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nmdar inhibitors

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https://www.readbyqxmd.com/read/28919534/glutamate-induced-rapid-induction-of-arc-arg3-1-requires-nmda-receptor-mediated-phosphorylation-of-erk-and-creb
#1
Tao Chen, Jie Zhu, Li-Kun Yang, Yi Feng, Wei Lin, Yu-Hai Wang
Arc/Arg3.1 is a unique immediate early gene whose expression is highly dynamic and correlated with various forms of synaptic plasticity. Many previous reports highlight the complexity of mechanisms that regulate Arc/Arg3.1 expression in neurons. In the present study, the expression and regulation of Arc/Arg3.1 after glutamate treatment in primary cultured cortical neurons were investigated. We found that both Arc/Arg3.1 mRNA and Arc/Arg3.1 protein dynamically increased within 24h after glutamate treatment. The results of immunostaining showed that abundant amounts of Arc/Arg3...
September 14, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28912160/dopamine-d2-receptors-modulate-pyramidal-neurons-in-mouse-medial-prefrontal-cortex-through-a-stimulatory-g-protein-pathway
#2
Sarah E Robinson, Vikaas S Sohal
Dopaminergic modulation of prefrontal cortex is believed to play key roles in many cognitive functions and to be disrupted in pathological conditions such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically-projecting (SC) pyramidal neurons within L5 of the prefrontal cortex. These D2R-induced ADPs only occur following synaptic input which activates NMDA receptors (NMDARs) even when the delay between the synaptic input and afterdepolarizations is relatively long, e...
September 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28886955/successful-combined-targeting-of-b-and-plasma-cells-in-treatment-refractory-anti-nmdar-encephalitis
#3
Olafur Sveinsson, Mathias Granqvist, Yngve Forslin, Kaj Blennow, Henrik Zetterberg, Fredrik Piehl
We describe an extremely severe case of therapy refractory NMDA receptor encephalitis (NMDAe) in a 26-year-old woman. After rituximab, bilateral oophorectomy, repeated cycles of high dose methylprednisolone and plasma exchange, she received repeated cyclophosphamide, tocilizumab (interleukin-6 inhibitor) and finally bortezomib (plasma cell depleting drug) leading to remission after 204days in intensive care. Two years after disease onset her cognitive functions are still affected, but slowly improving and the cerebral atrophy has been partly reversed...
August 25, 2017: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/28838956/adenylyl-cyclase-1-is-required-for-ethanol-induced-locomotor-sensitization-and-associated-increases-in-nmda-receptor-phosphorylation-and-function-in-the-dorsal-medial-striatum
#4
Kelly E Bosse, Max F Oginsky, Laura L Susick, Sailesh Ramalingam, Carrie R Ferrario, Alana C Conti
Neuroadaptive responses to chronic ethanol, such as behavioral sensitization, are associated with NMDA receptor (NMDAR) recruitment. Ethanol enhances GluN2B-containing NMDAR function and phosphorylation (Tyr-1472) of the GluN2B-NMDAR subunit in the dorsal medial striatum (DMS) through a protein kinase A (PKA)-dependent pathway. Ethanol-induced phosphorylation of PKA substrates is partially mediated by calcium-stimulated adenylyl cyclase 1 (AC1), which is enriched in the dorsal striatum. As such, AC1 is poised as an upstream modulator of ethanol-induced DMS neuroadaptations that promote drug responding and, thus, represents a therapeutic target...
