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nmdar inhibitors

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https://www.readbyqxmd.com/read/28439098/uncoupling-dapk1-from-nmda-receptor-glun2b-subunit-exerts-rapid-antidepressant-like-effects
#1
S-X Li, Y Han, L-Z Xu, K Yuan, R-X Zhang, C-Y Sun, D-F Xu, M Yuan, J-H Deng, S-Q Meng, X-J Gao, Q Wen, L-J Liu, W-L Zhu, Y-X Xue, M Zhao, J Shi, L Lu
Several preclinical studies have reported the rapid antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) antagonists, although the underlying mechanisms are still unclear. Death-associated protein kinase 1 (DAPK1) couples GluN2B subunits at extrasynaptic sites to regulate NMDAR channel conductance. In the present study, we found that chronic unpredictable stress (CUS) induced extracellular glutamate accumulation, accompanied by an increase in the DAPK1-NMDAR interaction, the high expression of DAPK1 and phosphorylated GluN2B at Ser1303, a decrease in phosphorylated DAPK1 at Ser308 and synaptic protein deficits in the rat medial prefrontal cortex (mPFC)...
April 25, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28359951/acute-stress-regulates-phosphorylation-of-n-methyl-d-aspartate-receptor-glun2b-at-s1284-in-hippocampus
#2
Heng Ai, Xiao-Fang Shi, Xu-Pang Hu, Wei-Qing Fang, Bin Zhang, Wen Lu
Exposure to acute stress leads to diverse changes, which include either beneficial or deleterious effects on molecular levels that are implicated in stress-related disorders. N-methyl-d-aspartate receptor (NMDAR)-mediated signalings, are thought to be vital players in stress-related mental disorders as well as attractive therapeutic targets for clinical treatment. In the present study, we utilized acute stress models in mice to explore regulation of phosphorylation level of S1284 in GluN2B subunit of NMDAR...
March 27, 2017: Neuroscience
https://www.readbyqxmd.com/read/28322842/simultaneous-blockade-of-nmda-receptors-and-parp-1-activity-synergistically-alleviate-immunoexcitotoxicity-and-bioenergetics-in-3-nitropropionic-acid-intoxicated-mice-evidences-from-memantine-and-3-aminobenzamide-interventions
#3
Saravana Babu Chidambaram, Ranju Vijayan, Sathiya Sekar, Sugumar Mani, Barathidsan Rajamani, Ramakrishnan Ganapathy
Interlink between excitotoxicity and cellular bioenergetics depletion is implicated as one of the central deteriorative pathways in many neurodegenerative diseases including Huntington's disease (HD). Chronic administration of 3-nitropropionic acid (3-NP) depletes ATP and NAD(+;) and increases TNFα, IL-6 and glutamate content resulting in "immunoexcitotoxicity". Present study was designed to determine whether the combination of memantine (MN) and 3-aminobenzamide (3-AB), PARP inhibitor, can ameliorate immunoexcitotoxicity and improve bioenergetics in a better manner than individual administration against 3-NP intoxication in mice...
May 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28321180/multiple-kinases-involved-in-the-nicotinic-modulation-of-gamma-oscillations-in-the-rat-hippocampal-ca3-area
#4
JianGang Wang, XiaoLong He, Fangli Guo, XiangLin Cheng, Yali Wang, XiaoFang Wang, ZhiWei Feng, Martin Vreugdenhil, ChengBiao Lu
Neuronal synchronization at gamma band frequency (20-80 Hz, γ oscillations) is closely associated with higher brain function, such as learning, memory and attention. Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the hippocampus, and modulate hippocampal γ oscillations, but the intracellular mechanism underlying such modulation remains elusive. We explored multiple kinases by which nicotine can modulate γ oscillations induced by kainate in rat hippocampal area CA3 in vitro. We found that inhibitors of cyclic AMP dependent kinase (protein kinase A, PKA), protein kinase C (PKC), N-methyl-D-aspartate receptor (NMDA) receptors, Phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinases (ERK), each individually could prevent the γ oscillation-enhancing effect of 1 μM nicotine, whereas none of them affected baseline γ oscillation strength...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28318835/improvement-in-mismatch-negativity-generation-during-d-serine-treatment-in-schizophrenia-correlation-with-symptoms
#5
Joshua T Kantrowitz, Michael L Epstein, Migyung Lee, Nayla Lehrfeld, Karen A Nolan, Constance Shope, Eva Petkova, Gail Silipo, Daniel C Javitt
BACKGROUND: Deficits in N-methyl-d-aspartate-type (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia. The efficacy of NMDAR agonists in the treatment of persistent symptoms of schizophrenia has been variable, potentially reflecting limitations in functional target engagement. We recently demonstrated significant improvement in auditory mismatch negativity (MMN) with once-weekly treatment with d-serine, a naturally occurring NMDAR glycine-site agonist. This study investigates effects of continuous (daily) NMDAR agonists in schizophrenia/schizoaffective disorder...
