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https://www.readbyqxmd.com/read/29128144/the-antipsychotic-drug-brexpiprazole-reverses-phencyclidine-induced-disruptions-of-thalamocortical-networks
#1
Hanna E van den Munkhof, Jørn Arnt, Pau Celada, Francesc Artigas
Brexpiprazole (BREX), a recently approved antipsychotic drug in the US and Canada, improves cognitive dysfunction in animal models, by still largely unknown mechanisms. BREX is a partial agonist at 5-HT1A and D2 receptors and antagonist at α1B- and α2C-adrenergic and 5-HT2A receptors all with a similar potency. The NMDA receptor antagonist phencyclidine (PCP), used as pharmacological model of schizophrenia, activates thalamocortical networks and decreases low frequency oscillations (LFO; <4 Hz). These effects are reversed by antipsychotics...
November 8, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29127015/oxotremorine-m-potentiates-nmda-receptors-by-muscarinic-receptor-dependent-and-independent-mechanisms
#2
Ruud Zwart, Hannah Reed, Emanuele Sher
Muscarinic acetylcholine M1 receptors play an important role in synaptic plasticity in the hippocampus and cortex. Potentiation of NMDA receptors as a consequence of muscarinic acetylcholine M1 receptor activation is a crucial event mediating the cholinergic modulation of synaptic plasticity, which is a cellular mechanism for learning and memory. In Alzheimer's disease, the cholinergic input to the hippocampus and cortex is severely degenerated, and agonists or positive allosteric modulators of M1 receptors are therefore thought to be of potential use to treat the deficits in cognitive functions in Alzheimer's disease...
November 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29121294/low-dose-buprenorphine-infusion-to-prevent-postoperative-hyperalgesia-in-patients-undergoing-major-lung-surgery-and-remifentanil-infusion-a-double-blind-randomized-active-controlled-trial
#3
Marco Mercieri, Stefano Palmisani, Roberto A De Blasi, Antonio D'Andrilli, Alessia Naccarato, Barbara Silvestri, Sara Tigano, Domenico Massullo, Monica Rocco, Roberto Arcioni
Background: Postoperative secondary hyperalgesia arises from central sensitization due to pain pathways facilitation and/or acute opioid exposure. The latter is also known as opioid-induced hyperalgesia (OIH). Remifentanil, a potent μ-opioid agonist, reportedly induces postoperative hyperalgesia and increases postoperative pain scores and opioid consumption. The pathophysiology underlying secondary hyperalgesia involves N-methyl-D-aspartate (NMDA)-mediated pain pathways. In this study, we investigated whether perioperatively infusing low-dose buprenorphine, an opioid with anti-NMDA activity, in patients receiving remifentanil infusion prevents postoperative secondary hyperalgesia...
October 1, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/29106899/vinpocetine-protects-inner-retinal-neurons-with-functional-nmda-glutamate-receptors-against-retinal-ischemia
#4
Lisa Nivison-Smith, Pauline Khoo, Monica L Acosta, Michael Kalloniatis
Retinal ischemia is involved in the pathogenesis of many major vision threatening diseases. Vinpocetine is a natural drug, which has a range of neuroprotective actions against retinal ischemia including modulating cation flow, improving metabolic activity and preventing apoptosis. The exact mechanism behind these actions remains unknown but may involve glutamate receptors, major components of the ischemic cascade. This study examined the effects of vinpocetine in association with specific ionotropic glutamate receptor agonists: N-methyl-D-aspartate (NMDA) and kainate...
November 4, 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/29106383/s-sulfocysteine-nmda-receptor-dependentsignaling-underlies-neurodegeneration-in-molybdenum-cofactor-deficiency
#5
Avadh Kumar, Borislav Dejanovic, Florian Hetsch, Marcus Semtner, Debora Fusca, Sita Arjune, Jose Angel Santamaria-Araujo, Aline Winkelmann, Scott Ayton, Ashley I Bush, Peter Kloppenburg, Jochen C Meier, Guenter Schwarz, Abdel Ali Belaidi
Molybdenum cofactor deficiency (MoCD) is an autosomal recessive inborn error of metabolism characterized by neurodegeneration and death in early childhood. The rapid and progressive neurodegeneration in MoCD presents a major clinical challenge and may relate to the poor understanding of the molecular mechanisms involved. Recently, we reported that treating patients with cyclic pyranopterin monophosphate (cPMP) is a successful therapy for a subset of infants with MoCD and prevents irreversible brain damage. Here, we studied S-sulfocysteine (SSC), a structural analog of glutamate that accumulates in the plasma and urine of patients with MoCD, and demonstrated that it acts as an N-methyl D-aspartate receptor (NMDA-R) agonist, leading to calcium influx and downstream cell signaling events and neurotoxicity...
