WorldWideScience

Sample records for n-methyl-d-aspartate glutamate receptor

  1. The N-Methyl d-Aspartate Glutamate Receptor Antagonist Ketamine Disrupts the Functional State of the Corticothalamic Pathway

    NARCIS (Netherlands)

    Anderson, P.M.; Jones, N.C.; O'Brien, T.J.; Pinault, D.

    2017-01-01

    The non-competitive N-methyl d-aspartate glutamate receptor (NMDAR) antagonist ketamine elicits a brain state resembling high-risk states for developing psychosis and early stages of schizophrenia characterized by sensory and cognitive deficits and aberrant ongoing gamma (30-80 Hz) oscillations in

  2. Solubilization, partial purification, and reconstitution of glutamate- and N-methyl-D-aspartate-activated cation channels from brain synaptic membranes

    International Nuclear Information System (INIS)

    Ly, A.M.; Michaelis, E.K.

    1991-01-01

    L-Glutamate-activated cation channel proteins from rat brain synaptic membranes were solubilized, partially purified, and reconstituted into liposomes. Optimal conditions for solubilization and reconstitution included treatment of the membranes with nonionic detergents in the presence of neutral phospholipids plus glycerol. Quench-flow procedures were developed to characterize the rapid kinetics of ion flux induced by receptor agonists. [ 14 C]Methylamine, a cation that permeates through the open channel of both vertebrate and invertebrate glutamate receptors, was used to measure the activity of glutamate receptor-ion channel complexes in reconstituted liposomes. L-Glutamate caused an increase in the rate of [ 14 C]methylamine influx into liposomes reconstituted with either solubilized membrane proteins or partially purified glutamate-binding proteins. Of the major glutamate receptor agonists, only N-methyl-D-aspartate activated cation fluxes in liposomes reconstituted with glutamate-binding proteins. In liposomes reconstituted with glutamate-binding proteins, N-methyl-D-aspartate- or glutamate-induced influx of NA + led to a transient increase in the influx of the lipid-permeable anion probe S 14 CN - . These results indicate the functional reconstitution of N-methyl-D-aspartate-sensitive glutamate receptors and the role of the ∼69-kDa protein in the function of these ion channels

  3. Tweaking agonist efficacy at N-methyl-D-aspartate receptors by site-directed mutagenesis

    DEFF Research Database (Denmark)

    Hansen, Kasper B; Clausen, Rasmus P; Bjerrum, Esben J

    2005-01-01

    The structural basis for partial agonism at N-methyl-D-aspartate (NMDA) receptors is currently unresolved. We have characterized several partial agonists at the NR1/NR2B receptor and investigated the mechanisms underlying their reduced efficacy by introducing mutations in the glutamate binding site...

  4. Pediatric Opsoclonus-Myoclonus-Ataxia Syndrome Associated With Anti-N-methyl-D-aspartate Receptor Encephalitis.

    Science.gov (United States)

    Player, Brittany; Harmelink, Matthew; Bordini, Brett; Weisgerber, Michael; Girolami, Michael; Croix, Michael

    2015-11-01

    The full clinical spectrum of anti-N-methyl-D-aspartate receptor encephalitis is unknown in the pediatric population. We describe a previously healthy 4-year-old girl presenting with opsoclonus-myoclonus together with ataxia who had NR1-specific, anti-N-methyl-D-aspartate receptor antibodies in the cerebral spinal fluid. The presence of NR1-specific, anti-N-methyl-D-aspartate receptor antibodies in the setting of opsoclonus-myoclonus and ataxia syndrome may represent an expansion of the clinical presentations of anti-N-methyl-D-aspartate receptor encephalitis. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Circadian and developmental regulation of N-methyl-d-aspartate-receptor 1 mRNA splice variants and N-methyl-d-aspartate-receptor 3 subunit expression within the rat suprachiasmatic nucleus

    DEFF Research Database (Denmark)

    Bendová, Z; Sumová, A; Mikkelsen, Jens D.

    2009-01-01

    The circadian rhythms of mammals are generated by the circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Its intrinsic period is entrained to a 24 h cycle by external cues, mainly by light. Light impinging on the SCN at night causes either advancing or delaying phase...... shifts of the circadian clock. N-methyl-d-aspartate receptors (NMDAR) are the main glutamate receptors mediating the effect of light on the molecular clockwork in the SCN. They are composed of multiple subunits, each with specific characteristics whose mutual interactions strongly determine properties...

  6. D-aspartate and NMDA, but not L-aspartate, block AMPA receptors in rat hippocampal neurons

    DEFF Research Database (Denmark)

    Gong, Xiang-Qun; Frandsen, Anne; Lu, Wei-Yang

    2005-01-01

    1 The amino acid, D-aspartate, exists in the mammalian brain and is an agonist at the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors. Here, for the first time, we studied the actions of D-aspartate on alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptors (AMPARs......) in acutely isolated rat hippocampal neurons. 2 In the presence of the NMDA receptor channel blocker, MK801, D-aspartate inhibited kainate-induced AMPAR current in hippocampal neurons. The inhibitory action of D-aspartate on kainate-induced AMPAR current was concentration-dependent and was voltage......-independent in the tested voltage range (-80 to +60 mV). 3 The estimated EC50 of the L-glutamate-induced AMPAR current was increased in the presence of D-aspartate, while the estimated maximum L-glutamate-induced AMPAR current was not changed. D-aspartate concentration-dependently shifted the dose-response curve of kainate...

  7. N-methyl-D-aspartic acid receptor agonists

    DEFF Research Database (Denmark)

    Madsen, U; Frydenvang, Karla Andrea; Ebert, B

    1996-01-01

    (R,S)-2-Amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid [(R,S)-AMAA, 4] is a potent and selective agonist at the N-methyl-D-aspartic acid (NMDA) subtype of excitatory amino acid receptors. Using the Ugi "four-component condensation" method, the two diastereomers (2R)- and (2S)-2-[3-(benzyloxy......) showed peak affinity for [3H]AMPA receptor sites (IC50 = 72 +/- 13 microM) and was shown to be a more potent inhibitor of [3H]CPP binding (IC50 = 3.7 +/- 1.5 microM) than (S)-AMAA (9) (IC50 = 61 +/- 6.4 microM). Neither enantiomer of AMAA affected [3H]kainic acid receptor binding significantly...

  8. Anti-N-methyl-D-aspartate receptor encephalitis in Taiwan--a comparison between children and adults.

    Science.gov (United States)

    Lin, Jainn-Jim; Lin, Kuang-Lin; Hsia, Shao-Hsuan; Chou, Min-Liang; Hung, Po-Cheng; Hsieh, Meng-Ying; Chou, I-Jun; Wang, Huei-Shyong

    2014-06-01

    Since the discovery of antibodies against the N-methyl-D-aspartate receptor in 2007, anti-N-methyl-D-aspartate receptor encephalitis is increasingly recognized worldwide. We compare the clinical features of adults and children with this disorder in Taiwan. Patients admitted to Chang Gung Memorial Hospital and Chang Gung Children's Hospital and those who were referred from other institutions because of unknown encephalitis from 2009 to 2013 were enrolled, and their clinical features were analyzed. Data on cases from a review of the literature were also included in the analysis. Twelve patients (10 females) aged between 7 years and 28 years with anti-N-methyl-D-aspartate receptor encephalitis were identified. Six patients (50%) were Anti-N-methyl-D-aspartate receptor encephalitis is increasingly recognized in Taiwan. It is characterized by its clinical features, predominantly affects females with and/or without an ovarian tumor, and it is a potentially treatable disorder. It is important for neurologists to be familiar with the clinical presentations of the disease in children and young adults. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Identification of AICP as a GluN2C-Selective N-Methyl-d-Aspartate Receptor Superagonist at the GluN1 Glycine Site

    DEFF Research Database (Denmark)

    Jessen, Maja; Frederiksen, Kristen; Yi, Feng

    2017-01-01

    N-methyl-d-aspartate (NMDA)-type ionotropic glutamate receptors mediate excitatory neurotransmission in the central nervous system and are critically involved in brain function. NMDA receptors are also implicated in psychiatric and neurological disorders and have received considerable attention....../2A-D), in which DCS is a superagonist at GluN2C-containing receptors compared with glycine and a partial agonist at GluN2B-containing receptors. Here, we identify (R)-2-amino-3-(4-(2-ethylphenyl)-1H-indole-2-carboxamido)propanoic acid (AICP) as a glycine site agonist with unique GluN2-dependent...

  10. Anti-N-methyl-D-aspartate receptor encephalitis with an imaging-invisible ovarian teratoma: a case report.

    Science.gov (United States)

    Abdul-Rahman, Zainab M; Panegyres, Peter K; Roeck, Margareta; Hawkins, David; Bharath, Jude; Grolman, Paul; Neppe, Cliffe; Palmer, David

    2016-10-24

    Anti-N-methyl-D-aspartate receptor encephalitis is a recently discovered disease entity of paraneoplastic limbic encephalitis. It largely affects young women and is often associated with an ovarian teratoma. It is a serious yet treatable condition if diagnosed early. Its remedy involves immunotherapy and surgical removal of the teratoma of the ovaries. This case of anti-N-methyl-D-aspartate receptor encephalitis involves an early surgical intervention with bilateral oophorectomy, despite negative imaging evidence of a teratoma. A 25-year-old white woman with anti-N-methyl-D-aspartate receptor encephalitis presented with behavioral changes and seizures that were confirmed to be secondary to anti-N-methyl-D-aspartate receptor encephalitis. She required an admission to our intensive care unit for ventilator support and received a number of immunological therapies. Multiple imaging investigations showed no evidence of an ovarian teratoma; she had a bilateral oophorectomy 29 days after admission. Ovarian histology confirmed the presence of a teratoma with neuronal cells. A few days after the operation she began to show signs of improvement and, apart from mild short-term memory loss, she returned to normal function. Our patient is an example of teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis, in which the teratoma was identified only microscopically. Her case highlights that even with negative imaging evidence of a teratoma, ovarian pathology should still be considered and explored.

  11. The Blockade of Glutamate N-methyl-D-aspartate Receptors into the Prelimbic of Prefrontal Cortex Decreases Morphine-induced Conditioned Place Preference in Rat

    Directory of Open Access Journals (Sweden)

    Samad Javadi

    2017-12-01

    Full Text Available BACKGROUND: The prelimbic area (PL of the prefrontal cortex is susceptible to abnormal developmental stimuli that raises the risk of addiction. Glutamate receptors play a key role in opiate reinforcement and reward functions in this area. Therefore, we examined the effect of the DL-2-amino-5-phosphonopentanoic acid (AP5, as N-methyl-D-aspartate (NMDA receptor antagonist into the PL on the phases of conditioned place preference (CPP induced by morphine. METHODS: Male Wistar rats were divided into 12 groups (3 surgical groups for each dose of morphine in any phase of CPP and anaesthetized with chloral hydrate. Cannula was implanted into the PL and the AP5 was injected into this area and morphine-induced CPP was investigated. Data were processed with the commercially available SPSS 22 software using one-way ANOVA and Tukey's test. p<0.05 were considered statistically significant. RESULTS: Our findings indicated, morphine in doses of 2.5 to 10 mg/kg induced CPP. Microinjection of various doses of the AP5 into the PL before the administration of the effective dose of morphine significantly reduced place preference in the acquisition and the expression phases of the CPP test compared to the sham group (p<0.001. In another set of our experiments was seen that, different doses of the AP5 with the ineffective dose of morphine only reduced the expression phase of the CPP (p<0.001 while, produced neither preference nor aversion effect on the acquisition phase (p=0.147. CONCLUSION: It seems that the glutamate NMDA receptors in the PL through memory formation and morphine-related reward signals play a critical role in addiction process during morphine-induced CPP. KEYWORDS: N-methyl-aspartate, morphine, glutamate receptor, prefrontal cortex, reward

  12. Anesthesia in anti-N-methyl-D-aspartate receptor encephalitis - is general anesthesia a requisite? A case report

    Directory of Open Access Journals (Sweden)

    Sook Hui Chaw

    Full Text Available Abstract Anti-N-methyl-D-aspartate receptor encephalitis is a recently described neurological disorder and an increasingly recognized cause of psychosis, movement disorders and autonomic dysfunction. We report 20-year-old Chinese female who presented with generalized tonic-clonic seizures, recent memory loss, visual hallucinations and abnormal behavior. Anti-N-methyl-D-aspartate receptor encephalitis was diagnosed and a computed tomography scan of abdomen reviewed a left adnexal tumor. We describe the first such case report of a patient with anti-N-methyl-D-aspartate receptor encephalitis who was given a bilateral transversus abdominis plane block as the sole anesthetic for removal of ovarian tumor. We also discuss the anesthetic issues associated with anti-N-methyl-D-aspartate receptor encephalitis. As discovery of tumor and its removal is the focus of initial treatment in this group of patients, anesthetists will encounter more such cases in the near future.

  13. [Anesthesia in anti-N-methyl-d-aspartate receptor encephalitis - is general anesthesia a requisite? A case report].

    Science.gov (United States)

    Chaw, Sook Hui; Foo, Li Lian; Chan, Lucy; Wong, Kang Kwong; Abdullah, Suhailah; Lim, Boon Kiong

    Anti-N-methyl-d-aspartate receptor encephalitis is a recently described neurological disorder and an increasingly recognized cause of psychosis, movement disorders and autonomic dysfunction. We report 20-year-old Chinese female who presented with generalized tonic-clonic seizures, recent memory loss, visual hallucinations and abnormal behavior. Anti-N-methyl-d-aspartate receptor encephalitis was diagnosed and a computed tomography scan of abdomen reviewed a left adnexal tumor. We describe the first such case report of a patient with anti-N-methyl-d-aspartate receptor encephalitis who was given a bilateral transversus abdominis plane block as the sole anesthetic for removal of ovarian tumor. We also discuss the anesthetic issues associated with anti-N-methyl-d-aspartate receptor encephalitis. As discovery of tumor and its removal is the focus of initial treatment in this group of patients, anesthetists will encounter more such cases in the near future. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  14. Atypical presentation of anti-N-methyl-D-aspartate receptor encephalitis: two case reports.

    Science.gov (United States)

    Maggio, Maria Cristina; Mastrangelo, Greta; Skabar, Aldo; Ventura, Alessandro; Carrozzi, Marco; Santangelo, Giuseppe; Vanadia, Francesca; Corsello, Giovanni; Cimaz, Rolando

    2017-08-16

    Anti-N-methyl-D-aspartate receptor encephalitis is a rare autoimmune disease characterized by severe neurological and psychiatric symptoms and a difficult diagnosis. The disease is often secondary to a neoplastic lesion, seldom diagnosed years later. Psychiatric symptoms are prevalent in adults; neurologic symptoms are more evident in children, who typically present primarily with neurological symptoms. To the best of our knowledge, the association with juvenile idiopathic arthritis has not been described. We report the cases of two caucasian girls with an atypical presentation. The first patient was an 8-year-old girl with normal psychomotor development. Over a 4-month period she developed behavioral problems, speech impairment, and deterioration in academic skills. Within 8 months from the onset of symptoms, choreic movements gradually appeared. Hematological, neuroradiological, and neurophysiological examinations were negative; however, her symptoms worsened and treatment with prednisone was started. Although her choreic movements improved within 1 month, her neuropsychological and behavioral symptoms continued. Anti-N-methyl-D-aspartate receptor antibodies in cerebrospinal fluid and in blood were detected. Therapy with intravenously administered immunoglobulins was administered, without improvement of symptoms. After 2 months of steroid treatment, she suddenly started to pronounce some words with a progressive improvement in language and behavior. The second patient was a 14-year-old girl with classic anti-N-methyl-D-aspartate receptor encephalitis, treated successfully with intravenously administered immunoglobulins and methylprednisolone, followed by orally administered prednisone, who developed chronic arthritis of the hip. The arthritis was confirmed by magnetic resonance imaging and associated to antinuclear antigen antibody positivity. One year after the encephalitis presentation, an ovarian cystic mass was identified as a teratoma. The surgical resection

  15. Nonparaneoplastic anti-N-methyl-D-aspartate receptor encephalitis: a case series of four children.

    Science.gov (United States)

    Raha, Sarbani; Gadgil, Pradnya; Sankhla, Charulata; Udani, Vrajesh

    2012-04-01

    A rare, severe form of immune-mediated encephalitis recently has been described, associated with antibodies against N-methyl-D-aspartate receptors. It is reported mostly in women with ovarian tumors. Nonparaneoplastic presentations are less common. We describe four children with a neuropsychiatric and extrapyramidal syndrome associated with the presence of anti-N-methyl-D-aspartate receptor antibodies in cerebrospinal fluid and serum, without evidence of neoplasia. Three children recovered completely after immunomodulatory therapy, i.e., intravenous immunoglobulin and/or steroids, methylprednisolone, and/or adrenocorticotrophic hormone. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Effects of pilocarpine and kainate-induced seizures on N-methyl-d-aspartate receptor gene expression in the rat hippocampus

    Energy Technology Data Exchange (ETDEWEB)

    Przewlocka, B.; Labuz, D.; Machelska, H.; Przewlocki, R.; Turchan, J.; Lason, W. [Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow (Poland)

    1997-04-14

    The effects of pilocarpine- and kainate-induced seizures on N-methyl-d-aspartate receptor subunit-1 messenger RNA and [{sup 3}H]dizocilpine maleate binding were studied in the rat hippocampal formation. Pilocarpine- but not kainate-induced seizures decreased N-methyl-d-aspartate receptor subunit-1 messenger RNA level in dentate gyrus at 24 and 72 h after drug injection. Both convulsants decreased the messenger RNA level in CA1 pyramidal cells at 24 and 72 h, the effects of kainate being more profound. Kainate also decreased the N-methyl-d-aspartate receptor subunit-1 messenger RNA level in CA3 region after 24 and 72 h, whereas pilocarpine decreased the messenger RNA level at 72 h only. At 3 h after kainate, but not pilocarpine, an increased binding of [{sup 3}H]dizocilpine maleate in several apical dendritic fields of pyramidal cells was found. Pilocarpine reduced the [{sup 3}H]dizocilpine maleate binding in stratum lucidum only at 3 and 24 h after the drug injection. Pilocarpine but not kainate induced prolonged decrease in N-methyl-d-aspartate receptor subunit-1 gene expression in dentate gyrus. However, at the latest time measured, kainate had the stronger effect in decreasing both messenger RNA N-methyl-d-aspartate receptor subunit-1 and [{sup 3}H]dizocilpine maleate binding in CA1 and CA3 hippocampal pyramidal cells. The latter changes corresponded, however, to neuronal loss and may reflect higher neurotoxic potency of kainate.These data point to some differences in hippocampal N-methyl-d-aspartate receptor regulation in pilocarpine and kainate models of limbic seizures. Moreover, our results suggest that the N-methyl-d-aspartate receptor subunit-1 messenger RNA level is more susceptible to limbic seizures than is [{sup 3}H]dizocilpine maleate binding in the rat hippocampal formation. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  17. Effects of pilocarpine and kainate-induced seizures on N-methyl-d-aspartate receptor gene expression in the rat hippocampus

    International Nuclear Information System (INIS)

    Przewlocka, B.; Labuz, D.; Machelska, H.; Przewlocki, R.; Turchan, J.; Lason, W.

    1997-01-01

    The effects of pilocarpine- and kainate-induced seizures on N-methyl-d-aspartate receptor subunit-1 messenger RNA and [ 3 H]dizocilpine maleate binding were studied in the rat hippocampal formation. Pilocarpine- but not kainate-induced seizures decreased N-methyl-d-aspartate receptor subunit-1 messenger RNA level in dentate gyrus at 24 and 72 h after drug injection. Both convulsants decreased the messenger RNA level in CA1 pyramidal cells at 24 and 72 h, the effects of kainate being more profound. Kainate also decreased the N-methyl-d-aspartate receptor subunit-1 messenger RNA level in CA3 region after 24 and 72 h, whereas pilocarpine decreased the messenger RNA level at 72 h only. At 3 h after kainate, but not pilocarpine, an increased binding of [ 3 H]dizocilpine maleate in several apical dendritic fields of pyramidal cells was found. Pilocarpine reduced the [ 3 H]dizocilpine maleate binding in stratum lucidum only at 3 and 24 h after the drug injection. Pilocarpine but not kainate induced prolonged decrease in N-methyl-d-aspartate receptor subunit-1 gene expression in dentate gyrus. However, at the latest time measured, kainate had the stronger effect in decreasing both messenger RNA N-methyl-d-aspartate receptor subunit-1 and [ 3 H]dizocilpine maleate binding in CA1 and CA3 hippocampal pyramidal cells. The latter changes corresponded, however, to neuronal loss and may reflect higher neurotoxic potency of kainate.These data point to some differences in hippocampal N-methyl-d-aspartate receptor regulation in pilocarpine and kainate models of limbic seizures. Moreover, our results suggest that the N-methyl-d-aspartate receptor subunit-1 messenger RNA level is more susceptible to limbic seizures than is [ 3 H]dizocilpine maleate binding in the rat hippocampal formation. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  18. Evidence for spinal N-methyl-d-aspartate receptor involvement in prolonged chemical nociception in the rat.

    Science.gov (United States)

    Haley, Jane E; Dickenson, Anthony H

    2016-08-15

    We used in vivo electrophysiology and a model of more persistent nociceptive inputs to monitor spinal cord neuronal activity in anaesthetised rats to reveal the pharmacology of enhanced pain signalling. The study showed that all responses were blocked by non-selective antagonism of glutamate receptors but a selective and preferential role of the N-methyl-d-aspartate (NMDA) receptor in the prolonged plastic responses was clearly seen. The work lead to many publications, initially preclinical but increasingly from patient studies, showing the importance of the NMDA receptor in central sensitisation within the spinal cord and how this could relate to persistent pain states. This article is part of a Special Issue entitled SI:50th Anniversary Issue. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Extrasynaptic N-methyl-D-aspartate (NMDA) receptor stimulation induces cytoplasmic translocation of the CDKL5 kinase and its proteasomal degradation.

    Science.gov (United States)

    Rusconi, Laura; Kilstrup-Nielsen, Charlotte; Landsberger, Nicoletta

    2011-10-21

    Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been found in patients with epileptic encephalopathy characterized by early onset intractable epilepsy, including infantile spasms and other types of seizures, severe developmental delay, and often the development of Rett syndrome-like features. Despite its clear involvement in proper brain development, CDKL5 functions are still far from being understood. In this study, we analyzed the subcellular localization of the endogenous kinase in primary murine hippocampal neurons. CDKL5 was localized both in nucleus and cytoplasm and, conversely to proliferating cells, did not undergo constitutive shuttling between these compartments. Nevertheless, glutamate stimulation was able to induce the exit of the kinase from the nucleus and its subsequent accumulation in the perinuclear cytoplasm. Moreover, we found that sustained glutamate stimulation promoted CDKL5 proteasomal degradation. Both events were mediated by the specific activation of extrasynaptic pool of N-methyl-d-aspartate receptors. Proteasomal degradation was also induced by withdrawal of neurotrophic factors and hydrogen peroxide treatment, two different paradigms of cell death. Altogether, our results indicate that both subcellular localization and expression of CDKL5 are modulated by the activation of extrasynaptic N-methyl-D-aspartate receptors and suggest regulation of CDKL5 by cell death pathways.

  20. Extrasynaptic N-Methyl-d-aspartate (NMDA) Receptor Stimulation Induces Cytoplasmic Translocation of the CDKL5 Kinase and Its Proteasomal Degradation*

    Science.gov (United States)

    Rusconi, Laura; Kilstrup-Nielsen, Charlotte; Landsberger, Nicoletta

    2011-01-01

    Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been found in patients with epileptic encephalopathy characterized by early onset intractable epilepsy, including infantile spasms and other types of seizures, severe developmental delay, and often the development of Rett syndrome-like features. Despite its clear involvement in proper brain development, CDKL5 functions are still far from being understood. In this study, we analyzed the subcellular localization of the endogenous kinase in primary murine hippocampal neurons. CDKL5 was localized both in nucleus and cytoplasm and, conversely to proliferating cells, did not undergo constitutive shuttling between these compartments. Nevertheless, glutamate stimulation was able to induce the exit of the kinase from the nucleus and its subsequent accumulation in the perinuclear cytoplasm. Moreover, we found that sustained glutamate stimulation promoted CDKL5 proteasomal degradation. Both events were mediated by the specific activation of extrasynaptic pool of N-methyl-d-aspartate receptors. Proteasomal degradation was also induced by withdrawal of neurotrophic factors and hydrogen peroxide treatment, two different paradigms of cell death. Altogether, our results indicate that both subcellular localization and expression of CDKL5 are modulated by the activation of extrasynaptic N-methyl-d-aspartate receptors and suggest regulation of CDKL5 by cell death pathways. PMID:21832092

  1. Anti-N-methyl-D-aspartate receptor-mediated encephalitis in infants and toddlers: case report and review of the literature.

    Science.gov (United States)

    Goldberg, Ethan M; Titulaer, Maarten; de Blank, Peter M; Sievert, Angela; Ryan, Nicole

    2014-02-01

    Anti-N-methyl-D-aspartate receptor encephalitis is an increasingly well-recognized inflammatory encephalitis in children and adults. We report a previously healthy 21-month-old girl who presented with behavioral change, self-mutilatory behavior, and echolalia. Over the ensuing weeks, symptoms progressed to include unilateral upper extremity dystonia, gait impairment, dysphagia, and mutism. Magnetic resonance imaging of the brain showed a tiny area of signal abnormality in the subcortical white matter, but was otherwise normal. Continuous video electroencephalography showed slowing of the background rhythm, but was without epileptiform discharges. Lumbar puncture showed a mild pleocytosis of mixed cellularity; bacterial culture and testing for various viral encephalitides were negative. Serum and cerebrospinal fluid was positive for autoantibodies directed against the N-methyl-D-aspartate receptor, and she was diagnosed with anti-N-methyl-D-aspartate receptor encephalitis. The patient was successfully treated with a regimen of immunotherapy that included dexamethasone, intravenous immunoglobulin, and rituximab. One year after initial presentation, the patient remained symptom-free. We further review the clinical characteristics, results of diagnostic studies, treatment, and outcome of infants and toddlers diagnosed with anti-N-methyl-D-aspartate receptor encephalitis that have been previously reported in the literature. Anti-N-methyl-D-aspartate receptor encephalitis is relatively common among infants and toddlers and often presents with a pattern of defining characteristics in this age group, particularly the absence of associated tumor. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Glufosinate ammonium stimulates nitric oxide production through N-methyl D-aspartate receptors in rat cerebellum.

    Science.gov (United States)

    Nakaki, T; Mishima, A; Suzuki, E; Shintani, F; Fujii, T

    2000-09-01

    Glufosinate ammonium, a structural analogue of glutamate, is an active herbicidal ingredient. The neuronal activities of this compound were investigated by use of a microdialysis system that allowed us to measure nitric oxide production in the rat cerebellum in vivo. Kainate (0.3-30 nmol/10 microliter), N-methyl-D-aspartate (NMDA) (3-300 nmol/10 microliter) and glufosinate ammonium (30-3000 nmol/10 microliter), which were administered through the microdialysis probe at a rate of 1 microliter/min for 10 min, stimulated nitric oxide production. The glufosinate ammonium-elicited increase in nitric oxide production was suppressed by an inhibitor of nitric oxide synthase and was antagonized by NMDA receptor antagonists, but not by a kainate/(+/-)-alphaamino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist. These results suggest that glufosinate ammonium stimulates nitric oxide production through NMDA receptors.

