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ACS Chemical Neuroscience

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https://www.readbyqxmd.com/read/28732166/mel-n16-a-series-of-novel-endomorphin-analogs-with-good-analgesic-activity-and-a-favorable-side-effect-profile
#1
Xin Liu, Long Zhao, Yuan Wang, Jingjing Zhou, Dan Wang, Yixin Zhang, Xianghui Zhang, Zhaojuan Wang, Dongxu Yang, Lingyun Mou, Rui Wang
Opioid peptides are neuromodulators that bind to opioid receptors and reduce pain sensitivity. Endomorphins are one of the most active endogenous opioid peptides, and they have good affinity and selectivity toward the μ opioid receptor. However, their clinical usage is hindered by their inability to cross the blood-brain barrier, and their poor in vivo activity after peripheral injection. In order to overcome these defects, we have designed and synthesized a series of novel endomorphin analogs with multiple site modifications...
July 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28731692/quinolinyl-nitrone-rp19-induces-neuroprotection-after-transient-brain-ischemia
#2
Maria Irene Ayuso, Emma Martinez-Alonso, Mourad Chioua, Alejandro Escobar-Peso, Rafael Gonzalo-Gobernado, Joan Montaner, José Marco-Contelles, Alberto Alcazar
There is a need to develop additional effective therapies for ischemic stroke. Nitrones, which were first developed as reactive oxygen species (ROS)-trapping compounds, have been proposed as neuroprotective agents for ischemic stroke, a ROS-related disorder. The previous reported ROS-trapping compound, quinolyl nitrone RP19, is here being assayed to induce neuroprotection to ischemia-reperfusion injury in three experimental ischemia models: (i), oxygen-glucose deprivation (OGD) on primary neuronal cultures; (ii), transient global cerebral ischemia in four-vessel occlusion model; and (iii), transient focal cerebral ischemia in middle cerebral artery occlusion (tMCAO) model...
July 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28692245/insight-into-a-new-binding-site-of-zinc-ions-in-fibrillar-amylin
#3
Vered Wineman-Fisher, Yifat Miller
Amylin peptides are secreted together with insulin and zinc ions from pancreatic β-cells. Under unknown conditions, the amylin peptides aggregate to produce oligomers and fibrils, and in some cases Zn(2+) ions can bind to amylin peptides to form Zn(2+)-aggregate complexes. Consequently, these aggregates lead to the death of the β-cells and a decrease in insulin, which is one of the symptoms of type-2 diabetes (T2D). Therefore, it is crucial to investigate the binding sites of the Zn(2+) ions in fibrillary amylin...
July 20, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28689412/bexarotene-does-not-clear-amyloid-beta-plaques-but-delays-fibril-growth-molecular-mechanisms
#4
Pham Dinh Quoc Huy, Nguyen Quoc Thai, Zuzana Bednarikova, Le Huu Phuc, Huynh Quang Linh, Zuzana Gazova, Mai Suan Li
In 2012, it was reported that anticancer drug bexarotene reduced amyloid plaque and improved mental functioning in a small sample of mice engineered to exhibit Alzheimer's like symptoms. It has been suggested that bexarotene stimulates expression of apolipoprotein E (ApoE) leading to intracellular clearance of amyloid beta (Aβ). However, the effect of bexarotene on clearance of plaques has not been seen in some mouse models. Two interesting questions include whether bexarotene can destroy Aβ fibrils via direct interaction with them and how this compound impacts the lag phase in the fibril growth process...
July 20, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28719178/the-therapeutic-role-and-drug-delivery-potential-of-neuroinflammation-as-a-target-in-neurodegenerative-disorders
#5
Abhijeet Singh, Ankit Chokriwal, Madan Mohan Sharma, Devendra Jain, Juhi Saxena, Bjorn John Stephen
Neuroinflammation, the condition associated with the hyper activity of immune cells within the CNS (central nervous system) has recently been linked to a host range of neurodegenerative disorders. Targeting neuroinflammation could be of prime importance as recent research highlights the beneficial aspects associated with modulating the inflammatory mediators associated with the CNS. One of the main obstructions in neuroinflammatory treatments is the hindrance posed by the Blood Brain Barrier for the delivery of drugs...
