferreira da Costa, David Silva, Olga Caamaño, José M Brea, Maria Isabel Loza, Cristian R Munteanu, Alejandro Pazos, Xerardo García-Mera, Humbert González-Díaz
Predicting Drug-Protein Interactions (DPIs) for target proteins involved in Dopamine pathways is very important goal in medicinal chemistry. We can tackle this problem using Molecular Docking or Machine Learning (ML) models for one specific protein. Unfortunately, these models fail to account for large and complex Big Data sets of preclinical assays reported in public databases. This includes multiple conditions of assay like different experimental parameters, biological assays, target proteins, cell lines, organism of the target, organism of assay, etc...
May 23, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29786422/mechanisms-regulating-the-association-of-protein-phosphatase-1-with-spinophilin-and-neurabin
#3
Michael C Edler, Asma B Salek, Darryl S Watkins, Harjot Kaur, Cameron W Morris, Bryan K Yamamoto, Anthony J Baucum
Protein phosphorylation is a key mediator of signal transduction, allowing for dynamic regulation of substrate activity. Whereas protein kinases obtain substrate specificity by targeting specific amino acid sequences, serine/threonine phosphatase catalytic subunits are much more promiscuous in their ability to dephosphorylate substrates. To obtain substrate specificity, serine/threonine phosphatases utilize targeting proteins to regulate phosphatase subcellular localization and catalytic activity. Spinophilin and its homolog neurabin are two of the most abundant dendritic spine-localized protein phosphatase 1 (PP1) targeting proteins...
May 22, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29783840/discovery-of-melanocortin-ligands-via-a-double-simultaneous-substitution-strategy-based-on-the-ac-his-dphe-arg-trp-nh-2-template
#4
Aleksandar Todorovic, Cody J Lensing, Jerry Ryan Holder, Joseph W Scott, Nicholas B Sorensen, Carrie Haskell-Luevano
The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-DPhe2-Arg3-Trp4-NH2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R)...
May 21, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29782798/regulatory-activities-of-dopamine-and-its-derivatives-towards-metal-free-and-metal-induced-amyloid-%C3%AE-aggregation-oxidative-stress-and-inflammation-in-alzheimer-s-disease
#5
Eunju Nam, Jeffrey S Derrick, Seunghee Lee, Juhye Kang, Jiyeon Han, Shin Jung C Lee, Su Wol Chung, Mi Hee Lim
A catecholamine neurotransmitter, dopamine (DA), is suggested to be linked to the pathology of dementia; however, the involvement of DA and its structural analogues in the pathogenesis of Alzheimer's disease (AD), the most common form of dementia, composed of multiple pathogenic factors has not been clear. Herein, we report that DA and its rationally designed structural derivatives (1-6) based on DA's oxidative transformation are able to modulate multiple pathological elements found in AD [ i.e., metal ions, metal-free amyloid-β (Aβ), metal-bound Aβ (metal-Aβ), and reactive oxygen species (ROS)], with demonstration of detailed molecular-level mechanisms...
May 21, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29782794/peptides-peptidomimetics-and-carbohydrate-peptide-conjugates-as-amyloidogenic-aggregation-inhibitors-for-alzheimer-s-disease
#6
Philip Ryan, Bhautikkumar Patel, Vivek Makwana, Hemant Jadhav, Milton John Kiefel, Andrew Davey, Tristan Reekie, Santosh Rudrawar, Michael Kassiou
Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for 60-80% of dementia cases. For many years, AD causality was attributed to amyloid-β (Aβ) aggregated species. Recently, multiple therapies that target Aβ aggregation have failed in clinical trials, since Aβ aggregation is found in AD and healthy patients. Attention has therefore shifted towards the aggregation of the peptide tau as a major driver of AD. Numerous inhibitors of tau-based pathology have recently been developed...
May 21, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29775277/cid-9998128-compound-is-a-potential-multi-target-drug-for-alzheimer-s-disease
#7
Nguyen Quoc Thai, Zuzana Bednarikova, Miroslav Gancar, Huynh Quang Linh, Chin-Kun Hu, Mai Suan Li, Zuzana Gazova
We have probed capability of small CID 9998128 compound as a potential multi-target drug for the Alzheimer's disease (AD) using in silico and in vitro experiments. By all-atom simulation and MM-PBSA method we have demonstrated that this compound strongly binds to both amyloid beta 42 (Aβ42 ) fibrils and β-secretase and the van der Waals interaction is dominating over the electrostatic interaction in binding affinity. A detailed analysis at the atomic level revealed that indazole in CID 99998128 structure made a major contribution to instability of all studied complexes...
