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nmdar inhibitors

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https://www.readbyqxmd.com/read/28045032/mechanical-stress-activates-nmda-receptors-in-the-absence-of-agonists
#1
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
#2
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 co-agonist, 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 co-localized with D-serine and NMDARs...
December 29, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/28003505/bortezomib-for-treatment-of-therapy-refractory-anti-nmda-receptor-encephalitis
#3
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...
December 21, 2016: 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
#4
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
https://www.readbyqxmd.com/read/27976681/amphetamine-and-methamphetamine-increase-nmdar-glun2b-synaptic-currents-in-midbrain-dopamine-neurons
#5
Minghua Li, Suzanne M Underhill, Cheryl Reed, Tamara J Phillips, Susan G Amara, Susan L Ingram
The psychostimulants amphetamine (AMPH) and methamphetamine (MA) are widely abused illicit drugs. Here we show that both psychostimulants acutely increase NMDA receptor (NMDAR)-mediated synaptic currents and decrease AMPAR/NMDAR ratios in midbrain dopamine neurons. The potentiation depends on the transport of AMPH into the cell by the dopamine transporter (DAT). NMDAR-GluN2B receptor inhibitors, ifenprodil, RO 25-6981 and RO 04-5595 inhibit the potentiation without affecting basal evoked NMDA currents, indicating that NMDAR-GluN2B receptors are activated by AMPH...
December 15, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27872582/separate-ionotropic-and-metabotropic-glutamate-receptor-functions-in-depotentiation-vs-ltp-a-distinct-role-for-group1-mglur-subtypes-and-nmdars
#6
Amira Latif-Hernandez, Enrico Faldini, Tariq Ahmed, Detlef Balschun
Depotentiation (DP) is a mechanism by which synapses that have recently undergone long-term potentiation (LTP) can reverse their synaptic strengthening within a short time-window after LTP induction. Group 1 metabotropic glutamate receptors (mGluRs) were shown to be involved in different forms of LTP and long-term depression (LTD), but little is known about their roles in DP. Here, we generated DP by applying low-frequency stimulation (LFS) at 5 Hz after LTP had been induced by a single train of theta-burst-stimulation (TBS)...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27862359/the-conversion-of-glutamate-by-glutamine-synthase-in-neocortical-astrocytes-from-juvenile-rat-is-important-to-limit-glutamate-spillover-and-peri-extrasynaptic-activation-of-nmda-receptors
#7
Yosra Trabelsi, Mohamed Amri, Hélène Becq, Florence Molinari, Laurent Aniksztejn
Glutamate transporters (EAATs) are important to maintain spatial and temporal specificity of synaptic transmission. Their efficiency to uptake and transport glutamate into the intracellular space depends on several parameters including the intracellular concentrations of Na(+) and glutamate, the elevations of which may slow down the cycling rate of EAATs. In astrocytes, glutamate is maintained at low concentration due to the presence of specific enzymes such as glutamine synthase (GS). GS inhibition results in cytosolic accumulation of glutamate suggesting that the conversion of glutamate by GS is important for EAATs operation...
February 2017: Glia
https://www.readbyqxmd.com/read/27859797/in-vitro-and-in%C3%A2-vivo-effects-of-a-novel-dimeric-inhibitor-of-psd-95-on-excitotoxicity-and-functional-recovery-after-experimental-traumatic-brain-injury
#8
Jens Bak Sommer, Anders Bach, Hana Malá, Kristian Strømgaard, Jesper Mogensen, Darryl S Pickering
PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor of PSD-95, UCCB01-147, on histopathology and long-term cognitive outcome after controlled cortical impact (CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology of TBI, we also investigated the neuroprotective effects of UCCB01-147 and related compounds on NMDA-induced cell death in cultured cortical neurons...
November 17, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27847466/glun2a-subunit-containing-nmda-receptors-are-the-preferential-neuronal-targets-of-homocysteine
#9
Dmitry A Sibarov, Polina A Abushik, Rashid Giniatullin, Sergei M Antonov
Homocysteine (HCY) is an endogenous redox active amino acid, best known as contributor to various neurodegenerative disorders. Although it is known that HCY can activate NMDA receptors (NMDARs), the mechanisms of its action on receptors composed of different NMDA receptor subunits remains almost unknown. In this study, using imaging and patch clamp technique in cultured cortical neurons and heterologous expression in HEK293T cells we tested the agonist activity of HCY on NMDARs composed of GluN1 and GluN2A subunits (GluN1/2A receptors) and GluN1 and GluN2B subunits (GluN1/2B receptors)...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27845242/neo-adjuvant-chemotherapy-with-cisplatin-induces-low-expression-of-nmda-receptors-and-postoperative-cognitive-impairment
#10
Jing Cheng, Xiaoqing Liu, Longhui Cao, Tianhua Zhang, Huiting Li, Wenqian Lin
Whether Neo-adjuvant chemotherapy can affect patients' postoperative brain function is not clear. In this study, we investigated the effect of preoperative cisplatin treatment on postoperative cognitive function and its possible mechanism in rats. Moreover, we also tested whether the NMDAR inhibitor memantine could attenuate cisplatin-induced alterations. 12-month-oldSprague-Dawley rats randomly received an intraperitoneal injection of either cisplatin once a week at a dose of 3mg/kg for three consecutive weeks or an equivalent volume of normal saline...