July 18, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28719177/classics-in-neuroimaging-imaging-the-dopaminergic-pathway-with-pet
#6
Meghna Kanthan, Paul Cumming, Jacob M Hooker, Neil Vasdev
The success of positron emission tomography (PET) for observing molecular processes underlying brain function and disease is underpinned by radiotracer chemistry. From the earliest applications of PET to measure dopamine synthesis capacity and the abundance of neuroreceptors and transporters, to the more recent topic of dynamic neurochemical imaging, interrogation of brain dopamine in conditions such as neurodegenerative diseases, schizophrenia, mood disorders, and addictions has been a driving force that challenges the ingenuity of radiopharmaceutical scientists...
July 18, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28715630/misfolded-sod1-accumulation-and-mitochondrial-association-contribute-to-the-selective-vulnerability-of-motor-neurons-in-familial-als-correlation-to-human-disease
#7
Salah Abu-Hamad, Joy Kahn, Marcel F Leyton-Jaimes, Jonathan Rosenblatt, Adrian Israelson
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, with a 10% genetic linkage, of which 20% of these cases may be attributed to mutations in superoxide dismutase (SOD1). Specific mutations in SOD1 have been associated with disease duration, which can be highly variable ranging from a life expectancy of three to beyond ten years. SOD1 neurotoxicity has been attributed to aberrant accumulation of misfolded SOD1, which in its soluble form, binds to intracellular organelles disrupting their function, or forms insoluble toxic aggregates...
July 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28714693/stochastic-simulation-of-dopamine-neuromodulation-for-implementation-of-fluorescent-neurochemical-probes-in-the-striatal-extracellular-space
#8
Abraham Beyene, Ian McFarlane, Rebecca Pinals, Markita P Landry
Imaging the dynamic behavior of neuromodulatory neurotransmitters in the extracelluar space arising from individual quantal releases would constitute a major advance in neurochemical imaging. Spatial and temporal resolution of these highly stochastic neuromodulatory events requires concurrent advances in the chemical development of optical nanosensors selective for neuromodulators in concert with advances in imaging methodologies to capture millisecond neurotransmitter release. Herein, we develop and implement a stochastic model to describe dopamine dynamics in the extracellular space (ECS) of the brain dorsal striatum to guide the design and implementation of fluorescent neurochemical probes that record neurotransmitter dynamics in the ECS...
July 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28707894/vitamin-d-receptor-regulates-amyloid-beta-1-42-production-with-protein-disulfide-isomerase-a3
#9
Duygu Gezen-Ak, Irem L Atasoy, Esin Candas, Merve Alaylioglu, Selma Yilmazer, Erdinc Dursun
The challenge of understanding the biology of neuronal amyloid processing could provide a basis for understanding the amyloid pathology in Alzheimer's disease (AD). Based on our previous studies we have suggested that AD might be the consequence of a hormonal imbalance in which the critical hormone is vitamin D. The present study primarily focused on the creation of a condition that prevents the genomic or non-genomic action of vitamin D by disrupting vitamin D receptors (VDR or PDIA3/1,25MARRS); the effects of these disruptions on the series of proteins involved in secretases that play a crucial role in amyloid pathology and on amyloid beta (Aβ) production in primary cortical neurons were observed...
July 14, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28707873/light-activation-of-calcein-inhibits-vesicle-release-of-catecholamines
#10
Brooke A Miller, Jason B Papke, Vytas P Bindokas, Amy B Harkins
Calcein, a fluorescent fluid phase marker, has been used to track and visualize cellular processes such as synaptic vesicle fusion. It is also the fluorophore for Live cells in the commonly used Live/Dead viability assay. In pilot studies designed to determine fusion pore open size and vesicle movement in secretory cells, imaging analysis revealed that calcein reduced the number of vesicles released from the cells when stimulated with nicotine. Using amperometry to detect individual vesicle release events, we show that when calcein is present in the media, the number of vesicles that fuse with the cellular membrane are reduced when cells are stimulated with either nicotine or high K+...