  3. N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands

    DEFF Research Database (Denmark)

    Clausen, Rasmus Prætorius; Christensen, Caspar; Hansen, Kasper Bø

    2008-01-01

    A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl glyc...

  4. Glufosinate ammonium induces convulsion through N-methyl-D-aspartate receptors in mice.

    Science.gov (United States)

    Matsumura, N; Takeuchi, C; Hishikawa, K; Fujii, T; Nakaki, T

    2001-05-18

    Glufosinate ammonium, a broad-spectrum herbicide, causes convulsion in rodents and humans. Because of the structural similarities between glufosinate and glutamate, the convulsion induced by glufosinate ammonium may be ascribed to glutamate receptor activation. Three N-methyl-D-asparate (NMDA) receptor antagonists, dizocilpine, LY235959, and Compound 40, and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist, NBQX, were coadministrated with glufosinate ammonium (80 mg/kg, intraperitoneally) in mice. Statistical analyses showed that the NMDA receptor antagonists markedly inhibited the convulsions, while the AMPA/kainate receptor antagonist had no effect on the convulsion. These results suggest that the convulsion caused by glufosinate ammonium is mediated through NMDA receptors.

  5. Propofol effectively inhibits lithium-pilocarpine- induced status epilepticus in rats via downregulation of N-methyl-D-aspartate receptor 2B subunit expression

    Science.gov (United States)

    Wang, Henglin; Wang, Zhuoqiang; Mi, Weidong; Zhao, Cong; Liu, Yanqin; Wang, Yongan; Sun, Haipeng

    2012-01-01

    Status epilepticus was induced via intraperitoneal injection of lithium-pilocarpine. The inhibitory effects of propofol on status epilepticus in rats were judged based on observation of behavior, electroencephalography and 24-hour survival rate. Propofol (12.5–100 mg/kg) improved status epilepticus in a dose-dependent manner, and significantly reduced the number of deaths within 24 hours of lithium-pilocarpine injection. Western blot results showed that, 24 hours after induction of status epilepticus, the levels of N-methyl-D-aspartate receptor 2A and 2B subunits were significantly increased in rat cerebral cortex and hippocampus. Propofol at 50 mg/kg significantly suppressed the increase in N-methyl-D-aspartate receptor 2B subunit levels, but not the increase in N-methyl-D-aspartate receptor 2A subunit levels. The results suggest that propofol can effectively inhibit status epilepticus induced by lithium-pilocarpine. This effect may be associated with downregulation of N-methyl-D-aspartate receptor 2B subunit expression after seizures. PMID:25737709

  6. Searsia species with affinity to the N-methyl-d-aspartic acid (NMDA) receptor

    DEFF Research Database (Denmark)

    Jäger, Anna; Knap, D.M.; Nielsen, Birgitte

    2012-01-01

    Species of Searsia are used in traditional medicine to treat epilepsy. Previous studies on S. dentata and S. pyroides have shown that this is likely mediated via the N-methyl-d-aspartic acid (NMDA) receptor. Ethanolic extracts of leaves of six Searsia species were tested in a binding assay...

  7. N-Methyl D-Aspartic Acid (NMDA Receptors and Depression

    Directory of Open Access Journals (Sweden)

    Enver Yusuf Sivrioglu

    2009-06-01

    Full Text Available The monoaminergic hypothesis of depression has provided the basis for extensive research into the pathophysiology of mood disorders and has been of great significance for the development of effective antidepressants. Current antidepressant treatments not only increase serotonin and/or noradrenaline bioavailability but also originate adaptive changes increasing synaptic plasticity. Novel approaches to depression and to antidepressant therapy are now focused on intracellular targets that regulate neuroplasticity and cell survival. Accumulating evidence indicates that there is an anatomical substrate for such a devastating neuropsychiatric disease as major depression. Loss of synaptic plasticity and hippocampal atrophy appear to be prominent features of this highly prevalent disorder. A combination of genetic susceptibility and environmental factors make hippocampal neurons more vulnerable to stress. Abundant experimental evidence indicates that stress causes neuronal damage in brain regions, notably in hippocampal subfields. Stress-induced activation of glutamatergic transmission may induce neuronal cell death through excessive stimulation of N-methyl-D-aspartic acid (NMDA receptors. Recent studies mention that the increase of nitric oxide synthesis and inflammation in major depression may contribute to neurotoxicity through NMDA receptor. Both standard antidepressants and NMDA receptor antagonists are able to prevent stress-induced neuronal damage. NMDA antagonists are effective in widely used animal models of depression and some of them appear to be effective also in the few clinical trials performed to date. We are still far from understanding the complex cellular and molecular events involved in mood disorders. There appears to be an emerging role for glutamate neurotransmission in the search for the pathogenesis of major depression. Attenuation of NMDA receptor function mechanism appears to be a promising target in the search for a more

  8. Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer's Disease.

    Science.gov (United States)

    Rodríguez-Ruiz, Mar; Moreno, Estefanía; Moreno-Delgado, David; Navarro, Gemma; Mallol, Josefa; Cortés, Antonio; Lluís, Carme; Canela, Enric I; Casadó, Vicent; McCormick, Peter J; Franco, Rafael

    2017-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D 1 , histamine H 3 , and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by co-immunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H 3 receptor agonists, via negative cross-talk, and H 3 receptor antagonists, via cross-antagonism, decreased D 1 receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D 1 receptor-mediated excitotoxic cell death. Both D 1 and H 3 receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D 1 -H 3 receptor heteromer function. Likely due to heteromerization, H 3 receptors act as allosteric regulator for D 1 and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D 1 or H 3 receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D 1 -H 3 -NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H 3 receptor antagonists reduced NMDA or D 1 receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H 3 receptor antagonists reverted the toxicity induced by ß 1-42 -amyloid peptide. Thus, histamine H 3 receptors in D 1 -H 3 -NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.

  9. [N-methyl-D-aspartate receptor antibody encephalitis: value of immunomodulatory therapy].

    Science.gov (United States)

    Le Moigno, L; Ternant, D; Paintaud, G; Thibault, G; Cloarec, S; Tardieu, M; Lagrue, E; Castelnau, P

    2014-06-01

    Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is little known to pediatricians and likely underdiagnosed. The child's vital and cognitive prognosis is at stake. The use of immunomodulatory drugs, such as rituximab has led to spectacular results, but many questions remain about its mode of action in this type of pathology. We report the case of a 6-year-old girl with no medical history, admitted for status epilepticus preceded by behavior symptoms and sleep disorders. Gradually, the child became bedridden, mute, and animated by predominantly orofacial dyskinesia. Examinations were normal (cerebrospinal fluid [CSF] analysis, brain MRI). The diagnosis was established by the presence of NMDA-R antibodies in the CSF. After exclusion of a tumor-associated syndrome, treatment was started initially by intravenous immunoglobulins, then by plasma exchange, and finally rituximab. The patient was cured with rituximab despite an unusually early recovery of the B-cell pool. Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is a severe but potentially reversible neurologic disorder only recently described, even in childhood. It may be reversible without sequelae if diagnosed and treated early. The use of immunomodulatory therapy, such as rituximab seemingly improves the outcome. Immunological monitoring is needed to better understand its mechanism of action in autoimmune diseases of the nervous system in childhood. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. Memantine (a N-Methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: A randomised, double-blinded, crossover study

    DEFF Research Database (Denmark)

    Nikolajsen, Lone; Gottrup, Hanne; Kristensen, Anders Due

    2000-01-01

    Evidence has accumulated that the N:-methyl-D-aspartate receptor system plays a role in continuous and particularly, in stimulus-evoked pain after nerve injury. We examined, in a randomized, double-blinded, cross-over fashion, the analgesic effect of memantine (a N:-methyl-D-aspartate receptor an...

  11. Cognitive disorder and changes in cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury

    Institute of Scientific and Technical Information of China (English)

    Weiliang Zhao; Dezhi Kang; Yuanxiang Lin

    2008-01-01

    BACKGROUND: Learning and memory damage is one of the most permanent and the severest symptoms of traumatic brain injury; it can seriously influence the normal life and work of patients. Some research has demonstrated that cognitive disorder is closely related to nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor. OBJECTIVE: To summarize the cognitive disorder and changes in nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury. RETRIEVAL STRATEGY: A computer-based online search was conducted in PUBMED for English language publications containing the key words "brain injured, cognitive handicap, acetylcholine, N-methyl-D aspartate receptors, neural cell adhesion molecule, brain-derived neurotrophic factor" from January 2000 to December 2007. There were 44 papers in total. Inclusion criteria: ① articles about changes in nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury; ② articles in the same researching circle published in authoritative journals or recently published. Exclusion criteria: duplicated articles.LITERATURE EVALUATION: References were mainly derived from research on changes in these four factors following brain injury. The 20 included papers were clinical or basic experimental studies. DATA SYNTHESIS: After craniocerebral injury, changes in these four factors in brain were similar to those during recovery from cognitive disorder, to a certain degree. Some data have indicated that activation of nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor could greatly improve cognitive disorder following brain injury. However, there are still a lot of questions remaining; for example, how do these

  12. Clinically significant response to zolpidem in disorders of consciousness secondary to anti-N-methyl-D-aspartate receptor encephalitis in a teenager: a case report.

    Science.gov (United States)

    Appu, Merveen; Noetzel, Michael

    2014-03-01

    Anti-N-methyl-d-aspartate receptor encephalitis has been associated with a prolonged neuropsychiatric phase that may last for months to years. We report the case of a 16-year-old girl who was diagnosed with anti-N-methyl-d-aspartate receptor encephalitis resulting from left ovarian mature teratoma 2 weeks after presentation with psychosis. Following tumor removal and immunotherapy, recovery from a minimally conscious state was accelerated significantly by zolpidem that was used for her sleep disturbance. Our patient was discharged home 8 weeks after admission with marked improvement in her neurological function. Zolpidem has been reported to improve arousal in disorders of consciousness but there are no previous reports of its benefit among patients with anti-N-methyl-d-aspartate receptor encephalitis. Zolpidem would be a reasonable consideration as an adjunctive treatment in anti-N-methyl-d-aspartate receptor encephalitis after tumor removal and immunotherapy to accelerate recovery and rehabilitation. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Blockade of N-methyl-D-aspartate induced convulsions by 1-aminocyclopropanecarboxylates

    International Nuclear Information System (INIS)

    Skolnick, P.; Marvizon, J.C.G.; Jackson, B.W.; Monn, J.A.; Rice, K.C.; Lewin, A.H.

    1989-01-01

    1-Aminocyclopropanecarboxylic acid is a potent and selective ligand for the glycine modulatory site on the N-methyl-D-aspartate receptor complex. This compound blocks the convulsions and deaths produced by N-methyl-D-aspartate in a dose dependent fashion. In contrast, 1-aminocyclopropanecarboxylic acid does not protect mice against convulsions induced by pentylenetetrazole, strychnine, bicuculline, or maximal electroshock, and does not impair motor performance on either a rotarod or horizontal wire at doses of up to 2 g/kg. The methyl- and ethyl- esters of 1-aminocyclopropanecarboxylic acid are 5- and 2.3-fold more potent, respectively, than the parent compound in blocking the convulsant and lethal effects of N-methyl-D-aspartate. However, these esters are several orders of magnitude less potent than 1-aminocyclopropanecarboxylic acid as inhibitors of strychnine-insensitive [ 3 H]glycine binding, indicating that conversion to the parent compound may be required to elicit an anticonvulsant action

  14. An N-methyl-D-aspartate receptor mediated large, low-frequency, spontaneous excitatory postsynaptic current in neonatal rat spinal dorsal horn neurons.

    Science.gov (United States)

    Thomson, L M; Zeng, J; Terman, G W

    2006-09-01

    Examples of spontaneous oscillating neural activity contributing to both pathological and physiological states are abundant throughout the CNS. Here we report a spontaneous oscillating intermittent synaptic current located in lamina I of the neonatal rat spinal cord dorsal horn. The spontaneous oscillating intermittent synaptic current is characterized by its large amplitude, slow decay time, and low-frequency. We demonstrate that post-synaptic N-methyl-D-aspartate receptors (NMDARs) mediate the spontaneous oscillating intermittent synaptic current, as it is inhibited by magnesium, bath-applied d-2-amino-5-phosphonovalerate (APV), or intracellular MK-801. The NR2B subunit of the NMDAR appears important to this phenomenon, as the NR2B subunit selective NMDAR antagonist, alpha-(4-hydroxphenyl)-beta-methyl-4-benzyl-1-piperidineethanol tartrate (ifenprodil), also partially inhibited the spontaneous oscillating intermittent synaptic current. Inhibition of spontaneous glutamate release by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Gly5] enkephalin-ol (DAMGO) inhibited the spontaneous oscillating intermittent synaptic current frequency. Marked inhibition of spontaneous oscillating intermittent synaptic current frequency by tetrodotoxin (TTX), but not post-synaptic N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314), suggests that the glutamate release important to the spontaneous oscillating intermittent synaptic current is dependent on active neural processes. Conversely, increasing dorsal horn synaptic glutamate release by GABAA or glycine inhibition increased spontaneous oscillating intermittent synaptic current frequency. Moreover, inhibiting glutamate transporters with threo-beta-benzyloxyaspartic acid (DL-TBOA) increased spontaneous oscillating intermittent synaptic current frequency and decay time. A possible functional role of this spontaneous NMDAR

  15. Anti-N-methyl-D-aspartate receptor encephalitis with serum anti-thyroid antibodies and IgM antibodies against Epstein-Barr virus viral capsid antigen: a case report and one year follow-up

    Directory of Open Access Journals (Sweden)

    Xu Chun-Ling

    2011-11-01

    Full Text Available Abstract Background Anti-N-methyl-D-aspartate receptor encephalitis is an increasingly common autoimmune disorder mediated by antibodies to certain subunit of the N-methyl-D-aspartate receptor. Recent literatures have described anti-thyroid and infectious serology in this encephalitis but without follow-up. Case presentation A 17-year-old Chinese female patient presented with psychiatric symptoms, memory deficits, behavioral problems and seizures. She then progressed through unresponsiveness, dyskinesias, autonomic instability and central hypoventilation during treatment. Her conventional blood work on admission showed high titers of IgG antibodies to thyroglobulin, thyroid peroxidase and IgM antibodies to Epstein-Barr virus viral capsid antigen. An immature ovarian teratoma was found and removal of the tumor resulted in a full recovery. The final diagnosis of anti-N-methyl-D-aspartate receptor encephalitis was made by the identification of anti-N-methyl-D-aspartate receptor antibodies in her cerebral spinal fluid. Pathology studies of the teratoma revealed N-methyl-D-aspartate receptor subunit 1 positive ectopic immature nervous tissue and Epstein-Barr virus latent infection. She was discharged with symptoms free, but titers of anti-thyroid peroxidase and anti-thyroglobulin antibodies remained elevated. One year after discharge, her serum remained positive for anti-thyroid peroxidase and anti-N-methyl-D-aspartate receptor antibodies, but negative for anti-thyroglobulin antibodies and IgM against Epstein-Barr virus viral capsid antigen. Conclusions Persistent high titers of anti-thyroid peroxidase antibodies from admission to discharge and until one year later in this patient may suggest a propensity to autoimmunity in anti- N-methyl-D-aspartate receptor encephalitis and support the idea that neuronal and thyroid autoimmunities represent a pathogenic spectrum. Enduring anti-N-methyl-D-aspartate receptor antibodies from admission to one year

  16. Stimulation of the N-methyl-D-aspartate receptor has a trophic effect on differentiating cerebellar granule cells

    DEFF Research Database (Denmark)

    Balázs, R; Hack, N; Jørgensen, Ole Steen

    1988-01-01

    N-methyl-D-aspartate (NMDA) supplementation of cerebellar cultures enriched in granule neurones (about 90%) prevented the extensive cell loss which occurs when cultivation takes place, in serum containing media, in the presence of 'low' K+ (5-15 mM). Estimation of tetanus toxin receptors and N-CA...

  17. Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties

    International Nuclear Information System (INIS)

    Keana, J.F.W.; McBurney, R.N.; Scherz, M.W.

    1989-01-01

    Four diarylguanidine derivatives were synthesized. These compounds were found to displace, at submicromolar concentrations, 3 H-labeled 1-[1-(2-thienyl)cyclohexyl]piperidine and (+)-[ 3 H]MK-801 from phencyclidine receptors in brain membrane preparations. In electrophysiological experiments the diarylguanidines blocked N-methyl-D-aspartate (NMDA)-activated ion channels. These dairylguanidines also protected rat hippocampal neurons in vitro from glutamate-induced cell death. The results show that some diarylguanidines are noncompetitive antagonists of NMDA receptor-mediated responses and have the neuroprotective property that is commonly associated with blockers of the NMDA receptor-gated cation channel. Diarylguanidines are structurally unrelated to known blockers of NMDA channels and, therefore, represent a new compound series for the development of neuroprotective agents with therapeutic value in patients suffering from stroke, from brain or spinal cord trauma, from hypoglycemia, and possibly from brain ischemia due to heart attack

  18. Hippocampal N-methyl-d-aspartate and kainate binding in response to entorhinal cortex aspiration or 192 IgG-saporin lesions of the basal forebrain

    International Nuclear Information System (INIS)

    Gallagher, M.; Gill, T.M.; Shivers, A.; Nicolle, M.M.

    1997-01-01

    Lesion models in the rat were used to examine the effects of removing innervation of the hippocampal formation on glutamate receptor binding in that system. Bilateral aspiration of the entorhinal cortex was used to remove the cortical innervation of the hippocampal formation and the dentate gyrus. The subcortical input to the hippocampus from cholinergic neurons of the basal forebrain was lesioned by microinjection of the immunotoxin 192 IgG-saporin into the medial septum and vertical limb of diagonal band. After a 30-day postlesion survival, the effects of these lesions on N-methyl-d-aspartate-displaceable [ 3 H]glutamate and [ 3 H]kainate binding in the hippocampus were quantified using in vitro autoradiography. The bilateral entorhinal lesion induced a sprouting response in the dentate gyrus, measured by an increase in the width of [ 3 H]kainate binding. It also induced an increase in the density of [ 3 H]kainate binding in CA3 stratum lucidum and an increase in N-methyl-d-aspartate binding throughout the hippocampus proper and the dentate gyrus. The selective lesion of cholinergic septal input did not have any effect on hippocampal [ 3 H]kainate binding and induced only a moderate decrease in N-methyl-d-aspartate binding that was not statistically reliable.The entorhinal and cholinergic lesions were used as in vivo models of the degeneration of hippocampal input that occurs in normal aging and Alzheimer's disease. The results from the present lesion study suggest that some, but not all, of the effects on hippocampal [ 3 H]kainate and N-methyl-d-aspartate binding induced by the lesions are consistent with the status of binding to these receptors in aging and Alzheimer's disease. Consistent with the effects of aging and Alzheimer's disease is an altered topography of [ 3 H]kainate binding after entorhinal cortex lesion and a modest decline in N-methyl-d-aspartate binding after lesions of the cholinergic septal input to the hippocampus. (Copyright (c) 1997

  19. Relationship between structure, conformational flexibility, and biological activity of agonists and antagonists at the N-methyl-D-aspartic acid subtype of excitatory amino acid receptors

    DEFF Research Database (Denmark)

    Madsen, U; Brehm, L; Schaumburg, Kjeld

    1990-01-01

    The relationship between conformational flexibility and agonist or antagonist actions at the N-Methyl-D-aspartic acid (NMDA) subtype of central L-glutamic acid (GLU) receptors of a series of racemic piperidinedicarboxylic acids (PDAs) was studied. The conformational analyses were based on 1H NMR...... receptors. Each of the three cyclic acidic amino acids showing NMDA agonist activities was found to exist as an equilibrium mixture of two conformers in aqueous solution. In contrast, the NMDA antagonists cis-2,3-PDA and cis-2,4-PDA as well as the inactive compounds trans-2,5-PDA and cis-2,6-PDA were shown...

  20. Effect of the low-affinity, noncompetitive N-methyl-D-aspartate receptor antagonist dextromethorphan on visceral perception in healthy volunteers

    NARCIS (Netherlands)

    Kuiken, S. D.; Lei, A.; Tytgat, G. N. J.; Holman, R.; Boeckxstaens, G. E. E.

    2002-01-01

    Background: The use of N-methyl-d-aspartate (NMDA) receptor antagonists may hold promise for the treatment of pain of visceral origin, in particular in conditions characterized by visceral hypersensitivity. Aim: To study the effect of dextromethorphan, a low affinity, non-competitive NMDA receptor

  1. Extended Clinical Spectrum of Anti-N-Methyl-d-Aspartate Receptor Encephalitis in Children: A Case Series.

    Science.gov (United States)

    Goenka, Ajay; Jain, Vivek; Nariai, Hiroki; Spiro, Alfred; Steinschneider, Mitchell

    2017-07-01

    There is a wide spectrum of clinical manifestations in children with anti-N-methyl-d-aspartate (NMDA) receptor antibody encephalitis from two different health care settings. We describe our experience with 13 patients (median age, 7 years; range, 5 months to 19 years) presenting to tertiary referral centers in India and the United States. Initial manifestations were neurological (seizures or movement disorders) in eight patients, and psychiatric (e.g., emotional lability and hallucination) in five patients. Symptoms during the clinical course included seizures in ten patients, movement disorders (dyskinesia and choreiform movements) in 11 patients, and behavioral changes (aggressiveness and insomnia) in ten patients. Concomitant infections (herpes simplex virus 1, tuberculous meningitis, and influenza A) were present in three patients. Analysis of the cerebrospinal fluid in all except two cases preceded by infection (herpes simplex virus encephalitis and tuberculous meningitis) was unremarkable. Treatment included intravenous immunoglobulin/methylprednisolone (11 patients), rituximab (eight patients), plasmapheresis (two patients), and cyclophosphamide (two patients). Six patients recovered completely. Two patients had mild residual neurological deficits, whereas four had severe residual neurological deficits. Two patients had profound autonomic instability, which was the cause of death for one of them. Two patients relapsed at two and six months after the initial recovery. We describe the differences and similarities of clinical presentation, test results, and response to treatment of children with anti-N-methyl-d-aspartate receptor encephalitis from India and the United States. Included is a description of one of the youngest patients with anti-N-methyl-d-aspartate receptor encephalitis (five months) and the first patient to be reported in association with tuberculous meningitis. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. N-Methyl-D-aspartic Acid (NMDA in the nervous system of the amphioxus Branchiostoma lanceolatum

    Directory of Open Access Journals (Sweden)

    Garcia-Fernàndez Jordi

    2007-12-01

    Full Text Available Abstract Background NMDA (N-methyl-D-aspartic acid is a widely known agonist for a class of glutamate receptors, the NMDA type. Synthetic NMDA elicits very strong activity for the induction of hypothalamic factors and hypophyseal hormones in mammals. Moreover, endogenous NMDA has been found in rat, where it has a role in the induction of GnRH (Gonadotropin Releasing Hormone in the hypothalamus, and of LH (Luteinizing Hormone and PRL (Prolactin in the pituitary gland. Results In this study we show evidence for the occurrence of endogenous NMDA in the amphioxus Branchiostoma lanceolatum. A relatively high concentration of NMDA occurs in the nervous system of this species (3.08 ± 0.37 nmol/g tissue in the nerve cord and 10.52 ± 1.41 nmol/g tissue in the cephalic vesicle. As in rat, in amphioxus NMDA is also biosynthesized from D-aspartic acid (D-Asp by a NMDA synthase (also called D-aspartate methyl transferase. Conclusion Given the simplicity of the amphioxus nervous and endocrine systems compared to mammalian, the discovery of NMDA in this protochordate is important to gain insights into the role of endogenous NMDA in the nervous and endocrine systems of metazoans and particularly in the chordate lineage.

  3. Influence of Genetic Variants of the N-Methyl-D-Aspartate Receptor on Emotion and Social Behavior in Adolescents.

    Science.gov (United States)

    Lee, Li-Ching; Cho, Ying-Chun; Lin, Pei-Jung; Yeh, Ting-Chi; Chang, Chun-Yen; Yeh, Ting-Kuang

    2016-01-01

    Considerable evidence has suggested that the epigenetic regulation of N-methyl-D-aspartate (NMDA) glutamate receptors plays a crucial role in neuropsychiatric disorders. Previous exploratory studies have been primarily based on evidence from patients and have rarely sampled the general population. This exploratory study examined the relationship of single-nucleotide polymorphism (SNP) variations in the genes encoding the NMDA receptor (i.e., GRIN1, GRIN2A, GRIN2B, GRIN2C, and GRIN2D) with emotion and social behavior in adolescents. For this study, 832 tenth-grade Taiwanese volunteers were recruited, and their scores from the Beck Youth Inventories were used to evaluate their emotional and social impairments. Based on these scores, GRIN1 (rs4880213) was significantly associated with depression and disruptive behavior. In addition, GRIN2B (rs7301328) was significantly associated with disruptive behavior. Because emotional and social impairment greatly influence learning ability, the findings of this study provide important information for clinical treatment and the development of promising prevention and treatment strategies, especially in the area of psychological adjustment.

  4. Influence of Genetic Variants of the N-Methyl-D-Aspartate Receptor on Emotion and Social Behavior in Adolescents

    Directory of Open Access Journals (Sweden)

    Li-Ching Lee

    2016-01-01

    Full Text Available Considerable evidence has suggested that the epigenetic regulation of N-methyl-D-aspartate (NMDA glutamate receptors plays a crucial role in neuropsychiatric disorders. Previous exploratory studies have been primarily based on evidence from patients and have rarely sampled the general population. This exploratory study examined the relationship of single-nucleotide polymorphism (SNP variations in the genes encoding the NMDA receptor (i.e., GRIN1, GRIN2A, GRIN2B, GRIN2C, and GRIN2D with emotion and social behavior in adolescents. For this study, 832 tenth-grade Taiwanese volunteers were recruited, and their scores from the Beck Youth Inventories were used to evaluate their emotional and social impairments. Based on these scores, GRIN1 (rs4880213 was significantly associated with depression and disruptive behavior. In addition, GRIN2B (rs7301328 was significantly associated with disruptive behavior. Because emotional and social impairment greatly influence learning ability, the findings of this study provide important information for clinical treatment and the development of promising prevention and treatment strategies, especially in the area of psychological adjustment.

  5. Costimulation of N-methyl-d-aspartate and muscarinic neuronal receptors modulates gap junctional communication in striatal astrocytes

    OpenAIRE

    Rouach, N.; Tencé, M.; Glowinski, J.; Giaume, C.

    2002-01-01

    Cocultures of neurons and astrocytes from the rat striatum were used to determine whether the stimulation of neuronal receptors could affect the level of intercellular communication mediated by gap junctions in astrocytes. The costimulation of N-methyl-D-asparte (NMDA) and muscarinic receptors led to a prominent reduction of astrocyte gap junctional communication (GJC) in coculture. This treatment was not effective in astrocyte cultures, these cells being devoid of NMDA receptors. Both types ...

  6. Differential regulation of glutamate receptors in trigeminal ganglia following masseter inflammation

    OpenAIRE

    Lee, Jongseok; Ro, Jin Y.

    2007-01-01

    The present study examined whether N-methyl-D-aspartate receptor (NMDAR) and 5-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits and group I metabotropic glutamate receptors (mGluRs) are constitutively expressed in trigeminal ganglia (TG) using Western blot analysis in male Sprague Dawley rats. We then investigated whether experimental induction of masseter inflammation influences glutamate receptor expressions by comparing the protein levels from naïve rats to th...

  7. Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F-fluoro-2-deoxy-d-glucose positron emission tomography.

