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https://www.readbyqxmd.com/read/28807674/phenylglycine-analogs-are-inhibitors-of-the-neutral-amino-acid-transporters-asct1-and-asct2-and-enhance-nmda-receptor-mediated-ltp-in-rat-visual-cortex-slices
#1
Alan C Foster, Natalie Rangel-Diaz, Ursula Staubli, Jia-Ying Yang, Mahmud Penjwini, Veena Viswanath, Yong-Xin Li
The N-methyl-d-aspartate receptor (NMDA) co-agonist d-serine is a substrate for the neutral amino acid transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5). We identified l-phenylglycine (PG) and its analogs as inhibitors of ASCT1 and ASCT2. PG analogs were shown to be non-substrate inhibitors of ASCT1 and ASCT2 with a range of activities relative to other amino acid transport systems, including sodium-dependent glutamate transporters, the sodium-independent d-serine transporter asc-1 and system L. L-4-chloroPG was the most potent and selective ASCT1/2 inhibitor identified...
August 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28803978/intraperitoneal-injection-of-d-serine-inhibits-high-fat-diet-intake-and-preference-in-male-mice
#2
Tsutomu Sasaki, Yasunobu Yasoshima, Sho Matsui, Hiromi Yokota-Hashimoto, Masaki Kobayashi, Tadahiro Kitamura
d-serine is a co-agonist of the N-methyl d-aspartate (NMDA) receptor, an important modulator of glutamatergic excitatory synaptic transmission. We previously reported that oral d-serine ingestion inhibited the intake of highly preferred food and promoted the intake of less preferred food in mice. Here, we analyzed the effects of intraperitoneal (IP) d-serine injections on feeding behavior in mice. We assessed the effects of d-serine during both the acquisition and maintenance of a preference for high-fat diets (HFDs)...
August 10, 2017: Appetite
https://www.readbyqxmd.com/read/28795439/g-protein-coupled-receptor-37-like-1-modulates-astrocyte-glutamate-transporters-and-neuronal-nmda-receptors-and-is-neuroprotective-in-ischemia
#3
Sarah Jolly, Narges Bazargani, Alejandra C Quiroga, Nigel P Pringle, David Attwell, William D Richardson, Huiliang Li
We show that the G protein-coupled receptor GPR37-like 1 (GPR37L1) is expressed in most astrocytes and some oligodendrocyte precursors in the mouse central nervous system. This contrasts with GPR37, which is mainly in mature oligodendrocytes. Comparison of wild type and Gpr37l1(-/-) mice showed that loss of GPR37L1 did not affect the input resistance or resting potential of astrocytes or neurons in the hippocampus. However, GPR37L1-mediated signalling inhibited astrocyte glutamate transporters and - surprisingly, given its lack of expression in neurons - reduced neuronal NMDA receptor (NMDAR) activity during prolonged activation of the receptors as occurs in ischemia...
August 10, 2017: Glia
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
#4
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/28756461/adolescent-stress-leads-to-glutamatergic-disturbance-through-dopaminergic-abnormalities-in-the-prefrontal-cortex-of-genetically-vulnerable-mice
#5
Yurie Matsumoto, Minae Niwa, Akihiro Mouri, Yukihiro Noda, Takeshi Fukushima, Norio Ozaki, Toshitaka Nabeshima
BACKGROUND: Stress during the adolescent period influences postnatal maturation and behavioral patterns in adulthood. Adolescent stress-induced molecular and functional changes in neurons are the key clinical features of psychiatric disorders including schizophrenia. OBJECTIVE: In the present study, we exposed genetically vulnerable mice to isolation stress to examine the molecular changes in the glutamatergic system involving N-methyl-d-aspartate (NMDA) receptors via dopaminergic disturbance in the prefrontal cortex (PFc)...
July 29, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28748374/alterations-in-amino-acid-levels-in-mouse-brain-regions-after-adjunctive-treatment-of-brexpiprazole-with-fluoxetine-comparison-with-r-ketamine
#6
Min Ma, Qian Ren, Yuko Fujita, Chun Yang, Chao Dong, Yuta Ohgi, Takashi Futamura, Kenji Hashimoto
RATIONALE: Brexpiprazole, a serotonin-dopamine activity modulator, is approved in the USA as an adjunctive therapy to antidepressants for treating major depressive disorders. Similar to the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, the combination of brexpiprazole and fluoxetine has demonstrated antidepressant-like effects in animal models of depression. OBJECTIVES: The present study was conducted to examine whether the combination of brexpiprazole and fluoxetine could affect the tissue levels of amino acids [glutamate, glutamine, γ-aminobutyric acid (GABA), D-serine, L-serine, and glycine] that are associated with NMDAR neurotransmission...