March 17, 2017: Schizophrenia Research
https://www.readbyqxmd.com/read/28285942/small-molecule-inhibitors-of-psd95-nnos-protein-protein-interactions-suppress-formalin-evoked-fos-protein-expression-and-nociceptive-behavior-in-rats
#6
Lawrence M Carey, Wan-Hung Lee, Tannia Gutierrez, Pushkar M Kulkarni, Ganesh A Thakur, Yvonne Y Lai, Andrea G Hohmann
Excessive activation of NMDA receptor (NMDAR) signaling within the spinal dorsal horn contributes to central sensitization and the induction and maintenance of pathological pain states. However, direct antagonism of NMDARs produces undesirable side effects which limit their clinical use. NMDAR activation produces central sensitization, in part, by initiating a signaling cascade that activates the enzyme neuronal nitric oxide synthase (nNOS) and generates the signaling molecule nitric oxide. NMDAR-mediated activation of nNOS requires a scaffolding protein, postsynaptic density protein 95kDa (PSD95), which tethers nNOS to NMDARs...
May 4, 2017: Neuroscience
https://www.readbyqxmd.com/read/28283345/cystathionine-%C3%AE-synthase-derived-hydrogen-sulfide-is-required-for-amygdalar-long-term-potentiation-and-cued-fear-memory-in-rats
#7
Hai-Bo Chen, Wen-Ning Wu, Wei Wang, Xun-Hu Gu, Bin Yu, Bo Wei, Yuan-Jian Yang
Hydrogen sulfide (H2S) is an endogenous gaseous molecule that functions as a neuromodulator in the brain. We previously reported that H2S regulated amygdalar synaptic plasticity and cued fear memory in rats. However, whether endogenous H2S is required for amygdalar long-term potentiation (LTP) induction and cued fear memory formation remains unclear. Here, we show that cystathionine-β-synthase (CBS), the predominant H2S-producing enzyme in the brain, was highly expressed in the amygdala of rats. Suppressing CBS activity by inhibitor prevented activity-triggered generation of H2S in the lateral amygdala (LA) region...
March 8, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28240305/increased-pkc-activity-and-altered-gsk3%C3%AE-nmdar-function-drive-behavior-cycling-in-hint1-deficient-mice-bipolarity-or-opposing-forces
#8
Javier Garzón-Niño, María Rodríguez-Muñoz, Elsa Cortés-Montero, Pilar Sánchez-Blázquez
Mice with histidine triad nucleotide-binding protein 1 (HINT1) deletion exhibit manic-like symptoms that evolve into depressive-like behavior in response to stressful paradigms. Molecular and electrophysiological studies have indicated that HINT1(-/-) mice exhibit increased PKC, PKA, and GSK3β activities, as well as glutamate N-methyl-D-aspartate receptor (NMDAR)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and NR2B/NR2A subunit ratios. Pharmacological interventions stabilized their behavior but through different mechanisms...
February 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28222314/systematic-variation-of-the-benzenesulfonamide-part-of-the-glun2a-selective-nmda-receptor-antagonist-tcn-201
#9
Sebastian L Müller, Julian A Schreiber, Dirk Schepmann, Nathalie Strutz-Seebohm, Guiscard Seebohm, Bernhard Wünsch
GluN2A subunit containing N-methyl-d-aspartate receptors (NMDARs) are highly involved in various physiological processes in the central nervous system, but also in some diseases, such as anxiety, depression and schizophrenia. However, the role of GluN2A subunit containing NMDARs in pathological processes is not exactly elucidated. In order to obtain potent and selective inhibitors of GluN2A subunit containing NMDARs, the selective negative allosteric modulator 2 was systematically modified at the benzenesulfonamide part...
March 31, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28202572/differential-regulation-of-nmda-receptors-by-d-serine-and-glycine-in-mammalian-spinal-locomotor-networks
#10
David Acton, Gareth Brian Miles
Activation of N-methyl-D-aspartate receptors (NMDARs) requires the binding of a co-agonist, either D-serine or glycine, in addition to glutamate. Changes in occupancy of the co-agonist binding site are proposed to modulate neural networks including those controlling swimming in frog tadpoles. Here, we characterize regulation of the NMDAR co-agonist binding site in mammalian spinal locomotor networks. Blockade of NMDARs by D(-)-2-amino-5-phosphonopentanoic acid (D-APV) or 5,7-dichlorokynurenic acid reduced the frequency and amplitude of pharmacologically induced locomotor-related activity recorded from the ventral roots of spinal-cord preparations from neonatal mice...