    Science.gov (United States)

    Wegner, Florian; Wilke, Florian; Raab, Peter; Tayeb, Said Ben; Boeck, Anna-Lena; Haense, Cathleen; Trebst, Corinna; Voss, Elke; Schrader, Christoph; Logemann, Frank; Ahrens, Jörg; Leffler, Andreas; Rodriguez-Raecke, Rea; Dengler, Reinhard; Geworski, Lilli; Bengel, Frank M; Berding, Georg; Stangel, Martin; Nabavi, Elham

    2014-06-20

    Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis. The brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls. Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism. This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis.

  8. Anti-N-methyl-D-aspartate receptor encephalitis associated with intracranial Angiostrongylus cantonensis infection: a case report.

    Science.gov (United States)

    Peng, Yu; Liu, Xiaojia; Pan, Suyue; Xie, Zuoshan; Wang, Honghao

    2017-04-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a recently described paraneoplastic syndrome with prominent neuropsychiatric symptoms. Many of these cases are associated with neoplasma especially teratoma. In addition, a few of cases with anti-NMDAR antibodies triggered by viral infection have been reported, but never by parasitic infection. Here, we report a novel case of NMDA receptor encephalitis in a 51-year-old male related to the development of anti-NMDAR antibodies triggered by Angiostrongylus cantonensis infection.

  9. Analysis of variations in the glutamate receptor, N-methyl D-aspartate 2A (GRIN2A gene reveals their relative importance as genetic susceptibility factors for heroin addiction.

    Directory of Open Access Journals (Sweden)

    Bin Zhao

    Full Text Available The glutamate receptor, N-methyl D-aspartate 2A (GRIN2A gene that encodes the 2A subunit of the N-methyl D-aspartate (NMDA receptor was recently shown to be involved in the development of opiate addiction. Genetic polymorphisms in GRIN2A have a plausible role in modulating the risk of heroin addiction. An association of GRIN2A single-nucleotide polymorphisms (SNPs with heroin addiction was found earlier in African Americans. To identify markers that contribute to the genetic susceptibility to heroin addiction, we examined the potential association between heroin addiction and forty polymorphisms of the GRIN2A gene using the MassARRAY system and GeneScan in this study. The frequency of the (GT26 repeats (rs3219790 in the heroin addiction group was significantly higher than that in the control group (χ(2 = 5.360, P = 0.021. The allele frequencies of three polymorphisms (rs1102972, rs1650420, and rs3104703 in intron 3 were strongly associated with heroin addiction (P<0.001, 0.0002, and <0.001, after Bonferroni correction. Three additional SNPs from the same intron (rs1071502, rs6497730, and rs1070487 had nominally significant P values for association (P<0.05, but did not pass the threshold value. Haplotype analysis revealed that the G-C-T-C-C-T-A (block 6 and T-T (block 10 haplotypes of the GRIN2A gene displayed a protective effect (P = <0.001 and 0.003. These findings point to a role for GRIN2A polymorphisms in heroin addiction among the Han Chinese from Shaanxi province, and may be informative for future genetic or neurobiological studies on heroin addiction.

  10. Adolescent with acute psychosis due to anti-N-methyl-D-aspartate receptor encephalitis: successful recovery

    OpenAIRE

    Jonuskaite, Dovile; Kalibatas, Paulius; Praninskiene, Ruta; Zalubiene, Asta; Jucaite, Aurelija; Cerkauskiene, Rimante

    2017-01-01

    Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a relatively new autoimmune disorder of the central nervous system. We report the first case of anti-NMDAR autoimmune encephalitis combined with anti-voltage-gated potassium channel (anti-VGKC) antibodies in Lithuania in a 16-year-old girl. The patient was admitted to psychiatry unit because of an acute psychotic episode. She was unsuccessfully treated with antipsychotics, and electroconvulsive therapy was initiated because of he...

  11. Anti-N-Methyl-D-Aspartate Receptor Encephalitis, an Underappreciated Disease in the Emergency Department

    Directory of Open Access Journals (Sweden)

    Daniel R. Lasoff

    2016-05-01

    Full Text Available Anti-N-Methyl-D-Aspartate Receptor (NMDAR Encephalitis is a novel disease discovered within the past 10 years. Antibodies directed at the NMDAR cause the patient to develop a characteristic syndrome of neuropsychiatric symptoms. Patients go on to develop autonomic dysregulation and often have prolonged hospitalizations and intensive care unit stays. There is little literature in the emergency medicine community regarding this disease process, so we report on a case we encountered in our emergency department to help raise awareness of this disease process.

  12. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists

    DEFF Research Database (Denmark)

    Ebert, B; Thorkildsen, C; Andersen, S

    1998-01-01

    Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However...... for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak...

  13. Cloning and expression of the human N-methyl-D-aspartate receptor subunit NR3A

    DEFF Research Database (Denmark)

    Eriksson, Maria; Nilsson, Anna; Froelich-Fabre, Susanne

    2002-01-01

    Native N-methyl-D-aspartate (NMDA) receptors are heteromeric assemblies of four or five subunits. The NMDA receptor subunits, NR1, NR2A, NR2B, NR2C, and NR2D have been cloned in several species, including man. The NR3A subunit, which in rodents is predominantly expressed during early development......, seems to function by reducing the NMDA receptor response. The human homologue to the rat NR3A, however, had not been cloned. In order to study the functions of the human NR3A (hNR3A), we have cloned and sequenced the hNR3A. It was found to share 88% of the DNA sequence with the rat gene, corresponding...

  14. Serum uric acid and anti-N-methyl-d-aspartate receptor encephalitis.

    Science.gov (United States)

    Shu, Yaqing; Wang, Yuge; Lu, Tingting; Li, Rui; Sun, Xiaobo; Li, Jing; Chang, Yanyu; Hu, Xueqiang; Lu, Zhengqi; Qiu, Wei

    2017-09-01

    Uric acid (UA) levels are associated with autoimmune and neurodegenerative disorders, but their relationship with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is unknown. UA levels were evaluated in 58 patients with anti-NMDAR encephalitis, and 58 age- and sex-matched healthy controls (CTLs). Follow-up evaluations of 30 out of the 58 patients with anti-NMDAR encephalitis were conducted 3 months after admission. Modified Rankin scale (mRS) scores and clinical and cerebrospinal fluid parameters were evaluated in all anti-NMDAR encephalitis patients. Serum UA levels were significantly lower in patients with anti-NMDAR encephalitis than those in CTLs (p anti-NMDAR encephalitis are reduced during attacks compared with those in CTLs, are normalized after treatment, and are associated with disease severity. Copyright © 2017. Published by Elsevier Ltd.

  15. Synthesis and characterization of a radiolabeled derivative of the phencyclidine/N-methyl-D-aspartate receptor ligand (+)MK-801 with high specific radioactivity

    International Nuclear Information System (INIS)

    Keana, J.F.W.; Scherz, M.W.; Quarum, M.; Sonders, M.S.; Weber, E.

    1988-01-01

    A [ 3 H]-labelled derivative of the drug (+)MK-801 with a high specific radioactivity was synthesized by first preparing a tribromo derivative of (+)MK-801 followed by catalytic reduction in the presence of [ 3 H]-gas and subsequent purification of the radioactive product by reversed-phase high performance liquid chromatography (RP-HPLC). This resulted in pure (+) [ 3 H]MK-801 with a specific radioactivity of 97 Ci/mmol. The (+) [ 3 H]MK-801 was shown to interact with high affinity and selectivity with the phencyclidine (PCP) receptor in guinea pig brain membrane suspensions. The PCP receptor is associated with a cation channel that is chemically gated by glutamate and N-methyl-D-aspartate (NMDA). Drugs that interact with the PCP receptor block this channel. The (+) [ 3 H]MK-801 described here will be useful to investigate the biochemistry of PCP/NMDA receptors in experiments where a high specific radioactivity is essential

  16. Iron mediates N-methyl-D-aspartate receptor-dependent stimulation of calcium-induced pathways and hippocampal synaptic plasticity.

    Science.gov (United States)

    Muñoz, Pablo; Humeres, Alexis; Elgueta, Claudio; Kirkwood, Alfredo; Hidalgo, Cecilia; Núñez, Marco T

    2011-04-15

    Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-D-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine-reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP.

  17. N-methyl-D-aspartate promotes the survival of cerebellar granule cells: pharmacological characterization

    DEFF Research Database (Denmark)

    Balázs, R; Hack, N; Jørgensen, Ole Steen

    1989-01-01

    The survival of cerebellar granule cells in culture is promoted by chronic exposure to N-methyl-D-aspartate (NMDA). The effect is due to the stimulation of 'conventional' NMDA receptor-ionophore complex: it is concentration dependent, voltage dependent and blocked by the selective antagonists D-2...

  18. Anti-N-methyl-D-aspartate receptor encephalitis concomitant with multifocal subcortical white matter lesions on magnetic resonance imaging: a case report and review of the literature.

    Science.gov (United States)

    Wang, Rui-Jin; Chen, Bu-Dong; Qi, Dong

    2015-07-08

    Anti-N-methyl-D-aspartate receptor encephalitis is a severe autoimmune disorder characterized by severe psychiatric symptoms, seizures, decreased consciousness, autonomic dysregulation, and dyskinesias. Multifocal subcortical white matter lesions on fluid-attenuated inversion recovery and diffuse weighted images have rarely been reported in previous literature, and serial magnetic resonance imaging changes after plasma exchange have not been presented before. A previously healthy 24-year-old Chinese woman presented with acute psychiatric symptoms characterized by fear and agitation followed by decreased consciousness, dyskinesias, and seizures. Magnetic resonance imaging revealed hyperintense lesions on fluid-attenuated inversion recovery and diffuse weighted images in bilateral subcortical white matter. Cerebrospinal fluid analysis revealed a mild pleocytosis with lymphocytic predominance. Protein and glucose levels were normal. Aquaporin-4 antibodies in serum and cerebrospinal fluid were negative. Identification of anti-N-methyl-D-aspartate receptor antibodies in serum and cerebrospinal fluid confirmed the diagnosis of anti-N-methyl-D-aspartate receptor encephalitis. She was initially treated with combined intravenous immunoglobulin and methylprednisolone without improvement. Plasma exchange was then initiated with good response; the patient made a full recovery after several cycles of plasma exchange. Repeat magnetic resonance imaging performed 1 month after plasma exchange showed partial resolution of the hyperintense lesions in bilateral subcortical white matter, and follow-up magnetic resonance imaging 2 months after plasma exchange showed complete resolution. Anti-N-methyl-D-aspartate receptor encephalitis may be concomitant with multifocal subcortical white matter lesions. Such lesions may resolve after appropriate immunotherapy.

  19. Postpartum Anti-N-methyl-D-aspartate Receptor Encephalitis: A Case Report and Literature Review.

    Science.gov (United States)

    Doden, Tadashi; Sekijima, Yoshiki; Ikeda, Junji; Ozawa, Kazuki; Ohashi, Nobuhiko; Kodaira, Minori; Hineno, Akiyo; Tachibana, Naoko; Ikeda, Shu-Ichi

    2017-01-01

    We describe a 24-year-old woman with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis that developed 3 weeks after normal delivery. She was treated with methylprednisolone, intravenous immunoglobulin, and plasmapheresis, in addition to teratoma excision. However, her recovery was slow, and dysmnesia and mental juvenility persisted even two years after onset. To date, five patients with postpartum anti-NMDAR encephalitis have been reported. All of those patients showed psychotic symptoms and were suspected of having postpartum psychosis in the early period of the encephalitis. Changes in hormonal factors, modification of immune tolerance, or retrograde infection of the ovary may be contributing factors for postpartum anti-NMDAR encephalitis.

  20. Anti-N-Methyl-D-aspartate Receptor Encephalitis: A Severe, Potentially Reversible Autoimmune Encephalitis

    Science.gov (United States)

    Liu, Cai-yun; Zheng, Xiang-Yu; Ma, Chi

    2017-01-01

    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is potentially lethal, but it is also a treatable autoimmune disorder characterized by prominent psychiatric and neurologic symptoms. It is often accompanied with teratoma or other neoplasm, especially in female patients. Anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum are characteristic features of the disease, thereby suggesting a pathogenic role in the disease. Here, we summarize recent studies that have clearly documented that both clinical manifestations and the antibodies may contribute to early diagnosis and multidisciplinary care. The clinical course of the disorder is reversible and the relapse could occur in some patients. Anti-NMDAR encephalitis coexisting with demyelinating disorders makes the diagnosis more complex; thus, clinicians should be aware of the overlapping diseases. PMID:28698711

  1. Fulminant course in a patient with anti-N-methyl-D-aspartate receptor encephalitis with bilateral ovarian teratomas: A case report and literature review.

    Science.gov (United States)

    Lee, Kuo-Wei; Liou, Li-Min; Wu, Meng-Ni

    2018-04-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune disorder that can be controlled and reversed by immunotherapy. The presentation of NMDA receptor encephalitis varies, but NMDA receptor encephalitis is seldom reported in patients with both bilateral teratomas and preexisting brain injury. A 28-year-old female with a history of traumatic intracranial hemorrhage presented acute psychosis, seizure, involuntary movement, and conscious disturbance with a fulminant course. Anti-NMDA receptor antibody was identified in both serum and cerebrospinal fluid, confirming the diagnosis of anti-NMDA receptor encephalitis. Bilateral teratomas were also identified during tumor survey. DIAGNOSES:: anti-N-methyl-D-aspartate receptor encephalitis. Tumor resection and immunotherapy were performed early during the course. The patient responded well to tumor resection and immunotherapy. Compared with other reports in the literature, her symptoms rapidly improved without further relapse. This case report demonstrates that bilateral teratomas may be related to high anybody titers and that the preexisting head injury may be responsible for lowering the threshold of neurological deficits. Early diagnosis and therapy are crucial for a good prognosis in such patients.

  2. Effects of metabotropic glutamate receptor block on the synaptic transmission and plasticity in the rat medial vestibular nuclei.

    Science.gov (United States)

    Grassi, S; Malfagia, C; Pettorossi, V E

    1998-11-01

    In rat brainstem slices, we investigated the possible role of metabotropic glutamate receptors in modulating the synaptic transmission within the medial vestibular nuclei, under basal and plasticity inducing conditions. We analysed the effect of the metabotropic glutamate receptor antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine on the amplitude of the field potentials and latency of unitary potentials evoked in the ventral portion of the medial vestibular nuclei by primary vestibular afferent stimulation, and on the induction and maintenance of long-term potentiation, after high-frequency stimulation. Two effects were observed, consisting of a slight increase of the field potentials and reduction of unit latency during the drug infusion, and a further long-lasting development of these modifications after the drug wash-out. The long-term effect depended on N-methyl-D-aspartate receptor activation, as D,L-2-amino-5-phosphonopentanoic acid prevented its development. We suggest that (R,S)-alpha-methyl-4carboxyphenylglycine enhances the vestibular responses and induces N-methyl-D-aspartate-dependent long-term potentiation by increasing glutamate release, through the block of presynaptic metabotropic glutamate receptors which actively inhibit it. The block of these receptors was indirectly supported by the fact that the agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid reduced the vestibular responses and blocked the induction of long-term potentiation by high-frequency stimulation. The simultaneous block of metabotropic glutamate receptors facilitating synaptic plasticity, impedes the full expression of the long-term effect throughout the (R,S)-alpha-methyl-4-carboxyphenylglycine infusion. The involvement of such a facilitatory mechanism in the potentiation is supported by its reversible reduction following a second (R,S)-alpha-methyl-4-carboxyphenylglycine infusion. The drug also reduced the expression of potentiation induced by high-frequency stimulation

  3. Small Interfering RNA Specific for N-Methyl-D-Aspartate Receptor 2B Offers Neuroprotection to Dopamine Neurons through Activation of MAP Kinase

    Directory of Open Access Journals (Sweden)

    Olivia T.W. Ng

    2012-02-01

    Full Text Available In the present study, N-methyl-D-aspartate receptor 2B (NR2B-specific siRNA was applied in parkinsonian models. Our previous results showed that reduction in expression of N-methyl-D-aspartate receptor 1 (NR1, the key subunit of N-methyl-D-aspartate receptors, by antisense oligos amelio-rated the motor symptoms in the 6-hydroxydopamine (6-OHDA-lesioned rat, an animal model of Parkinson's disease (PD [Lai et al.: Neurochem Int 2004;45:11-22]. To further the investigation on the efficacy of gene silencing, small interference RNA (siRNA specific for the NR2B subunit was designed and administered in the striatum of 6-OHDA-lesioned rats. The present results show that administration of NR2B-specific siRNA decreased the number of apomorphine-induced rotations in the lesioned rats and that there was a significant reduction in NR2B proteins levels after NR2B-specific siRNA administration. Furthermore, attenuation of the loss of dopaminergic neurons was found in both the striatal and substantia nigra regions of the 6-OHDA-lesioned rats that had been continuously infused with siRNA for 7 days. In addition, a significant upregulation of p-p44/42 MAPK (ERK1/2; Thr202/Tyr204 and p-CREB (Ser133 in striatal neurons was found. These results suggest that application of the gene silencing targeting NR2B could be a potential treatment of PD, and they also revealed the possibility of NR2B-specific siRNA being involved in the prosurvival pathway.

  4. Synaptic glutamate spillover increases NMDA receptor reliability at the cerebellar glomerulus

    OpenAIRE

    Mitchell, Cassie S.; Lee, Robert H.

    2011-01-01

    Glutamate spillover in the mossy fiber to granule cell cerebellar glomeruli has been hypothesized to increase neurotransmission reliability. In this study, we evaluate this hypothesis using an experimentally-based quantitative model of glutamate spillover on the N-methyl-d-aspartate receptors (NMDA-Rs) at the cerebellar glomerulus. The transient and steady-state responses of NMDA-Rs were examined over a physiological range of firing rates. Examined cases included direct glutamate release acti...

  5. Japanese encephalitis can trigger anti-N-methyl-D-aspartate receptor encephalitis.

    Science.gov (United States)

    Ma, Jiannan; Zhang, Ting; Jiang, Li

    2017-06-01

    Japanese encephalitis (JE) is usually a monophasic disease; however, in rare cases, patients with JE may have an early relapse after a partial recovery, giving rise to a biphasic pattern for the disease. In this study, we report three pediatric cases in which post-JE relapse was characterized by movement disorder and/or behavioral problems, and was related to anti-N-methyl-D-aspartate receptor (NMDAR) immunoglobulin G (IgG). Serum and cerebrospinal fluid were examined for anti-NMDAR IgG in three patients who had confirmed JE and then developed relapsing symptoms which were similar to those of anti-NMDAR encephalitis. The main symptoms of the two young children were choreoathetosis, irritability, and sleep disorder; while for the teenager, agitation, mutism, rigidity, and sleep disorder were the main symptoms. Samples of cerebrospinal fluid from all patients were positive for anti-NMDAR IgG, and all patients gradually improved with immunotherapy. Testing for NMDAR antibodies is highly recommend in patients with JE, especially those with a relapsing syndrome involving movement disorder and/or behavioral problems, as these patients may benefit from immunotherapy.

  6. Serum cystatin C and anti-N-methyl-D-aspartate receptor encephalitis.

    Science.gov (United States)

    Shu, Y; Chang, Y; Wu, H; Li, J; Cao, B; Sun, X; Wang, J; Peng, L; Hu, X; Yu, X; Qiu, W

    2018-05-01

    Cystatin C (CysC) is associated with many neurodegenerative disorders and autoimmune diseases, but its relationship with anti-N-Methyl-D-aspartate receptor (anti-NMDAR) encephalitis is unknown. Serum levels of CysC were determined in 66 patients with anti-NMDAR encephalitis and 115 healthy controls. Of the 66 patients, 30 had a follow-up evaluation at 3 months after admission. Association of CysC with anti-NMDAR encephalitis and its clinical parameters were evaluated in the patients. The serum levels of CysC were significantly lower in patients with anti-NMDAR encephalitis than in controls (0.70 ± 0.13 vs 0.83 ± 0.17 mg/mL, P anti-NMDAR encephalitis patients had significantly increased serum CysC levels (P anti-NMDAR encephalitis and its clinical parameters and that the changes in CysC levels correlate with therapeutic effect. Therefore, our findings provide new insights into the association between serum CysC and anti-NMDAR encephalitis. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists

    DEFF Research Database (Denmark)

    Hansen, Kasper Bø; Mullasseril, Praseeda; Dawit, Sara

    2010-01-01

    N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca(2+)-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe...... a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal...

  8. sigma receptor ligands attenuate N-methyl-D-aspartate cytotoxicity in dopaminergic neurons of mesencephalic slice cultures.

    Science.gov (United States)

    Shimazu, S; Katsuki, H; Takenaka, C; Tomita, M; Kume, T; Kaneko, S; Akaike, A

    2000-01-28

    We investigated the potential neuroprotective effects of several sigma receptor ligands in organotypic midbrain slice cultures as an excitotoxicity model system. When challenged with 100-microM N-methyl-D-aspartate (NMDA) for 24 h, dopaminergic neurons in midbrain slice cultures degenerated, and this was prevented by (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5, 10-imine (MK-801; 1-10 microM). Concomitant application of ifenprodil (1-10 microM) or haloperidol (1-10 microM), both of which are high-affinity sigma receptor ligands, significantly attenuated the neurotoxicity of 100 microM NMDA. The sigma(1) receptor-selective ligand (+)-N-allylnormetazocine ((+)-SKF 10047; 1-10 microM) was also effective in attenuating the toxicity of NMDA. The effect of R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ((-)-PPAP), a sigma receptor ligand with negligible affinity for the phencyclidine site of NMDA receptors, was also examined. (-)-PPAP (3-100 microM) caused a concentration-dependent reduction of NMDA cytotoxicity, with significant protection at concentrations of 30 and 100 microM. In contrast, (+)-SKF 10047 (10 microM) and (-)-PPAP (100 microM) showed no protective effects against cell death induced by the Ca(2+) ionophore ionomycin (1-3 microM). These results indicate that sigma receptor ligands attenuate the cytotoxic effects of NMDA on midbrain dopaminergic neurons, possibly via inhibition of NMDA receptor functions.

  9. Depolarization-induced release of [(3)H]D-aspartate from GABAergic neurons caused by reversal of glutamate transporters

    DEFF Research Database (Denmark)

    Jensen, J B; Pickering, D S; Schousboe, A

    2000-01-01

    if glutamate in addition to gamma-aminobutyric acid (GABA) could be released from these cultures. The neurons were preloaded with [(3)H]D-aspartate and subsequently its release was followed during depolarization induced by a high potassium concentration or the alpha-amino-3-hydroxy-5-methyl-4......-isoxazolepropionic acid (AMPA) receptor agonists, AMPA and kainate. Depolarization of the neurons with 55 mM potassium increased the release of [(3)H]D-aspartate by more than 10-fold. When the non-specific calcium-channel blockers cobalt or lanthanum were included in the stimulation buffer with potassium......, the release of [(3)H]D-aspartate was decreased by about 40%. These results indicated that some of the released [(3)H]D-aspartate might originate from a vesicular pool. When AMPA was applied to the neurons, the release of [(3)H]D-aspartate was increased 2-fold and could not be prevented or decreased...

  10. Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

    Directory of Open Access Journals (Sweden)

    Júlia Niehues da Cruz

    2017-04-01

    Full Text Available ABSTRACT Membrane/lipid rafts (MLRs are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (statins can disable the N-methyl-D-aspartate (NMDA receptor through disruption of MLRs and, in turn, decrease NMDA-mediated anxiety. This hypothesis will contribute to understanding the critical roles of simvastatin in treating anxiety via the NMDA receptor.

  11. Low serum vitamin D levels and anti-N-methyl-d-aspartate receptor encephalitis: A case-control study.

    Science.gov (United States)

    Shu, Yaqing; Su, Qingmei; Liao, Siyuan; Lu, Tingting; Li, Rui; Sun, Xiaobo; Qiu, Wei; Yang, Yu; Hu, Xueqiang; Lu, Zhengqi

    2017-01-01

    Low vitamin D levels are associated with autoimmunity, but the relationship with anti-N-Methyl-d-aspartate receptor (anti-NMDAR) encephalitis is unknown. 25(OH) D levels and clinical and cerebrospinal fluid parameters were evaluated in 30 patients with anti-NMDAR encephalitis and compared with 90 age-, sex-, and season-matched healthy controls. 25(OH)D levels were lower in patients with anti-NMDAR encephalitis compared to controls (43.89 ± 17.91 vs 64.24 ± 24.38 nmol/L, p  30 years, p = 0.002), severe impairment (mRS ≥ 5) (vs mRS D levels were associated with age (r = 0.393, p = 0.032), and mRS (r = -0.417, p = 0.022). Our data showed that serum 25(OH)D levels were reduced in patients with anti-NMDAR encephalitis. Copyright © 2016. Published by Elsevier Ltd.

  12. Anti-N-Methyl-D-Aspartate Receptor Encephalitis and Rasmussen-like Syndrome: An Association?

    Science.gov (United States)

    Gurcharran, Kevin; Karkare, Shefali

    2017-01-01

    N-methyl-D-aspartate (NMDA) receptor encephalitis is an immune-mediated condition that has a broad spectrum of manifestations, including seizures, coma, psychosis, and focal neurological deficits. Although usually a diffuse process, unihemispheric involvement mimicking early stages of Rasmussen encephalitis can occur. Rasmussen's encephalitis is a unique syndrome characterized by progressive hemiplegia, drug-resistant focal epilepsy, cognitive decline, and hemispheric brain atrophy contralateral to the hemiplegia. We describe a two-year-old girl with progressive right weakness and epilepsia partialis continua, concerning for early Rasmussen's encephalitis, who tested positive for anti-NMDA receptor antibodies. She experienced complete clinical recovery after immunotherapy. Anti-NMDA receptor antibodies were absent at three weeks and again at one year after the first treatment of intravenous immunoglobulin. There are few reports of Rasmussen-like encephalitis in individuals with anti-NMDA receptor antibody positivity. Thus the clinical significance of this association is yet to be determined. In addition, several other antibodies have been documented in individuals with Rasmussen encephalitis. The lack of a consistently reported antibody in Rasmussen encephalitis patients and the temporary nature of the anti-NMDA receptor antibody in our patient raise the following question: Is the presence of anti-NMDA receptor antibodies the cause of the symptoms or secondary to the pathogenic process? Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Anti-N-Methyl-D-Aspartate Receptor Encephalitis in Children and Adolescents.

    Science.gov (United States)

    Scheer, Shelly; John, Rita Marie

    2016-01-01

    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease that is becoming increasingly recognized in the pediatric population. It may be the most common cause of treatable autoimmune encephalitis. The majority of cases of anti-NMDAR encephalitis are idiopathic in etiology, but a significant minority can be attributed to a paraneoplastic origin. Children with anti-NMDAR encephalitis initially present with a prodrome of neuropsychiatric symptoms, often with orofacial dyskinesias followed by progressively worsening seizures, agitation, and spasticity, which may result in severe neurologic deficits and even death. Definitive diagnosis requires detection of NMDAR antibodies in the cerebrospinal fluid. Optimal outcomes are associated with prompt removal of the tumor in paraneoplastic cases, as well as aggressive immunosuppressive therapy. Early detection is essential for increasing the chances for a good outcome. Close follow-up is required to screen for relapse and later onset tumor presentation. The nurse practitioner plays a major role in the research, screening, diagnosis, treatment, follow-up, and rehabilitation of a child or adolescent with anti-NMDAR encephalitis. Copyright © 2016 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.