July 26, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28734458/rett-like-severe-encephalopathy-caused-by-a-de%C3%A2-novo-grin2b-mutation-is-attenuated-by-d-serine-dietary-supplement
#7
David Soto, Mireia Olivella, Cristina Grau, Judith Armstrong, Clara Alcon, Xavier Gasull, Macarena Gómez de Salazar, Esther Gratacòs-Batlle, David Ramos-Vicente, Víctor Fernández-Dueñas, Francisco Ciruela, Àlex Bayés, Carlos Sindreu, Anna López-Sala, Àngels García-Cazorla, Xavier Altafaj
BACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about their pathogenic mechanisms and potential therapeutic interventions. Here we report a case study of a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B(p...
June 16, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28714867/enhanced-astrocytic-d-serine-underlies-synaptic-damage-after-traumatic-brain-injury
#8
Enmanuel J Perez, Stephen A Tapanes, Zachary B Loris, Darrick T Balu, Thomas J Sick, Joseph T Coyle, Daniel J Liebl
After traumatic brain injury (TBI), glial cells have both beneficial and deleterious roles in injury progression and recovery. However, few studies have examined the influence of reactive astrocytes in the tripartite synapse following TBI. Here, we have demonstrated that hippocampal synaptic damage caused by controlled cortical impact (CCI) injury in mice results in a switch from neuronal to astrocytic d-serine release. Under nonpathological conditions, d-serine functions as a neurotransmitter and coagonist for NMDA receptors and is involved in mediating synaptic plasticity...
August 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28696262/human-serine-racemase-structure-activity-relationship-studies-provide-mechanistic-insight-and-point-to-position-84-as-a-hotspot-for-%C3%AE-elimination-function
#9
David L Nelson, Gregory A Applegate, Matthew L Beio, Danielle L Graham, David B Berkowitz
There is currently great interest in human serine racemase (hSR), the enzyme responsible for producing the NMDA co-agonist D-serine. Reported correlation of D-serine levels with disorders including Alzheimers disease, ALS and ischemic brain damage (elevated D-serine), and schizophrenia (reduced D-serine) has further piqued this interest. Reported is a structure/activity relationships (SAR) study of position-(S)84, the putative re-face base. In the most extreme case of functional reprogramming, the S84D mutant displays a dramatic reversal of β-elimination substrate specificity in favor of L-serine over the normally preferred L-serine-O-sulfate (L-SOS; ~1200-fold change in kcat/Km ratios) and L-threo-β-hydroxyaspartate (L-THA; ~5000-fold change in kcat/Km ratios) alternative substrates...
July 10, 2017: Journal of Biological Chemistry
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
#10
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/28681245/an-overview-on-d-amino-acids
#11
REVIEW
Giuseppe Genchi
More than half a century ago researchers thought that D-amino acids had a minor function compared to L-enantiomers in biological processes. Many evidences have shown that D-amino acids are present in high concentration in microorganisms, plants, mammals and humans and fulfil specific biological functions. In the brain of mammals, D-serine (D-Ser) acts as a co-agonist of the N-methyl-D-aspartate (NMDA)-type glutamate receptors, responsible for learning, memory and behaviour. D-Ser metabolism is relevant for disorders associated with an altered function of the NMDA receptor, such as schizophrenia, ischemia, epilepsy and neurodegenerative disorders...
July 5, 2017: Amino Acids
https://www.readbyqxmd.com/read/28674984/schizophrenia-basic-and-clinical
#12
Joseph T Coyle
Schizophrenia is a chronic severe mental disorder characterized by psychosis, cognitive impairments, and social and motivational deficits. It is associated with a progressive loss of cortical volume after onset of psychosis; nevertheless, cortical atrophy correlates with the cognitive impairments and the negative symptoms but not with the psychosis. The cortical atrophy is not primarily due to neuronal degeneration but rather to neuronal atrophy and loss of glutamatergic synapses. A downregulation of the presynaptic markers for the parvalbumin-expressing GABAergic interneurons that provide recurrent inhibition to cortical pyramidal neurons is another consistent pathologic feature...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28671605/glycine-binding-site-stimulants-of-nmda-receptors-alleviate-extrapyramidal-motor-disorders-by-activating-the-nigrostriatal-dopaminergic-pathway
#13
Saki Shimizu, Shunsaku Sogabe, Ryoto Yanagisako, Akiyoshi Inada, Megumi Yamanaka, Higor A Iha, Yukihiro Ohno
Dysfunction of the N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathogenesis of schizophrenia. Although agonists for the glycine-binding sites of NMDA receptors have potential as new medication for schizophrenia, their modulation of antipsychotic-induced extrapyramidal side effects (EPS) has not yet been clarified. We herein evaluated the effects of glycine-binding site stimulants of NMDA receptors on antipsychotic-induced EPS in mice and rats. d-cycloserine (DCS) and d-serine significantly improved haloperidol (HAL)-induced bradykinesia in mice, whereas glycine showed no effects...