August 24, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28828606/glycine-transporters-and-its-coupling-with-nmda-receptors
#5
Francisco Zafra, Ignacio Ibáñez, David Bartolomé-Martín, Dolores Piniella, Marina Arribas-Blázquez, Cecilio Giménez
Glycine plays two roles in neurotransmission. In caudal areas like the spinal cord and the brainstem, it acts as an inhibitory neurotransmitter, but in all regions of the CNS, it also works as a co-agonist with L-glutamate at N-methyl-D-aspartate receptors (NMDARs). The glycine fluxes in the CNS are regulated by two specific transporters for glycine, GlyT1 and GlyT2, perhaps with the cooperation of diverse neutral amino acid transporters like Asc-1 or SNAT5/SN2. While GlyT2 and Asc-1 are neuronal proteins, GlyT1 and SNAT5 are mainly astrocytic, although neuronal forms of GlyT1 also exist...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28825789/multifunctional-analogs-of-kynurenic-acid-for-the-treatment-of-alzheimer-s-disease-synthesis-pharmacology-and-molecular-modeling-studies
#6
Girdhar Singh Deora, Srinivas Kantham, Stephen Chan, Satish N Dighe, Suresh K Veliyath, Gawain McColl, Marie-Odile Parat, Ross P McGeary, Benjamin P Ross
We report the synthesis and pharmacological investigation of analogs of the endogenous molecule kynurenic acid (KYNA) as multifunctional agents for the treatment of Alzheimer's disease (AD). Synthesized KYNA analogs were tested for their N-methyl-d-aspartate (NMDA) receptor binding, mGluR5 binding and function, acetylcholinesterase (AChE) inhibition, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, interference with the amyloid β peptide (Aβ) fibrillation process, and protection against Aβ-induced toxicity in transgenic Caenorhabditis elegans strain GMC101 expressing full-length Aβ42...
September 8, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28802646/involvement-of-extracellular-signal-regulated-kinase-erk-in-the-short-and-long-lasting-antidepressant-like-activity-of-nmda-receptor-antagonists-zinc-and-ro-25-6981-in-the-forced-swim-test-in-rats
#7
Bartłomiej Pochwat, Anna Rafało-Ulińska, Helena Domin, Paulina Misztak, Gabriel Nowak, Bernadeta Szewczyk
Short and long acting NMDA receptor (NMDAR) antagonists exert their antidepressant-like effects by activating signaling pathways involved in the synthesis of synaptic proteins and formation of new synaptic connections in the prefrontal cortex (PFC) of rats. The blockade of the ERK pathway abolishes ketamine and Ro 25-6981 antidepressant potency. However, the role of ERK in the antidepressant-like activity of short acting NMDAR antagonists is still unclear. More puzzling is the fact that the precise role of ERK in the short and long lasting effects of long-acting NMDAR antagonists is unknown...
August 9, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28780732/assessment-of-the-target-engagement-and-d-serine-biomarker-profiles-of-the-d-amino-acid-oxidase-inhibitors-sodium-benzoate-and-pgm030756
#8
Eimear Howley, Michael Bestwick, Rosa Fradley, Helen Harrison, Mathew Leveridge, Kengo Okada, Charlotte Fieldhouse, Will Farnaby, Hannah Canning, Andy P Sykes, Kevin Merchant, Katherine Hazel, Catrina Kerr, Natasha Kinsella, Louise Walsh, David G Livermore, Isaac Hoffman, Jonathan Ellery, Phillip Mitchell, Toshal Patel, Mark Carlton, Matt Barnes, David J Miller
Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids...
August 5, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28777252/n-methyl-d-aspartate-receptor-nmdar-driven-calcium-influx-potentiates-the-adverse-effects-of-myocardial-ischemia-reperfusion-injury-ex-vivo
#9
Zi-You Liu, Shou Hu, Qin-Wen Zhong, Cheng-Nan Tian, Hou-Mou Ma, Jun-Jian Yu
BACKGROUND: Despite the adverse effects of N-methyl-D-aspartate receptor (NMDAR) activity in cardiomyocytes, no study has yet examined the effects of NMDAR activity under ex vivo ischemic-reperfusion (I/R) conditions. Therefore, our aim was to comprehensively evaluate the effects of NMDAR activity through an ex vivo myocardial I/R rat model. METHODS: Isolated rat hearts were randomly segregated into six groups (n=20 in each group): (i) an untreated control group; (ii) a NMDA-treated control group; (iii) an untreated I/R group; (iv) an I/R+NMDA group treated with NMDA; (v) an I/R+NMDA+MK-801 group treated with NMDA and the NMDAR inhibitor MK-801; and (vi) an I/R+NMDA+[Ca]-free group treated with NMDA and [Ca]-free buffer...
