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https://www.readbyqxmd.com/read/29793154/juvenile-treatment-with-mglur2-3-agonist-prevents-schizophrenia-like-phenotypes-in-adult-by-acting-through-gsk3%C3%AE
#1
Bo Xing, Genie Han, Min-Juan Wang, Melissa A Snyder, Wen-Jun Gao
Prodromal memory deficits represent an important marker for the development of schizophrenia (SZ), in which glutamatergic hypofunction occurs in the prefrontal cortex (PFC). The mGluR2/3 agonist LY379268 (LY37) attenuates excitatory N-methyl-D-aspartate receptor (NMDAR)-induced neurotoxicity, a central pathological characteristic of glutamatergic hypofunction. We therefore hypothesized that early treatment with LY37 would rescue cognitive deficits and confer benefits for SZ-like behaviors in adults. To test this, we assessed whether early intervention with LY37 would improve learning outcomes in the Morris Water Maze for rats prenatally exposed to methylazoxymethanol acetate (MAM), a neurodevelopmental SZ model...
May 14, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29792594/an-nmdar-positive-and-negative-allosteric-modulator-series-share-a-binding-site-and-are-interconverted-by-methyl-groups
#2
Riley Perszyk, Brooke M Katzman, Hirofumi Kusumoto, Steven A Kell, Matthew P Epplin, Yesim A Tahirovic, Rhonda L Moore, David Menaldino, Pieter Burger, Dennis C Liotta, Stephen F Traynelis
N-methyl-d-aspartate receptors (NMDARs) are an important receptor in the brain and have been implicated in multiple neurological disorders. Many non-selective NMDAR-targeting drugs are poorly tolerated, leading to efforts to target NMDAR subtypes to improve the therapeutic index. We describe here a series of negative allosteric NMDAR modulators with submaximal inhibition at saturating concentrations. Modest changes to the chemical structure interconvert negative and positive modulation. All modulators share the ability to enhance agonist potency and are use-dependent, requiring the binding of both agonists before modulators act with high potency...
May 24, 2018: ELife
https://www.readbyqxmd.com/read/29792022/bidirectional-synthesis-of-di-t-butyl-2s-6s-8s-and-2r-6r-8r-1-7-diazaspiro-5-5-undecane-2-8-dicarboxylate-and-related-spirodiamines
#3
Josh Almond-Thynne, Jiaxu Han, Andrew J P White, Anastasios Polyzos, Philip James Parsons, Anthony G M Barrett
Efficient syntheses of both enantiomers of a spirodiamine diester from (L)- and (D)-aspartic acid are described. The key transformation was the conversion of Boc-protected t-butyl aspartate into the derived aldehyde, two directional Horner Emmons olefination, hydrogenation and selective acid-catalyzed Boc-deprotection and spirocyclization. An alternative, two-directional approaches to derivatives of 1,7-diazaspiro[5.5]undecane is described.
May 23, 2018: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/29790849/-n-methyl-d-aspartate-receptor-antibody-encephalitis-the-janus-faced-disorder
#4
Ildiko Sipos
The recognition of the antibody-mediated encephalitis as a separate entity among the immune disorders of the central nervous system was one of the greatest breakthroughs of the last two decades in neurology. Unlike viral or tumor-related encephalitis, the antibody-mediated form has a good response to immunotherapy, which gives a special clinical importance to the discovery. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is one of the first fully characterized antibody-mediated encephalitises. This article attempts to summarize the clinical features of this complex neuropsychiatric disorder with the aim to help its early recognition and to report the clinical course and the outcome of our six seropositive anti-NMDAR cases...
March 2018: Neuropsychopharmacologia Hungarica
https://www.readbyqxmd.com/read/29790837/modulation-of-spinal-motor-networks-by-astrocyte-derived-adenosine-is-dependent-on-d1-like-dopamine-receptor-signalling
#5
David Acton, Matthew J Broadhead, Gareth Brian Miles
Astrocytes modulate many neuronal networks, including spinal networks responsible for the generation of locomotor behaviour. Astrocytic modulation of spinal motor circuits involves release of ATP from astrocytes, hydrolysation of ATP to adenosine, and subsequent activation of neuronal A1 adenosine receptors (A1Rs). The net effect of this pathway is a reduction in the frequency of locomotor-related activity. Recently, it was proposed that A1Rs modulate burst frequency by blocking the D1-like dopamine receptor (D1LR) signalling pathway; however, adenosine also modulates ventral horn circuits by dopamine-independent pathways...