July 3, 2017: International Journal of Molecular Sciences
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
#14
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/28631721/disc1-in-astrocytes-influences-adult-neurogenesis-and-hippocampus-dependent-behaviors-in-mice
#15
Chantelle E Terrillion, Bagrat Abazyan, Zhongxi Yang, Joshua Crawford, Alexey V Shevelkin, Yan Jouroukhin, Ki Hyun Yoo, Chang Hoon Cho, Robin Roychaudhuri, Solomon H Snyder, Mi-Hyeon Jang, Mikhail V Pletnikov
The functional role of genetic variants in glia in the pathogenesis of psychiatric disorders remains poorly studied. Disrupted-In-Schizophrenia 1 (DISC1), a genetic risk factor implicated in major mental disorders, has been implicated in regulation of astrocyte functions. As both astrocytes and DISC1 influence adult neurogenesis in the dentate gyrus (DG) of the hippocampus, we hypothesized that selective expression of dominant-negative C-terminus truncated human DISC1 (mutant DISC1) in astrocytes would affect adult hippocampal neurogenesis and hippocampus-dependent behaviors...
June 20, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28604057/heterogeneity-of-d-serine-distribution-in-the-human-central-nervous-system
#16
Masataka Suzuki, Nobuaki Imanishi, Masashi Mita, Kenji Hamase, Sadakazu Aiso, Jumpei Sasabe
D-serine is an endogenous ligand for N-methyl-D-aspartate glutamate receptors. Accumulating evidence including genetic associations of D-serine metabolism with neurological or psychiatric diseases suggest that D-serine is crucial in human neurophysiology. However, distribution and regulation of D-serine in humans are not well understood. Here, we found that D-serine is heterogeneously distributed in the human central nervous system (CNS). The cerebrum contains the highest level of D-serine among the areas in the CNS...
May 2017: ASN Neuro
https://www.readbyqxmd.com/read/28598327/co-agonists-differentially-tune-glun2b-nmda-receptor-trafficking-at-hippocampal-synapses
#17
Joana S Ferreira, Thomas Papouin, Laurent Ladépêche, Andrea Yao, Valentin C Langlais, Delphine Bouchet, Jérôme Dulong, Jean-Pierre Mothet, Silvia Sacchi, Loredano Pollegioni, Pierre Paoletti, Stéphane Henri Richard Oliet, Laurent Groc
The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative content of GluN2A- and GluN2B-containing receptors, greatly influences the glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine, have intriguingly emerged as potential regulators of the receptor trafficking in addition to their requirement for its activation. Using a combination of single-molecule imaging, biochemistry and electrophysiology, we show that glycine and D-serine relative availability at rat hippocampal glutamatergic synapses regulate the trafficking and synaptic content of NMDAR subtypes...
June 9, 2017: ELife
https://www.readbyqxmd.com/read/28590364/neurophysiological-effects-of-bitopertin-in-schizophrenia
#18
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/28589394/single-and-chronic-l-serine-treatments-exert-antidepressant-like-effects-in-rats-possibly-by-different-means
#19
Mao Nagasawa, Tsuyoshi Otsuka, Yuki Togo, Masakazu Yamanaga, Junki Yoshida, Nobuo Uotsu, Sachiyuki Teramoto, Shinobu Yasuo, Mitsuhiro Furuse
In the present study, the effects of both single (6 mmol L-serine/10 ml/kg orally administrated) and chronic (2% L-serine solution freely given for 28 days) treatments on depression-like behavior were evaluated in Wistar rats, representing the control, and Wistar Kyoto rats, representing an animal model of depression. Both single and chronic L-serine treatments decreased the duration of immobility, which is an index of a depressive-like state, in the forced swimming test in both strains. However, the decreases in the duration of immobility appear to be regulated differently by the different mechanisms involved in single and chronic L-serine treatments...
June 6, 2017: Amino Acids
https://www.readbyqxmd.com/read/28570965/neurochemical-evidence-based-suggested-therapy-for-safe-management-of-epileptogenesis
#20
Navjot Kaur, Tanveer Singh, Sandeep Kumar, Rajesh Kumar Goel
Most of the clinically available antiepileptic drugs have only antiseizure effects and are reported unable to prevent epileptogenesis. In the past decade, several drugs underwent clinical trials for management of epileptogenesis, but none of the drugs tested was found effective. One of the major lacunas is availability of appropriate preclinical approaches to delineate mechanisms of epileptogenesis. Thus, the present study attempts to suggest a neurochemistry based approach for safe management of epileptogenesis...
May 29, 2017: Epilepsy & Behavior: E&B
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