November 6, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29099938/nyx-2925-is-a-novel-nmda-receptor-specific-spirocyclic-%C3%AE-lactam-that-modulates-synaptic-plasticity-processes-associated-with-learning-and-memory
#6
M Amin Khan, David R Houck, Amanda L Gross, Xiao-Lei Zhang, Cassia Cearley, Torsten M Madsen, Roger A Kroes, Patric K Stanton, Jeffrey Burgdorf, Joseph R Moskal
Background: N-methyl-D-aspartate receptors (NMDAR) are one member of a family of ionotropic glutamate receptors that play a pivotal role in synaptic plasticity processes associated with learning and have become attractive therapeutic targets for diseases such as depression, anxiety, schizophrenia, and neuropathic pain. NYX-2925 ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide) is one member of a spiro--lactam-based chemical platform that mimics some of the dipyrrolidine structural features of rapastinel (formerly GLYX-13: threonine-proline-proline-threonine) and is distinct from known NMDAR agonists or antagonists such as D-cycloserine, ketamine, MK-801, kynurenic acid or ifenprodil...
November 1, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29076028/safety-tolerability-and-pharmacokinetics-of-oral-bi-425809-a-glycine-transporter-1-inhibitor-in-healthy-male-volunteers-a-partially-randomised-single-blind-placebo-controlled-first-in-human-study
#7
Viktoria Moschetti, Michael Desch, Sophia Goetz, Karl-Heinz Liesenfeld, Holger Rosenbrock, Klaus-Peter Kammerer, Glen Wunderlich, Sven Wind
BACKGROUND AND OBJECTIVES: Schizophrenia and Alzheimer's disease are characterised by glutamatergic pathway abnormalities related to N-methyl-D-aspartate (NMDA) receptor hypofunction and cognitive impairment. Glycine is an NMDA receptor co-agonist; inhibition of glycine transporter 1 (GlyT1) should improve NMDA receptor hypofunction. This study evaluated safety and pharmacokinetic properties of BI 425809-a potent and selective GlyT1 inhibitor. METHODS: In the single-rising dose (SRD) component of this study, subjects were randomised to a single dose of BI 425809 [doses (mg): 0...
October 26, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29074619/presynaptic-mglur5-receptor-controls-glutamatergic-input-through-protein-kinase-c-nmda-receptors-in-paclitaxel-induced-neuropathic-pain
#8
Jing-Dun Xie, Shao-Rui Chen, Hui-Lin Pan
Chemotherapeutic drugs such as paclitaxel cause painful peripheral neuropathy in many cancer patients and survivors. Although NMDA receptors (NMDARs) at primary afferent terminals are known to be critically involved in chemotherapy-induced chronic pain, the upstream signaling mechanism that leads to presynaptic NMDAR activation is unclear. Group I metabotropic glutamate receptors (mGluRs) play a role in synaptic plasticity and NMDAR regulation. Here we report that the Group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the frequency of miniature excitatory postsynaptic currents (EPSCs) and the amplitude of monosynaptic EPSCs evoked from the dorsal root...
October 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29072857/astrocytes-drive-cortical-vasodilatory-signaling-by-activating-endothelial-nmda-receptors
#9
Lingling Lu, Adam D Hogan-Cann, Andrea K Globa, Ping Lu, James I Nagy, Shernaz X Bamji, Christopher M Anderson
Astrocytes express neurotransmitter receptors that serve as sensors of synaptic activity and initiate signals leading to activity-dependent local vasodilation and increases in blood flow. We previously showed that arteriolar vasodilation produced by activation of cortical astrocytes is dependent on endothelial nitric oxide synthase (eNOS) and endogenous agonists of N-methyl-D-aspartate (NMDA) receptors. Here, we tested the hypothesis that these effects are mediated by NMDA receptors expressed by brain endothelial cells...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/29061509/monoacylglycerol-lipase-inhibitor-jzl184-prevents-hiv-1-gp120-induced-synapse-loss-by-altering-endocannabinoid-signaling
#10
Xinwen Zhang, Stanley A Thayer
Monoacylglycerol lipase (MGL) hydrolyzes 2-arachidonoylglycerol to arachidonic acid and glycerol. Inhibition of MGL may attenuate neuroinflammation by enhancing endocannabinoid signaling and decreasing prostaglandin (PG) production. Almost half of HIV infected individuals are afflicted with HIV-associated neurocognitive disorder (HAND), a neuroinflammatory disease in which cognitive decline correlates with synapse loss. HIV infected cells shed the envelope protein gp120 which is a potent neurotoxin that induces synapse loss...