May 18, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29771492/hyperpolarized-13c-mrs-reveals-the-rate-limiting-role-of-the-blood-brain-barrier-on-the-cerebral-uptake-and-metabolism-of-l-lactate-in-vivo
#8
Yuhei Takado, Tian Cheng, Jessica A M Bastiaansen, Hikari Yoshihara, Bernard Lanz, Mor Mishkovsky, Sylvain Lengacher, Arnaud Comment
The dynamics of L-lactate transport across the blood-brain barrier (BBB) and its cerebral metabolism are still subject to debate. We studied lactate uptake and intracellular metabolism in the mouse brain using hyperpolarized 13C magnetic resonance spectroscopy (MRS). Following the intravenous injection of hyperpolarized [1-13C]lactate, we observed that the distribution of 13C label between lactate and pyruvate, which has been shown to be representative of their pool size ratio, is different in NMRI and C57BL/6 mice, the latter exhibiting a higher cerebral lactate dehydrogenase A (Ldha) expression...
May 17, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29767953/pharmacological-and-electrophysiological-characterization-of-novel-nmda-receptor-antagonists
#9
Rosana Leiva, Matthew B Phillips, Andreea Larisa Turcu, Esther Gratacòs-Batlle, Lara León-García, Francesc X Sureda, David Soto, Jon W Johnson, Santiago Vazquez
This work reports the synthesis, and pharmacological and electrophysiological evaluation of new N-methyl-D-aspartic acid receptor (NMDAR) channel blocking antagonists featuring polycyclic scaffolds. Changes in the chemical structure modulate the potency and voltage dependence of inhibition. Two of the new antagonists display properties comparable to those of memantine, a clinically approved NMDAR antagonist.
May 16, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29763549/development-of-positron-emission-tomography-pet-radiotracers-for-the-gaba-transporter-1-gat-1
#10
Alexandra R Sowa, Allen F Brooks, Xia Shao, Bradford D Henderson, Phillip S Sherman, Janna Arteaga, Jenelle Stauff, Adam C Lee, Robert A Koeppe, Peter J H Scott, Michael R Kilbourn
In vivo PET imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril® ) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter...
May 15, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29763291/classics-in-neuroimaging-the-serotonergic-2a-receptor-system-from-discovery-to-modern-molecular-imaging
#11
Elina T L'Estrade, Hanne D Hansen, Maria Erlandsson, Tomas G Ohlsson, Gitte M Knudsen, Matthias M Herth
Already in 1953, Woolley and Shaw speculated that serotonin could be involved in a range of central nervous system (CNS) disorders. Lysergic acid diethylamide (LSD) displayed an important role in this respect. It was used not only to antagonize biological effects of serotonin and to study the system itself, but also to identify serotonergic subtype receptors. The 5-HT2A receptor was discovered in the 1970s and identified as the responsible receptor mediating psychedelic effects of LSD. The development of positron emission tomography (PET) allowed to study this receptor system in vivo...
May 15, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29762014/selective-and-sensitive-pull-down-of-amyloid-fibrils-produced-in-vitro-and-in-vivo-by-the-use-of-pentameric-thiophene-coupled-resins
#12
Anna Beatriz Wreden, Luiza Fernandes, Mirian Kelley, Antônio Pereira-Neves, Caroline S Moreira, David R da Rocha, Fernando L Palhano
Protein aggregation is a hallmark of several degenerative diseases, including Alzheimer's disease, Parkinson's disease and familial amyloidosis (Finnish type) (FAF). A method to isolate and detect amyloids is desired for the diagnosis of amyloid diseases. Here, we report the synthesis of pentameric thiophene amyloid ligand (p-FTAA) linked to agarose resin for selective purification of amyloid aggregates produced in vitro and in vivo. Using amyloid fibrils produced in vitro from alpha-synuclein, gelsolin and Aβ1-40 and gelsolin amyloid aggregates extracted from tissue homogenates of a mouse model of FAF, we observed that p-FTAA resin was able to pull down amyloid aggregates...
May 15, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29757603/alzheimer-s-disease-dendritic-spines-and-calcineurin-inhibitors-a-new-approach
#13
Melissa A O'Neal, Nancy R Stallings, James S Malter
Therapeutics to effectively treat Alzheimer's disease (AD) are lacking. In vitro, animal and human studies have implicated the excessive activation of the protein phosphatase calcineurin (CN) as an early step in the pathogenesis of AD. We discuss recent data showing that the prolyl isomerase Pin1 is suppressed by CN-mediated dephosphorylation induced by Aβ42 signaling. Pin1 loss directly leads to the reductions in dendritic spines and synapses characteristic of early AD pathology. Pin1 activity, and synapse and dendritic spine numbers are rescued by FK506, a highly specific and United States Food and Drug Administration approved CN inhibitor...
May 14, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29757600/dark-classics-in-chemical-neuroscience-morphine
#14
Andrea L Devereaux, Susan L Mercer, Christopher W Cunningham
As the major psychoactive agent in opium and direct precursor for heroin, morphine is a historically critical molecule in chemical neuroscience. A structurally complex phenanthrene alkaloid produced by Papaver somniferum, morphine has fascinated chemists seeking to disentangle pharmacologically beneficial analgesic effects from addiction, tolerance, and dependence liabilities. In this review, we will detail the history of morphine, from the first extraction and isolation by Sertürner in 1804 to the illicit use of morphine and proliferation of opioid use and abuse disorders currently ravaging the United States...