  14. Arcaine uncovers dual interactions of polyamines with the N-methyl-D-aspartate receptor

    Energy Technology Data Exchange (ETDEWEB)

    Reynolds, I.J. (Univ. of Pittsburgh, PA (USA))

    1990-12-01

    This study investigated the interaction between the polyamines spermine and spermidine and the N-methyl-D-aspartate (NMDA) receptor by using (+)-(3H)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-im ine maleate ((3H)MK801) binding to well washed rat brain membranes. The actions of arcaine, agmatine, diethylenetriamine and 1,8-octanediamine as polyamine antagonists were compared to use as tools in this study. Arcaine was found to be the antagonist of choice due to its greater potency. Several divalent cations, including Ba++, Ca++ and Sr++, but not Zn++, decreased the apparent potency of arcaine. These cations enhance (3H)MK801 binding in a similar fashion to spermidine and spermine suggesting that they may share a common site and mechanism of action. Moreover, arcaine competitively reduced the enhancement of (3H)MK801 binding produced by Sr++ did not alter the inhibition produced by higher concentrations of this cation, a phenomenon that also occurs with spermidine. The distinct arcaine sensitivity of the two separate phases of the concentration-response curves of both spermidine and Sr++ suggests two separate mechanisms underlying the action of spermidine-like drugs on the NMDA receptor. Further investigation of the increase in (3H)MK801 binding produced by spermidine revealed that spermidine increased the equilibrium affinity of this ligand by 2-fold without significantly altering the density of binding sites. In contrast, polyamine induced increases in the dissociation of (3H)MK801 required higher polyamine concentrations than necessary to increase ligand binding and were relatively insensitive to arcaine. These findings suggest that polyamines do not activate or promote the activation of the NMDA receptor, but instead enhance (3H)MK801 binding by allosterically increasing ligand affinity.

  15. Arcaine uncovers dual interactions of polyamines with the N-methyl-D-aspartate receptor

    International Nuclear Information System (INIS)

    Reynolds, I.J.

    1990-01-01

    This study investigated the interaction between the polyamines spermine and spermidine and the N-methyl-D-aspartate (NMDA) receptor by using (+)-[3H]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine maleate ([3H]MK801) binding to well washed rat brain membranes. The actions of arcaine, agmatine, diethylenetriamine and 1,8-octanediamine as polyamine antagonists were compared to use as tools in this study. Arcaine was found to be the antagonist of choice due to its greater potency. Several divalent cations, including Ba++, Ca++ and Sr++, but not Zn++, decreased the apparent potency of arcaine. These cations enhance [3H]MK801 binding in a similar fashion to spermidine and spermine suggesting that they may share a common site and mechanism of action. Moreover, arcaine competitively reduced the enhancement of [3H]MK801 binding produced by Sr++ did not alter the inhibition produced by higher concentrations of this cation, a phenomenon that also occurs with spermidine. The distinct arcaine sensitivity of the two separate phases of the concentration-response curves of both spermidine and Sr++ suggests two separate mechanisms underlying the action of spermidine-like drugs on the NMDA receptor. Further investigation of the increase in [3H]MK801 binding produced by spermidine revealed that spermidine increased the equilibrium affinity of this ligand by 2-fold without significantly altering the density of binding sites. In contrast, polyamine induced increases in the dissociation of [3H]MK801 required higher polyamine concentrations than necessary to increase ligand binding and were relatively insensitive to arcaine. These findings suggest that polyamines do not activate or promote the activation of the NMDA receptor, but instead enhance [3H]MK801 binding by allosterically increasing ligand affinity

  16. High sensitivity and specificity in proposed clinical diagnostic criteria for anti-N-methyl-D-aspartate receptor encephalitis.

    Science.gov (United States)

    Ho, Alvin C C; Mohammad, Shekeeb S; Pillai, Sekhar C; Tantsis, Esther; Jones, Hannah; Ho, Reena; Lim, Ming; Hacohen, Yael; Vincent, Angela; Dale, Russell C

    2017-12-01

    To determine the validity of the proposed clinical diagnostic criteria for anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in paediatric patients. The diagnostic criteria for anti-NMDAR encephalitis proposed by Graus et al. (2016) use clinical features and conventional investigations to facilitate early immunotherapy before antibody status is available. The criteria are satisfied if patients develop four out of six symptom groups within 3 months, together with at least one abnormal investigation (electroencephalography/cerebrospinal fluid) and reasonable exclusion of other disorders. We evaluated the validity of the criteria using a retrospective cohort of paediatric patients with encephalitis. Twenty-nine patients with anti-NMDAR encephalitis and 74 comparison children with encephalitis were included. As expected, the percentage of patients with anti-NMDAR encephalitis who fulfilled the clinical criteria increased over time. During the hospital inpatient admission, most patients (26/29, 90%) with anti-NMDAR encephalitis fulfilled the criteria, significantly more than the comparison group (3/74, 4%) (panti-NMDAR encephalitis was 2 weeks from first symptom onset (range 1-6). The sensitivity of the criteria was 90% (95% confidence interval 73-98) and the specificity was 96% (95% confidence interval 89-99). The proposed diagnostic criteria for anti-NMDAR encephalitis have good sensitivity and specificity. Incomplete criteria do not exclude the diagnosis. The proposed clinical diagnostic criteria for anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis by Graus et al. (2016) have high sensitivity and specificity in paediatric patients. The median time of fulfilling the criteria in patients with anti-NMDAR was 2 weeks from first symptom onset. © 2017 Mac Keith Press.

  17. Anti-N-methyl-D-aspartate receptor encephalitis associated with hepatic neuroendocrine carcinoma: A case report.

    Science.gov (United States)

    Lim, Ee Wei; Yip, Chun Wai

    2017-07-01

    Anti-N-methyl-D-aspartate receptor (Anti-NMDAR) encephalitis can present with and without tumor. Tumor associations are less common in older patients. We report a 65-year-old gentleman who presented with one week history of cough, chills, rigor and altered behavior, followed by florid visual and auditory hallucinations. Mini mental status examination score was 16/30. Both cerebrospinal fluid and plasma anti-NMDA receptor antibodies were detected. A course of intravenous methylprednisolone was given with partial symptom improvement. A hepatic neuroendocrine carcinoma was detected and confirmed on biopsy. Unfortunately, he developed several medical complications: non-ST elevation myocardial infarction, infected foot gangrene and peripheral vascular disease, which made him unsuitable for both surgery and chemotherapy. He passed away 6months later due to the progression of the malignancy. This case illustrated that NMDAR encephalitis may be associated with an uncommon hepatic neuroendocrine carcinoma in an older person, which is responsive to early treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Effects of the noncompetitive N-methyl-d-aspartate receptor antagonists ketamine and MK-801 on pain-stimulated and pain-depressed behaviour in rats.

    Science.gov (United States)

    Hillhouse, T M; Negus, S S

    2016-09-01

    Pain is a significant public health concern, and current pharmacological treatments have problematic side effects and limited effectiveness. N-methyl-d-aspartate (NMDA) glutamate receptor antagonists have emerged as one class of candidate treatments for pain because of the significant contribution of glutamate signalling in nociceptive processing. This study compared effects of the NMDA receptor antagonists ketamine and MK-801 in assays of pain-stimulated and pain-depressed behaviour in rats. The nonsteroidal anti-inflammatory drug ketoprofen was examined for comparison as a positive control. Intraperitoneal injection of dilute acid served as an acute visceral noxious stimulus to stimulate a stretching response or depress intracranial self-stimulation (ICSS) in male Sprague-Dawley rats. Ketamine (1.0-10.0 mg/kg) blocked acid-stimulated stretching but failed to block acid-induced depression of ICSS, whereas MK-801 (0.01-0.1 mg/kg) blocked both acid-stimulated stretching and acid-induced depression of ICSS. These doses of ketamine and MK-801 did not alter control ICSS in the absence of the noxious stimulus; however, higher doses of ketamine (10 mg/kg) and MK-801 (0.32 mg/kg) depressed all behaviour. Ketoprofen (1.0 mg/kg) blocked both acid-induced stimulation of stretching and depression of ICSS without altering control ICSS. These results support further consideration of NMDA receptor antagonists as analgesics; however, some NMDA receptor antagonists are more efficacious at attenuating pain-depressed behaviours. NMDA receptor antagonists produce dissociable effects on pain-depressed behaviour. Provides evidence that pain-depressed behaviours should be considered and evaluated when determining the antinociceptive effects of NMDA receptor antagonists. © 2016 European Pain Federation - EFIC®

  19. High Concentrations of Tranexamic Acid Inhibit Ionotropic Glutamate Receptors.

    Science.gov (United States)

    Lecker, Irene; Wang, Dian-Shi; Kaneshwaran, Kirusanthy; Mazer, C David; Orser, Beverley A

    2017-07-01

    The antifibrinolytic drug tranexamic acid is structurally similar to the amino acid glycine and may cause seizures and myoclonus by acting as a competitive antagonist of glycine receptors. Glycine is an obligatory co-agonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Thus, it is plausible that tranexamic acid inhibits NMDA receptors by acting as a competitive antagonist at the glycine binding site. The aim of this study was to determine whether tranexamic acid inhibits NMDA receptors, as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate subtypes of ionotropic glutamate receptors. Tranexamic acid modulation of NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate receptors was studied using whole cell voltage-clamp recordings of current from cultured mouse hippocampal neurons. Tranexamic acid rapidly and reversibly inhibited NMDA receptors (half maximal inhibitory concentration = 241 ± 45 mM, mean ± SD; 95% CI, 200 to 281; n = 5) and shifted the glycine concentration-response curve for NMDA-evoked current to the right. Tranexamic acid also inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (half maximal inhibitory concentration = 231 ± 91 mM; 95% CI, 148 to 314; n = 5 to 6) and kainate receptors (half maximal inhibitory concentration = 90 ± 24 mM; 95% CI, 68 to 112; n = 5). Tranexamic acid inhibits NMDA receptors likely by reducing the binding of the co-agonist glycine and also inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors. Receptor blockade occurs at high millimolar concentrations of tranexamic acid, similar to the concentrations that occur after topical application to peripheral tissues. Glutamate receptors in tissues including bone, heart, and nerves play various physiologic roles, and tranexamic acid inhibition of these receptors may contribute to adverse drug effects.

  20. Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Review and Neuropsychological Case Study.

    Science.gov (United States)

    Loughan, Ashlee R; Allen, Aislyn; Perna, Robert; Malkin, Mark G

    2016-01-01

    Anti-N-Methyl-d-Aspartate Receptor (NMDAR) Encephalitis is an autoimmune-mediated encephalitis, which may be associated with a tumor, which occurs when antibodies bind central NMDA receptors. Although typically diagnosed in women, approximately 20% of cases have been males. Due to the challenges with identification, imaging, and diverse symptom presentation, this syndrome is often misdiagnosed. Accurate diagnosis may provide an opportunity for introduction of disease-modifying therapies, which may alter disease trajectory. Moreover, neuropsychology has yet to fully clarify the pattern of impairments expected with this disorder. This manuscript reviews a single case study of a 42-year-old male diagnosed with NMDAR encephalitis. Neuropsychological evaluation was completed subsequent to diagnosis, treatment, and rehabilitation. Ongoing patient complaints, approximately six months post diagnosis, included reduced sustained attention, poor word retrieval, and daily forgetfulness. Adaptive skills were improved following rehabilitation. Direct testing revealed mildly impaired sustained attention, processing speed, oral word fluency, and executive functioning. All other cognitive domains were within estimated premorbid range, low average to average. Neuropsychological deficits were consistent with mild frontal brain dysfunction and continued recovery. This case illustrates the need for medical and psychological practitioners to understand NMDAR encephalitis, its symptom presentation, and related neuropsychological impact; particularly with the potential for misdiagnosis.

  1. Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals

    Energy Technology Data Exchange (ETDEWEB)

    Krueger, Katharina; Gruner, Janina; Madeja, Michael; Musshoff, Ulrich [Universitaetsklinikum Muenster, Institut fuer Physiologie I, Muenster (Germany); Hartmann, Louise M.; Hirner, Alfred V. [Universitaet Duisburg-Essen, Institut fuer Umweltanalytik, Essen (Germany); Binding, Norbert [Universitaetsklinikum Muenster, Institut fuer Arbeitsmedizin, Muenster (Germany)

    2006-08-15

    Pentavalent and trivalent organoarsenic compounds belong to the major metabolites of inorganic arsenicals detected in humans. Recently, the question was raised whether the organic arsenicals represent metabolites of a detoxification process or methylated species with deleterious biological effects. In this study, the effects of trivalent arsenite (AsO{sub 3} {sup 3-}; iA{sup III}), the pentavalent organoarsenic compounds monomethylarsonic acid (CH{sub 3}AsO(OH){sub 2}; MMA{sup V}) and dimethylarsinic acid ((CH{sub 3}){sub 2}AsO(OH); DMA{sup V}) and the trivalent compounds monomethylarsonous acid (CH{sub 3}As(OH){sub 2}, MMA{sup III}) and dimethylarsinous acid ((CH{sub 3}){sub 2}As(OH); DMA{sup III}) were tested on glutamate receptors and on voltage-operated potassium and sodium channels heterologously expressed in Xenopus oocytes. Membrane currents of ion channels were measured by conventional two-electrode voltage-clamp techniques. The effects of arsenite were tested in concentrations of 1-1,000 {mu}mol/l and the organic arsenical compounds were tested in concentrations of 0.1-100 {mu}mol/l. We found no significant effects on voltage-operated ion channels; however, the arsenicals exert different effects on glutamate receptors. While MMA{sup V} and MMA{sup III} significantly enhanced ion currents through N-methyl-d-aspartate (NMDA) receptor ion channels with threshold concentrations <10 {mu}mol/l, DMA{sup V} and DMA{sup III} significantly reduced NMDA-receptor mediated responses with threshold concentrations <0.1 {mu}mol/l; iA{sup III} had no effects on glutamate receptors of the NMDA type. MMA{sup III} and DMA{sup V} significantly reduced ion currents through {alpha}-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor ion channels with threshold concentrations <10 {mu}mol/l (MMA{sup III}) and <1 {mu}mol/l (DMA{sup V}). MMA{sup V} and iA{sup III} had no significant effects on glutamate receptors of the AMPA type. The effects of MMA{sup V}, MMA

  2. Binding of L-glutamic acid to non-receptor materials

    International Nuclear Information System (INIS)

    Periyasamy, S.; Ito, M.; Chiu, T.H.

    1986-01-01

    [ 3 H]L-glutamic acid ([ 3 H]Glu) binding to microfuge tubes, glass fiber filters, and glass tubes was studied in 4 buffers (50 mM, pH 7.4 at 4 0 C). Binding assays were done at 0-4 0 C. Binding to these materials was negligible in the absence of external force, but was increased by suction or centrifugation in Tris-HCl or Tris-citrate buffer. The force-induced binding was much less or was eliminated in Tris-acetate or HEPES-KOH buffer. [ 3 H]Glu binding to microfuge tubes was inhibited by L- but not D- isomers of glutamate and aspartate. DL-2-amino-7-phosphonoheptanoic acid was without effect. Other compounds that showed low to moderate inhibitory activity were N-methyl-D-aspartate, quisqualate, L-glutamic acid diethyl ester. N-methyl-L-aspartate, kainate, and 2-amino-4-phosphonobutyrate. Binding was inhibited by denatured P 2 membrane preparation in Tris-acetate buffer was used. It is suggested that Tris-acetate or HEPES-KOH buffer should be used in the glutamate binding assay

  3. A novel photoaffinity ligand for the phencyclidine site of the N-methyl-D-aspartate receptor labels a Mr 120,000 polypeptide

    International Nuclear Information System (INIS)

    Sonders, M.S.; Barmettler, P.; Lee, J.A.; Kitahara, Y.; Keana, J.F.; Weber, E.

    1990-01-01

    A radiolabeled photoaffinity ligand has been developed for the N-methyl-D-aspartate (NMDA)-preferring excitatory amino acid receptor complex. [3H]3-Azido-(5S, 10R)(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine [3H]3-azido-MK-801 demonstrated nearly identical affinity, density of binding sites, selectivity, pH sensitivity, and pharmacological profile in reversible binding assays with guinea pig brain homogenates to those displayed by its parent compound, MK-801. When employed in a photo-labeling protocol designed to optimize specific incorporation, [3H]3-azido-MK-801 labeled a single protein band which migrated in sodium dodecyl sulfate-polyacrylamide gels with Mr = 120,000. Incorporation of tritium into this band was completely inhibited when homogenates and [3H]3-azido-MK-801 were coincubated with 10 microM phencyclidine. These data suggest that the phencyclidine site of the NMDA receptor complex is at least in part comprised of a Mr = 120,000 polypeptide

  4. Anti-N-methyl-d-aspartate receptor encephalitis in a patient with neuromyelitis optica spectrum disorders.

    Science.gov (United States)

    Luo, Jing-Jing; Lv, He; Sun, Wei; Zhao, Juan; Hao, Hong-Jun; Gao, Feng; Huang, Yi-Ning

    2016-07-01

    We described a female patient with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis occurring sequentially with neuromyelitis optica spectrum disorders (NMOSD). The 19-year-old patient initially presented a diencephalic syndrome with aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) and brain lesions which involving bilateral medial temporal lobes and periependymal surfaces of the third ventricle on magnetic resonance imaging (MRI). Ten months later, the patient developed cognitive impairment, psychiatric symptoms and dyskinesia with left basal ganglia lesions on brain MRI. Meanwhile, the anti-NMDAR antibodies were positive in the patient's serum and cerebrospinal fluid, while the screening tests for an ovarian teratoma and other tumors were all negative. Hence, the patient was diagnosed NMOSD and anti-NMDAR encephalitis followed by low-dose rituximab treatment with a good response. This case was another evidence for demyelinating syndromes overlapping anti-NMDAR encephalitis in Chinese patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Auto-immune anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis: three case reports.

    Science.gov (United States)

    Bashiri, Fahad A; Al-Rasheed, Abdulrahman A; Hassan, Saeed M; Hamad, Muddathir H A; El Khashab, Heba Y; Kentab, Amal Y; AlBadr, Fahad B; Salih, Mustafa A

    2017-08-01

    Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a recently identified auto-immune disorder characterised by severe memory deficit, a decreased level of consciousness, seizures, autonomic dysfunction and movement disorders. Three girls with the disorder are reported; they were aged 4 years, 5 years and 10 months. The 10-month-old infant who is one of the youngest patients reported with anti-NMDAR encephalitis worldwide, had MRI features suggestive of herpes simplex encephalitis (known to trigger anti-NMDAR encephalitis), but CSF PCR for herpes simplex was negative. All the patients presented with seizures, behavioural change, regression of speech, dystonia and choreo-athetosis. Anti-NMDAR antibodies were detected in all patients' sera and cerebrospinal fluid (CSF). Intravenous immunoglobulin, corticosteroids and rituximab were administered at different intervals. Cases 1 and 2 made a full recovery, but case 3 has mild motor and speech delay. Patients who present with encephalopathy, seizures and movement disorders should be tested for anti-NMDAR antibodies in serum and CSF in addition to being screened for herpes simplex encephalitis.

  6. Sex differences in hippocampal estradiol-induced N-methyl-D-aspartic acid binding and ultrastructural localization of estrogen receptor-alpha.

    Science.gov (United States)

    Romeo, Russell D; McCarthy, J Brian; Wang, Athena; Milner, Teresa A; McEwen, Bruce S

    2005-01-01

    Estradiol increases dendritic spine density and synaptogenesis in the CA1 region of the female hippocampus. This effect is specific to females, as estradiol-treated males fail to show increases in hippocampal spine density. Estradiol-induced spinogenesis in the female is dependent upon upregulation of the N-methyl-D-aspartic acid (NMDA) receptor as well as on non-nuclear estrogen receptors (ER), including those found in dendrites. Thus, in the male, the inability of estradiol to induce spinogenesis may be related to a failure of estradiol to increase hippocampal NMDA receptors as well as a paucity of dendritic ER. In the first experiment, we sought to investigate this possibility by assessing NMDA receptor binding, using [(3)H]-glutamate autoradiography, in estradiol-treated males and females. We found that while estradiol increases NMDA binding in gonadectomized females, estradiol fails to modulate NMDA binding in gonadectomized males. To further investigate sex differences in the hippocampus, we conducted a second separate, but related, ultrastructural study in which we quantified ERalpha-immunoreactivity (ERalpha-ir) in neuronal profiles in the CA1 region of the hippocampus in intact males and females in diestrus and proestrus. Consistent with previous reports in the female, we found ERalpha-ir in several extranuclear sites including dendrites, spines, terminals and axons. Statistical analyses revealed that females in proestrus had a 114.3% increase in ERalpha-labeled dendritic spines compared to females in diestrus and intact males. Taken together, these studies suggest that both the ability of estrogen to increase NMDA binding in the hippocampus and the presence of ERalpha in dendritic spines may contribute to the observed sex difference in estradiol-induced hippocampal spinogenesis. Copyright (c) 2005 S. Karger AG, Basel.

  7. Electroconvulsive Therapy in Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Case Report and Review of the Literature.

    Science.gov (United States)

    Coffey, M Justin; Cooper, Joseph J

    2016-12-01

    There is a growing scientific literature describing the neuropsychiatric symptoms of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, including the use of electroconvulsive therapy (ECT) to treat those symptoms. We sought to consolidate this literature into a review that highlights its relevance to ECT practitioners. We performed a PubMed search using the terms electroconvulsive therapy and encephalitis, autoimmune encephalitis, or anti-NMDA receptor encephalitis. We reviewed all relevant studies in detail, cross-referenced all bibliographies, and collected key clinical information related to the practice of ECT. We identified 6 studies offering patient-level descriptions of the use of ECT in patients with anti-NMDA receptor encephalitis. In all cases ECT was used to target symptoms of catatonia. Electroconvulsive therapy was delivered safely and effectively irrespective of the timing of diagnosis, tumor removal, or immunotherapy. There are no controlled data on the use of ECT in anti-NMDA receptor encephalitis. Further investigation is needed to determine whether ECT has a disease-modifying effect on this form of autoimmune encephalitis.

  8. Biochemical characterization of an autoradiographic method for studying excitatory amino acid receptors using L-[3H]glutamate

    International Nuclear Information System (INIS)

    Cincotta, M.; Summers, R.J.; Beart, P.M.

    1989-01-01

    A method was developed for radiolabeling excitatory amino acid receptors of rat brain with L-[ 3 H]glutamate. Effective labeling of glutamate receptors in slide-mounted 10-microns sections was obtained using a low incubation volume (0.15 ml) and rapid washing: a procedure where high ligand concentrations were achieved with minimal waste. Saturation experiments using [ 3 H]glutamate revealed a single binding site of micromolar affinity. The Bmax was trebled in the presence of Ca2+ (2.5 mM) and Cl- (20 mM) with no change in the Kd. Binding was rapid, saturable, stereospecific, and sensitive to glutamate receptor agonists. The proportions of [ 3 H]glutamate binding sensitive to N-methyl-D-aspartate (NMDA), kainate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were 34, 54, and 51%, respectively. NMDA inhibited binding at a distinct subset of L-[ 3 H]glutamate sites, whereas AMPA and kainate competed for some common sites. Labeling of sections with L-[ 3 H]glutamate in the presence of the selective agonists allowed autoradiographic visualization of glutamate receptor subtypes in brain tissue

  9. KB-R7943, an inhibitor of the reverse Na+/Ca2+ exchanger, blocks N-methyl-D-aspartate receptor and inhibits mitochondrial complex I

    Science.gov (United States)

    Brustovetsky, Tatiana; Brittain, Matthew K; Sheets, Patrick L; Cummins, Theodore R; Pinelis, Vsevolod; Brustovetsky, Nickolay

    2011-01-01

    BACKGROUND AND PURPOSE An isothiourea derivative (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methane sulfonate (KB-R7943), a widely used inhibitor of the reverse Na+/Ca2+ exchanger (NCXrev), was instrumental in establishing the role of NCXrev in glutamate-induced Ca2+ deregulation in neurons. Here, the effects of KB-R7943 on N-methyl-D-aspartate (NMDA) receptors and mitochondrial complex I were tested. EXPERIMENTAL APPROACH Fluorescence microscopy, electrophysiological patch-clamp techniques and cellular respirometry with Seahorse XF24 analyzer were used with cultured hippocampal neurons; membrane potential imaging, respirometry and Ca2+ flux measurements were made in isolated rat brain mitochondria. KEY RESULTS KB-R7943 inhibited NCXrev with IC50= 5.7 ± 2.1 µM, blocked NMDAR-mediated ion currents, and inhibited NMDA-induced increase in cytosolic Ca2+ with IC50= 13.4 ± 3.6 µM but accelerated calcium deregulation and mitochondrial depolarization in glutamate-treated neurons. KB-R7943 depolarized mitochondria in a Ca2+-independent manner. Stimulation of NMDA receptors caused NAD(P)H oxidation that was coupled or uncoupled from ATP synthesis depending on the presence of Ca2+ in the bath solution. KB-R7943, or rotenone, increased NAD(P)H autofluorescence under resting conditions and suppressed NAD(P)H oxidation following glutamate application. KB-R7943 inhibited 2,4-dinitrophenol-stimulated respiration of cultured neurons with IC50= 11.4 ± 2.4 µM. With isolated brain mitochondria, KB-R7943 inhibited respiration, depolarized organelles and suppressed Ca2+ uptake when mitochondria oxidized complex I substrates but was ineffective when mitochondria were supplied with succinate, a complex II substrate. CONCLUSIONS AND IMPLICATIONS KB-R7943, in addition to NCXrev, blocked NMDA receptors in cultured hippocampal neurons and inhibited complex I in the mitochondrial respiratory chain. These findings are critical for the correct interpretation of experimental

  10. Rehabilitation for a child with recalcitrant anti-N-methyl-d-aspartate receptor encephalitis: case report and literature review

    Science.gov (United States)

    Guo, Yao-Hong; Kuan, Ta-Shen; Hsieh, Pei-Chun; Lien, Wei-Chih; Chang, Chun-Kai; Lin, Yu-Ching

    2014-01-01

    Anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis is a newly recognized, potentially fatal, but treatable autoimmune disease. Good outcome predictors include milder severity of symptoms, no need for intensive care unit admission, early aggressive immunotherapy, and prompt tumor removal. We report a case of a young girl aged 3 years 2 months and diagnosed as recalcitrant anti-NMDA receptor encephalitis without any underlying neoplasm. The patient had initial symptoms of behavioral changes that progressed to generalized choreoathetosis and orofacial dyskinesia, which resulted in 6 months of hospitalization in the pediatric intensive care unit. One year after initial onset of the disease, she had only achieved the developmental age of an infant aged 6–8 months in terms of gross and fine motor skills, but she resumed total independence in activities of daily living after receiving extensive immunotherapy and 28 months of rehabilitation. Our brief review will help clinical practitioners become more familiar with this disease and the unique rehabilitation programs. PMID:25473290

  11. N-Methyl-d-Aspartate (NMDA Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection

    Directory of Open Access Journals (Sweden)

    Vivian V. Costa

    2017-04-01

    Full Text Available Zika virus (ZIKV infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801, agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration.

  12. Involvement of direct inhibition of NMDA receptors in the effects of sigma-receptor ligands on glutamate neurotoxicity in vitro.