May 23, 2018: Journal of Neurophysiology
https://www.readbyqxmd.com/read/29787770/lateral-hypothalamic-orexin-glucose-inhibited-neurons-may-regulate-reward-based-feeding-by-modulating-glutamate-transmission-in-the-ventral-tegmental-area
#6
Suraj B Teegala, Zhenyu Sheng, Miloni S Dalal, Pamela R Hirschberg, Kevin D Beck, Vanessa H Routh
Glucose inhibits ∼60% of lateral hypothalamic (LH) orexin neurons. Fasting increases the activation of LH orexin glucose-inhibited (GI) neurons in low glucose. Increases in spontaneous glutamate excitatory postsynaptic currents (sEPSCs) onto putative VTA DA neurons in low glucose are orexin dependent (Sheng et al., 2014). VTA DA neurons modulate reward-based feeding (Aston-Jones et al., 2010). We tested the hypothesis that increased activation of LH orexin-GI neurons in low glucose increases glutamate signaling onto VTA DA neurons and contributes to reward-based feeding in food restricted animals...
May 19, 2018: Brain Research
https://www.readbyqxmd.com/read/29780755/ovarian-teratoma-associated-anti-n-methyl-d-aspartate-receptor-encephalitis-a-difficult-diagnosis-with-a-favorable-prognosis
#7
Ananya Datta Mitra, Alaa Afify
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a recently described auto-immune and paraneoplastic encephalitis with prominent neuropsychiatric manifestations affecting young adults with ovarian teratoma. The availability of a novel assay to measure these antibodies might suggest an etiology for this potentially life-threatening disease, which if early recognized can be treated promptly with surgery with chances of a good clinical outcome. Reported prognostic indicators for a good outcome depend on the presence of a tumor, prompt treatment and no admission to an intensive care unit...
April 2018: Autopsy & Case Reports
https://www.readbyqxmd.com/read/29779943/astroglial-cb-1-receptors-determine-synaptic-d-serine-availability-to-enable-recognition-memory
#8
Laurie M Robin, José F Oliveira da Cruz, Valentin C Langlais, Mario Martin-Fernandez, Mathilde Metna-Laurent, Arnau Busquets-Garcia, Luigi Bellocchio, Edgar Soria-Gomez, Thomas Papouin, Marjorie Varilh, Mark W Sherwood, Ilaria Belluomo, Georgina Balcells, Isabelle Matias, Barbara Bosier, Filippo Drago, Ann Van Eeckhaut, Ilse Smolders, Francois Georges, Alfonso Araque, Aude Panatier, Stéphane H R Oliet, Giovanni Marsicano
Bidirectional communication between neurons and astrocytes shapes synaptic plasticity and behavior. D-serine is a necessary co-agonist of synaptic N-methyl-D-aspartate receptors (NMDARs), but the physiological factors regulating its impact on memory processes are scantly known. We show that astroglial CB1 receptors are key determinants of object recognition memory by determining the availability of D-serine at hippocampal synapses. Mutant mice lacking CB1 receptors from astroglial cells (GFAP-CB1 -KO) displayed impaired object recognition memory and decreased in vivo and in vitro long-term potentiation (LTP) at CA3-CA1 hippocampal synapses...
May 15, 2018: Neuron
https://www.readbyqxmd.com/read/29777287/decreased-plasma-levels-of-gasotransmitter-hydrogen-sulfide-in-patients-with-schizophrenia-correlation-with-psychopathology-and-cognition
#9
Jian-Wen Xiong, Bo Wei, Yan-Kun Li, Jin-Qiong Zhan, Shu-Zhen Jiang, Hai-Bo Chen, Kun Yan, Bin Yu, Yuan-Jian Yang
OBJECTIVE: Aberrant N-methyl-D-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. Hydrogen sulfide (H2 S) is an endogenous gasotransmitter that regulates NMDAR function. The current study investigated the relationship between plasma H2 S levels and both psychopathological and cognitive symptoms in schizophrenia. MATERIALS AND METHODS: Forty-one patients with schizophrenia and 40 healthy control subjects were recruited in present study...
May 18, 2018: Psychopharmacology
https://www.readbyqxmd.com/read/29777135/n-methyl-d-aspartate-receptor-subtype-2b-antagonist-ro-25-6981-attenuates-neuropathic-pain-by-inhibiting-postsynaptic-density-95-expression
#10
Ling-Er Huang, Shao-Hui Guo, Lalita Thitiseranee, Yan Yang, Yan-Feng Zhou, Yong-Xing Yao
Postsynaptic density-95 (PSD-95) is a synaptic scaffolding protein that plays a crucial role in the development of neuropathic pain. However, the underlying mechanism remains unclear. To address the role of PSD-95 in N-methyl-D-aspartate receptor subtype 2B (NR2B) -mediated chronic pain, we investigated the relationship between PSD-95 activation and NR2B function in the spinal cord, by using a rat model of sciatic nerve chronic constriction injury (CCI). We demonstrate that the expression levels of total PSD-95 and cAMP response element binding protein (CREB), as well as phosphorylated NR2B, PSD-95, and CREB, in the spinal dorsal horn, and the interaction of NR2B with PSD-95 were increased in the CCI animals...
