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David R Houck, Laurel Sindelar, Carlos R Sanabria, Stephanie H Stanworth, Maggie Krueger, Mary Suh, Torsten M Madsen
NYX-2925, a new chemical entity, acts as a co-agonist to glutamate at the N-methyl-D-aspartate receptor (NMDAR). At low concentrations of endogenous agonists (glycine/D-serine), NYX-2925 partially activates NMDARs, modulating neural pathways relevant for chronic pain. NYX-2925 is being developed for the treatment of chronic pain conditions, including painful diabetic peripheral neuropathy and fibromyalgia. In this first-in-human, Phase 1, single- (50-1200 mg) and multiple-ascending dose (150-900 mg) study, the safety, tolerability, and pharmacokinetics of NYX-2925 were evaluated in 84 healthy adult volunteers...
September 22, 2018: Clinical and Translational Science
Jelena Radulovic, Lynn Y Ren, Can Gao
N-Methyl D-aspartate receptors (NMDAR) are central mediators of glutamate actions underlying learning and memory processes including those required for extinction of fear and fear-related behaviors. Consistent with this view, in animal models, antagonists of NMDAR typically impair fear extinction, whereas partial agonists have facilitating effects. Promoting NMDAR function has thus been recognized as a promising strategy towards reduction of fear symptoms in patients suffering from anxiety disorders and post-traumatic disorder (PTSD)...
September 20, 2018: Psychopharmacology
Han-Fang Wu, Yi-Ju Chen, Ming-Chia Chu, Ya-Ting Hsu, Ting-Yi Lu, I-Tuan Chen, Po See Chen, Hui-Ching Lin
Deep brain stimulation (DBS) is known to be a promising treatment for resistant depression, which acts via the serotonin (5-hydroxytryptamine, 5-HT) system in the infralimbic prefrontal cortex (ILPFC). Previous study revealed that dysfunction of brain 5-HT homeostasis is related to a valproate (VPA)-induced rat autism spectrum disorder (ASD) model. Whether ILPFC DBS rescues deficits in VPA-induced offspring through the 5-HT system is not known. Using VPA-induced offspring, we therefore explored the effect of DBS in autistic phenotypes and further investigated the underlying mechanism...
September 19, 2018: International Journal of Molecular Sciences
Rafael Franco, David Aguinaga, Irene Reyes, Enric I Canela, Jaume Lillo, Airi Tarutani, Masato Hasegawa, Anna Del Ser-Badia, José A Del Rio, Michael R Kreutz, Carlos A Saura, Gemma Navarro
N -methyl-D-aspartate receptors (NMDARs) respond to glutamate to allow the influx of calcium ions and the signaling to the mitogen-activated protein kinase (MAPK) cascade. Both MAPK- and Ca2+ -mediated events are important for both neurotransmission and neural cell function and fate. Using a heterologous expression system, we demonstrate that NMDAR may interact with the EF-hand calcium-binding proteins calmodulin, calneuron-1, and NCS1 but not with caldendrin. NMDARs were present in primary cultures of both neurons and microglia from cortex and hippocampus...
2018: Frontiers in Molecular Neuroscience
Chao Zhang, Qinghua Xu, Xia Xiao, Weihao Li, Qiang Kang, Xiong Zhang, Tinghua Wang, Yan Li
Background: Pyrethroids have been widely used in residential and agricultural areas. However, little is known about the effects of prenatal exposure to deltamethrin on cognition in early development of offspring. In this study, the effects of prenatal exposure to deltamethrin on learning and memory abilities, N -methyl-D-aspartate receptor (NMDAR) subunits, brain derived neurotrophic factor (BDNF), Tyrosine kinase B (TrkB) receptor, and phosphorylated cAMP response element binding protein (pCREB) in the hippocampus of offspring rats were investigated...
2018: Frontiers in Neuroscience
Weinan Sun, Jonathan M Wong, John A Gray, Brett C Carter
NMDA receptors (NMDARs) are essential components in glutamatergic synaptic signaling. The NMDAR antagonist MK-801 has been a valuable pharmacological tool in evaluating NMDAR function because it binds with high affinity to the NMDAR ion channel pore and is non-competitive with ligand binding. MK-801 has also been used to selectively inhibit NMDAR current in only the cell being recorded by including the drug in the intracellular recording solution. Here, we report that intracellular MK-801 (iMK-801) only partially inhibits synaptic NMDAR currents at +40 mV at both cortical layer 4 to layer 2/3 and hippocampal Schaffer collateral to CA1 synapses...