    Science.gov (United States)

    Nishikawa, H; Hashino, A; Kume, T; Katsuki, H; Kaneko, S; Akaike, A

    2000-09-15

    This study was performed to examine the roles of the N-methyl-D-aspartate (NMDA) receptor/phencyclidine (PCP) channel complex in the protective effects of sigma-receptor ligands against glutamate neurotoxicity in cultured cortical neurons derived from fetal rats. A 1-h exposure of cultures to glutamate caused a marked loss of viability, as determined by Trypan blue exclusion. This acute neurotoxicity of glutamate was prevented by NMDA receptor antagonists. Expression of sigma(1) receptor mRNA in cortical cultures was confirmed by reverse transcription polymerase chain reaction (RT-PCR). sigma Receptor ligands with affinity for NMDA receptor channels including the PCP site, such as (+)-N-allylnormetazocine ((+)-SKF10,047), haloperidol, and R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane ((-)-PPAP), prevented glutamate neurotoxicity in a concentration-dependent manner. In contrast, other sigma-receptor ligands without affinity for NMDA receptors, such as carbetapentane and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP), did not show neuroprotective effects. Putative endogenous sigma receptor ligands such as pregnenolone, progesterone, and dehydroepiandrosterone did not affect glutamate neurotoxicity. The protective effects of (+)-SKF10,047, haloperidol, and (-)-PPAP were not affected by the sigma(1) receptor antagonist rimcazole. These results suggested that a direct interaction with NMDA receptors but not with sigma receptors plays a crucial role in the neuroprotective effects of sigma receptor ligands with affinity for NMDA receptors.

  13. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents.

    Science.gov (United States)

    Florance, Nicole R; Davis, Rebecca L; Lam, Christopher; Szperka, Christina; Zhou, Lei; Ahmad, Saba; Campen, Cynthia J; Moss, Heather; Peter, Nadja; Gleichman, Amy J; Glaser, Carol A; Lynch, David R; Rosenfeld, Myrna R; Dalmau, Josep

    2009-07-01

    To report the clinical features of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in patients ELISA) using HEK293 cells ectopically expressing NR1. Over an 8-month period, 81 patients (12 male) with anti-NMDAR encephalitis were identified. Thirty-two (40%) were 18 years old, 31% in girls < or =18 years old (p = 0.05), and 9% in girls < or =14 years old (p = 0.008). None of the male patients had tumors. Of 32 patients < or =18 years old, 87.5% presented with behavioral or personality change, sometimes associated with seizures and frequent sleep dysfunction; 9.5% with dyskinesias or dystonia; and 3% with speech reduction. On admission, 53% had severe speech deficits. Eventually, 77% developed seizures, 84% stereotyped movements, 86% autonomic instability, and 23% hypoventilation. Responses to immunotherapy were slow and variable. Overall, 74% had full or substantial recovery after immunotherapy or tumor removal. Neurological relapses occurred in 25%. At the last follow-up, full recovery occurred more frequently in patients who had a teratoma that was removed (5/8) than in those without a teratoma (4/23; p = 0.03). Anti-NMDAR encephalitis is increasingly recognized in children, comprising 40% of all cases. Younger patients are less likely to have tumors. Behavioral and speech problems, seizures, and abnormal movements are common early symptoms. The phenotype resembles that of the adults, although dysautonomia and hypoventilation are less frequent or severe in children. Ann Neurol 2009;66:11-18.

  14. Targeting the D1-N-methyl-D-aspartate receptor complex reduces L-dopa-induced dyskinesia in 6-hydroxydopamine-lesioned Parkinson’s rats

    Directory of Open Access Journals (Sweden)

    Song L

    2016-02-01

    Full Text Available Lu Song,1,* Zhanzhao Zhang,2,* Rongguo Hu,1 Jie Cheng,1 Lin Li,1 Qinyi Fan,1 Na Wu,1 Jing Gan,1 Mingzhu Zhou,1 Zhenguo Liu11Department of Neurology, Xinhua Hospital, 2Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workAbstract: L-3,4-dihydroxyphenylalanine (L-dopa remains the most effective therapy for Parkinson’s disease (PD, but its long-term administration is associated with the development of debilitating motor complications known as L-dopa-induced dyskinesia (LID. Enhanced function of dopamine D1 receptor (D1R and N-methyl-d-aspartate receptor (NMDAR is believed to participate in the pathogenesis of LID. Given the existence of physical and functional interactions between D1R and NMDAR, we explored the effects of uncoupling D1R and NMDA GluN1 (GluN1 interaction on LID by using the Tat-conjugated interfering peptide (Tat-D1-t2. In this study, we demonstrated in 6-hydroxydopamine (6-OHDA-lesioned PD rat model that intrastriatal injection of Tat-D1-t2 alleviated dyskinetic behaviors and downregulated the phosphorylation of DARPP-32 at Thr34 induced by levodopa. Moreover, we also showed intrastriatal administration of Tat-D1-t2 elicited alterations in membranous GluN1 and D1R expression. These findings indicate that D1R/GluN1 complexes may be a molecular target with therapeutic potential for the treatment of dyskinesia in Parkinson’s patients.Keywords: 6-hydroxydopamine, Parkinson’s disease, dyskinesia, L-dopa, D1 receptor, NMDA, protein–protein interaction

  15. Effects of sarcosine and N, N-dimethylglycine on NMDA receptor-mediated excitatory field potentials.

    Science.gov (United States)

    Lee, Mei-Yi; Lin, Yi-Ruu; Tu, Yi-Shu; Tseng, Yufeng Jane; Chan, Ming-Huan; Chen, Hwei-Hsien

    2017-02-28

    Sarcosine, a glycine transporter type 1 inhibitor and an N-methyl-D-aspartate (NMDA) receptor co-agonist at the glycine binding site, potentiates NMDA receptor function. Structurally similar to sarcosine, N,N-dimethylglycine (DMG) is also N-methyl glycine-derivative amino acid and commonly used as a dietary supplement. The present study compared the effects of sarcosine and DMG on NMDA receptor-mediated excitatory field potentials (EFPs) in mouse medial prefrontal cortex brain slices using a multi-electrode array system. Glycine, sarcosine and DMG alone did not alter the NMDA receptor-mediated EFPs, but in combination with glutamate, glycine and its N-methyl derivatives significantly increased the frequency and amplitude of EFPs. The enhancing effects of glycine analogs in combination with glutamate on EFPs were remarkably reduced by the glycine binding site antagonist 7-chlorokynurenate (7-CK). However, DMG, but not sarcosine, reduced the frequency and amplitude of EFPs elicited by co-application of glutamate plus glycine. D-cycloserine, a partial agonist at the glycine binding site on NMDA receptors, affected EFPs in a similar manner to DMG. Furthermore, DMG, but not sarcosine, reduced the frequencies and amplitudes of EFPs elicited by glutamate plus D-serine, another endogenous ligand for glycine binding site. These findings suggest that sarcosine acts as a full agonist, yet DMG is a partial agonist at glycine binding site of NMDA receptors. The molecular docking analysis indicated that the interactions of glycine, sarcosine, and DMG to NMDA receptors are highly similar, supporting that the glycine binding site of NMDA receptors is a critical target site for sarcosine and DMG.

  16. The relaxing effect of perivascular tissue on porcine retinal arterioles in vitro is mimicked by N-methyl-D-aspartate and is blocked by prostaglandin synthesis inhibition

    DEFF Research Database (Denmark)

    Jensen, Kim Holmgaard; Aalkjær, Christian; Lambert, John D. C.

    2008-01-01

    . However, previous in vitro studies of the influence of perivascular retinal tissue on retinal tone regulation have been hampered by the release of an endogenous relaxing factor that renders the arteriole insensitive to vasoconstrictors. The purpose of the present study was to test whether N-methyl-D-aspartate...... (NMDA) and gamma-amino butyric acid (GABA) receptors, and a cyclooxygenase (COX) product influence this effect of perivascular retinal tissue in vitro. METHODS: Porcine retinal arterioles were mounted in a wire myograph for isometric force measurements. The contractile effect of the prostaglandin...... analogue U46619 was studied on vessels with preserved perivascular retinal tissue and after this tissue had been removed. The influence of the perivascular tissue was studied after addition of NMDA (a specific agonist for a subtype of the glutamate receptor), DL-amino-5-phosphonovaleric acid (DL...

  17. N-methyl-D-aspartate prevented memory deficits induced by MK-801 in mice

    Czech Academy of Sciences Publication Activity Database

    Hliňák, Zdeněk; Krejčí, I.

    2003-01-01

    Roč. 52, č. 6 (2003), s. 809-812 ISSN 0862-8408 R&D Projects: GA ČR GA309/00/1644 Institutional research plan: CEZ:AV0Z5011922 Keywords : N-methyl-D-aspartate * MK-801 * spatial memory Subject RIV: FH - Neurology Impact factor: 0.939, year: 2003

  18. Relationship between changes of N-methyl-D-aspartate receptor activity and brain edema after brain injury in rats

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To investigate the relationship between the changes of N-methyl-D-aspartate (NMDA) receptor activity and brain edema after injury in rats.   Methods: The brain injury models were made by using a free-falling body. The treatment model was induced by means of injecting AP5 into lateral ventricle before brain injury; water contents in brain cortex were measured with dry-wet method; and NMDA receptor activity was detected with a radio ligand binding assay.   Results: The water contents began to increase at 30 minutes and reached the peak at 6 hours after brain injury. The maximal binding (Bmax) of NMDA receptor increased significantly at 15 minutes and reached the peak at 30 minutes, then decreased gradually and had the lowest value 6 hours after brain injury. Followed the treatment with AP5, NMDA receptor activity in the injured brain showed a normal value; and the water contents were lower than that of AP5-free injury group 24 hours after brain injury.   Conclusions: It suggests that excessive activation of NMDA receptor may be one of the most important factors to induce the secondary cerebral impairments, and AP5 may protect the brain from edema after brain injury.

  19. Large variability in synaptic N-methyl-D-aspartate receptor density on interneurons and a comparison with pyramidal-cell spines in the rat hippocampus.

    Science.gov (United States)

    Nyíri, G; Stephenson, F A; Freund, T F; Somogyi, P

    2003-01-01

    Pyramidal cells receive input from several types of GABA-releasing interneurons and innervate them reciprocally. Glutamatergic activation of interneurons involves both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) type glutamate receptors expressed in type I synapses, mostly on their dendritic shafts. On average, the synaptic AMPA receptor content is several times higher on interneurons than in the spines of pyramidal cells. To compare the NMDA receptor content of synapses, we used a quantitative postembedding immunogold technique on serial electron microscopic sections, and analysed the synapses on interneuron dendrites and pyramidal cell spines in the CA1 area. Because all NMDA receptors contain the obligatory NR1 subunit, receptor localisation was carried out using antibodies recognising all splice variants of the NR1 subunit. Four populations of synapse were examined: i). on spines of pyramidal cells in stratum (str.) radiatum and str. oriens; ii). on parvalbumin-positive interneuronal dendritic shafts in str. radiatum; iii). on randomly found dendritic shafts in str. oriens and iv). on somatostatin-positive interneuronal dendritic shafts and somata in str. oriens. On average, the size of the synapses on spines was about half of those on interneurons. The four populations of synapse significantly differed in labelling for the NR1 subunit. The median density of NR1 subunit labelling was highest on pyramidal cell spines. It was lowest in the synapses on parvalbumin-positive dendrites in str. radiatum, where more than half of these synapses were immunonegative. In str. oriens, synapses on interneurons had a high variability of receptor content; some dendrites were similar to those in str. radiatum, including the proximal synapses of somatostatin-positive cells, whereas others had immunoreactivity for the NR1 subunit similar to or higher than synapses on pyramidal cell spines. These results show that synaptic NMDA

  20. Integration of contextual cues into memory depends on "prefrontal" N-methyl-D-aspartate receptors.

    Science.gov (United States)

    Starosta, Sarah; Bartetzko, Isabelle; Stüttgen, Maik C; Güntürkün, Onur

    2017-10-01

    Every learning event is embedded in a context, but not always does the context become an integral part of the memory; however, for extinction learning it usually does, resulting in context-specific conditioned responding. The neuronal mechanisms underlying contextual control have been mainly investigated for Pavlovian fear extinction with a focus on hippocampal structures. However, the initial acquisition of novel responses can be subject to contextual control as well, although the neuronal mechanisms are mostly unknown. Here, we tested the hypothesis that contextual control of acquisition depends on glutamatergic transmission underlying executive functions in forebrain areas, e.g. by shifting attention to critical cues. Thus, we antagonized N-methyl-D-aspartate (NMDA) receptors with 2-amino-5-phosphonovaleric acid (AP5) in the pigeon nidopallium caudolaterale, the functional analogue of mammalian prefrontal cortex, during the concomitant acquisition and extinction of conditioned responding to two different stimuli. This paradigm has previously been shown to lead to contextual control over extinguished as well as non-extinguished responding. NMDA receptor blockade resulted in an impairment of extinction learning, but left the acquisition of responses to a novel stimulus unaffected. Critically, when responses were tested in a different context in the retrieval phase, we observed that NMDA receptor blockade led to the abolishment of contextual control over acquisition performance. This result is predicted by a model describing response inclination as the product of associative strength and contextual gain. In this model, learning under AP5 leads to a change in the contextual gain on the learned association, possibly via the modulation of attentional mechanisms. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Anti-N-methyl-D-aspartate receptor encephalitis: analysis of three cases

    Directory of Open Access Journals (Sweden)

    Hui SU

    2015-07-01

    Full Text Available Objective To study clinical features, diagnosis, therapy response and prognosis of anti-N-methyl-D-aspartate receptor (anti-NMDAR encephalitis.  Methods Three cases with anti-NMDAR encephalitis were reported. The clinical features, laboratory examinations, imaging, EEG and therapy response of 3 cases were retrospectively analyzed, and also related literatures were reviewed.  Results Two patients were young male and one patient was old female. Main symptoms included psychiatric symptoms in 3 cases (mania in 2 male patients and stupor in the female patient, epilepsy in 2 cases and respiratory failure in one case. The results of MRI examination revealed normal, while EEG examination showed abnormal in all cases. No tumor was detected in any of these patients. Lumbar puncture revealed normal cerebrospinal fluid (CSF pressure (3 cases, elevated white blood cell (WBC, 3 cases and protein quantification (one case. All cases were confirmed to have the disease by detection of anti-NMDAR antibodies in serum and CSF. One male patient got better after receiving immunotherapy with methylprednisolone and intravenous immunoglobulin (IVIg, but psychiatric symptoms were left over. Another male patient had no response to the above treatment. But the female patient was improved without immunotherapy. All 3 cases were followed up for one year after being discharged. One male patient died by accident because of mental disorders. Another male patient showed no sign of relief. The female patient got mild personality and memory change.  Conclusions Anti-NMDAR encephalitis is a new type of autoimmune encephalitis. It is characterized by fever, memory deficits, seizures, disturbance of consciousness, and autonomic dysfunction in males and females of all ages. This type of encephalitis is often associated with teratoma, and has a good response to immunotherapy. There is a certain correlation between progression and prognosis. DOI: 10.3969/j.issn.1672-6731.2015.07.013

  2. Allergy in patients with anti-N-methyl-d-aspartate receptor encephalitis.

    Science.gov (United States)

    Jiang, Xin-Yue; Zhang, Le; Jiang, Xian; Abdulaziz, Ammar Taha Abdullah; Wang, Yun-Hui; Li, Jin-Mei; Zhou, Dong

    2018-02-01

    Allergy is a potential outcome of dysregulated immune system. Previous studies have shown the association of allergy and autoimmune diseases, however, there is few study to investigate the relationship between allergy and anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. Thus, we investigate the rate of allergy in patients with anti-NMDAR encephalitis and analyze the risk factors. The rate of allergy was investigated in patients with anti-NMDAR encephalitis and was compared with patients with virus encephalitis. The clinical cutaneous characters were described in details. All patients with anti-NMDAR encephalitis were divided into allergic and nonallergic group. Clinical factors were compared in the two groups, and logistic regression model was also used to analyze possible risk factors of allergy. Patients with anti-NMDAR encephalitis had a higher rate of allergy than those with viral encephalitis (22.1% vs 9.2%, odds ratio (OR)=3.23, confidence interval (CI)=1.40-7.42, P=0.006). In patients with anti-NMDAR encephalitis, allergic patients exhibited longer days in hospital (30days vs 22days, P=0.005) and higher occurrence of decreased consciousness (81.5% vs 58.9%, P=0.031), higher rate of complications (77.8% vs 57.9%, P=0.046) and abnormal electroencephalography (EEG) (100% vs 78.6%, P=0.021) than patients without allergy. Cerebrospinal fluid (CSF) antibody titers of allergic patients during the disease course were also higher than nonallergic patients (P=0.004). However, further logistic regression analysis did not reveal independent predictors of allergy. Patients with anti-NMDAR encephalitis show higher allergic rate than those with virus encephalitis. Patients with allergy show higher CSF antibody titers and greater illness severity. However, the final outcome of anti-NMDAR encephalitis was not influenced. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Inhibition by sigma receptor ligand, MS-377, of N-methyl- D-aspartate-induced currents in dopamine neurons of the rat ventral tegmental area.

    Science.gov (United States)

    Yamazaki, Yuu; Ishioka, Miwa; Matsubayashi, Hiroaki; Amano, Taku; Sasa, Masashi

    2002-04-01

    MS-377 [( R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl) piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate] is a novel anti-psychotic drug candidate with high affinity for sigma receptors but devoid of binding affinity for PCP binding site of NMDA receptor/ion channel complex. The effects of MS-377 on NMDA receptor and/or its ion channel complex were examined to elucidate the antipsychotic properties of MS-377. We examined the effect of MS-377 on NMDA ( N-methyl- D-aspartate)-induced current in acutely dissociated dopamine neurons of rat ventral tegmental area (VTA) using patch clamp whole cell recording. MS-377 applied in a bath inhibited the peak current evoked by NMDA applied via the U-tube method for 2 s in a concentration-dependent manner. Other sigma receptor ligands, BD-1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), NE-100 ( N, N-dipropyl-2-[4-methoxy-3-(2-phenylenoxy)-phenyl]-ethylamine monohydrochloride) and haloperidol also inhibited NMDA-induced current in a concentration-dependent manner. Interestingly, concomitant application of MS-377 with BD-1063, NE-100 or haloperidol at concentrations that had no effects on NMDA-induced current, potentiated the MS-377-induced inhibition. The results suggest that MS-377, as well as other sigma receptor ligands, indirectly acts on the sigma receptor to inhibit glutaminergic transmission mediated by NMDA receptor/ion channel complex in VTA dopamine neurons, thereby inhibiting dopamine release in target VTA areas.

  4. Comparison of the neuropsychological mechanisms of 2,6-diisopropylphenol and N-methyl-D-aspartate receptor antagonist against electroconvulsive therapy-induced learning and memory impairment in depressed rats.

    Science.gov (United States)

    Liu, Gang; Liu, Chao; Zhang, Xue-Ning

    2015-09-01

    The present study aimed to examine the neurophysiological mechanisms of the 2,6-diisopropylphenol and N-methyl-D-aspartate (NMDA) receptor antagonist against learning and memory impairment, induced by electroconvulsive therapy (ECT). A total of 48 adult depressed rats without olfactory bulbs were randomly divided into six experimental groups: i) saline; ii) 10 mg/kg MK‑801; iii) 10 mg/kg MK‑801 and a course of ECT; iv) 200 mg/kg 2,6‑diisopropylphenol; v) 200 mg/kg 2,6‑diisopropylphenol and a course of ECT; and vi) saline and a course of ECT. The learning and memory abilities of the rats were assessed using a Morris water maze 1 day after a course of ECT. The hippocampus was removed 1 day after assessment using the Morris water maze assessment. The content of glutamate in the hippocampus was detected using high‑performance liquid chromatography. The expression levels of p‑AT8Ser202 and GSK‑3β1H8 in the hippocampus were determined using immunohistochemical staining and western blot analysis. The results demonstrated that the 2,6‑diisopropylphenol NMDA receptor antagonist, MK‑801 and ECT induced learning and memory impairment in the depressed rats. The glutamate content was significantly upregulated by ECT, reduced by 2,6‑diisopropylphenol, and was unaffected by the NMDA receptor antagonist in the hippocampus of the depressed rats. Tau protein hyperphosphorylation in the hippocampus was upregulated by ECT, but was reduced by 2,6‑diisopropylphenol and the MK‑801 NMDA receptor antagonist. It was also demonstrated that 2,6‑diisopropylphenol prevented learning and memory impairment and reduced the hyperphosphorylation of the Tau protein, which was induced by eECT. GSK‑3β was found to be the key protein involved in this signaling pathway. The ECT reduced the learning and memory impairment, caused by hyperphosphorylation of the Tau protein, in the depressed rats by upregulating the glutamate content.

  5. Brain infection with Staphylococcus aureus leads to high extracellular levels of glutamate, aspartate, γ-aminobutyric acid, and zinc.

    Science.gov (United States)

    Hassel, Bjørnar; Dahlberg, Daniel; Mariussen, Espen; Goverud, Ingeborg Løstegaard; Antal, Ellen-Ann; Tønjum, Tone; Maehlen, Jan

    2014-12-01

    Staphylococcal brain infections may cause mental deterioration and epileptic seizures, suggesting interference with normal neurotransmission in the brain. We injected Staphylococcus aureus into rat striatum and found an initial 76% reduction in the extracellular level of glutamate as detected by microdialysis at 2 hr after staphylococcal infection. At 8 hr after staphylococcal infection, however, the extracellular level of glutamate had increased 12-fold, and at 20 hr it had increased >30-fold. The extracellular level of aspartate and γ-aminobutyric acid (GABA) also increased greatly. Extracellular Zn(2+) , which was estimated at ∼2.6 µmol/liter in the control situation, was increased by 330% 1-2.5 hr after staphylococcal infection and by 100% at 8 and 20 hr. The increase in extracellular glutamate, aspartate, and GABA appeared to reflect the degree of tissue damage. The area of tissue damage greatly exceeded the area of staphylococcal infiltration, pointing to soluble factors being responsible for cell death. However, the N-methyl-D-aspartate receptor antagonist MK-801 ameliorated neither tissue damage nor the increase in extracellular neuroactive amino acids, suggesting the presence of neurotoxic factors other than glutamate and aspartate. In vitro staphylococci incubated with glutamine and glucose formed glutamate, so bacteria could be an additional source of infection-related glutamate. We conclude that the dramatic increase in the extracellular concentration of neuroactive amino acids and zinc could interfere with neurotransmission in the surrounding brain tissue, contributing to mental deterioration and a predisposition to epileptic seizures, which are often seen in brain abscess patients. © 2014 Wiley Periodicals, Inc.

  6. Glutamate in dorsolateral prefrontal cortex and auditory verbal hallucinations in patients with schizophrenia : A (1)H MRS study

    NARCIS (Netherlands)

    Curcic-Blake, Branisalava; Bais, Leonie; Sibeijn-Kuiper, Anita; Pijnenborg, Hendrika Maria; Knegtering, Henderikus; Liemburg, Edith; Aleman, André

    2017-01-01

    Purpose: Glutamatergic models of psychosis propose that dysfunction of N-methyl-D-aspartate (NMDA) receptors, and associated excess of glutamate, may underlie psychotic experiences in people with schizophrenia. However, little is known about the specific relation between glutamate and auditory

  7. Anti-N-Methyl-d-Aspartate Receptor Encephalitis in Adult Patients Requiring Intensive Care.

    Science.gov (United States)

    de Montmollin, Etienne; Demeret, Sophie; Brulé, Noëlle; Conrad, Marie; Dailler, Frédéric; Lerolle, Nicolas; Navellou, Jean-Christophe; Schwebel, Carole; Alves, Mikaël; Cour, Martin; Engrand, Nicolas; Tonnelier, Jean-Marie; Maury, Eric; Ruckly, Stéphane; Picard, Géraldine; Rogemond, Véronique; Magalhaes, Éric; Sharshar, Tarek; Timsit, Jean-François; Honnorat, Jérôme; Sonneville, Romain

    2017-02-15

    Encephalitis caused by anti-N-methyl-d-aspartate receptor (NMDAR) antibodies is the leading cause of immune-mediated encephalitis. There are limited data on intensive care unit (ICU) management of these patients. To identify prognostic factors of good neurologic outcome in patients admitted to an ICU with anti-NMDAR encephalitis. This was an observational multicenter study of all consecutive adult patients diagnosed with anti-NMDAR encephalitis at the French National Reference Centre, admitted to an ICU between 2008 and 2014. The primary outcome was a good neurologic outcome at 6 months after ICU admission, defined by a modified Rankin Scale score of 0-2. Seventy-seven patients were included from 52 ICUs. First-line immunotherapy consisted of steroids (n = 61/74; 82%), intravenous immunoglobulins (n = 71/74; 96%), and plasmapheresis (n = 17/74; 23%). Forty-five (61%) patients received second-line immunotherapy (cyclophosphamide, rituximab, or both). At 6 months, 57% of patients had a good neurologic outcome. Independent factors of good neurologic outcome were early (≤8 d after ICU admission) immunotherapy (odds ratio, 16.16; 95% confidence interval, 3.32-78.64; for combined first-line immunotherapy with steroids and intravenous immunoglobulins vs. late immunotherapy), and a low white blood cell count on the first cerebrospinal examination (odds ratio, 9.83 for 50 cells/mm 3 ; 95% confidence interval, 1.07-90.65). Presence of nonneurologic organ failures at ICU admission and occurrence of status epilepticus during ICU stay were not associated with neurologic outcome. The prognosis of adult patients with anti-NMDAR encephalitis requiring intensive care is good, especially when immunotherapy is initiated early, advocating for prompt diagnosis and early aggressive treatment.

  8. Anti-N-methyl-D-aspartate-receptor encephalitis: diagnosis, optimal management, and challenges

    Directory of Open Access Journals (Sweden)

    Mann AP

    2014-07-01

    Full Text Available Andrea P Mann,1 Elena Grebenciucova,2 Rimas V Lukas21Department of Psychiatry and Behavioral Neuroscience, 2Department of Neurology, University of Chicago, Chicago, IL, USAObjective: Anti-N-methyl-D-aspartate-receptor (NMDA-R encephalitis is a new autoimmune disorder, often paraneoplastic in nature, presenting with complex neuropsychiatric symptoms. Diagnosed serologically, this disorder is often responsive to immunosuppressant treatment. The objective of this review is to educate clinicians on the challenges of diagnosis and management of this disorder.Materials and methods: A review of the relevant literature on clinical presentation, pathophysiology, and recommended management was conducted using a PubMed search. Examination of the results identified articles published between 2007 and 2014.Results: The literature highlights the importance of recognizing early common signs and symptoms, which include hallucinations, seizures, altered mental status, and movement disorders, often in the absence of fever. Although the presence of blood and/or cerebrospinal fluid autoantibodies confirms diagnosis, approximately 15% of patients have only positive cerebrospinal fluid titers. Antibody detection should prompt a search for an underlying teratoma or other underlying neoplasm and the initiation of first-line immunosuppressant therapy: intravenous methylprednisolone, intravenous immunoglobulin, or plasmapheresis, or a combination thereof. Second-line treatment with rituximab or cyclophosphamide should be implemented if no improvement is noted after 10 days. Complications can include behavioral problems (eg, aggression and insomnia, hypoventilation, catatonia, and autonomic instability. Those patients who can be managed outside an intensive care unit and whose tumors are identified and removed typically have better rates of remission and functional outcomes.Conclusion: There is an increasing need for clinicians of different specialties, including

  9. N-Methyl-D aspartate receptor-mediated effect on glucose transporter-3 levels of high glucose exposed-SH-SY5Y dopaminergic neurons.

