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nmdar inhibitors

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https://www.readbyqxmd.com/read/28608233/alleviation-by-gabab-receptors-of-neurotoxicity-mediated-by-mitochondrial-permeability-transition-pore-in-cultured-murine-cortical-neurons-exposed-to-n-methyl-d-aspartate
#1
Toshihiko Kinjo, Yoshino Ashida, Hiroshi Higashi, Satoshi Sugimura, Miho Washida, Hiroki Niihara, Kiyokazu Ogita, Yukio Yoneda, Nobuyuki Kuramoto
Mitochondrial permeability transition pore (PTP) is supposed to at least in part participate in molecular mechanisms underlying the neurotoxicity seen after overactivation of N-methyl-D-aspartate (NMDA) receptor (NMDAR) in neurons. In this study, we have evaluated whether activation of GABAB receptor (GABABR), which is linked to membrane G protein-coupled inwardly-rectifying K(+) ion channels (GIRKs), leads to protection of the NMDA-induced neurotoxicity in a manner relevant to mitochondrial membrane depolarization in cultured embryonic mouse cortical neurons...
June 12, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28590364/neurophysiological-effects-of-bitopertin-in-schizophrenia
#2
Joshua T Kantrowitz, Karen A Nolan, Michael L Epstein, Nayla Lehrfeld, Constance Shope, Eva Petkova, Daniel C Javitt
PURPOSE/BACKGROUND: Deficits in N-methyl-D-aspartate receptor (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia and are associated with impaired generation of event-related potential measures including auditory mismatch negativity. Parallel studies of the NMDAR agonist d-serine have suggested that sensitivity of these measures to glutamate-based interventions is related to symptomatic and cognitive response. Bitopertin is a selective inhibitor of glycine transport...
June 5, 2017: Journal of Clinical Psychopharmacology
https://www.readbyqxmd.com/read/28550530/rtms-ameliorates-ptsd-symptoms-in-rats-by-enhancing-glutamate-transmission-and-synaptic-plasticity-in-the-acc-via-the-pten-akt-signalling-pathway
#3
Gaohua Liu, Dayun Feng, Jian Wang, Haifeng Zhang, Zhengwu Peng, Min Cai, Jing Yang, Ruiguo Zhang, Huaning Wang, Shengxi Wu, Qingrong Tan
Repetitive transcranial magnetic stimulation (rTMS) is a novel physiological therapy that has been adopted to clinically treat psychiatric disorders. Our previous study indicated the potential therapeutic effect of rTMS on posttraumatic stress disorder (PTSD). However, the exact molecular mechanism is elusive. Currently, using the single prolonged stress (SPS) rat model for PTSD, we investigated the glutamatergic transmission and neural plasticity changes in the anterior cingulate cortex (ACC) after SPS induction and explored the protective effects and mechanism of rTMS treatment...
May 26, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28533113/a-novel-serine-racemase-inhibitor-suppresses-neuronal-over-activation-in-vivo
#4
Hisashi Mori, Ryogo Wada, Satoyuki Takahara, Yoshikazu Horino, Hironori Izumi, Tetsuya Ishimoto, Tomoyuki Yoshida, Mineyuki Mizuguchi, Takayuki Obita, Hiroaki Gouda, Shuichi Hirono, Naoki Toyooka
Serine racemase (SRR) is an enzyme that produces d-serine from l-serine. d-Serine acts as an endogenous coagonist of NMDA-type glutamate receptors (NMDARs), which regulate many physiological functions. Over-activation of NMDARs induces excitotoxicity, which is observed in many neurodegenerative disorders and epilepsy states. In our previous works on the generation of SRR gene knockout (Srr-KO) mice and its protective effects against NMDA- and Aβ peptide-induced neurodegeneration, we hypothesized that the regulation of NMDARs' over-activation by inhibition of SRR activity is one such therapeutic strategy to combat these disease states...
May 11, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28497801/pde4-inhibition-restores-the-balance-between-excitation-and-inhibition-in-vta-dopamine-neurons-disrupted-by-repeated-in-vivo-cocaine-exposure
#5
Xiaojie Liu, Peng Zhong, Casey Vickstrom, Yan Li, Qing-Song Liu
Phosphodiesterase type 4 (PDE4) is a family of enzymes that selectively degrade intracellular cAMP. PDE4 inhibitors have been shown to regulate the rewarding and reinforcing effects of cocaine, but the underlying mechanisms remain poorly understood. Here we show that pretreatments with the PDE4 inhibitor rolipram attenuated cocaine-induced locomotor sensitization in mice. Repeated cocaine exposure in vivo caused a decrease in inhibitory postsynaptic currents (IPSCs) and an increase in the AMPAR/NMDAR ratio in ventral tegmental area (VTA) dopamine neurons in midbrain slices ex vivo...
May 12, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28439098/uncoupling-dapk1-from-nmda-receptor-glun2b-subunit-exerts-rapid-antidepressant-like-effects
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
David Acton, Gareth B Miles
Activation of N-methyl-d-aspartate receptors (NMDARs) requires the binding of a coagonist, either d-serine or glycine, in addition to glutamate. Changes in occupancy of the coagonist binding site are proposed to modulate neural networks including those controlling swimming in frog tadpoles. Here, we characterize regulation of the NMDAR coagonist 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...
May 1, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28163934/enhancing-nmda-receptor-function-recent-progress-on-allosteric-modulators
#16
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
#17
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
#18
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...
May 8, 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
#19
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
#20
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
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