January 10, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/27836791/pharmacological-inhibition-of-pten-attenuates-cognitive-deficits-caused-by-neonatal-repeated-exposures-to-isoflurane-via-inhibition-of-nr2b-mediated-tau-phosphorylation-in-rats
#11
Lei Tan, Xin Chen, Wei Wang, Jianfang Zhang, Shiyong Li, Yilin Zhao, Jintao Wang, Ailin Luo
Evidence has shown that children exposed to repeated anesthesia in early childhood display long-term cognitive disabilities. However, the underlying mechanisms remain largely unclear. Our previous study has indicated the involvement of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in isoflurane-induced decrease of self-renewal capacity in hippocampal neural precursor cells. Additionally, it is demonstrated by others that PTEN inhibition could protect against cognitive impairment via reduction of tau phosphorylation in the alzheimer's disease model...
March 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/27826117/neonatal-inhibition-of-na-k-2cl-cotransporter-prevents-ketamine-induced-spatial-learning-and-memory-impairments
#12
Ryan A Stevens, Brandon D Butler, Saurabh S Kokane, Andrew W Womack, Qing Lin
Prolonged ketamine exposure in neonates at anesthetic doses is known to cause long-term impairments of learning and memory. A current theoretical mechanism explains this phenomenon as being neuro-excitotoxicity mediated by compensatory upregulation of N-methyl-d-aspartate receptors (NMDARs), which then initiates widespread neuroapoptosis. Additionally, the excitatory behavior of GABAergic synaptic transmission mediated by GABAA receptors (GABAARs), occurring during the early neuronal development period, is proposed as contributing to the susceptibility of neonatal neurons to ketamine-induced injury...
November 5, 2016: Neurotoxicology and Teratology
https://www.readbyqxmd.com/read/27796759/increased-src-family-kinase-activity-disrupts-excitatory-synaptic-transmission-and-impairs-remote-fear-memory-in-forebrain-shp2-deficient-mice
#13
Xunyi Yan, Bin Zhang, Wen Lu, Lin Peng, Qian Yang, Wei Cao, Shen Lin, Wenyue Yu, Xiaoming Li, Yuehai Ke, Shengtian Li, Wei Yang, Jianhong Luo
Src homolog domain-containing phosphatase 2 (Shp2) signals a variety of cellular and physiological functions including learning and memory. Dysregulation of ERK signaling is known to be responsible for the cognitive deficits associated with gain-of-function mutated Shp2 mimicking Noonan syndrome. However, here, we report that CaMKIIα-cre induced knockout (CaSKO) of Shp2 in hippocampal pyramidal neurons resulted in increased Src activity, upregulated phosphorylation of N-methyl-D-aspartate receptors (NMDARs) at Y1325 of GluN2A and at Y1472 of GluN2B, disrupted the balance of synaptic transmission, and impaired long-term potentiation and remote contextual fear memory...
October 29, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27794462/long-term-depression-associated-signaling-is-required-for-an-in-vitro-model-of-nmda-receptor-dependent-synapse-pruning
#14
Maile A Henson, Charles J Tucker, Meilan Zhao, Serena M Dudek
Activity-dependent pruning of synaptic contacts plays a critical role in shaping neuronal circuitry in response to the environment during postnatal brain development. Although there is compelling evidence that shrinkage of dendritic spines coincides with synaptic long-term depression (LTD), and that LTD is accompanied by synapse loss, whether NMDA receptor (NMDAR)-dependent LTD is a required step in the progression toward synapse pruning is still unknown. Using repeated applications of NMDA to induce LTD in dissociated rat neuronal cultures, we found that synapse density, as measured by colocalization of fluorescent markers for pre- and postsynaptic structures, was decreased irrespective of the presynaptic marker used, post-treatment recovery time, and the dendritic location of synapses...
October 26, 2016: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/27769245/n-methyl-d-aspartate-receptor-activation-mediates-lung-fibroblast-proliferation-and-differentiation-in-hyperoxia-induced-chronic-lung-disease-in-newborn-rats
#15
YanRui Wang, ShaoJie Yue, ZiQiang Luo, ChuanDing Cao, XiaoHe Yu, ZhengChang Liao, MingJie Wang
BACKGROUND: Previous studies have suggested that endogenous glutamate and its N-methyl-D-aspartate receptors (NMDARs) play important roles in hyperoxia-induced acute lung injury in newborn rats. We hypothesized that NMDAR activation also participates in the development of chronic lung injury after withdrawal of hyperoxic conditions. METHODS: In order to rule out the anti-inflammatory effects of NMDAR inhibitor on acute lung injury, the efficacy of MK-801 was evaluated in vivo using newborn Sprague-Dawley rats treated starting 4 days after cessation of hyperoxia exposure (on postnatal day 8)...