    Science.gov (United States)

    Engin, Ayse Basak; Engin, Evren Doruk; Karakus, Resul; Aral, Arzu; Gulbahar, Ozlem; Engin, Atilla

    2017-11-01

    High glucose and insulin lead to neuronal insulin resistance. Glucose transport into the neurons is achieved by regulatory induction of surface glucose transporter-3 (GLUT3) instead of the insulin. N-methyl-D aspartate (NMDA) receptor activity increases GLUT3 expression. This study explored whether an endogenous NMDA receptor antagonist, kynurenic acid (KynA) affects the neuronal cell viability at high glucose concentrations. SH-SY5Y neuroblastoma cells were exposed to 150-250 mg/dL glucose and 40 μU/mL insulin. In KynA and N-nitro-l-arginine methyl ester (L-NAME) supplemented cultures, oxidative stress, mitochondrial metabolic activity (MTT), nitric oxide as nitrite+nitrate (NOx) and GLUT3 were determined at the end of 24 and 48-h incubation periods. Viable cells were counted by trypan blue dye. High glucose-exposed SH-SY5Y cells showed two-times more GLUT3 expression at second 24-h period. While GLUT3-stimulated glucose transport and oxidative stress was increased, total mitochondrial metabolic activity was significantly reduced. Insulin supplementation to high glucose decreased NOx synthesis and GLUT3 levels, in contrast oxidative stress increased three-fold. KynA significantly reduced oxidative stress, and increased MTT by regulating NOx production and GLUT3 expression. KynA is a noteworthy compound, as an endogenous, specific NMDA receptor antagonist; it significantly reduces oxidative stress, while increasing cell viability at high glucose and insulin concentrations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Anti-N-methyl-D-aspartate receptor encephalitis: three cases report and review of literature

    Directory of Open Access Journals (Sweden)

    Guan-en ZHOU

    2014-07-01

    Full Text Available Objective To study the clinical and laboratory features and diagnosis of the patient with anti-N-methyl-D-aspartate receptor (NMDAR encephalitis.  Methods The data of clinical features, laboratory findings, and radiological manifestations of 3 patients with anti-NMDAR encephalitis were reviewed and analyzed. Results Of the 3 patients, 2 were male and one was female. The age was from 33 to 34 years (33.30 years on average. Main symptoms included headache in 2 cases, psychiatric symptoms and speech disorder in 3 cases, different levels of movement disorder in one case and hallucinations in one case. The results of MRI examination revealed gyri swelling, abnormal signal and demyelination of temporal lobe. The EEG showed focal or diffuse slow waves. All cases were confirmed to have the disease by detection of anti-NMDAR antibodies. Both the white blood cell count (3 cases and protein quantification (2 cases elevated. No tumor was detected in any of the patients. All patients were coued after receiving immunotherapy with methylprednisolone and human immunoglobulin.  Conclusions Anti-NMDAR encephalitis is a severe but treatable disorder. The syndrome is highly recognizable clinically and can be confirmed with the demonstration of anti-NMDAR antibodies. Timely diagnosis and treatment may yield a favorable prognosis. doi: 10.3969/j.issn.1672-6731.2014.07.005

  11. Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggests Dentate Gyrus Pathology Linked to N-Methyl-D-Aspartate Receptor Hypofunction.

    Science.gov (United States)

    Kraguljac, Nina Vanessa; Carle, Matthew; Frölich, Michael A; Tran, Steve; Yassa, Michael A; White, David Matthew; Reddy, Abhishek; Lahti, Adrienne Carol

    2018-03-01

    Converging evidence from neuroimaging and postmortem studies suggests that hippocampal subfields are differentially affected in schizophrenia. Recent studies report dentate gyrus dysfunction in chronic schizophrenia, but the underlying mechanisms remain to be elucidated. Here we sought to examine if this deficit is already present in first-episode psychosis, and if N-methyl-D-aspartate receptor hypofunction, a putative central pathophysiological mechanism in schizophrenia, experimentally induced by ketamine, would result in a similar abnormality. We applied a mnemonic discrimination task selectively taxing pattern separation in two experiments: 1) a group of 23 first-episode psychosis patients and 23 matched healthy volunteers and 2) a group of 19 healthy volunteers before and during a ketamine challenge (0.27 mg/kg over 10 minutes, then 0.25 mg/kg/hour for 50 minutes, 0.01 mL/s). We calculated response bias-corrected pattern separation and recognition scores. We also examined the relationships between task performance and symptom severity as well as ketamine levels. We report a deficit in pattern separation but not recognition performance in first-episode psychosis patients compared with healthy volunteers (p = .04) and in volunteers during the ketamine challenge compared with baseline (p = .003). Exploratory analyses revealed no correlation between task performance and Repeatable Battery for the Assessment of Neuropsychological Status total scores or positive symptoms in first-episode psychosis patients, or with ketamine serum levels. We observed a mnemonic discrimination deficit but intact recognition in both datasets. Our findings suggest a tentative mechanistic link between dentate gyrus dysfunction in first-episode psychosis and N-methyl-D-aspartate receptor hypofunction. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. Molecular pharmacology of human NMDA receptors

    DEFF Research Database (Denmark)

    Hedegaard, Maiken; Hansen, Kasper Bø; Andersen, Karen Toftegaard

    2012-01-01

    N-methyl-d-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. NMDA receptors are also important drug targets that are implicated in a number of pathophysiological conditions. To facilitate the transition from lead compounds in pre-clinical ani...

  13. 7T Proton Magnetic Resonance Spectroscopy of Gamma-Aminobutyric Acid, Glutamate, and Glutamine Reveals Altered Concentrations in Patients With Schizophrenia and Healthy Siblings

    NARCIS (Netherlands)

    Thakkar, Katharine N; Rösler, Lara; Wijnen, Jannie P; Boer, Vincent O.; Klomp, Dennis W J; Cahn, Wiepke; Kahn, René S; Neggers, Sebastiaan F W

    BACKGROUND: The N-methyl-D-aspartate receptor hypofunction model of schizophrenia predicts dysfunction in both glutamatergic and gamma-aminobutyric acidergic (GABAergic) transmission. We addressed this hypothesis by measuring GABA, glutamate, glutamine, and the sum of glutamine plus glutamate

  14. Electrophysiological evidence for the presence of NR2C subunits of N-methyl-D-aspartate receptors in rat neurons of the nucleus tractus solitarius

    Directory of Open Access Journals (Sweden)

    V. Baptista

    2005-01-01

    Full Text Available The nucleus tractus solitarius (NTS plays an important role in the control of autonomic reflex functions. Glutamate, acting on N-methyl-D-aspartate (NMDA and non-NMDA ionotropic receptors, is the major neurotransmitter in this nucleus, and the relative contribution of each receptor to signal transmission is unclear. We have examined NMDA excitatory postsynaptic currents (NMDA-EPSCs in the subpostremal NTS using the whole cell patch clamp technique on a transverse brainstem slice preparation. The NMDA-EPSCs were evoked by stimulation of the solitary tract over a range of membrane potentials. The NMDA-EPSCs, isolated pharmacologically, presented the characteristic outward rectification and were completely blocked by 50 µM DL-2-amino-5-phosphonopentanoic acid. The I-V relationship of the NMDA response shows that current, with a mean (± SEM amplitude of -41.2 ± 5.5 pA, is present even at a holding potential of -60 mV, suggesting that the NMDA receptors are weakly blocked by extracellular Mg2+ at near resting membrane potentials. This weak block can also be inferred from the value of 0.67 ± 0.17 for parameter delta obtained from a fit of the Woodhull equation to the I-V relationship. The maximal inward current measured on the I-V relationship was at -38.7 ± 4.2 mV. The decay phase of the NMDA currents was fitted with one exponential function with a decay time constant of 239 ± 51 and 418 ± 80 ms at a holding potential of -60 and +50 mV, respectively, which became slower with depolarization (e-fold per 145 mV. The biophysical properties of the NMDA receptors observed in the present study suggest that these receptors in the NTS contain NR2C subunits and may contribute to the synaptic signal integration.

  15. Binding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate receptor during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit

    NARCIS (Netherlands)

    R.J. de Knegt (Robert); J. Kornhuber (Johannes); S.W. Schalm (Solko); K. Rusche (K.); P.F. Riederer (Peter); J. Tan (J.)

    1993-01-01

    textabstractBinding of the ligand [3H]MK-801 to the MK-801 binding site of the N-methyl-D-aspartate (NMDA) receptor population on brain homogenates in rabbits was studied during experimental encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. Homogenates were

  16. Anti–N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis in Children and Adolescents

    Science.gov (United States)

    Florance, Nicole R.; Davis, Rebecca L.; Lam, Christopher; Szperka, Christina; Zhou, Lei; Ahmad, Saba; Campen, Cynthia J.; Moss, Heather; Peter, Nadja; Gleichman, Amy J.; Glaser, Carol A.; Lynch, David R.; Rosenfeld, Myrna R.; Dalmau, Josep

    2010-01-01

    Objective To report the clinical features of anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis in patients ≤ 18 years old. Methods Information was obtained by the authors or referring physicians. Antibodies were determined by immunocytochemistry and enzyme-linked immunosorbent assay (ELISA) using HEK293 cells ectopically expressing NR1. Results Over an 8-month period, 81 patients (12 male) with anti-NMDAR encephalitis were identified. Thirty-two (40%) were ≤18 years old (youngest 23 months, median 14 years); 6 were male. The frequency of ovarian teratomas was 56% in women >18 years old, 31% in girls ≤18 years old (p = 0.05), and 9% in girls ≤14 years old ( p = 0.008). None of the male patients had tumors. Of 32 patients ≤18 years old, 87.5% presented with behavioral or personality change, sometimes associated with seizures and frequent sleep dysfunction; 9.5% with dyskinesias or dystonia; and 3% with speech reduction. On admission, 53% had severe speech deficits. Eventually, 77% developed seizures, 84% stereotyped movements, 86% autonomic instability, and 23% hypoventilation. Responses to immunotherapy were slow and variable. Overall, 74% had full or substantial recovery after immunotherapy or tumor removal. Neurological relapses occurred in 25%. At the last follow-up, full recovery occurred more frequently in patients who had a teratoma that was removed (5/8) than in those without a teratoma (4/23; p = 0.03). Interpretation Anti-NMDAR encephalitis is increasingly recognized in children, comprising 40% of all cases. Younger patients are less likely to have tumors. Behavioral and speech problems, seizures, and abnormal movements are common early symptoms. The phenotype resembles that of the adults, although dysautonomia and hypoventilation are less frequent or severe in children. PMID:19670433

  17. [Anti-N-methyl-D aspartate receptor encephalitis - guideline to the challenges of diagnosis and therapy].

    Science.gov (United States)

    Hau, Lídia; Csábi, Györgyi; Tényi, Tamás

    2015-01-01

    Anti-N-methyl-D-Aspartate encephalitis is a recently diagnosed autoimmune disorder with increasing significance. During this disease antibodies are produced against the subunit of the NMDA receptor, which cause different symptoms, both psychiatric and neurological. The aim of this publication is to introduce this disease, to facilitate the diagnosis and to recommend therapeutical guideline. In this review we summarized the relevant literature published between 2007 and 2015 giving emphasis on etiopathogenesis, diagnosis, differential diagnosis, treatment and prognosis. In the etiology an underlying tumor or a viral agent should be considered. During the disease we can discern 3 periods: first prodromal viral infections-like symptoms can be seen, 1-2 weeks later psychiatric symptoms, such as aggression, sleep and behavior disturbances appear. After that neurological symptoms (tonic-clonic convulsions, aphasia, catatonia, orofacial dyskinesia, autonom lability, altered mental state) are typical, and the patient's condition deteriorates. For the correct diagnosis it is necessary to detect antibodies against the NMDA receptor from the serum and the liquor. Steroids, immunoglobulins and plasmaheresis are the first-line therapies. If the disease is unresponsive, then as a second-line therapy anti-CD 20 (Rituximab) and cyclophosphamid can be useful. Most of the patients are improving without any neurological sequale with prompt detection and appropriate therapy. It is important to be familiar with the symptoms, diagnosis and therapy of this disease as a practicing clinician, especially as a psychiatrist or neurologist. 75 percentage of the patients are admitted to psychiatric departments first because of the leading symptoms. Autoimmune NMDA encephalitis is a reversible disease after early diagnosis and treatment.

  18. Anti-N-methyl-D-aspartate receptor encephalitis after Herpes simplex virus-associated encephalitis: an emerging disease with diagnosis and therapeutic challenges.

    Science.gov (United States)

    Schein, Flora; Gagneux-Brunon, Amandine; Antoine, Jean-Christophe; Lavernhe, Sylvie; Pillet, Sylvie; Paul, Stéphane; Frésard, Anne; Boutet, Claire; Grange, Rémi; Cazorla, Céline; Lucht, Frédéric; Botelho-Nevers, Elisabeth

    2017-08-01

    Morbidity and mortality of Herpes simplex virus encephalitis (HSE) remain high. Relapses of neurological signs may occur after initial clinical improvement under acyclovir treatment. We report here a case of post-HSE anti-N-methyl-d-aspartate receptor-mediated encephalitis in an adult and perform a systematic search on PubMed to identify other cases in adults. We identified 11 previously published cases, to discuss diagnostic and therapeutic management. Symptoms in adults are often inappropriate behaviors, confusion and agitation. Diagnosis of anti-NMDA-R encephalitis after HSE is often delayed. Treatment consists in steroids, plasma exchange, and rituximab. Prognosis is often favorable. Anti-NMDA-R antibodies should be searched in cerebrospinal fluid of patients with unexpected evolution of HSE. This emerging entity reopens the hot debate about steroids in HSE.

  19. Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors.

    Science.gov (United States)

    Haj-Mirzaian, Arya; Kordjazy, Nastaran; Ostadhadi, Sattar; Amiri, Shayan; Haj-Mirzaian, Arvin; Dehpour, AhmadReza

    2016-06-01

    Opioid and N-methyl-d-aspartate (NMDA) receptors mediate different effects of fluoxetine. We investigated whether opioid and NMDA receptors are involved in the protective effect of fluoxetine against the behavioral despair induced by acute physical stress in male mice. We used the forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) for behavioral evaluation. We used fluoxetine, naltrexone (opioid receptor antagonist), MK-801 (NMDA receptor antagonist), morphine (opioid receptor agonist), and NMDA (NMDA receptor agonist). Acute foot-shock stress (FSS) significantly induced behavioral despair (depressive-like) and anxiety-like behaviors in tests. Fluoxetine (5 mg/kg) reversed the depressant-like effect of FSS, but it did not alter the locomotion and anxiety-like behavior in animals. Acute administration of subeffective doses of naltrexone (0.3 mg/kg) or MK-801 (0.01 mg/kg) potentiated the antidepressant-like effect of fluoxetine, while subeffective doses of morphine (1 mg/kg) and NMDA (75 mg/kg) abolished this effect of fluoxetine. Also, co-administration of subeffective doses of naltrexone (0.05 mg/kg) and MK-801 (0.003 mg/kg) with fluoxetine (1 mg/kg) induced a significant decrease in the immobility time in FST and TST. Our results showed that opioid and NMDA receptors (alone or in combination) are involved in the antidepressant-like effect of fluoxetine against physical stress.

  20. Cholinergic cells in the nucleus basalis of mice express the N-methyl-D-aspartate-receptor subunit NR2C and its replacement by the NR2B subunit enhances frontal and amygdaloid acetylcholine levels

    NARCIS (Netherlands)

    De Souza Silva, M. A.; Dolga, Amalia; Pieri, I.; Marchetti, L.; Eisel, U. L. M.; Huston, J. P.; Dere, E.

    2006-01-01

    It is known that glutamatergic and cholinergic systems interact functionally at the level of the cholinergic basal forebrain. The N-methyl-D-aspartate receptor (NMDA-R) is a multiprotein complex composed of NR1, NR2 and/or NR3 subunits. The subunit composition of NMDA-R of cholinergic cells in the

  1. Role of Autoantibodies to N-Methyl-d-Aspartate (NMDA) Receptor in Relapsing Herpes Simplex Encephalitis: A Retrospective, One-Center Experience.

    Science.gov (United States)

    Sutcu, Murat; Akturk, Hacer; Somer, Ayper; Tatli, Burak; Torun, Selda Hancerli; Yıldız, Edibe Pembegul; Şık, Guntulu; Citak, Agop; Agacfidan, Ali; Salman, Nuran

    2016-03-01

    Post-herpes simplex virus encephalitis relapses have been recently associated with autoimmunity driven by autoantibodies against N-methyl-d-aspartate (NMDA) receptors. Because it offers different treatment options, determination of this condition is important. Between 2011 and 2014, 7 children with proven diagnosis of herpes simplex virus encephalitis were identified in a university hospital of Istanbul. Two patients had neurologic relapse characterized mainly by movement disorders 2 to 3 weeks after initial encephalitis. The first patient received a second 14 days of acyclovir treatment together with antiepileptic drugs and left with severe neurologic sequelae. The second patient was found to be NMDA receptors antibody positive in the cerebrospinal fluid. She was treated with intravenous immunoglobulin and prednisolone. She showed substantial improvement, gradually regaining lost neurologic abilities. Post-herpes simplex virus encephalitis relapses may frequently be immune-mediated rather than a viral reactivation, particularly in children displaying movement disorders like choreoathetosis. Immunotherapy may provide benefit for this potentially devastating condition, like the case described in this report. © The Author(s) 2015.

  2. The N-Methyl-d-Aspartate Receptor Antagonist MK-801 Prevents Thallium-Induced Behavioral and Biochemical Alterations in the Rat Brain.

    Science.gov (United States)

    Osorio-Rico, Laura; Villeda-Hernández, Juana; Santamaría, Abel; Königsberg, Mina; Galván-Arzate, Sonia

    2015-01-01

    Thallium (Tl(+)) is a toxic heavy metal capable of increasing oxidative damage and disrupting antioxidant defense systems. Thallium invades the brain cells through potassium channels, increasing neuronal excitability, although until now the possible role of glutamatergic transmission in this event has not been investigated. Here, we explored the possible involvement of a glutamatergic component in the Tl(+)-induced toxicity through the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) in rats. The effects of MK-801 (1 mg/kg, intraperitoneally [ip]) on early (24 hours) motor alterations, lipid peroxidation, reduced glutathione (GSH) levels, and GSH peroxidase activity induced by Tl(+) acetate (32 mg/kg, ip) were evaluated in adult rats. MK-801 attenuated the Tl(+)-induced hyperactivity and lipid peroxidation in the rat striatum, hippocampus and midbrain, and produced mild effects on other end points. Our findings suggest that glutamatergic transmission via NMDA receptors might be involved in the Tl(+)-induced altered regional brain redox activity and motor performance in rats. © The Author(s) 2015.

  3. Glutamate: Tastant and Neuromodulator in Taste Buds.

    Science.gov (United States)

    Vandenbeuch, Aurelie; Kinnamon, Sue C

    2016-07-01

    In taste buds, glutamate plays a double role as a gustatory stimulus and neuromodulator. The detection of glutamate as a tastant involves several G protein-coupled receptors, including the heterodimer taste receptor type 1, member 1 and 3 as well as metabotropic glutamate receptors (mGluR1 and mGluR4). Both receptor types participate in the detection of glutamate as shown with knockout animals and selective antagonists. At the basal part of taste buds, ionotropic glutamate receptors [N-methyl-d-aspartate (NMDA) and non-NMDA] are expressed and participate in the modulation of the taste signal before its transmission to the brain. Evidence suggests that glutamate has an efferent function on taste cells and modulates the release of other neurotransmitters such as serotonin and ATP. This short article reviews the recent developments in the field with regard to glutamate receptors involved in both functions as well as the influence of glutamate on the taste signal. © 2016 American Society for Nutrition.

  4. Initial clinical presentation of young children with N-methyl-d-aspartate receptor encephalitis.

    Science.gov (United States)

    Favier, Marion; Joubert, Bastien; Picard, Géraldine; Rogemond, Véronique; Thomas, Laure; Rheims, Sylvain; Bailhache, Marion; Villega, Frédéric; Pédespan, Jean-Michel; Berzero, Giulia; Psimaras, Dimitri; Antoine, Jean-Christophe; Desestret, Virginie; Honnorat, Jérôme

    2018-05-01

    Autoimmune encephalitis with anti-N-methyl-d-aspartate receptor autoantibodies (NMDA-R-Abs) is a recently described disease affecting adult and pediatric patients. Symptoms of the disease are now perfectly described in the adult population but the clinical presentation is less known in young children. The aim of the present study was to describe the clinical presentation and the specificities of symptoms presented by young children with NMDA-R-Abs encephalitis to improve diagnosis of this disease, and to compare these to a series of previously published female adult patients. Fifty cases of children younger than twelve years of age diagnosed with NMDA-R-Abs encephalitis between January 1, 2007 and December 31, 2016 (27 females and 23 males) were retrospectively studied. The first neurological symptoms observed in young children with NMDA-R-Abs encephalitis were characterized by seizure (72%), especially focal seizure (42%), within a median of 15 days before other encephalitis symptoms; other patients mostly had behavioral disorders (26%). The seizures were frequently difficult to diagnose because of the transient unilateral dystonic or tonic posturing presentation or sudden unilateral pain in the absence of clonic movements. A post-ictal motor deficit was also frequently observed. This clinical presentation is different from that observed in adult females with NMDA-R-Abs encephalitis who initially present mainly psychiatric disorders (67%) or cognitive impairment (19%), and less frequently seizures (14%). The diagnosis of NMDA-R-Abs encephalitis should be systematically considered in young children of both sexes who present neurological symptoms suggesting recent seizures (focal or generalized) without obvious other etiology. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  5. Clinical characteristics and outcomes between children and adults with anti-N-Methyl-D-Aspartate receptor encephalitis.

    Science.gov (United States)

    Huang, Qi; Wu, Yuan; Qin, Rongfa; Wei, Xing; Ma, Meigang

    2016-12-01

    Anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis is an acute neurological disorder affecting children and adults. We aimed to compare the clinical characteristics, treatments, and outcomes between children and adults with anti-NMDAR encephalitis and to assess the probable risk factors. In this observational study, patients who tested positive for anti-NMDAR antibody in the cerebrospinal fluid were enrolled. The patients were divided into children and adults group on the basis of age (whether <16 or not). Clinical outcomes were assessed at onset, 1, 3, 6, 9, and 12 months after the patients received treatment and were scored based on whether they required hospitalization and intensive care. A total of 15 children and 14 adults were examined. The adults more likely manifested status epilepticus, central hypoventilation, and pneumonia but less likely exhibited movement disorder than the children did. All of the patients were subjected to corticosteroid treatment, 11 children and 9 adults were treated with intravenous immunoglobulin, and only the adults received plasma exchange or cyclophosphamide. The children recovered faster than the adults, especially in the first 6 months. Risk factors included age, status epilepticus, changes in consciousness, central hypoventilation, and pneumonia. Adults exhibit worse outcomes than children mostly because of status epilepticus.

  6. Anti-N-methyl-D-aspartate receptor encephalitis associated with acute Toxoplasma gondii infection: A case report.

    Science.gov (United States)

    Cai, Xiaotang; Zhou, Hui; Xie, Yongmei; Yu, Dan; Wang, Zhiling; Ren, Haitao

    2018-02-01

    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been recognized as the most frequent autoimmune encephalitis in children. Several infectious agents have been implicated in anti-NMDA encephalitis. A previously healthy immunocompetent 9-year-old girl first presented with seizures, headaches and vomiting. Cerebrospinal fluid and brain magnetic resonance imaging were normal. After one week onset, the patient gradually developed unexplained personality and behavior changes, accompanied by fever and seizures again. Repeated CSF analysis revealed a slightly lymphocytic predominant pleocytosis and positive anti-NMDAR antibody. A variety of pathogenic examinations were negative, except for positive toxoplasma IgM and IgG. The patient was diagnoses for anti-NMDA encephalitis associated with acute acquired toxoplasma gondii infection. The patient received 10 days azithromycin for treatment of acquired toxoplasma infection. The parents refuse immunotherapy because substantial recovery from clinical symptoms. The patient was substantially recovered with residual mild agitation after therapy for acquired toxoplasma gondii infection. Two months later, the patient was completely devoid of symptoms, and the levels of serum IgM and IgG of toxoplasma gondii were decreased. Acquired toxoplasma gondii infection may trigger anti-NMDAR encephalitis in children, which has not been reported previously. Clinicians should assess the possibility of toxoplasma gondii infection when evaluating a patient with anti-NMDA encephalitis.

  7. Protective effect of methanol extract of Uncaria rhynchophylla against excitotoxicity induced by N-methyl-D-aspartate in rat hippocampus.

    Science.gov (United States)

    Lee, Jongseok; Son, Dongwook; Lee, Pyeongjae; Kim, Dae-Keun; Shin, Min-Chul; Jang, Mi-Hyeon; Kim, Chang-Ju; Kim, Yong-Sik; Kim, Sun-Yeou; Kim, Hocheol

    2003-05-01

    Uncaria rhynchophylla is a medicinal herb used for convulsive disorders in Oriental medicine. In this study, the effect of the methanol extract of Uncaria rhynchophylla against N-methyl-D-aspartate (NMDA)-induced excitotoxicity was investigated. Pretreatment with the extract of Uncaria rhynchopylla reduced the degree of neuronal damage induced by NMDA exposure in cultured hippocampal slices. In the patch clamp study, Uncaria rhynchophylla significantly inhibited NMDA receptor-activated ion current in acutely dissociated hippocampal CA1 neurons. These results indicate that Uncaria rhynchophylla offers protection against NMDA-induced neuronal injury and inhibitory action on NMDA receptor-mediated ion current may be a mechanism behind the neuroprotective effect of Uncaria rhynchophylla.

  8. Modification of the philanthotoxin-343 polyamine moiety results in different structure-activity profiles at muscle nicotinic ACh, NMDA and AMPA receptors

    DEFF Research Database (Denmark)

    Mellor, I R; Brier, T J; Pluteanu, F

    2003-01-01

    Voltage-dependent, non-competitive inhibition by philanthotoxin-343 (PhTX-343) analogues, with reduced charge or length, of nicotinic acetylcholine receptors (nAChR) of TE671 cells and ionotropic glutamate receptors (N-methyl-D-aspartate receptors (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4...

  9. Role of Ca+2 and other second messengers in excitatory amino acid receptor mediated neurodegeneration: clinical perspectives

    DEFF Research Database (Denmark)

    Schousboe, A; Belhage, B; Frandsen, A

    1997-01-01

    Neurodegeneration associated with neurological disorders such as epilepsy, Huntington's Chorea, Alzheimer's disease, and olivoponto cerebellar atrophy or with energy failure such as ischemia, hypoxia, and hypoglycemia proceeds subsequent to overexposure of neurons to excitatory amino acids of which...... glutamate and aspartate may be quantitatively the most important. The toxic action of glutamate and aspartate is mediated through activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) and non-NMDA subtypes. Antagonists for these receptors can act as neuroprotectants both in in vitro model...