February 15, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28163934/enhancing-nmda-receptor-function-recent-progress-on-allosteric-modulators
#11
REVIEW
Lulu Yao, Qiang Zhou
The N-methyl-D-aspartate receptors (NMDARs) are subtype glutamate receptors that play important roles in excitatory neurotransmission and synaptic plasticity. Their hypo- or hyperactivation are proposed to contribute to the genesis or progression of various brain diseases, including stroke, schizophrenia, depression, and Alzheimer's disease. Past efforts in targeting NMDARs for therapeutic intervention have largely been on inhibitors of NMDARs. In light of the discovery of NMDAR hypofunction in psychiatric disorders and perhaps Alzheimer's disease, efforts in boosting NMDAR activity/functions have surged in recent years...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28126851/functional-evaluation-of-a-de-novo-grin2a-mutation-identified-in-a-patient-with-profound-global-developmental-delay-and-refractory-epilepsy
#12
Wenjuan Chen, Anel Tankovic, Pieter B Burger, Hirofumi Kusumoto, Stephen F Traynelis, Hongjie Yuan
The N-methyl-d-aspartate receptor (NMDAR), a ligand-gated ionotropic glutamate receptor, plays important roles in normal brain development and a wide range of neurologic disorders, including epilepsy. Here, we evaluate for the first time the functional properties of a de novo GRIN2A missense mutation (p.M817V) in the pre-M4 linker in a child with profound global developmental delay and refractory epilepsy. Electrophysiologic recordings revealed that the mutant GluN2A(M817V)-containing receptors showed enhanced agonist potency, reduced sensitivity to endogenous negative inhibitors (Mg(2+), proton, and zinc), prolonged synaptic-like response time course, increased single-channel mean open time, and increased channel open probability...
April 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28119997/peripheral-nmda-receptor-no-system-blockage-inhibits-itch-responses-induced-by-chloroquine-in-mice
#13
Nazgol-Sadat Haddadi, Arash Foroutan, Sattar Ostadhadi, Ehsan Azimi, Nastaran Rahimi, Mehdi Nateghpour, Ethan A Lerner, Ahmad Reza Dehpour
Intradermal administration of chloroquine (CQ) provokes scratching behavior in mice. Chloroquine-induced itch is histamine-independent and we have reported that the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is involved in CQ-induced scratching behavior in mice. Previous studies have demonstrated that activation of N-methyl-d-aspartate receptors (NMDARs) induces NO production. Here we show that NMDAR antagonists significantly decrease CQ-induced scratching in mice while a non-effective dose of an NMDAR agonist potentiates the scratching behavior provoked by sub-effective doses of CQ...
January 25, 2017: Acta Dermato-venereologica
https://www.readbyqxmd.com/read/28108357/sigma-1-receptor-deficiency-reduces-gabaergic-inhibition-in-the-basolateral-amygdala-leading-to-ltd-impairment-and-depressive-like-behaviors
#14
Baofeng Zhang, Ling Wang, Tingting Chen, Juan Hong, Sha Sha, Jun Wang, Hang Xiao, Ling Chen
Sigma-1 receptor knockout (σ1R(-/-)) in male mice causes depressive-like phenotype. We observed the expression of σ1R in principal neurons of basolateral amygdala (BLA), a main region for affective regulation. The present study investigated the influence of σ1R deficiency in BLA neurons on synaptic properties and plasticity at cortico-BLA pathway. In comparison with wild-type (WT) mice, the slopes of field excitatory postsynaptic potentials (fEPSP) were reduced in σ1R(-/-) mice with the increases in paired-pulse facilitation (PPF) and paired-pulse inhibition (PPI) values...
