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nmdar inhibitors

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
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
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)...
August 19, 2016: Oncotarget
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)...
August 18, 2016: Neurobiology of Disease
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...
August 17, 2016: Steroids
Lu Li, Chuchu Qiao, Gang Chen, Hongyan Qian, Ying Hou, Tao Li, Xinshe Liu
Chronic discontinuous use of many psychomotor stimulants leads to behavioral sensitization and, owing to it shares common mechanisms with relapse, most researchers use its animal model to explore the neurobiological mechanisms of addiction. Recent studies have proved that N-methyl-d-aspartate receptors (NMDARs) are implicated in psychomotor stimulant-induced behavioral sensitization. However, the function of GluN2B-containing NMDARs and their potential downstream cascade(s) in the acquisition and expression of behavioral sensitization to methamphetamine (METH) have not been explored...
October 29, 2016: Neuroscience
Yang-Jung Yu, Chien-Hsuan Huang, Chih-Hua Chang, Po-Wu Gean
Destabilization refers to a memory that becomes unstable when reactivated and is susceptible to disruption by amnestic agents. Here we delineated the cellular mechanism underlying the destabilization of drug memory. Mice were conditioned with methamphetamine (MeAM) for 3 d, and drug memory was assessed with a conditioned place preference (CPP) protocol. Anisomycin (ANI) was administered 60 min after the CPP retrieval to disrupt reconsolidation. We found that destabilization of MeAM CPP after the application of ANI was blocked by the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 and the NR2B antagonist ifenprodil (IFN) but not by the NR2A antagonist NVP-AAM077 (NVP)...
September 2016: Learning & Memory
Abdul-Karim Abbas
In testing the hypothesis that long-term potentiation (LTP) maintenance depends on triggered protein synthesis, we found no effect of protein synthesis inhibitors (PSIs) on LTP stabilization. Similarly, some studies reported a lack of effect of PSIs on long-term depression (LTD); the lack of effect on LTD has been suggested to be resulting from the short time recordings. If this proposal were true, LTD might exhibit sensitivity to PSIs when the recording intervals were enough long. We firstly induced LTD by a standard protocol involving low frequency stimulation, which is suitable for eliciting NMDAR-LTD in CA1 area of hippocampal slices obtained from juvenile Sprague-Dawley rats...
2016: PloS One
Eun-Jin Kang, So-Hye Hong, Jae-Eon Lee, Seung Chul Kim, Hoe-Saeng Yang, Pyong In Yi, Sang-Myeong Lee, Beum-Soo An
Pregnenolone sulfate (PS) is a neuroactive steroid hormone produced in the brain. In this study, the effects of PS on synthesis and secretion of rat pituitary prolactin (PRL) were examined. To accomplish this, GH3 rat pituitary adenoma cells were treated with PS, which showed significantly increased mRNA and protein levels of PRL compared with the control. The mechanism of action responsible for the effects of PS on PRL synthesis and secretion was investigated by pretreating cells with inhibitors of traditional PRL- or the PS-related signaling pathway...
September 2016: Journal of Endocrinology
Valentina Vengeliene, Nazzareno Cannella, Tatiane Takahashi, Rainer Spanagel
RATIONALE: The glutamatergic system plays a key role in the maintenance of drug use and development of drug-related conditioned behaviours. In particular, hyper-glutamatergic activity and N-methyl-D-aspartate receptor (NMDAR) activation may drive drug craving and relapse. Inhibition of kynurenine-3-monooxygenase (KMO) shifts the metabolic kynurenine pathway towards production of kynurenic acid, which leads to a reduction of glutamatergic/NMDAR activity via different mechanisms. OBJECTIVES: In this study, we investigated whether drug-seeking and relapse behaviour could be modified by the metabolic shift of endogenous kynurenine pathway...
September 2016: Psychopharmacology
Hong-Yan Gong, Fang Zheng, Chao Zhang, Xi-Yan Chen, Jing-Jing Liu, Xiu-Qin Yue
Ischemic brain injury (IBI) can cause nerve injury and is a leading cause of morbidity and mortality worldwide. The neuroprotective effects of propofol against IBI have been previously demonstrated. However, the neuroprotective effects of propofol on hippocampal neurons are not yet entirely clear. In the present study, models of IBI were established in hypoxia-exposed hippocampal neuronal cells. Cell viability assay and apoptosis assay were performed to examine the neuroprotective effects of propofol on hippocampal neurons in IBI...
September 2016: International Journal of Molecular Medicine
Lingyun Hao, Xuewen Wei, Peng Guo, Guangyi Zhang, Suhua Qi
Nitric oxide (NO) can regulate signaling pathways via S-nitrosylation. Fyn can be post-translationally modified in many biological processes. In the present study, using a rat four-vessel-occlusion ischemic model, we aimed to assess whether Fyn could be S-nitrosylated and to evaluate the effects of Fyn S-nitrosylation on brain damage. In vitro, Fyn could be S-nitrosylated by S-nitrosoglutathione (GSNO, an exogenous NO donor), and in vivo, endogenous NO synthesized by NO synthases (NOS) could enhance Fyn S-nitrosylation...
2016: International Journal of Molecular Sciences
Zhen-Zhen Duan, Feng Zhang, Feng-Ying Li, Yi-Fei Luan, Peng Guo, Yi-Hang Li, Yong Liu, Su-Hua Qi
It has been demonstrated that Src could modulate NMDA receptor, and PAR1 could also affect NMDAR signaling. However, whether PAR1 could regulate NMDAR through Src under ICH has not yet been investigated. In this study, we demonstrated the role of Src-PSD95-GluN2A signaling cascades in rat ICH model and in vitro thrombin challenged model. Using the PAR1 agonist SFLLR, antagonist RLLFS and Src inhibitor PP2, electrophysiological analysis showed that PAR1 regulated NMDA-induced whole-cell currents (INMDA) though Src in primary cultured neurons...