May 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29774053/postherpes-simplex-encephalitis-a-case-series-of-viral-triggered-autoimmunity-synaptic-autoantibodies-and-response-to-therapy
#11
Harry Alexopoulos, Sofia Akrivou, Sotiria Mastroyanni, Maria Antonopoulou, Argirios Dinopoulos, Melpo Giorgi, Kostas Konstantinou, Evangelos Kouremenos, Maria Lariou, Dimitrios Naoumis, Efterpi Pavlidou, Evaggelos Pavlou, Konstantinos Voudris, Panayotis Vlachoyiannopoulos, Marinos C Dalakas
Background: Recent evidence suggests that patients with herpes simplex virus (HSV) encephalitis may relapse because of autoimmunity against the N-methyl-D-aspartate receptor (NMDAR). We present a case series of post-HSV relapsing encephalopathy associated with antibodies to central nervous system (CNS) synaptic antigens. Patient/Methods: Sera and cerebrospinal fluid (CSF) from five patients with HSV encephalitis who relapsed after antiviral therapy were tested for anti-NMDAR, gamma-aminobutyric acid b receptor (GABAbR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), Leucine-rich, glioma inactivated 1 (LGI1), anti -contactin-associated protein-like 2 (CASPR2) and dipeptidyl-peptidase-like protein-6 (DDPX) antibodies using cell-based assays...
2018: Therapeutic Advances in Neurological Disorders
https://www.readbyqxmd.com/read/29772491/calpain-inhibition-reduces-nmda-receptor-rundown-in-rat-substantia-nigra-dopamine-neurons
#12
Jerry Zhao, Michel Baudry, Susan Jones
Repeated activation of N-Methyl-d-aspartate receptors (NMDARs) causes a Ca2+ -dependent reduction in NMDAR-mediated current in dopamine (DA) neurons of the substantia nigra pars compacta (SNc) in one week old rats; however, a Ca2+ -dependent regulatory protein has not been identified. The role of the Ca2+ -dependent cysteine protease, calpain, in mediating NMDAR current rundown was investigated. In brain slices from rats aged postnatal day 7-9 ('P7'), bath application of either of the membrane permeable calpain inhibitors, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN, 20 μM) or MDL-28170 (30 μM) significantly reduced whole-cell NMDAR current rundown...
May 4, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29768996/a-systematic-review-on-donepezil-based-derivatives-as-potential-cholinesterase-inhibitors-for-alzheimer-s-disease
#13
Jan Korabecny, Katarina Spilovska, Eva Mezeiova, Ondrej Benek, Radomir Juza, Daniel Kaping, Ondrej Soukup
Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by memory loss, disorientation, and gradual deterioration of intellectual capacity. Its etiology has not been elucidated yet. To date, only one therapeutic approach has been approved for the treatment of AD. The pharmacotherapy of AD has relied on non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist - memantine, and acetylcholinesterase (AChE) inhibitors (AChEIs) - tacrine, donepezil, rivastigmine and galantamine...
May 16, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29767953/pharmacological-and-electrophysiological-characterization-of-novel-nmda-receptor-antagonists
#14
Rosana Leiva, Matthew B Phillips, Andreea Larisa Turcu, Esther Gratacòs-Batlle, Lara León-García, Francesc X Sureda, David Soto, Jon W Johnson, Santiago Vazquez
This work reports the synthesis, and pharmacological and electrophysiological evaluation of new N-methyl-D-aspartic acid receptor (NMDAR) channel blocking antagonists featuring polycyclic scaffolds. Changes in the chemical structure modulate the potency and voltage dependence of inhibition. Two of the new antagonists display properties comparable to those of memantine, a clinically approved NMDAR antagonist.
May 16, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29766293/nmda-receptor-subunits-change-in-the-prefrontal-cortex-of-pure-opioid-and-multi-drug-abusers-a-post-mortem-study
#15
Hamidreza Daneshparvar, Mitra-Sadat Sadat-Shirazi, Monir Fekri, Solmaz Khalifeh, Ali Ziaie, Nasrin Esfahanizadeh, Nasim Vousooghi, Mohammad-Reza Zarrindast
Addiction is a chronic relapsing disorder and is one of the most important issues in the world. Changing the level of neurotransmitters and the activities of their receptors, play a major role in the pathophysiology of substance abuse disorders. It is well-established that N-methyl-D-aspartate receptors (NMDARs) play a significant role in the molecular basis of addiction. NMDAR has two obligatory GluN1 and two regionally localized GluN2 subunits. This study investigated changes in the protein level of GluN1, GluN2A, and GluN2B in the prefrontal cortex of drug abusers...