January 17, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28095420/molecular-mechanism-of-disease-associated-mutations-in-the-pre-m1-helix-of-nmda-receptors-and-potential-rescue-pharmacology
#15
Kevin K Ogden, Wenjuan Chen, Sharon A Swanger, Miranda J McDaniel, Linlin Z Fan, Chun Hu, Anel Tankovic, Hirofumi Kusumoto, Gabrielle J Kosobucki, Anthony J Schulien, Zhuocheng Su, Joseph Pecha, Subhrajit Bhattacharya, Slavé Petrovski, Adam E Cohen, Elias Aizenman, Stephen F Traynelis, Hongjie Yuan
N-methyl-D-aspartate receptors (NMDARs), ligand-gated ionotropic glutamate receptors, play key roles in normal brain development and various neurological disorders. Here we use standing variation data from the human population to assess which protein domains within NMDAR GluN1, GluN2A and GluN2B subunits show the strongest signal for being depleted of missense variants. We find that this includes the GluN2 pre-M1 helix and linker between the agonist-binding domain (ABD) and first transmembrane domain (M1). We then evaluate the functional changes of multiple missense mutations in the NMDAR pre-M1 helix found in children with epilepsy and developmental delay...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28092019/urb597-and-the-cannabinoid-win55-212-2-reduce-behavioral-and-neurochemical-deficits-induced-by-mptp-in-mice-possible-role-of-redox-modulation-and-nmda-receptors
#16
Angel Escamilla-Ramírez, Esperanza García, Guadalupe Palencia-Hernández, Ana Laura Colín-González, Sonia Galván-Arzate, Isaac Túnez, Julio Sotelo, Abel Santamaría
Several physiological events in the brain are regulated by the endocannabinoid system (ECS). While synthetic cannabinoid receptor (CBr) agonists such as WIN55,212-2 act directly on CBr, agents like URB597, a fatty acid amide hydrolase (FAAH) inhibitor, induce a more "physiological" activation of CBr by increasing the endogenous levels of the endocannabinoid anandamide (AEA). Herein, we compared the pre- and post-treatment efficacy of URB597 and WIN55,212-2 on different endpoints evaluated in the toxic model produced by the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice...
May 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28045032/mechanical-stress-activates-nmda-receptors-in-the-absence-of-agonists
#17
Mohammad Mehdi Maneshi, Bruce Maki, Radhakrishnan Gnanasambandam, Sophie Belin, Gabriela K Popescu, Frederick Sachs, Susan Z Hua
While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca(2+) entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca(2+) influx...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28032990/iterative-focused-screening-with-biological-fingerprints-identifies-selective-asc-1-inhibitors-distinct-from-traditional-high-throughput-screening
#18
Peter S Kutchukian, Lee Warren, Brian C Magliaro, Adam Amoss, Jason A Cassaday, Gregory O'Donnell, Brian Squadroni, Paul Zuck, Danette Pascarella, J Chris Culberson, Andrew J Cooke, Danielle Hurzy, Kelly-Ann Sondra Schlegel, Fiona Thomson, Eric N Johnson, Victor N Uebele, Jeffrey D Hermes, Sophie Parmentier-Batteur, Michael Finley
N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer's disease. One approach to enhance the function of NMDAR is to increase the concentration of an NMDAR coagonist, such as glycine or d-serine, in the synaptic cleft. Inhibition of alanine-serine-cysteine transporter-1 (Asc-1), the primary transporter of d-serine, is attractive because the transporter is localized to neurons in brain regions critical to cognitive function, including the hippocampus and cortical layers III and IV, and is colocalized with d-serine and NMDARs...
January 6, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28003505/bortezomib-for-treatment-of-therapy-refractory-anti-nmda-receptor-encephalitis
#19
Franziska Scheibe, Harald Prüss, Annerose M Mengel, Siegfried Kohler, Astrid Nümann, Martin Köhnlein, Klemens Ruprecht, Tobias Alexander, Falk Hiepe, Andreas Meisel
OBJECTIVE: We assessed the therapeutic potential of the plasma-cell-depleting proteasome inhibitor bortezomib in severe and therapy-refractory cases of anti-NMDA receptor (anti-NMDAR) encephalitis. METHODS: Five severely affected patients with anti-NMDAR encephalitis with delayed treatment response or resistance to standard immunosuppressive and B-cell-depleting drugs (corticosteroids, IV immunoglobulins, plasma exchange, immunoadsorption, rituximab, cyclophosphamide) who required medical treatment and artificial ventilation on intensive care units were treated with 1-6 cycles of 1...
January 24, 2017: Neurology
https://www.readbyqxmd.com/read/27993520/overexpression-of-%C3%AE-camkii-impairs-behavioral-flexibility-and-nmdar-dependent-long-term-depression-in-the-dentate-gyrus
#20
Pengcheng Yin, Hao Xu, Qi Wang, Jiayue Wang, Liang Yin, Meichen Xu, Zhenyang Xie, Wenzhao Liu, Xiaohua Cao
Behavioral flexibility is in close proximity to dentate gyrus (DG) function and long-term depression (LTD), but the role of DG LTD in behavioral flexibility has hitherto been unexplored. Although the functions of alpha-Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) have been studied extensively, the role of βCaMKII, a constituent of the CaMKII holoenzyme, in LTD and behavioral flexibility has not been investigated in vivo. Here using the βCaMKII-F90G transgenic (TG) mice, in which the inducible and reversible overexpression of βCaMKII is restricted to dentate gyrus (DG), we found that TG mice exhibited defective behavioral flexibility in two reversal tasks and seriously impaired N-methyl-d-aspartic acid receptor (NMDAR)-dependent LTD in DG medial perforant path (MPP)...
December 16, 2016: Neuropharmacology
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