September 15, 2018: Neuropharmacology
María Rodríguez-Muñoz, Yara Onetti, Elsa Cortés-Montero, Javier Garzón, Pilar Sánchez-Blázquez
Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer's and Parkinson's, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer. CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified...
September 17, 2018: Molecular Brain
Radhika Sharma, Karan Razdan, Yashika Bansal, Anurag Kuhad
Alzheimer's disease (AD) is associated with cerebral cognitive deficits exhibiting two cardinal hallmarks: accruement of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The currently accessible therapeutic armamentarium merely provides symptomatic relief. Therefore, the cry for prospective neuroprotective strategies seems to be the need of the hour. Areas Covered: This review comprehensively establishes correlation between kynurenine pathway (KP) metabolites and AD with major emphasis on its two functionally contrasting neuroactive metabolites i...
September 18, 2018: Expert Opinion on Therapeutic Targets
Kohji Sato
Glycine is an important amino acid in the central nervous system. Interestingly, the content of glycine is about 9 times higher in the spinal cord grey matter than in the telencephalon. And this kind of caudal to rostral gradient is never seen in any other neurotransmitters. However, the cause of this phenomenon remains unknown. In the present report, I, thus, postulate the following theory. Glycine has dual roles as a neurotransmitter, one is the agonist for inhibitory glycine receptors (GlyRs), and the other is a co-agonist for excitatory NMDA receptors (NMDARs)...
November 2018: Medical Hypotheses
Francisco Mouro, Diogo M Rombo, Raquel B Dias, Joaquim A Ribeiro, Ana M Sebastião
BACKGROUND AND PURPOSE: N-methyl-D-aspartate receptors (NMDARs) play a key role in both synaptic plasticity and neurodegeneration. Adenosine is an endogenous neuromodulator and through membrane receptors of the A2A subtype (A2A Rs) can influence both synaptic plasticity and neuronal death. The present work was designed to evaluate the influence of adenosine A2A Rs upon NMDAR activity in CA1 hippocampal neurons. We discriminated between modulation of synaptic versus extrasynaptic receptors, since extrasynaptic NMDARs are mostly related to neurodegeneration while synaptic NMDARs are linked to plasticity phenomena...
September 16, 2018: British Journal of Pharmacology
Katarzyna Skowrońska, Marta Obara-Michlewska, Anna Czarnecka, Katarzyna Dąbrowska, Magdalena Zielińska, Jan Albrecht
Astrocytes express N-methyl-D-aspartate (NMDA) receptor (NMDAR) but its functions in these cells are not well defined. This study shows that the sustained exposure (8-72 h) of mouse astrocytes to NMDA decreases the expression of the functional astroglia-specific proteins, glutamine synthetase (GS), and the water channel protein aquaporin-4 (AQP4) and also reduces GS activity. Similar to rat astrocytes (Obara-Michlewska et al. Neurochem Int 88:20-25, 2015), the exposure of mouse astrocytes to NMDA also decreased the expression of the inward rectifying potassium channel Kir4...
September 15, 2018: Neurotoxicity Research
Bin Wang, Qiong Wu, Lei Lei, Hailun Sun, Ntim Michael, Xuan Zhang, Ying Wang, Yue Zhang, Biying Ge, Yi Xin, Jie Zhao, Shao Li
Social isolation in adolescence leads to lasting deficits in hippocampal-dependent tasks. The reported effects of isolation on learning and memory in the Morris water maze and synaptic-related proteins have been inconsistent. Moreover, the autophagy level and its effect on cognition in the isolation model are also not clear. In the present study, we did an extended isolation period up to six months to establish a stable and appropriate isolation model to investigate the cognitive changes associated with it...
September 13, 2018: Experimental Neurology
Julian A Schreiber, Sebastian L Müller, Stefanie E Westphälinger, Dirk Schepmann, Nathalie Strutz-Seebohm, Guiscard Seebohm, Bernhard Wünsch
GluN2A containing N-methyl-D-aspartate receptors (NMDARs) are important ion channels in the central nervous system and highly involved in several different neurophysiological but also neuropathophysiological processes. However, current understanding of the contribution of GluN2A containing NMDARs in these processes is incomplete. Therefore, highly selective compounds are required to further investigate these ion channels. In 2010, TCN-201 (2), one of the first selective negative allosteric modulators was reported...