  10. (/sup 3/H)MK-801 labels a site on the N-methyl-D-aspartate receptor channel complex in rat brain membranes

    Energy Technology Data Exchange (ETDEWEB)

    Wong, E H; Knight, A R; Woodruff, G N

    1988-01-01

    The potent noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist (/sup 3/H)MK-801 bound with nanomolar affinity to rat brain membranes in a reversible, saturable, and stereospecific manner. The affinity of (/sup 3/H)MK-801 was considerably higher in 5 mM Tris-HCl (pH 7.4) than in previous studies using Krebs-Henseleit buffer. (/sup 3/H)MK-801 labels a homogeneous population of sites in rat cerebral cortical membranes with KD of 6.3 nM and Bmax of 2.37 pmol/mg of protein. This binding was unevenly distributed among brain regions, with hippocampus greater than cortex greater than olfactory bulb = striatum greater than medulla-pons, and the cerebellum failing to show significant binding. Detailed pharmacological characterization indicated (/sup 3/H)MK-801 binding to a site which was competitively and potently inhibited by known noncompetitive NMDA receptor antagonists, such as phencyclidine, thienylcyclohexylpiperidine (TCP), ketamine, N-allylnormetazocine (SKF 10,047), cyclazocine, and etoxadrol, a specificity similar to sites labelled by (/sup 3/H)TCP. These sites were distinct from the high-affinity sites labelled by the sigma receptor ligand (+)-(/sup 3/H)SKF 10,047. (/sup 3/H)MK-801 binding was allosterically modulated by the endogenous NMDA receptor antagonist Mg2+ and by other active divalent cations. These data suggest that (/sup 3/H)MK-801 labels a high-affinity site on the NMDA receptor channel complex, distinct from the NMDA recognition site, which is responsible for the blocking action of MK-801 and other noncompetitive NMDA receptor antagonists.

  11. Glufosinate aerogenic exposure induces glutamate and IL-1 receptor dependent lung inflammation.

    Science.gov (United States)

    Maillet, Isabelle; Perche, Olivier; Pâris, Arnaud; Richard, Olivier; Gombault, Aurélie; Herzine, Ameziane; Pichon, Jacques; Huaux, Francois; Mortaud, Stéphane; Ryffel, Bernhard; Quesniaux, Valérie F J; Montécot-Dubourg, Céline

    2016-11-01

    Glufosinate-ammonium (GLA), the active component of an herbicide, is known to cause neurotoxicity. GLA shares structural analogy with glutamate. It is a powerful inhibitor of glutamine synthetase (GS) and may bind to glutamate receptors. Since these potentials targets of GLA are present in lung and immune cells, we asked whether airway exposure to GLA may cause lung inflammation in mice. A single GLA exposure (1 mg/kg) induced seizures and inflammatory cell recruitment in the broncho-alveolar space, and increased myeloperoxidase (MPO), inducible NO synthase (iNOS), interstitial inflammation and disruption of alveolar septae within 6-24 h. Interleukin 1β (IL-1β) was increased and lung inflammation depended on IL-1 receptor 1 (IL-1R1). We demonstrate that glutamate receptor pathway is central, since the N-methyl-D-aspartate (NMDA) receptor inhibitor MK-801 prevented GLA-induced lung inflammation. Chronic exposure (0.2 mg/kg 3× per week for 4 weeks) caused moderate lung inflammation and enhanced airway hyperreactivity with significant increased airway resistance. In conclusion, GLA aerosol exposure causes glutamate signalling and IL-1R-dependent pulmonary inflammation with airway hyperreactivity in mice. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  12. The effects of N-methyl D-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: a meta-analysis.

    Science.gov (United States)

    Das, Ravi K; Freeman, Tom P; Kamboj, Sunjeev K

    2013-03-01

    Pharmacological memory reconsolidation blockade provides a potential mechanism for ameliorating the maladaptive reward memories underlying relapse in addiction. Two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-D-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. We used meta-analysis and meta-regression to assess the effects of these drugs on the reconsolidation of reward memory in preclinical models of addiction. Pharmacokinetic, mnemonic and methodological factors were assessed for their moderating impact on effect sizes. An analysis of 52 independent effect sizes (NMDAR=30, B-AR=22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. Significant moderating effects of drug dose, relapse process and primary reinforcer were found. The findings suggest that reward memory reconsolidation can be robustly targeted by NMDAR antagonists and to a lesser extent, by B-AR antagonists. Implications for future clinical work are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Vesicular glutamate release from central axons contributes to myelin damage.

    Science.gov (United States)

    Doyle, Sean; Hansen, Daniel Bloch; Vella, Jasmine; Bond, Peter; Harper, Glenn; Zammit, Christian; Valentino, Mario; Fern, Robert

    2018-03-12

    The axon myelin sheath is prone to injury associated with N-methyl-D-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for example in ischemic stroke. Here, we show that in rats and mice, ischemic conditions trigger activation of myelinic NMDA receptors incorporating GluN2C/D subunits following release of axonal vesicular glutamate into the peri-axonal space under the myelin sheath. Glial sources of glutamate such as reverse transport did not contribute significantly to this phenomenon. We demonstrate selective myelin uptake and retention of a GluN2C/D NMDA receptor negative allosteric modulator that shields myelin from ischemic injury. The findings potentially support a rational approach toward a low-impact prophylactic therapy to protect patients at risk of stroke and other forms of excitotoxic injury.

  14. Repeated ketamine administration alters N-methyl-d-aspartic acid receptor subunit gene expression: Implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans

    Science.gov (United States)

    Lipsky, Robert H

    2015-01-01

    For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-d-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis. PMID:25245072

  15. Repeated ketamine administration alters N-methyl-D-aspartic acid receptor subunit gene expression: implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans.

    Science.gov (United States)

    Xu, Ke; Lipsky, Robert H

    2015-02-01

    For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis. © 2014 by the Society for Experimental Biology and Medicine.

  16. Cognitive outcomes following anti-N-methyl-D-aspartate receptor encephalitis: A systematic review.

    Science.gov (United States)

    McKeon, Gemma L; Robinson, Gail A; Ryan, Alexander E; Blum, Stefan; Gillis, David; Finke, Carsten; Scott, James G

    2018-04-01

    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an immune-mediated neurological disorder that (among other severe neuropsychiatric symptoms) affects cognition. This study aimed to summarize current knowledge regarding the rates, nature, and predictors of neuropsychological dysfunction in patients recovering from anti-NMDAR encephalitis. A systematic review of studies describing neuropsychological outcomes following anti-NMDAR encephalitis was conducted. Electronic databases Medline, PsycINFO, EMBASE, and CINAHL were searched from inception to September 2016. Results were summarized using descriptive statistics and a series of chi-square analyses. Of 4030 identified studies, 44 were included. These reported neuropsychological outcomes for 109 treated patients (83.5% female, M age  = 22.5 years, range = 2-67) recovering from anti-NMDAR encephalitis. High rates of neuropsychological dysfunction were identified, with diverse impairments of variable severity documented in >75% of patients at assessments conducted during acute, subacute, and longer term recovery periods. Despite this, cognitive outcomes were ultimately considered favorable in most cases (74.3%). This estimate does not account for the potential impact of relapses. The frequency of impairments in overall intellectual functioning, language, attention, working memory, and visuospatial functions were significantly higher within the acute recovery period than in later phases of convalescence. However, rates of impaired processing speed, episodic memory, and aspects of executive functioning were consistent across time points. Adverse neuropsychological outcomes occurred at significantly higher frequency in patients where immunotherapy was delayed, χ 2 (1, N = 66) = 10.84, p anti-NMDAR encephalitis, although improvement in cognitive outcomes can be expected as patients recover. Some cognitive deficits may be less likely than others to resolve. Close neuropsychological monitoring is warranted

  17. Contribution of N-methyl-D-aspartate receptors to attention and episodic spatial memory during senescence.

    Science.gov (United States)

    Guidi, Michael; Rani, Asha; Karic, Semir; Severance, Barrett; Kumar, Ashok; Foster, Thomas C

    2015-11-01

    A decrease in N-methyl-D-aspartate receptor (NMDAR) function is associated with age-related cognitive impairments. However, NMDAR antagonists are prescribed for cognitive decline associated with age-related neurodegenerative disease, raising questions as to the role of NMDAR activity in cognitive function during aging. The current studies examined effects of NMDAR blockade on cognitive task that are sensitive to aging. Young and middle-age rats were trained on the five-choice serial reaction time task (5-CSRTT) and challenged with MK-801 (0.025, 0.05, and 0.1mg/kg or vehicle). Attention deficits were apparent in middle-age and performance of young and middle-age rats was enhanced for low doses of MK-801 (0.025 and 0.05). The beneficial effects on attention were reversed by the highest dose of MK-801. Older animals exhibited a delay-dependent impairment of episodic spatial memory examined on a delayed-matching to place water maze task. Similarly, a low dose of MK-801 (0.05mg/kg) impaired performance with increasing delay and aged animals were more susceptible to disruption by NMDAR blockade. Despite MK-801 impairment of episodic spatial memory, MK-801 had minimal effects on spatial reference memory. Our results confirm that NMDARs contribute to rapidly acquired and flexible spatial memory and support the idea that a decline in NMDAR function contributes to the age-related impairments in cognition. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. N-Methyl-d-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection.

    Science.gov (United States)

    Costa, Vivian V; Del Sarto, Juliana L; Rocha, Rebeca F; Silva, Flavia R; Doria, Juliana G; Olmo, Isabella G; Marques, Rafael E; Queiroz-Junior, Celso M; Foureaux, Giselle; Araújo, Julia Maria S; Cramer, Allysson; Real, Ana Luíza C V; Ribeiro, Lucas S; Sardi, Silvia I; Ferreira, Anderson J; Machado, Fabiana S; de Oliveira, Antônio C; Teixeira, Antônio L; Nakaya, Helder I; Souza, Danielle G; Ribeiro, Fabiola M; Teixeira, Mauro M

    2017-04-25

    Zika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N -methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801), agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP) induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration. IMPORTANCE Zika virus (ZIKV) infection is a global health emergency associated with serious neurological complications, including microcephaly and Guillain-Barré syndrome. Infection of experimental animals with ZIKV causes significant neuronal damage and microgliosis. Treatment with drugs that block NMDARs prevented neuronal damage both in vitro and in vivo These results suggest that overactivation of NMDARs contributes significantly to the neuronal damage induced by ZIKV infection, and this is amenable to inhibition by drug treatment. Copyright © 2017 Costa et al.

  19. Alpha-Adrenoceptor Antagonists Improve Memory by Activating -methyl-D-Aspartate-Induced Ion Currents in the Rat Hippocampus

    Directory of Open Access Journals (Sweden)

    Chang Hee Kim

    2015-12-01

    Full Text Available Purpose: Alpha1 (α1-adrenoceptor antagonists are widely used to treat lower urinary tract symptoms. These drugs not only act on peripheral tissues, but also cross the blood-brain barrier and affect the central nervous system. Therefore, α1-adrenoceptor antagonists may enhance brain functions. In the present study, we investigated the effects of tamsulosin, an α1-adrenoceptor antagonist, on short-term memory, as well as spatial learning and memory, in rats. Methods: The step-down avoidance test was used to evaluate short-term memory, and an eight-arm radial maze test was used to evaluate spatial learning and memory. TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining was performed in order to evaluate the effect of tamsulosin on apoptosis in the hippocampal dentate gyrus. Patch clamp recordings were used to evaluate the effect of tamsulosin on ionotropic glutamate receptors, such as N-methyl-D-aspartate (NMDA, amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, and kainate receptors, in hippocampal CA1 neurons. Results: Tamsulosin treatment improved short-term memory, as well as spatial learning and memory, without altering apoptosis. The amplitudes of NMDA-induced ion currents were dose-dependently increased by tamsulosin. However, the amplitudes of AMPA- and kainate-induced ion currents were not affected by tamsulosin. Conclusions: Tamsulosin enhanced memory function by activating NMDA receptor-mediated ion currents in the hippocampus without initiating apoptosis. The present study suggests the possibility of using tamsulosin to enhance memory under normal conditions, in addition to its use in treating overactive bladder.

  20. Anti-N-methyl-D-aspartate receptor encephalitis associated with an ovarian teratoma: two cases report and anesthesia considerations.

    Science.gov (United States)

    Liu, Haiyang; Jian, Minyu; Liang, Fa; Yue, Hongli; Han, Ruquan

    2015-10-16

    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an immune-mediated syndrome caused by the production of anti-NMDAR receptor antibodies. The syndrome characterised by psychosis, seizures, sleep disorders, hallucinations and short-term memory loss. Ovarian teratoma is the confirmed tumour associated with anti-NMDAR antibodies. The patients with anti-NMDAR encephalitis complicated by ovarian teratoma require surgical treatment under general anesthesia. NMDARs are important targets of many anesthetic drugs. The perioperative management and complications of anti-NMDAR encephalitis, including hypoventilation, paroxysmal sympathetic hyperactivity (PSH) and epilepsy, are challenging for ansthesiologists. This report described two female patients who presented for resection of the ovarian teratoma, they had confirmed anti-NMDAR encephalitis accompanied by ovarian teratoma. Two patients received gamma globulin treatments and the resection of the ovarian teratoma under total intravenous anesthesia. They were recovered and discharged on the 20(th) and 46(th) postoperative day respectively. There is insufficient evidence about the perioperative management, monitoring and anesthesia management of anti-NMDAR encephalitis. This report was based on the consideration that controversial anesthetics that likely act on NMDARs should be avoided. Additionally, BIS monitoring should to be prudently applied in anti-NMDAR encephalitis because of abnormal electric encephalography (EEG). Anesthesiologists must be careful with regard to central ventilation dysfunctions and PSH due to anti-NMDAR encephalitis.

  1. Combination of behaviorally sub-effective doses of glutamate NMDA and dopamine D1 receptor antagonists impairs executive function.

    Science.gov (United States)

    Desai, Sagar J; Allman, Brian L; Rajakumar, Nagalingam

    2017-04-14

    Impairment of executive function is a core feature of schizophrenia. Preclinical studies indicate that injections of either N-methyl d-aspartate (NMDA) or dopamine D 1 receptor blockers impair executive function. Despite the prevailing notion based on postmortem findings in schizophrenia that cortical areas have marked suppression of glutamate and dopamine, recent in vivo imaging studies suggest that abnormalities of these neurotransmitters in living patients may be quite subtle. Thus, we hypothesized that modest impairments in both glutamate and dopamine function can act synergistically to cause executive dysfunction. In the present study, we investigated the effect of combined administration of "behaviorally sub-effective" doses of NMDA and dopamine D 1 receptor antagonists on executive function. An operant conditioning-based set-shifting task was used to assess behavioral flexibility in rats that were systemically injected with NMDA and dopamine D 1 receptor antagonists individually or in combination prior to task performance. Separate injections of the NMDA receptor antagonist, MK-801, and the dopamine D 1 receptor antagonist, SCH 23390, at low doses did not impair set-shifting; however, the combined administration of these same behaviorally sub-effective doses of the antagonists significantly impaired the performance during set-shifting without affecting learning, retrieval of the memory of the initial rule, latency of responses or the number of omissions. The combined treatment also produced an increased number of perseverative errors. Our results indicate that NMDA and D 1 receptor blockade act synergistically to cause behavioral inflexibility, and as such, subtle abnormalities in glutamatergic and dopaminergic systems may act cooperatively to cause deficits in executive function. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis.

    Science.gov (United States)

    Kreye, Jakob; Wenke, Nina K; Chayka, Mariya; Leubner, Jonas; Murugan, Rajagopal; Maier, Nikolaus; Jurek, Betty; Ly, Lam-Thanh; Brandl, Doreen; Rost, Benjamin R; Stumpf, Alexander; Schulz, Paulina; Radbruch, Helena; Hauser, Anja E; Pache, Florence; Meisel, Andreas; Harms, Lutz; Paul, Friedemann; Dirnagl, Ulrich; Garner, Craig; Schmitz, Dietmar; Wardemann, Hedda; Prüss, Harald

    2016-10-01

    SEE ZEKERIDOU AND LENNON DOI101093/AWW213 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Little is known about the cerebrospinal fluid autoantibody repertoire. Antibodies against the NR1 subunit of the NMDAR are thought to be pathogenic; however, direct proof is lacking as previous experiments could not distinguish the contribution of further anti-neuronal antibodies. Using single cell cloning of full-length immunoglobulin heavy and light chain genes, we generated a panel of recombinant monoclonal NR1 antibodies from cerebrospinal fluid memory B cells and antibody secreting cells of NMDAR encephalitis patients. Cells typically carried somatically mutated immunoglobulin genes and had undergone class-switching to immunoglobulin G, clonally expanded cells carried identical somatic hypermutation patterns. A fraction of NR1 antibodies were non-mutated, thus resembling 'naturally occurring antibodies' and indicating that tolerance induction against NMDAR was incomplete and somatic hypermutation not essential for functional antibodies. However, only a small percentage of cerebrospinal fluid-derived antibodies reacted against NR1. Instead, nearly all further antibodies bound specifically to diverse brain-expressed epitopes including neuronal surfaces, suggesting that a broad repertoire of antibody-secreting cells enrich in the central nervous system during encephalitis. Our functional data using primary hippocampal neurons indicate that human cerebrospinal fluid-derived monoclonal NR1 antibodies alone are sufficient to cause neuronal surface receptor downregulation and subsequent impairment of NMDAR-mediated currents, thus providing ultimate proof of antibody pathogenicity. The observed formation of immunological memory might be relevant for clinical relapses. © The Author (2016). Published by Oxford University Press on

  3. N-methyl-d-aspartate receptors, learning and memory: chronic intraventricular infusion of the NMDA receptor antagonist d-AP5 interacts directly with the neural mechanisms of spatial learning.

    Science.gov (United States)

    Morris, R G M; Steele, R J; Bell, J E; Martin, S J

    2013-03-01

    Three experiments were conducted to contrast the hypothesis that hippocampal N-methyl-d-aspartate (NMDA) receptors participate directly in the mechanisms of hippocampus-dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug-induced neuropathological and/or sensorimotor disturbances. In experiment 1, rats given a chronic i.c.v. infusion of d-AP5 (30 mm) at 0.5 μL/h were selectively impaired, relative to aCSF-infused animals, in place but not cued navigation learning when they were trained during the 14-day drug infusion period, but were unimpaired on both tasks if trained 11 days after the minipumps were exhausted. d-AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in d-AP5-treated rats whether killed during or after chronic drug infusion. In experiment 2, a deficit in spatial learning was also apparent in d-AP5-treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of d-AP5 in selected brain areas. In Experiment 3, rats treated with d-AP5 showed a delay-dependent deficit in spatial memory in the delayed matching-to-place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning. © 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  4. TAAR1 Modulates Cortical Glutamate NMDA Receptor Function

    Science.gov (United States)

    Espinoza, Stefano; Lignani, Gabriele; Caffino, Lucia; Maggi, Silvia; Sukhanov, Ilya; Leo, Damiana; Mus, Liudmila; Emanuele, Marco; Ronzitti, Giuseppe; Harmeier, Anja; Medrihan, Lucian; Sotnikova, Tatyana D; Chieregatti, Evelina; Hoener, Marius C; Benfenati, Fabio; Tucci, Valter; Fumagalli, Fabio; Gainetdinov, Raul R

    2015-01-01

    Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, also play an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high-o5rder cognitive processes. TAAR1-selective ligands have shown potential antipsychotic, antidepressant, and pro-cognitive effects in experimental animal models; however, it remains unclear whether TAAR1 can affect PFC-related processes and functions. In this study, we document a distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that the development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions. PMID:25749299

  5. α2-Adrenergic modulation of the glutamate receptor and transporter function in a chronic ocular hypertension model.

    Science.gov (United States)

    Jung, Kyoung In; Kim, Jie Hyun; Park, Chan Kee

    2015-10-15

    Excitotoxicity, glutamate-induced toxic effects to retinal ganglion cells (RGCs), is one of several mechanisms of RGC loss suggested in glaucoma. In this study, we focused on the role of glutamate transporter of glial cells as well as N-methyl-d-aspartate (NMDA) receptor with regard to glutamate toxicity in glaucoma. We also investigated whether α2-adrenoceptor activation could modulate glutamate transporters and NMDA receptors in a chronic ocular hypertension model. Brimonidine 0.15% was administered topically to the eyes of experimental glaucoma and control animals twice daily. After 8 weeks of intraocular pressure (IOP) elevation, staining with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) revealed an increase in the ganglion cell layer, and the number of TUNEL-positive cells was reduced by brimonidine treatment (P<0.05). Animals with experimentally induced glaucoma exhibited an increase in retinal stress marker glial fibrillary acidic protein (GFAP) immunoreactivity; brimonidine treatment reduced GFAP. Excitatory amino acid transporter 1(EAAT1) expression remained stable throughout the period of chronic ocular hypertension. α2-Adrenergic treatment upregulated EAAT1 protein levels (P<0.05). NMDA receptor (GluN1) expression was stimulated by chronic elevation of IOP, and GluN1-positive cells in ganglion cell layer were co-localized with TUNEL staining. Brimonidine administration suppressed GluN1 levels (P<0.05). These results indicate that brimonidine decreased RGC apoptosis, upregulating EAAT1 and downregulating NMDA receptors. We suggest that topical brimonidine treatment may decrease the glutamate excitotoxicity through modulation of glutamate transporter and NMDA receptor in glaucoma. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Prostaglandin E(2) stimulates glutamate receptor-dependent astrocyte neuromodulation in cultured hippocampal cells.

    Science.gov (United States)

    Sanzgiri, R P; Araque, A; Haydon, P G

    1999-11-05

    Recent Ca(2+) imaging studies in cell culture and in situ have shown that Ca(2+) elevations in astrocytes stimulate glutamate release and increase neuronal Ca(2+) levels, and that this astrocyte-neuron signaling can be stimulated by prostaglandin E(2) (PGE(2)). We investigated the electrophysiological consequences of the PGE(2)-mediated astrocyte-neuron signaling using whole-cell recordings on cultured rat hippocampal cells. Focal application of PGE(2) to astrocytes evoked a Ca(2+) elevation in the stimulated cell by mobilizing internal Ca(2+) stores, which further propagated as a Ca(2+) wave to neighboring astrocytes. Whole-cell recordings from neurons revealed that PGE(2) evoked a slow inward current in neurons adjacent to astrocytes. This neuronal response required the presence of an astrocyte Ca(2+) wave and was mediated through both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors. Taken together with previous studies, these data demonstrate that PGE(2)-evoked Ca(2+) elevations in astrocyte cause the release of glutamate which activates neuronal ionotropic receptors. Copyright 1999 John Wiley & Sons, Inc.

  7. In vitro autoradiography of ionotropic glutamate receptors in hippocampus and striatum of aged Long-Evans rats: relationship to spatial learning

    International Nuclear Information System (INIS)

    Gallagher, M.; Bizon, J.L.; Nicolle, M.M.

    1996-01-01

    Using in vitro autoradiography, we investigated [ 3 H]α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, [ 3 H]kainate and [ 3 H]N-methyl-d-aspartate binding in two forebrain regions, the hippocampus and striatum, of young (four months of age) and aged (24-25 months of age) Long-Evans rats that had previously been tested for spatial learning ability in the Morris water maze. Although there was substantial preservation of binding in the aged rats, reductions in binding were present in the aged rats that were specific to ligand and anatomical region. In the hippocampus of aged rats, [ 3 H]α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate binding in CA1 and [ 3 H]kainate binding in CA3 were reduced. In contrast, N-methyl-d-aspartate binding was not significantly different between age groups. There was evidence of sprouting in the dentate gyrus molecular layer of aged rats, indicated by changes in the topography of [ 3 H]kainate binding. Binding density was analysed with respect to patch/matrix compartmentalization in the striatum. The most striking result was a large decrease in N-methyl-d-aspartate binding in aged rats that was not limited to any dorsal/ventral or patch/matrix area of the striatum. Additionally, [ 3 H]kainate binding in striatal matrix was modestly reduced in aged rats. Of these age effects, only N-methyl-d-aspartate binding in the striatum and [ 3 H]kainate binding in the CA3 region of the hippocampus were correlated with spatial learning, with lower binding in the aged rats associated with better spatial learning ability.Age-related alterations in ionotropic glutamate receptors differ with respect to the receptor subtype and anatomical region examined. The age effects were not neccessarily indicative of cognitive decline, as only two age-related binding changes were correlated with spatial learning. Interestingly, in these instances, lower binding in the aged rats was associated with preserved spatial learning, suggesting a compensatory reduction

  8. Neurosteroid modulation of N-methyl-d-aspartate receptors: Molecular mechanism and behavioral effects

    Czech Academy of Sciences Publication Activity Database

    Kořínek, Miloslav; Kapras, Vojtěch; Vyklický, Vojtěch; Adamusová, Eva; Borovská, Jiřina; Valeš, Karel; Stuchlík, Aleš; Horák, Martin; Chodounská, Hana; Vyklický ml., Ladislav

    2011-01-01

    Roč. 76, č. 13 (2011), s. 1409-1418 ISSN 0039-128X R&D Projects: GA ČR(CZ) GA309/07/0271; GA ČR(CZ) GAP303/11/0075; GA MŠk(CZ) LC554; GA MŠk(CZ) 1M0517; GA MZd(CZ) NS10365; GA ČR(CZ) GPP303/11/P391 Grant - others:GA ČR(CZ) GD309/08/H079 Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z40550506 Keywords : neurosteroid * glutamate receptor * ion channel Subject RIV: ED - Physiology Impact factor: 2.829, year: 2011

  9. Competitive and noncompetitive antagonists at N-methyl-D-aspartate receptors protect against methamphetamine-induced dopaminergic damage in mice.

    Science.gov (United States)

    Sonsalla, P K; Riordan, D E; Heikkila, R E

    1991-02-01

    The administration of methamphetamine (METH) to experimental animals results in damage to nigrostriatal dopaminergic neurons. We have demonstrated previously that the excitatory amino acids may be involved in this neurotoxicity. For example, several compounds which bind to the phenyclidine site within the ion channel linked to the N-methyl-D-aspartate (NMDA) receptor protected mice from the METH-induced loss of neostriatal tyrosine hydroxylase activity and dopamine content. The present study was conducted to characterize further the role of the excitatory amino acids in mediating the neurotoxic effects of METH. The administration of three or four injections of METH (10 mg/kg) every 2 hr to mice produced large decrements in neostriatal dopamine content (80-84%) and in tyrosine hydroxylase activity (65-74%). A dose-dependent protection against these METH-induced decreases was seen with two noncompetitive NMDA antagonists, ifenprodil and SL 82.0715 (25-50 mg/kg/injection), both of which are thought to bind to a polyamine or sigma site associated with the NMDA receptor complex, and with two competitive NMDA antagonists, CGS 19755 (25-50 mg/kg/injection) and NPC 12626 (150-300 mg/kg/injection). Moreover, an intrastriatal infusion of NMDA (0.1 mumol) produced a slight but significant loss of neostriatal dopamine which was potentiated in mice that also received a systemic injection of METH. The results of these studies strengthen the hypothesis that the excitatory amino acids play a critical role in the nigrostriatal dopaminergic damage induced by METH.

  10. Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is a potent gamma-butyrolactone-like sedative

    International Nuclear Information System (INIS)

    Singh, L.; Donald, A.E.; Foster, A.C.; Hutson, P.H.; Iversen, L.L.; Iversen, S.D.; Kemp, J.A.; Leeson, P.D.; Marshall, G.R.; Oles, R.J.; Priestley, T.; Thorn, L.; Tricklebank, M.D.; Vass, C.A.; Williams, B.J.