May 16, 2018: European Archives of Psychiatry and Clinical Neuroscience
https://www.readbyqxmd.com/read/29764972/separate-functional-properties-of-nmdars-regulate-distinct-aspects-of-spatial-cognition
#16
Erin M Sanders, Akua O Nyarko-Odoom, Kevin Zhao, Michael Nguyen, Hong Hong Liao, Matthew Keith, Jane Pyon, Alyssa Kozma, Mohima Sanyal, Daniel G McHail, Theodore C Dumas
N -methyl-d-aspartate receptors (NMDARs) at excitatory synapses are central to activity-dependent synaptic plasticity and learning and memory. NMDARs act as ionotropic and metabotropic receptors by elevating postsynaptic calcium concentrations and by direct intracellular protein signaling. In the forebrain, these properties are controlled largely by the auxiliary GluN2 subunits, GluN2A and GluN2B. While calcium conductance through NMDAR channels and intracellular protein signaling make separate contributions to synaptic plasticity, it is not known if these properties individually influence learning and memory...
June 2018: Learning & Memory
https://www.readbyqxmd.com/read/29763637/neurosteroid-pregnenolone-sulfate-alone-and-as-augmentation-of-lurasidone-or-tandospirone-rescues-phencyclidine-induced-deficits-in-cognitive-function-and-social-interaction
#17
L Rajagopal, D Soni, H Y Meltzer
BACKGROUND: Pregnenolone sulfate (PregS), an endogenous neurosteroid, which negatively and positively modulates gamma amino butyric acid subunit A (GABAA ) and N-methyl D-aspartate (NMDA) receptors (R) respectively, among other potential neuroplastic changes on synaptic processes, has shown some beneficial effects on treating cognitive impairment associated with schizophrenia (CIAS) and negative symptoms. Lurasidone (Lur), an atypical antipsychotic drug (AAPD), and tandospirone (Tan), a 5-HT1A  R partial agonist, have also been reported to improve cognitive or negative symptoms, or both, in some schizophrenia patients...
May 12, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/29761122/bortezomib-treatment-for-severe-refractory-anti-nmda-receptor-encephalitis
#18
Yong-Won Shin, Soon-Tae Lee, Tae-Joon Kim, Jin-Sun Jun, Kon Chu
Objective: To evaluate the therapeutic potential of bortezomib, a proteasome inhibitor that target plasma cells, in order to revive stalled recovery in patients with anti- N -methyl-d-aspartate (NMDA) receptor encephalitis who remain bedridden even after aggressive immunotherapy. Methods: We consecutively enrolled patients with anti-NMDA receptor encephalitis who remained bedridden after first-line immunotherapy (steroids and intravenous immunoglobulin), second-line immunotherapy (rituximab), and tocilizumab treatment, and treated them with subcutaneous bortezomib...
May 2018: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29758384/disruption-of-shp1-nmda-receptor-signaling-in-spinal-cord-dorsal-horn-alleviated-inflammatory-pain
#19
Li Yang, Hu-Hu Bai, Zi-Yang Zhang, Jiang-Ping Liu, Zhan-Wei Suo, Xian Yang, Xiao-Dong Hu
Src-homology 2 domain-containing protein tyrosine phosphatase-1 (SHP1) is one of the non-receptor-like phosphatases that are highly enriched in hematopoietic cells. Although accumulating evidence has implicated the protein tyrosine phosphatases in the regulation of nociceptive transmission and plasticity, it is largely unknown whether SHP1 was expressed in pain-related spinal cord dorsal horn and engaged in the synaptic modification of nociceptive signals. Here we found that SHP1 was present in spinal neurons of rats and functionally coupled to GluN2A subunit-containing N-methyl-d-aspartate subtype of glutamate receptors, one of the key players in central sensitization of nociceptive behaviors...
April 30, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29756234/inhaling-xenon-ameliorates-l-dopa-induced-dyskinesia-in-experimental-parkinsonism
#20
Jérôme Baufreton, Tomislav Milekovic, Qin Li, Steve McGuire, Eduardo Martin Moraud, Grégory Porras, Shiqi Sun, Wai Kin D Ko, Marine Chazalon, Stéphanie Morin, Elisabeth Normand, Géraldine Farjot, Aude Milet, Jan Pype, Elsa Pioli, Gregoire Courtine, Baptiste Bessière, Erwan Bezard
Parkinson's disease motor symptoms are treated with levodopa, but long-term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N-methyl-d-aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa-induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold-standard rat and primate models of PD and levodopa-induced dyskinesia...
May 14, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
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