October 20, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29058353/fast-ca-2-responses-in-astrocyte-end-feet-and-neurovascular-coupling-in-mice
#11
Barbara Lykke Lind, Sanne Barsballe Jessen, Micael Lønstrup, Charlène Joséphine, Gilles Bonvento, Martin Lauritzen
Cerebral blood flow (CBF) is regulated by the activity of neurons and astrocytes. Understanding how these cells control activity-dependent increases in CBF is crucial to interpreting functional neuroimaging signals. The relative importance of neurons and astrocytes is debated, as are the functional implications of fast Ca(2+) changes in astrocytes versus neurons. Here, we used two-photon microscopy to assess Ca(2+) changes in neuropil, astrocyte processes, and astrocyte end-feet in response to whisker pad stimulation in mice...
October 23, 2017: Glia
https://www.readbyqxmd.com/read/29042318/mechanisms-of-%C3%AE-opioid-receptor-inhibition-of-nmda-receptor-induced-substance-p-release-in-the-rat-spinal-cord
#12
Wenling Chen, Helena S Ennes, James A McRoberts, Juan Carlos Marvizón
The interaction between NMDA receptors and μ-opioid receptors in primary afferent terminals was studied by using NMDA to induce substance P release, measured as neurokinin 1 receptor internalization. In rat spinal cord slices, the μ-opioid receptor agonists morphine, DAMGO and endomorphin-2 inhibited NMDA-induced substance P release, whereas the antagonist CTAP right-shifted the concentration response of DAMGO. In vivo, substance P release induced by intrathecal NMDA after priming with BDNF was inhibited by DAMGO...
October 16, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29029315/7-8-dihydroxyflavone-rescues-lead-induced-impairment-of-vesicular-release-a-novel-therapeutic-approach-for-lead-intoxicated-children
#13
Xiao-Lei Zhang, Jennifer L McGlothan, Omid Miry, Kirstie H Stansfield, Meredith K Loth, Patric K Stanton, Tomás R Guilarte
Childhood lead (Pb2+) intoxication is a public health problem of global proportion. Lead exposure during development produces multiple effects on the central nervous system including impaired synapse formation, altered synaptic plasticity, and learning deficits.In primary hippocampal neurons in culture and hippocampal slices, Pb2+ exposure inhibits vesicular release and reduces the number of fast-releasing sites, an effect associated with Pb2+ inhibition of NMDA receptor-mediated trans-synaptic Brain-Derived Neurotrophic Factor (BDNF) signaling...
October 4, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29021742/neuroprotective-mechanisms-of-lycium-barbarum-polysaccharides-against-ischemic-insults-by-regulating-nr2b-and-nr2a-containing-nmda-receptor-signaling-pathways
#14
Zhongshan Shi, Lihui Zhu, Tingting Li, Xiaoya Tang, Yonghui Xiang, Xinjia Han, Luoxing Xia, Ling Zeng, Junhua Nie, Yongxia Huang, Chi Kwan Tsang, Ying Wang, Zhigang Lei, Zaocheng Xu, Kwok-Fai So, Yiwen Ruan
Glutamate excitotoxicity plays an important role in neuronal death after ischemia. However, all clinical trials using glutamate receptor inhibitors have failed. This may be related to the evidence that activation of different subunit of NMDA receptor will induce different effects. Many studies have shown that activation of the intrasynaptic NR2A subunit will stimulate survival signaling pathways, whereas upregulation of extrasynaptic NR2B will trigger apoptotic pathways. A Lycium barbarum polysaccharide (LBP) is a mixed compound extracted from Lycium barbarum fruit...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29019687/simulated-dynamics-of-glycans-on-ligand-binding-domain-of-nmda-receptors-reveals-strong-dynamic-coupling-between-glycans-and-protein-core
#15
Anton V Sinitskiy, Vijay S Pande
N-Methyl-d-aspartate (NMDA) receptors, key neuronal receptors playing the central role in learning and memory, are heavily glycosylated in vivo. Astonishingly little is known about the structure, dynamics, and physiological relevance of glycans attached to them. We recently demonstrated that certain glycans on the ligand binding domain (LBD) of NMDA receptors (NMDARs) can serve as intramolecular potentiators, changing EC50 of NMDAR coagonists. In this work, we use molecular dynamics trajectories, in aggregate 86...