September 6, 2018: European Journal of Medicinal Chemistry
Johansen B Amin, Xiaoling Leng, Aaron Gochman, Huan-Xiang Zhou, Lonnie P Wollmuth
A variety of de novo and inherited missense mutations associated with neurological disorders are found in the NMDA receptor M4 transmembrane helices, which are peripheral to the pore domain in eukaryotic ionotropic glutamate receptors. Subsets of these mutations affect receptor gating with dramatic effects, including in one instance halting it, occurring at a conserved glycine near the extracellular end of M4. Functional experiments and molecular dynamic simulations of constructs with and without substitutions at this glycine indicate that it acts as a hinge, permitting the intracellular portion of the ion channel to laterally expand...
September 14, 2018: Nature Communications
Kai Zhang, Hidetoh Toki, Yuko Fujita, Min Ma, Lijia Chang, Youge Qu, Shingo Harada, Tetsuhiro Nemoto, Akiko Mizuno-Yasuhira, Jun-Ichi Yamaguchi, Shigeyuki Chaki, Kenji Hashimoto
RATIONALE: (R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits rapid and long-lasting antidepressant effects and anti-suicidal ideation in treatment-resistant patients with depression. However, the precise mechanisms underlying the antidepressant actions of (R,S)-ketamine are unknown. Although the previous report demonstrated the deuterium isotope effects in the antidepressant actions of (R,S)-ketamine, the deuterium isotope effects in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown...
September 13, 2018: Psychopharmacology
Samantha K Saland, Mohamed Kabbaj
Recent work from our group and others has revealed a higher sensitivity of female rodents to the antidepressant-like effects of N-methyl d-aspartate receptor (NMDAR) antagonist, ketamine, strongly influenced by circulating estrogen (E2) and progesterone (P4) levels. However, in the absence of any preclinical studies of pharmacokinetic sex differences using low-dose ketamine in rats, it is unclear whether the effects of sex and hormonal milieu on ketamine's behavioral actions are influenced by differences in ketamine metabolism between male and female rats...
September 13, 2018: Journal of Pharmacology and Experimental Therapeutics
Laura J Blakemore, John T Corthell, Paul Q Trombley
Glutamate is the neurotransmitter used at most excitatory synapses in the mammalian brain, including those in the olfactory bulb (OB). There, ionotropic glutamate receptors including N-methyl-d-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) play a role in processes such as reciprocal inhibition and glomerular synchronization. Kainate receptors (KARs) represent another type of ionotropic glutamate receptor, which are composed of five (GluK1-GluK5) subunits...
September 11, 2018: Neuroscience
Ji Yuanyuan, Zhu Junyan, DeJi Cuola, Cui Jingjing, Shi Yuhui, Xu Dan, Dang Wei, Zhu Yongsheng
Alcohol abuse and anxiety disorders often occur concurrently, but their underlying cellular mechanisms remain unclear. N-methyl-D-aspartic acid receptors (NMDARs) have recently received attention from those interested in the neurobiology of anxiety. A chronic alcohol exposure rat model (28 consecutive days of 20% alcohol intake and 6 h of withdrawal) was established. Here, we investigated the NMDAR1 (NR1), Ca2+ /calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinases (ERK) pathway in the modulation of anxiety-like behaviors in rats exposed to an open field and elevated plus maze (EPM) through systematic injections of memantine (a NMDAR inhibitor)...
September 10, 2018: Neuroscience Letters
Zhan Zhang, Feng Fang
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune encephalitis that was reported in recent years. At present, there remains no unified treatment regimen for the children and adolescents with this disease around the world. Immunotherapy is still the preferred way of treatment, mainly including first-line immunotherapy, second-line immunotherapy, and long-term immunotherapy. In recent years, some researchers have tried new immunosuppressants or modified immunotherapy regimens to improve the treatment outcome of the patients...
September 2018: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
Christofer S Tautermann, Florian Binder, Frank H Büttner, Christian Eickmeier, Dennis Fiegen, Ulrike Gross, Marc A Grundl, Ralf Heilker, Scott Hobson, Stefan Hoerer, Andreas Luippold, Volker Mack, Florian Montel, Stefan Peters, Supriyo Bhattacharya, Nagarajan Vaidehi, Gisela Schnapp, Sven Thamm, Markus Zeeb
Protein tyrosine phosphatase non-receptor type 5 (PTPN5, STEP) is a brain specific phosphatase that regulates synaptic function and plasticity by modulation of N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking. Dysregulation of STEP has been linked to neurodegenerative and neuropsychiatric diseases, highlighting this enzyme as an attractive therapeutic target for drug discovery. Selective targeting of STEP with small molecules has been hampered by high conservation of the active site among protein tyrosine phosphatases...
September 12, 2018: Journal of Medicinal Chemistry
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