August 4, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28711909/h2o2-attenuates-igf-1r-tyrosine-phosphorylation-and-its-survival-signaling-properties-in-neuronal-cells-via-nr2b-containing-nmda-receptor
#10
Zhiwen Zeng, Dejun Wang, Uma Gaur, Liao Rifang, Haitao Wang, Wenhua Zheng
Impairment of insulin-like growth factor I (IGF-I) signaling plays an important role in the development of neurodegeneration. In the present study, we investigated the effect of H2O2 on the survival signaling of IGF-1 and its underlying mechanisms in human neuronal cells SH-SY5Y. Our results showed that IGF-1 promoted cell survival and stimulated phosphorylation of IGF-1R as well as its downstream targets like AKT and ERK1/2 in these cells. Meanwhile, these effects of IGF-1 were abolished by H2O2 at 200μM concentration which did not cause any significant toxicity to cells itself in our experiments...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28695335/glutamatergic-system-and-mtor-signaling-pathway-participate-in-the-antidepressant-like-effect-of-inosine-in-the-tail-suspension-test
#11
Filipe Marques Gonçalves, Vivian Binder Neis, Débora Kurrle Rieger, Tanara V Peres, Mark William Lopes, Isabella A Heinrich, Ana Paula Costa, Ana Lúcia S Rodrigues, Manuella P Kaster, Rodrigo Bainy Leal
Glutamatergic system and mTOR signaling pathway have been proposed to be important targets for pharmacological treatment of major depressive disorder. Previous studies have shown that inosine, an endogenous purine, is able to exert a remarkable antidepressant-like effect in mice. Nevertheless, the role of glutamatergic system and mTOR in this effect was not previously determined. This study was designed to investigate the possible modulation of NMDA receptors (NMDAR), AMPA receptors (AMPAR) and mTOR complex 1 (mTORC1) signaling pathway in the inosine anti-immobility effect in the tail suspension test (TST) in mice...
July 10, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28663117/bortezomib-induces-neuropathic-pain-through-protein-kinase-c-mediated-activation-of-presynaptic-nmda-receptors-in-the-spinal-cord
#12
Jing-Dun Xie, Shao-Rui Chen, Hong Chen, Hui-Lin Pan
Chemotherapeutic drugs, including bortezomib, often cause painful peripheral neuropathy, which is a severe dose-limiting adverse effect experienced by many cancer patients. The glutamate N-methyl-d-aspartate receptors (NMDARs) at the spinal cord level are critically involved in the synaptic plasticity associated with neuropathic pain. In this study, we determined whether treatment with bortezomib, a proteasome inhibitor, affects the NMDAR activity of spinal dorsal horn neurons. Systemic treatment with bortezomib in rats did not significantly affect postsynaptic NMDAR currents elicited by puff application of NMDA directly to dorsal horn neurons...
September 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28649199/glyx-13-a-nmda-receptor-glycine-site-functional-partial-agonist-attenuates-cerebral-ischemia-injury-in-vivo-and-vitro-by-differential-modulations-of-nmda-receptors-subunit-components-at-different-post-ischemia-stage-in-mice
#13
Chen Zheng, Zhi H Qiao, Meng Z Hou, Nan N Liu, Bin Fu, Ran Ding, Yuan Y Li, Liang P Wei, Ai L Liu, Hui Shen
Excessive activation of NMDA receptors (NMDARs) is implicated in pathological synaptic plasticity also known as post-ischemic long-term potentiation (i-LTP) which was produced by glutamate mediated excitotoxicity after stroke. In the past decades, many NMDARs inhibitors failed in clinical investigations due to severe psychotomimetic side effects. GLYX-13 is a NMDAR modulator with glycine site partial agonist properties and has potential protective effects on ischemic neuronal death. However, the underlying molecular mechanism of GLYX-13 attenuating the ischemic neuronal damage remains elusive...
2017: Frontiers in Aging Neuroscience
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
#14
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
#15
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...
August 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
#16
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
#17
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
#18
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...
September 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
#19
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
#20
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
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