October 21, 2016: Respiratory Research
https://www.readbyqxmd.com/read/27713495/allosteric-regulation-in-nmda-receptors-revealed-by-the-genetically-encoded-photo-cross-linkers
#16
Meilin Tian, Shixin Ye
Allostery is essential to neuronal receptor function, but its transient nature poses a challenge for characterization. The N-terminal domains (NTDs) distinct from ligand binding domains are a major locus for allosteric regulation of NMDA receptors (NMDARs), where different modulatory binding sites have been observed. The inhibitor ifenprodil, and related phenylethanoamine compounds specifically targeting GluN1/GluN2B NMDARs have neuroprotective activity. However, whether they use differential structural pathways than the endogenous inhibitor Zn(2+) for regulation is unknown...
October 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27650422/central-neural-alterations-predominate-in-an-insect-model-of-nociceptive-sensitization
#17
Dennis R Tabuena, Allan Solis, Ken Geraldi, Christopher A Moffatt, Megumi Fuse
Many organisms respond to noxious stimuli with defensive maneuvers. This is noted in the hornworm, Manduca sexta, as a defensive strike response. After tissue damage, organisms typically display sensitized responses to both noxious or normally innocuous stimuli. To further understand this phenomenon, we used novel in situ and in vitro preparations based on paired extracellular nerve recordings and videography to identify central and peripheral nerves responsible for nociception and sensitization of the defensive behavior in M...
September 21, 2016: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/27557499/glutamatergic-stimulation-induces-glun2b-translation-by-the-nitric-oxide-heme-regulated-eif2%C3%AE-kinase-in-cortical-neurons
#18
Eva Ramos-Fernández, Marta Tajes, Gerard Ill-Raga, Lina Vargas, Arnau Busquets-García, Mònica Bosch-Morató, Biuse Guivernau, Victòria Valls-Comamala, Maria Gomis, Cristina Grau, César Fandos, Mark D Rosen, Michael H Rabinowitz, Nibaldo Inestrosa, Rafael Maldonado, Xavier Altafaj, Andrés Ozaita, Alejandra Alvarez, Rubén Vicente, Miguel A Valverde, Francisco J Muñoz
The activation of N-Methyl D-Aspartate Receptor (NMDAR) by glutamate is crucial in the nervous system function, particularly in memory and learning. NMDAR is composed by two GluN1 and two GluN2 subunits. GluN2B has been reported to participate in the prevalent NMDAR subtype at synapses, the GluN1/2A/2B. Here we studied the regulation of GluN2B expression in cortical neurons finding that glutamate up-regulates GluN2B translation through the action of nitric oxide (NO), which induces the phosphorylation of the eukaryotic translation initiation factor 2 α (eIF2α)...
September 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27546057/effects-of-memantine-on-the-excitation-inhibition-balance-in-prefrontal-cortex
#19
Nadezhda V Povysheva, Jon W Johnson
Memantine is one of the few drugs currently approved for treatment of Alzheimer's disease (AD). The clinical effects of memantine are thought to be associated with inhibition of NMDA receptors (NMDARs). Surprisingly, other open-channel NMDAR blockers have unacceptable side effects that prevent their consideration for AD treatment. One of the mechanisms proposed to explain the therapeutic benefits of memantine involves preferential decrease of excitatory drive to inhibitory neurons in the cortical circuitry and consequent changes in balance between excitation and inhibition (E/I)...
December 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27544449/physicochemical-and-biological-properties-of-novel-amide-based-steroidal-inhibitors-of-nmda-receptors
#20
Santosh Kumar Adla, Barbora Slavikova, Marketa Smidkova, Eva Tloustova, Martin Svoboda, Vojtech Vyklicky, Barbora Krausova, Pavla Hubalkova, Michaela Nekardova, Kristina Holubova, Karel Vales, Milos Budesinsky, Ladislav Vyklicky, Hana Chodounska, Eva Kudova
Herein, we report a new class of amide-based inhibitors (1-4) of N-methyl-d-aspartate receptors (NMDARs) that were prepared as analogues of pregnanolone sulfate (PAS) and pregnanolone glutamate (PAG) - the steroidal neuroprotective NMDAR inhibitors. A series of experiments were conducted to evaluate their physicochemical and biological properties: (i) the inhibitory effect of compounds 3 and 4 on NMDARs was significantly improved (IC50=1.0 and 1.4μM, respectively) as compared with endogenous inhibitor - pregnanolone sulfate (IC50=24...
January 2017: Steroids
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