October 31, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/29018191/d-serine-released-by-astrocytes-in-brainstem-regulates-breathing-response-to-co2-levels
#16
S Beltrán-Castillo, M J Olivares, R A Contreras, G Zúñiga, I Llona, R von Bernhardi, J L Eugenín
Central chemoreception is essential for adjusting breathing to physiological demands, and for maintaining CO2 and pH homeostasis in the brain. CO2-induced ATP release from brainstem astrocytes stimulates breathing. NMDA receptor (NMDAR) antagonism reduces the CO2-induced hyperventilation by unknown mechanisms. Here we show that astrocytes in the mouse caudal medullary brainstem can synthesize, store, and release D-serine, an agonist for the glycine-binding site of the NMDAR, in response to elevated CO2 levels...
October 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28991505/modulation-of-sk-channels-regulates-locomotor-alternating-bursting-activity-in-the-functionally-mature-spinal-cord
#17
Amr A Mahrous, Sherif M Elbasiouny
The spinal cord contains specialized groups of cells called pattern generators, which are capable of orchestrating rhythmic firing activity in an isolated preparation. Different patterns of activity could be generated in vitro including right-left alternating bursting and bursting in which both sides are synchronized. The cellular and network mechanisms that enable these behaviors are not fully understood. We have recently shown that Ca(2+)-activated K(+) channels (SK channels) control the initiation and amplitude of synchronized bursting in the spinal cord...
October 9, 2017: Channels
https://www.readbyqxmd.com/read/28991238/the-structure-energy-landscape-of-nmda-receptor-gating
#18
Drew M Dolino, Sudeshna Chatterjee, David M MacLean, Charlotte Flatebo, Logan D C Bishop, Sana A Shaikh, Christy F Landes, Vasanthi Jayaraman
N-Methyl-D-aspartate (NMDA) receptors are the main calcium-permeable excitatory receptors in the mammalian central nervous system. The NMDA receptor gating is complex, exhibiting multiple closed, open, and desensitized states; however, central questions regarding the conformations and energetics of the transmembrane domains as they relate to the gating states are still unanswered. Here, using single-molecule Förster resonance energy transfer (smFRET), we map the energy landscape of the first transmembrane segment of the Rattus norvegicus NMDA receptor under resting and various liganded conditions...
December 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28990517/anesthetic-agents-and-neuronal-autophagy-what-we-know-and-what-we-don-t
#19
Lili Xu, Jianjun Shen, Patrick M McQuillan, Zhiyong Hu
Numerous experimental data have demonstrated that neonatal animal exposure to commonly used anesthetic agents may cause neuronal death resulting in cognitive impairment. The underlying mechanism(s) remain elusive. Depending on the circumstances, autophagy may produce an effect that can be either protective or deleterious. Recent evidence demonstrates that this process can reduce the development of ethanol induced neurotoxicity and, as we know, ethanol has γ-Aminobutyric acid (GABA) agonist and N-methyl-D-aspartate (NMDA) antagonist characteristics similar to commonly used volatile anesthetic agents...
October 9, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28986867/genetic-and-functional-analysis-of-grin2a-in-tumor-samples
#20
Todd D Prickett, Jared J Gartner, Yardena Samuels
Ionotropic glutamate receptors (iGluRs) are large integral membrane multi-protein complexes that create ion channels in plasma membranes. Upon binding of receptor specific ligands (e.g., glutamate), increased efflux or influx of mono- or divalent cations (e.g., Ca(2+)) promotes synaptic transmission, cellular migration, and survival. Three classes of iGluRs were originally defined after their respective agonists: AMPA, kainate, and NMDA receptors (NMDARs). Recently, we examined iGluR families at the genetic level using Next-Generation Sequencing (NGS) (whole-exome sequencing (WES)) and discovered a high prevalence of somatic mutations within the gene for one of the NMDAR subunits, GRIN2A, specifically in malignant melanoma...
2017: Methods in Molecular Biology
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