2016: Scientific Reports
Qi Zhao, Linlin Zhang, Ruichen Shu, Chunyan Wang, Yonghao Yu, Haiyun Wang, Guolin Wang
Up-regulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) expression and trafficking is the key mechanism for remifentanil-induced hyperalgesia (RIH), nevertheless, the signaling pathway and pivotal proteins involved in RIH remain equivocal. PKMζ, an isoform of protein kinase C (PKC), maintains pain memory storage in neuropathic pain and inflammatory pain, which plays a parallel role regulated by NMDARs in long-term memory trace. In the present study, Zeta Inhibitory Peptide (ZIP), a PKMζ inhibitor, and a selective GluN2B antagonist Ro-256981 are injected intrathecally before remifentanil infusion (1 μg kg(-1) min(-1) for 1 h, iv) in order to detect whether GluN2B contributes to RIH through affecting synthesis and activity of PKMζ in spinal dorsal horn...
July 5, 2016: Cellular and Molecular Neurobiology
Rui Zhao, Jiaojiao Chen, Zhaoxiang Ren, Hui Shen, Xuechu Zhen
Nucleus accumbens receives glutamatergic projection from the prefrontal cortex (PFC) and dopaminergic input from the Ventral tegmental area (VTA). Recent studies have suggested a critical role for serine/threonine kinase glycogen synthase kinase 3β (GSK3β) in cocaine-induced hyperactivity; however, the effect of GSK3β on the modulation of glutamatergic and dopaminergic afferents is unclear. In this study, we found that the GSK3 inhibitors, LiCl (100 mg/kg, i.p.) or SB216763 (2.5 mg/kg, i.p.), blocked the cocaine-induced hyperlocomotor activity in rats...
November 2016: Synapse
Rachel Asselot, Emmanuelle Simon-O'Brien, Sophie Lebourgeois, Gérald Nee, Virgile Delaunay, Pascal Duchatelle, Valentine Bouet, François Dauphin
Selective antagonists at serotonin 5-HT6 receptors (5-HT6R) improve memory performance in rodents and are currently under clinical investigations. If blockade of 5-HT6R is known to increase glutamate release, only two studies have so far demonstrated an interaction between 5-HT6R and glutamate transmission, but both, using the non-competitive NMDA antagonist MK-801, insensitive to variations of glutamate concentrations. In a place recognition task, we investigated here in mice the role of glutamate transmission in the beneficial effects of 5-HT6R blockade (SB-271046)...
June 30, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Hongyan Duan, Yongqiang Li, Lijie Yan, Haitao Yang, Jintao Wu, Peng Qian, Bing Li, Shanling Wang
Hyperhomocysteine has become a critical risk for atherosclerosis and can stimulate proliferation and migration of vascular smooth muscle cells (VSMCs). N-methyl-D-aspartic acid receptor (NMDAR) is a receptor of homocysteine and mediates the effects of homocysteine on VSMCs. Bioinformatics analysis has shown NMDAR is a potential target of microRNA-217 (miR-217), which exerts multiple functions in cancer tumorigenesis and carotid plaque progression. In this study, we sought to investigate the role of miR-217 in VSMCs phenotype transition under homocysteine exposure and elucidate its effect on atherosclerotic plaque formation...
October 2016: Clinical and Experimental Pharmacology & Physiology
Yan Sun, Jonathan O Lipton, Lara M Boyle, Joseph R Madsen, Marti C Goldenberg, Alvaro Pascual-Leone, Mustafa Sahin, Alexander Rotenberg
OBJECTIVE: To obtain insights into mechanisms mediating changes in cortical excitability induced by cathodal transcranial direct current stimulation (tDCS). METHODS: Neocortical slices were exposed to direct current stimulation (DCS) delivered through Ag/AgCl electrodes over a range of current orientations, magnitudes, and durations. DCS-induced cortical plasticity and its receptor dependency were measured as the change in layer II/III field excitatory postsynaptic potentials by a multielectrode array, both with and without neurotransmitter receptor blockers or allosteric modulators...
August 2016: Annals of Neurology
Andréia S Cunha, Filipe C Matheus, Morgana Moretti, Tuane B Sampaio, Anicleto Poli, Danúbia B Santos, Dirleise Colle, Mauricio P Cunha, Carlos H Blum-Silva, Louis P Sandjo, Flávio H Reginatto, Ana Lúcia S Rodrigues, Marcelo Farina, Rui D Prediger
Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i...
October 1, 2016: Behavioural Brain Research
Ana Laura Colín-González, Ariana Lizbeth Paz-Loyola, María Eduarda de Lima, Sonia Galván-Arzate, Bianca Seminotti, César Augusto João Ribeiro, Guilhian Leipnitz, Diogo Onofre Souza, Moacir Wajner, Abel Santamaría
3-Methylglutaric acid (3MGA) is an organic acid that accumulates in various organic acidemias whose patients present neurodegeneration events in children coursing with metabolic acidurias. Limited evidence describes the toxic mechanisms elicited by 3MGA in the brain. Herein, we explored the effects of 3MGA on different toxic endpoints in synaptosomal and mitochondrial-enriched fractions of adult rat brains to provide novel information on early mechanisms evoked by this metabolite. At 1 and 5 mM concentration, 3MGA increased lipid peroxidation, but decreased mitochondrial function only at 5 mM concentration...
June 9, 2016: Neurochemical Research
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