July 14, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28704038/eosinophilic-meningitis-caused-by-angiostrongylus-cantonensis
#11
Shan Lv, Xiao-Nong Zhou, Jason R Andrews
Rat lungworm, Angiostrongylus cantonensis, is one major cause of human eosinophilic meningitis. This helminth is endemic in Southeast Asia, Pacific Islands, and the Caribbean and has recently expanded to South America. The infection is characterized by an elevated eosinophil count in cerebrospinal fluid. Common symptoms and signs include headache, neck stiffness, paresthesia and nausea/vomiting. The unique history of eating freshwater and land snails or slugs within 2 weeks before onset is helpful for diagnosis...
July 13, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28653829/development-and-characterization-of-a-hydroxyl-sulfonamide-analogue-5-chloro-n-2-4-hydroxysulfamoyl-phenyl-ethyl-2-methoxy-benzamide-as-a-novel-nlrp3-inflammasome-inhibitor-for-potential-treatment-of-multiple-sclerosis
#12
Chunqing Guo, Jacob W Fulp, Yuqi Jiang, Xia Li, Jeremy E Chojnacki, Jingde Wu, Xiang-Yang Wang, Shijun Zhang
In our efforts to develop novel small-molecule inhibitors for the NOD-like receptor family pyrin-domain-containing 3 (NLRP3) inflammasome as potential disease-modifying agents to treat neurological disorders including multiple sclerosis (MS), a hydroxyl sulfonamide analogue JC-171 has been rationally designed and biologically characterized both in vitro and in vivo. Our studies established that JC-171 dose dependently inhibited LPS/ATP-induced interleukin-1β (IL-1β) release from J774A.1 macrophages with an IC50 of 8...
July 13, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28699350/analgesic-properties-of-opioid-nk1-multitarget-ligands-with-distinct-in-vitro-profiles-in-naive-and-chronic-constriction-injury-cci-mice
#13
Joanna Starnowska, Roberto Costante, Karel Guillemyn, Katarzyna Popiolek-Barczyk, Nga N Chung, Carole Lemieux, Attila Keresztes, Joost Van Duppen, Adriano Mollica, John M Streicher, Jozef Vanden Broeck, Peter W Schiller, Dirk Tourwé, Joanna Mika, Steven Ballet, Barbara Przewlocka
The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. To improve opioid efficacy in neuropathic pain, novel compounds containing opioid agonist and neurokinin 1 (NK1) receptor antagonist pharmacophores were designed...
July 12, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28628299/dihydropyrimidine-thiones-and-clioquinol-synergize-to-target-%C3%AE-amyloid-cellular-pathologies-through-a-metal-dependent-mechanism
#14
Daniel F Tardiff, Lauren E Brown, Xiaohui Yan, Richard Trilles, Nathan T Jui, M Inmaculada Barrasa, Kim A Caldwell, Guy A Caldwell, Scott E Schaus, Susan Lindquist
The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by β-amyloid (Aβ), the peptide implicated in Alzheimer's disease. Rescue of Aβ toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action...
July 12, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28697302/discovery-and-characterization-of-1h-pyrazol-5-yl-2-phenylacetamides-as-novel-non-urea-containing-girk1-2-potassium-channel-activators
#15
Joshua M Wieting, Anish K Vadukoot, Swagat H Sharma, Kristopher K Abney, Thomas M Bridges, J Scott Daniels, Ryan D Morrison, Kevin Wickman, C David Weaver, Corey R Hopkins
The G protein regulated inwardly rectifying potassium channels (GIRK, Kir3) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiological processes and as potential targets for numerous indications. Previously reported urea containing molecules as GIRK1/2 preferring activators have had significant pharmacokinetic liabilities. Here we report a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties...