May 14, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29750499/alpha-synuclein-fibrils-contain-multiple-binding-sites-for-small-molecules
#15
Chia-Ju Hsieh, John J Ferrie, Kuiying Xu, Iljung Lee, Thomas J A Graham, Zhude Tu, Jennifer Yu, Dhruva Dhavale, Paul Kotzbauer, E James Petersson, Robert H Mach
The fibrillary aggregation of the protein alpha synuclein (Asyn) is a hallmark of Parkinson's disease, and the identification of small molecule binding sites on fibrils is essential to the development of diagnostic imaging probes. A series of molecular modelling, photoaffinity labeling, mass spectrometry, and radioligand binding studies were conducted on Asyn fibrils. The results of these studies revealed the presence of three different binding sites within fibrillar Asyn capable of binding small molecules with moderate to high affinity...
May 11, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29750497/improved-synthesis-of-caged-glutamate-and-caging-each-functional-group
#16
Charitha Guruge, Yannick P Ouedraogo, Richard Louis Comitz, Jingxuan Ma, Attila Losonczy, Nasri Nesnas
Glutamate is an excitatory neurotransmitter that controls numerous pathways in the brain. Neuroscientists make use of photoremovable protecting groups, also known as cages, to release glutamate with precise spatial and temporal control. Various cage designs have been developed and amongst the most effective has been the nitroindolinyl caging of glutamate. We, hereby, report an improved synthesis of one of the current leading molecules of caged glutamate, 4-carboxymethoxy-5,7-dinitroindolinyl glutamate (CDNI-Glu), which possesses efficiencies with the highest reported quantum yield of at least 0...
May 11, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29746089/physiological-a%C3%AE-concentrations-produce-a-more-biomimetic-representation-of-the-alzheimer-s-disease-phenotype-in-ipsc-derived-human-neurons
#17
Bonnie J Berry, Alec S T Smith, Christopher J Long, Candace C Martin, James J Hickman
Alzheimer's disease (AD) is characterized by slow, progressive neurodegeneration leading to severe neurological impairment, but current drug development efforts are limited by the lack of robust, human-based disease models. Amyloid-β (Aβ) is known to play an integral role in AD progression as it has been shown to interfere with neurological function. However, studies into AD pathology commonly apply Aβ to neurons for short durations at non-physiological concentrations to induce an exaggerated dysfunctional phenotype...
May 10, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29741354/extracellular-potassium-and-glutamate-interact-to-modulate-mitochondria-in-astrocytes
#18
Theresa S Rimmele, Haissa de Castro Abrantes, Joel Wellbourne-Wood, Sylvain Lengacher, Jean-Yves Chatton
Astrocytes clear glutamate and potassium, both of which are released into the extracellular space during neuronal activity. These processes are intimately linked with energy metabolism. Whereas astrocyte glutamate uptake causes cytosolic and mitochondrial acidification, extracellular potassium induces bicarbonate-dependent cellular alkalinization. This study aimed at quantifying the combined impact of glutamate and extracellular potassium on mitochondrial parameters of primary cultured astrocytes. Glutamate in 3mM potassium caused a stronger acidification of mitochondria compared to cytosol...
May 9, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29733572/synergistic-effect-of-transient-receptor-potential-antagonist-and-amiloride-against-maitotoxin-induced-calcium-increase-and-cytotoxicity-in-human-neuronal-stem-cells
#19
Andrea Boente Juncal, Carmen Vale, Amparo Alfonso, Luis M Botana
Maitotoxins (MTX) are among the most potent marine toxins identified to date causing cell death trough massive calcium influx. However, the exact mechanism for the MTX-induced calcium entry and cytotoxicity is still unknown. In this work, the effect of MTX-1 on the cytosolic free calcium concentration and cellular viability of human neuronal stem cells was evaluated. MTX elicited a concentration-dependent decrease in cell viability which was already evident after 1 hour of treatment with 0.25 nM MTX; however at a concentration of 0...
May 7, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29727167/dendritic-learning-as-a-paradigm-shift-in-brain-learning
#20
Shira Sardi, Roni Vardi, Amir Goldental, Yael Tugendhaft, Herut Uzan, Ido Kanter
Experimental and theoretical results reveal a new underlying mechanism for fast brain learning process, dendritic learning, as opposed to the misdirected research in neuroscience over decades, which is based solely on slow synaptic plasticity. The presented paradigm indicates that learning occurs in closer proximity to the neuron, the computational unit, dendritic strengths are self-oscillating, and weak synapses, which comprise the majority of our brain and previously were assumed to be insignificant, play a key role in plasticity...
May 4, 2018: ACS Chemical Neuroscience
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