July 11, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28657708/combined-proteomic-molecular-epidemiology-approach-to-identify-precision-targets-in-brain-cancer
#16
Ekaterina Mostovenko, Yanhong Liu, E Susan Amirian, Spiridon Tsavachidis, Georgina N Armstrong, Melissa L Bondy, Carol L Nilsson
Primary brain tumors are predominantly malignant gliomas. Grade IV astrocytomas (glioblastomas, GBM) are among the most deadly of all tumors; most patients will succumb to their disease within 2 years of diagnosis despite standard of care. The grim outlook for brain tumor patients indicates that novel precision therapeutic targets must be identified. Our hypothesis is that the cancer proteomes of glioma tumors may contain protein variants that are linked to the aggressive pathology of the disease. To this end, we devised a novel workflow that combined variant proteomics with molecular epidemiological mining of public cancer data sets to identify 10 previously unrecognized variants linked to the risk of death in low grade glioma or GBM...
July 11, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28692243/biosynthesis-of-astrocytic-trehalose-regulates-neuronal-arborisation-in-hippocampal-neurons
#17
Giuseppe Martano, Laura Gerosa, Ilaria Prada, Giulia Garrone, Vittorio Krogh, Claudia Verderio, Maria Passafaro
Trehalose is a non-reducing disaccharide that has recently attracted much attention because of its ability to inhibit protein aggregation, induce autophagy, and protect against dissections and strokes. In vertebrates, the biosynthesis of trehalose was long considered absent due to the lack of annotated genes involved in this process. In contrast, trehalase (TreH), which is an enzyme required for the cleavage of trehalose, is known to be conserved and expressed. Here, we show that trehalose is present as an endogenous metabolite in the rodent hippocampus...
July 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28691798/structure-and-affinity-of-two-bicyclic-glutamate-analogues-at-ampa-and-kainate-receptors
#18
Stine Møllerud, Andrea Pinto, Laura Marconi, Karla Frydenvang, Thor S Thorsen, Saara K Laulumaa, Raminta Venskutonyte, Sebastian Winther, Ana M C Moral, Lucia Tamborini, Paola Conti, Darryl S Pickering, Jette Sandholm Kastrup
Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer's disease, epilepsy and depression. In order to understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1-3 and GluK5)...
July 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28691794/ligand-dependent-switch-from-rxr-homo-to-rxr-nurr1-heterodimerization
#19
Marcel Scheepstra, Sebastian A Andrei, Rens M J M de Vries, Femke A Meijer, Jian-Nong Ma, Ethan S Burstein, Roger Olsson, Christian Ottmann, Lech-Gustav Milroy, Luc Brunsveld
Retinoid X Receptors (RXRs) play key roles in many physiological processes in both the periphery and central nervous system. In addition, RXRs form heterodimers with other nuclear receptors to exert their physiological effects. The Nuclear Receptor Related 1 protein (NURR1) is particularly interesting because of its role in promoting differentiation and survival of dopamine neurons. However only a small number of RXR-heterodimer selective modulators are available, with limited chemical diversity. This work describes the synthesis, biochemical evaluation and structural elucidation of a novel series of RXR ligands with strongly biased interactions with RXRα-NURR1 heterodimers...
July 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28677385/minimal-nucleation-state-of-%C3%AE-synuclein-is-stabilized-by-dynamic-threonine-water-networks
#20
Tod D Romo, Andrew K Lewis, Anthony R Braun, Alan Grossfield, Jonathan N Sachs
The first structures of α-synuclein (αSyn) fibrils have recently been solved. Here, we use a unique combination of molecular dynamics simulation strategies to address the minimal nucleation size of the 11-amino acid NAC protofibril solved by X-ray and to interrogate the dynamic behavior of unexpected crystal waters in the steric zipper. We found that protofibrils of >8 chains are thermodynamically stabilized due to protection of the fibril core from solvent influx and ordering of the end strands by the fibril core...
July 10, 2017: ACS Chemical Neuroscience
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