    1990-01-01

    The antagonist effect of ±-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of ±-HA-966 were resolved, the (R)-(+)-enantiomer was found to be a selective glycine/NMDA receptor antagonist, a property that accounts for its anticonvulsant activity in vivo. In contrast, the (S)-(-)-enantiomer was only weakly active as an NMDA-receptor antagonist, but nevertheless it possessed a marked sedative and muscle relaxant action in vivo. In radioligand binding experiments, (+)-HA-966 inhibited strychnine-insensitive [ 3 H]glycine binding to rat cerebral cortex synaptic membranes with an IC 50 of 12.5 μM, whereas (-)-HA-966 had an IC 50 value of 339 μM. In mice, (+)-HA-966 antagonized sound and N-methyl-DL-aspartic acid (NMDLA)-induced seizures. The coadministration of D-serine dose-dependently antagonized the anticonvulsant effect of a submaximal dose of (+)-HA-966 against NMDLA-induced seizures. The sedative/ataxic effect of racemic HA-966 was mainly attributable to the (-)-enantiomer. It is suggested that, as in the case of the sedative γ-butyrolactone, disruption of striatal dopaminergic mechanisms may be responsible for this action

  11. N-Methyl-D-aspartate Receptor Excessive Activation Inhibited Fetal Rat Lung Development In Vivo and In Vitro

    Directory of Open Access Journals (Sweden)

    Zhengchang Liao

    2016-01-01

    Full Text Available Background. Intrauterine hypoxia is a common cause of fetal growth and lung development restriction. Although N-methyl-D-aspartate receptors (NMDARs are distributed in the postnatal lung and play a role in lung injury, little is known about NMDAR’s expression and role in fetal lung development. Methods. Real-time PCR and western blotting analysis were performed to detect NMDARs between embryonic days (E 15.5 and E21.5 in fetal rat lungs. NMDAR antagonist MK-801’s influence on intrauterine hypoxia-induced retardation of fetal lung development was tested in vivo, and NMDA’s direct effect on fetal lung development was observed using fetal lung organ culture in vitro. Results. All seven NMDARs are expressed in fetal rat lungs. Intrauterine hypoxia upregulated NMDARs expression in fetal lungs and decreased fetal body weight, lung weight, lung-weight-to-body-weight ratio, and radial alveolar count, whereas MK-801 alleviated this damage in vivo. In vitro experiments showed that NMDA decreased saccular circumference and area per unit and downregulated thyroid transcription factor-1 and surfactant protein-C mRNA expression. Conclusions. The excessive activation of NMDARs contributed to hypoxia-induced fetal lung development retardation and appropriate blockade of NMDAR might be a novel therapeutic strategy for minimizing the negative outcomes of prenatal hypoxia on lung development.

  12. Characterisation of the human NMDA receptor subunit NR3A glycine binding site

    DEFF Research Database (Denmark)

    Nilsson, A; Duan, J; Mo-Boquist, L-L

    2007-01-01

    In this study, we characterise the binding site of the human N-methyl-d-aspartate (NMDA) receptor subunit NR3A. Saturation radioligand binding of the NMDA receptor agonists [(3)H]-glycine and [(3)H]-glutamate showed that only glycine binds to human NR3A (hNR3A) with high affinity (K(d)=535nM (277...

  13. Control of βAR- and N-methyl-D-aspartate (NMDA Receptor-Dependent cAMP Dynamics in Hippocampal Neurons.

    Directory of Open Access Journals (Sweden)

    Andrew Chay

    2016-02-01

    Full Text Available Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs, facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs. To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA, and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory.

  14. Controversial Effects of D-Amino Acid Oxidase Activator (DAOA)/G72 on D-Amino Acid Oxidase (DAO) Activity in Human Neuronal, Astrocyte and Kidney Cell Lines: The N-methyl D-aspartate (NMDA) Receptor Hypofunction Point of View.

    Science.gov (United States)

    Jagannath, Vinita; Brotzakis, Zacharias Faidon; Parrinello, Michele; Walitza, Susanne; Grünblatt, Edna

    2017-01-01

    Dysfunction of D-amino acid oxidase ( DAO ) and DAO activator ( DAOA )/ G72 genes have been linked to neuropsychiatric disorders. The glutamate hypothesis of schizophrenia has proposed that increased DAO activity leads to decreased D-serine, which subsequently may lead to N-methyl-D-aspartate (NMDA) receptor hypofunction. It has been shown that DAOA binds to DAO and increases its activity. However, there are also studies showing DAOA decreases DAO activity. Thus, the effect of DAOA on DAO is controversial. We aimed to understand the effect of DAOA on DAO activity in neuron-like (SH-SY5Y), astrocyte-like (1321N1) and kidney-like (HEK293) human cell lines. DAO activity was measured based on the release of hydrogen peroxide and its interaction with Amplex Red reagent. We found that DAOA increases DAO activity only in HEK293 cells, but has no effect on DAO activity in SH-SY5Y and 1321N1 cells. This might be because of different signaling pathways, or due to lower DAO and DAOA expression in SH-SY5Y and 1321N1 cells compared to HEK293 cells, but also due to different compartmentalization of the proteins. The lower DAO and DAOA expression in neuron-like SH-SY5Y and astrocyte-like 1321N1 cells might be due to tightly regulated expression, as previously reported in the human post-mortem brain. Our simulation experiments to demonstrate the interaction between DAOA and human DAO (hDAO) showed that hDAO holoenzyme [hDAO with flavine adenine dinucleotide (FAD)] becomes more flexible and misfolded in the presence of DAOA, whereas DAOA had no effect on hDAO apoprotein (hDAO without FAD), which indicate that DAOA inactivates hDAO holoenzyme. Furthermore, patch-clamp analysis demonstrated no effect of DAOA on NMDA receptor activity in NR1/NR2A HEK293 cells. In summary, the interaction between DAO and DAOA seems to be cell type and its biochemical characteristics dependent which still needs to be elucidated.

  15. Controversial Effects of D-Amino Acid Oxidase Activator (DAOA/G72 on D-Amino Acid Oxidase (DAO Activity in Human Neuronal, Astrocyte and Kidney Cell Lines: The N-methyl D-aspartate (NMDA Receptor Hypofunction Point of View

    Directory of Open Access Journals (Sweden)

    Vinita Jagannath

    2017-10-01

    Full Text Available Dysfunction of D-amino acid oxidase (DAO and DAO activator (DAOA/G72 genes have been linked to neuropsychiatric disorders. The glutamate hypothesis of schizophrenia has proposed that increased DAO activity leads to decreased D-serine, which subsequently may lead to N-methyl-D-aspartate (NMDA receptor hypofunction. It has been shown that DAOA binds to DAO and increases its activity. However, there are also studies showing DAOA decreases DAO activity. Thus, the effect of DAOA on DAO is controversial. We aimed to understand the effect of DAOA on DAO activity in neuron-like (SH-SY5Y, astrocyte-like (1321N1 and kidney-like (HEK293 human cell lines. DAO activity was measured based on the release of hydrogen peroxide and its interaction with Amplex Red reagent. We found that DAOA increases DAO activity only in HEK293 cells, but has no effect on DAO activity in SH-SY5Y and 1321N1 cells. This might be because of different signaling pathways, or due to lower DAO and DAOA expression in SH-SY5Y and 1321N1 cells compared to HEK293 cells, but also due to different compartmentalization of the proteins. The lower DAO and DAOA expression in neuron-like SH-SY5Y and astrocyte-like 1321N1 cells might be due to tightly regulated expression, as previously reported in the human post-mortem brain. Our simulation experiments to demonstrate the interaction between DAOA and human DAO (hDAO showed that hDAO holoenzyme [hDAO with flavine adenine dinucleotide (FAD] becomes more flexible and misfolded in the presence of DAOA, whereas DAOA had no effect on hDAO apoprotein (hDAO without FAD, which indicate that DAOA inactivates hDAO holoenzyme. Furthermore, patch-clamp analysis demonstrated no effect of DAOA on NMDA receptor activity in NR1/NR2A HEK293 cells. In summary, the interaction between DAO and DAOA seems to be cell type and its biochemical characteristics dependent which still needs to be elucidated.

  16. Role of astrocytes in depolarization-coupled release of glutamate in cerebellar cultures

    DEFF Research Database (Denmark)

    Bak, Lasse K; Waagepetersen, Helle S; Schousboe, Arne

    2004-01-01

    Release of preloaded D-[3H]aspartate in response to depolarization induced by high potassium, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) or the endogenous agonist glutamate was studied using cultured glutamatergic cerebellar granule neurons, cerebell...

  17. Excitatory amino acid receptors and disease.

    Science.gov (United States)

    Meldrum, B S

    1992-08-01

    Recent advances in the molecular biology of excitatory amino acid receptors are reviewed. Evidence that drugs blocking the excitatory action of glutamate at the N-methyl-D-aspartate (NMDA) and non-NMDA receptors may be of clinical use in epilepsy, Parkinson's disease, cerebral ischaemia and trauma, acquired immune deficiency syndrome (AIDS) encephalopathy and neuropathic pain is summarized.

  18. Structure and organization of heteromeric AMPA-type glutamate receptors.

    Science.gov (United States)

    Herguedas, Beatriz; García-Nafría, Javier; Cais, Ondrej; Fernández-Leiro, Rafael; Krieger, James; Ho, Hinze; Greger, Ingo H

    2016-04-29

    AMPA-type glutamate receptors (AMPARs), which are central mediators of rapid neurotransmission and synaptic plasticity, predominantly exist as heteromers of the subunits GluA1 to GluA4. Here we report the first AMPAR heteromer structures, which deviate substantially from existing GluA2 homomer structures. Crystal structures of the GluA2/3 and GluA2/4 N-terminal domains reveal a novel compact conformation with an alternating arrangement of the four subunits around a central axis. This organization is confirmed by cysteine cross-linking in full-length receptors, and it permitted us to determine the structure of an intact GluA2/3 receptor by cryogenic electron microscopy. Two models in the ligand-free state, at resolutions of 8.25 and 10.3 angstroms, exhibit substantial vertical compression and close associations between domain layers, reminiscent of N-methyl-D-aspartate receptors. Model 1 resembles a resting state and model 2 a desensitized state, thus providing snapshots of gating transitions in the nominal absence of ligand. Our data reveal organizational features of heteromeric AMPARs and provide a framework to decipher AMPAR architecture and signaling. Copyright © 2016, American Association for the Advancement of Science.

  19. Short-term sleep deprivation impairs spatial working memory and modulates expression levels of ionotropic glutamate receptor subunits in hippocampus.

    Science.gov (United States)

    Xie, Meilan; Yan, Jie; He, Chao; Yang, Li; Tan, Gang; Li, Chao; Hu, Zhian; Wang, Jiali

    2015-06-01

    Hippocampus-dependent learning memory is sensitive to sleep deprivation (SD). Although the ionotropic glutamate receptors play a vital role in synaptic plasticity and learning and memory, however, whether the expression of these receptor subunits is modulated by sleep loss remains unclear. In the present study, western blotting was performed by probing with specific antibodies against the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluA1, GluA2, GluA3, and against the N-methyl-d-aspartate (NMDA) glutamate receptor subunits GluN1, GluN2A, GluN2B. In hippocampus, down regulation of surface GluA1 and GluN2A surface expression were observed in both SD groups. However, surface expression level of GluA2, GluA3, GluN1 and GluN2B was significantly up-regulated in 8h-SD rats when compared to the 4h-SD rats. In parallel with the complex changes in AMPA and NMDA receptor subunit expressions, we found the 8h-SD impaired rat spatial working memory in 30-s-delay T-maze task, whereas no impairment of spatial learning was observed in 4h-SD rats. These results indicate that sleep loss alters the relative expression levels of the AMPA and NMDA receptors, thus affects the synaptic strength and capacity for plasticity and partially contributes to spatial memory impairment. Copyright © 2015. Published by Elsevier B.V.

  20. Modulation of seizure activity in mice by metabotropic glutamate receptor ligands

    DEFF Research Database (Denmark)

    Dalby, Nils Ole; Thomsen, C

    1996-01-01

    The anticonvulsant properties of ligands at metabotropic glutamate receptors (mGluRs) were examined in different seizure models by use of intracerebroventricular infusion. The mGluR1a antagonist/mGluR2 agonist, (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG] dose-dependently antagonized...... pentylenetetrazol- and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-2-carboxylate (DMCM)-induced clonic convulsions in mice with ED50 values of 400 and 180 nmol/mice, respectively. A modest increase in electrical seizure threshold was observed in mice injected with (S)-4C3HPG. No effect on seizures induced...... by systemic administration of N-methyl-D-aspartate was observed by prior intracerebroventricular infusion of (S)-4C3HPG. The more selective (but less potent) mGluR1a antagonist, (S)-4-carboxyphenylglycine, was a weak anticonvulsant in similar seizure models with the exception of convulsions induced...

  1. Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine-binding site of N-methyl-D-aspartate receptor.

    Science.gov (United States)

    Moriguchi, Shigeki; Tanaka, Tomoya; Narahashi, Toshio; Fukunaga, Kohji

    2013-10-01

    Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine-binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of α-amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase Cα (PKCα). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKCα (Ser-657) and Src family (Tyr-416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKCα (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high

  2. The effects of DL-AP5 and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived broiler cockerels

    NARCIS (Netherlands)

    Taati, Majid; Nayebzadeh, Hassan; Zendehdel, Morteza

    This study was designed to examine the effects of intracerebroventricular injection of DL-AP5 (N-methyl-D-aspartate (NMDA) receptor antagonist) and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived (FD3) broiler cockerels. At first, guide cannula was surgically implanted in the

  3. Modulation of the activity of N-methyl-D-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13

    Directory of Open Access Journals (Sweden)

    Vasilescu AN

    2017-03-01

    Full Text Available Andrei-Nicolae Vasilescu,1,* Nina Schweinfurth,2,* Stefan Borgwardt,2,* Peter Gass,1 Undine E Lang,2,* Dragos Inta,1,2,* Sarah Eckart2,* 1Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; 2Department of Psychiatry (Universitäre Psychiatrische Kliniken, University of Basel, Basel, Switzerland *These authors contributed equally to this work Abstract: Classical monoaminergic antidepressants show several disadvantages, such as protracted onset of therapeutic action. Conversely, the fast and sustained antidepressant effect of the N-methyl-d-aspartate receptor (NMDAR antagonist ketamine raises vast interest in understanding the role of the glutamate system in mood disorders. Indeed, numerous data support the existence of glutamatergic dysfunction in major depressive disorder (MDD. Drawback to this short-latency therapy is its side effect profile, especially the psychotomimetic action, which seriously hampers the common and widespread clinical use of ketamine. Therefore, there is a substantial need for alternative glutamatergic antidepressants with milder side effects. In this article, we review evidence that implicates NMDARs in the prospective treatment of MDD with focus on rapastinel (formerly known as GLYX-13, a novel synthetic NMDAR modulator with fast antidepressant effect, which acts by enhancing NMDAR function as opposed to blocking it. We summarize and discuss current clinical and animal studies regarding the therapeutic potential of rapastinel not only in MDD but also in other psychiatric disorders, such as obsessive–compulsive disorder and posttraumatic stress disorder. Additionally, we discuss current data concerning the molecular mechanisms underlying the antidepressant effect of rapastinel, highlighting common aspects as well as differences to ketamine. In 2016, rapastinel received the Breakthrough Therapy designation for the treatment

  4. Chronic ethanol exposure induces SK-N-SH cell apoptosis by increasing N-methyl-D-aspartic acid receptor expression and intracellular calcium.

    Science.gov (United States)

    Wang, Hongbo; Wang, Xiaolong; Li, Yan; Yu, Hao; Wang, Changliang; Feng, Chunmei; Xu, Guohui; Chen, Jiajun; You, Jiabin; Wang, Pengfei; Wu, Xu; Zhao, Rui; Zhang, Guohua

    2018-04-01

    It has been identified that chronic ethanol exposure damages the nervous system, particularly neurons. There is scientific evidence suggesting that neuronal loss caused by chronic ethanol exposure has an association with neuron apoptosis and intracellular calcium oscillation is one of the primary inducers of apoptosis. Therefore, the present study aimed to investigate the inductive effects of intracellular calcium oscillation on apoptosis in SK-N-SH human neuroblastoma cells and the protective effects of the N-methyl-D-aspartic acid receptor (NMDAR) antagonist, memantine, on SK-N-SH cell apoptosis caused by chronic ethanol exposure. SK-N-SH cells were treated with 100 mM ethanol and memantine (4 µM) for 2 days. Protein expression of NR1 was downregulated by RNA interference (RNAi). Apoptosis was detected by Annexin V/propidium iodide (PI) double-staining and flow cytometry and cell viability was detected using an MTS kit. Fluorescence dual wavelength spectrophotometry was used to determine the intracellular calcium concentration and the levels of NR1 and caspase-3 were detected using western blotting. NR1 mRNA levels were also detected using qPCR. It was found that chronic ethanol exposure reduced neuronal cell viability and caused apoptosis of SK-N-SH cells, and the extent of damage in SK-N-SH cells was associated with ethanol exposure concentration and time. In addition, chronic ethanol exposure increased the concentration of intracellular calcium in SK-N-SH cells by inducing the expression of NMDAR, resulting in apoptosis, and memantine treatment reduced ethanol-induced cell apoptosis. The results of the present study indicate that the application of memantine may provide a novel strategy for the treatment of alcoholic dementia.

  5. The effect of chronic ethanol on glutamate binding in human and rat brain

    International Nuclear Information System (INIS)

    Cummins, J.T.; Sack, M.; von Hungen, K.

    1990-01-01

    Quantitative autoradiographic techniques demonstrate that chronic alcohol administration causes a decrease in [ 3 H]-glutamate binding to hippocampal N-methyl-D-aspartate (NMDA) receptors. A 14% decrease in [ 3 H]-glutamate binding in the hippocampal CA 1 region is seen both in the rat after five days of ethanol administration and in postmortem hippocampal tissues from alcoholics. In the rat, 24 hr ethanol withdrawal values are intermediate between control and alcohol binding levels. There was no significant effect of ethanol on [ 3 H]-glutamate binding in the cortex or caudate

  6. Management of Refractory Orofacial Dyskinesia Caused by Anti-N-methyl-d-aspartate Receptor Encephalitis Using Botulinum Toxin

    Directory of Open Access Journals (Sweden)

    Feixia Zheng

    2018-02-01

    Full Text Available The use of botulinum neurotoxin serotype A (BoNT-A injections for the treatment of orofacial dyskinesia secondary to anti-N-methyl-d-aspartate receptor (NMDAR encephalitis is rarely reported. Here, we report a case of an urgent, successful management of severe orofacial dyskinesia in an 8-year-old girl with anti-NMDAR encephalitis using BoNT-A injection. The patient presented with de novo unilateral paroxysmal movement disorder progressing to generalized dystonia and repetitive orofacial dyskinesia. Diagnosis was confirmed by the presence of NMDAR antibodies in serum and cerebrospinal fluid. The orofacial dyskinesia worsened despite the aggressive use of first-line immunotherapy and second-line immunotherapy (rituximab, and resulted in a potentially fatal self-inflicted oral injury. We urgently attempted symptomatic management using BoNT-A injections in the masseter, and induced muscle paralysis using vecuronium. The patient’s severe orofacial dyskinesia was controlled. We observed the effects of the BoNT-A injections and a tapering off of the effects of vecuronium 10 days after the treatment. The movement disorder had improved significantly 4 weeks after the first administration of rituximab. The injection of BoNT-A into the masseter may be an effective treatment for medically refractory orofacial dyskinesia in pediatric patients with anti-NMDAR encephalitis. We propose that the use of BoNT-A injections should be considered early to avoid self-inflicted oral injury due to severe refractory orofacial dyskinesia in patients with anti-NMDAR encephalitis.

  7. Anti-N-methyl-D-aspartate receptor encephalitis: a common cause of encephalitis in the intensive care unit.

    Science.gov (United States)

    Chen, Xueping; Li, Jin-Mei; Liu, Fan; Wang, Qiong; Zhou, Dong; Lai, Xiaohui

    2016-12-01

    Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDAR encephalitis) is the most common type of immune-mediated encephalitis. This study aimed to assess the incidence and mortality of anti-NMDAR encephalitis in intensive care unit (ICU) to evaluate the clinical manifestations, laboratory findings, managements and outcomes, and to compare these characteristics with patients with non-anti-NMDAR encephalitis admitted to ICU. Patients admitted to the neurological ICU with suspected encephalitis were included between January 1, 2012 and July 31, 2015. Cerebrospinal fluid (CSF) of enrolled patients was screened for anti-NMDAR antibodies using a cell-based assay. 72 critically ill patients with encephalitis of uncertain etiology were investigated, and 16 patients were positive for anti-NMDAR antibodies in CSF. Compared to patients with non-anti-NMDAR encephalitis, patients with anti-NMDAR encephalitis were younger, more likely to present with the psychiatric symptoms, dyskinesia, and autonomic dysfunction, and had longer ICU stays. The abnormal movements were so difficult to control that complicated the management. The outcome was favorable in ten patients 1 year after the disease onset, and the mortality was as high as 25 % overall. The incidence of anti-NMDAR encephalitis is high among critically ill patients with encephalitis of uncertain etiology. Controlling dyskinesia proved to be a challenge. Persistent dysautonomias were additional difficult to manage confounders. Same points being highlighted in this study may aid clinicians in the management of patients with anti-NMDAR encephalitis in intensive care practice.

  8. Roles of N-methyl-d-aspartate receptors during the sensory stimulation-evoked field potential responses in mouse cerebellar cortical molecular layer.

    Science.gov (United States)

    Xu, Yin-Hua; Zhang, Guang-Jian; Zhao, Jing-Tong; Chu, Chun-Ping; Li, Yu-Zi; Qiu, De-Lai

    2017-11-01

    The functions of N-methyl-d-aspartate receptors (NMDARs) in cerebellar cortex have been widely studied under in vitro condition, but their roles during the sensory stimulation-evoked responses in the cerebellar cortical molecular layer in living animals are currently unclear. We here investigated the roles of NMDARs during the air-puff stimulation on ipsilateral whisker pad-evoked field potential responses in cerebellar cortical molecular layer in urethane-anesthetized mice by electrophysiological recording and pharmacological methods. Our results showed that cerebellar surface administration of NMDA induced a dose-dependent decrease in amplitude of the facial stimulation-evoked inhibitory responses (P1) in the molecular layer, accompanied with decreases in decay time, half-width and area under curve (AUC) of P1. The IC 50 of NMDA induced inhibition in amplitude of P1 was 46.5μM. In addition, application of NMDA induced significant increases in the decay time, half-width and AUC values of the facial stimulation-evoked excitatory responses (N1) in the molecular layer. Application of an NMDAR blocker, D-APV (250μM) abolished the facial stimulation-evoked P1 in the molecular layer. These results suggested that NMDARs play a critical role during the sensory information processing in cerebellar cortical molecular layer in vivo in mice. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Anti-N-Methyl-d-Aspartate receptor (NMDAR) encephalitis during pregnancy: Clinical analysis of reported cases.

    Science.gov (United States)

    Shi, Yan-Chao; Chen, Xiu-Ju; Zhang, Hong-Mei; Wang, Zhen; Du, Da-Yong

    2017-06-01

    To analyze the clinical features of 13 pregnant patients with anti-N-Methyl-d-Aspartate receptor (NMDAR) encephalitis. Retrospective review of thirteen reported cases was conducted for anti-NMDAR encephalitis patients during pregnancy. The clinical data were collected from papers published in PubMed prior to 16 February 2016. Statistical analysis of the data was performed, which encompasses the patients' age, past medical history, onset of symptoms, concomitant with ovarian teratomas, immunotherapy, outcomes of mothers and newborns. Thirteen cases were reported in 11 articles with a median age of 23 (interquartile range, 19-27) years old. There were eight cases in which the onset periods of gestation happened in the first trimester and five cases in the second trimester. Among 13 cases, five patients had a past medical history, one concomitant with autoimmune Graves' hyperthyroidism, one with bilateral ovarian teratomas removed history, one with anti-NMDAR encephalitis five years before pregnancy and two with psychiatric symptoms. Five patients were found with ovarian teratomas. Seven patients responded to first-line immunotherapy whereas all of two patients responded to second-line immunotherapy when the first-line immunotherapy failed. Following up all the 13 patients, most experienced a substantial recovery, except one had spasticity and dystonia in one hand, and one died of a superimposed infection. Three fetuses were miscarried or aborted in total. Most newborns were healthy, except two cases (2/10) with abnormal neurologic signs. Clinical analysis of the data indicates that most patients respond to first-line immunotherapy. A second-line immunotherapy is effective when first-line immunotherapy fails. It has also been found that most mothers and newborns can have good outcomes. Copyright © 2017. Published by Elsevier B.V.

  10. Fractalkine/CX3CL1 engages different neuroprotective responses upon selective glutamate receptor overactivation.

    Directory of Open Access Journals (Sweden)

    Clotilde eLauro

    2015-01-01

    Full Text Available Neuronal death induced by overactivation of N-methyl-d-aspartate receptors (NMDARs is implicated in the pathophysiology of many neurodegenerative diseases such as stroke, epilepsy and traumatic brain injury. This toxic effect is mainly mediated by NR2B-containing extrasynaptic NMDARs, while NR2A-containing synaptic NMDARs contribute to cell survival, suggesting the possibility of therapeutic approaches targeting specific receptor subunits. We report that fractalkine/CX3CL1 protects hippocampal neurons from NMDA-induced cell death with a mechanism requiring the adenosine receptors type 2A (A2AR. This is different from CX3CL1-induced protection from glutamate-induced cell death, that fully depends on A1R and requires in part A3R. We show that CX3CL1 neuroprotection against NMDA excitotoxicity involves D-serine, a co-agonist of NR2A/NMDAR, resulting in cyclic AMP-dependent transcription factor (CREB phosphorylation.

  11. Rehabilitation for a child with recalcitrant anti-N-methyl-D-aspartate receptor encephalitis: case report and literature review

    Directory of Open Access Journals (Sweden)

    Guo YH

    2014-11-01

    Full Text Available Yao-Hong Guo,1 Ta-Shen Kuan,1,2 Pei-Chun Hsieh,1 Wei-Chih Lien,1 Chun-Kai Chang,1 Yu-Ching Lin1–3 1Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Physical Medicine and Rehabilitation, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan Abstract: Anti-N-methyl-d-aspartate (anti-NMDA receptor encephalitis is a newly recognized, potentially fatal, but treatable autoimmune disease. Good outcome predictors include milder severity of symptoms, no need for intensive care unit admission, early aggressive immunotherapy, and prompt tumor removal. We report a case of a young girl aged 3 years 2 months and diagnosed as recalcitrant anti-NMDA receptor encephalitis without any underlying neoplasm. The patient had initial symptoms of behavioral changes that progressed to generalized choreoathetosis and orofacial dyskinesia, which resulted in 6 months of hospitalization in the pediatric intensive care unit. One year after initial onset of the disease, she had only achieved the developmental age of an infant aged 6–8 months in terms of gross and fine motor skills, but she resumed total independence in activities of daily living after receiving extensive immunotherapy and 28 months of rehabilitation. Our brief review will help clinical practitioners become more familiar with this disease and the unique rehabilitation programs. Keywords: anti-NMDA receptor encephalitis, autoimmune encephalitis, rehabilitation, cognition deficits

  12. Postoperative pain impairs subsequent performance on a spatial memory task via effects on N-methyl-D-aspartate receptor in aged rats.

    Science.gov (United States)

    Chi, Haidong; Kawano, Takashi; Tamura, Takahiko; Iwata, Hideki; Takahashi, Yasuhiro; Eguchi, Satoru; Yamazaki, Fumimoto; Kumagai, Naoko; Yokoyama, Masataka

    2013-12-18

    Pain may be associated with postoperative cognitive dysfunction (POCD); however, this relationship remains under investigated. Therefore, we examined the impact of postoperative pain on cognitive functions in aged animals. Rats were allocated to the following groups: control (C), 1.2 % isoflurane for 2 hours alone (I), I with laparotomy (IL), IL with analgesia using local ropivacaine (IL+R), and IL with analgesia using systemic morphine (IL+M). Pain was assessed by rat grimace scale (RGS). Spatial memory was evaluated using a radial maze from postoperative days (POD) 3 to 14. NMDA receptor (NR) 2 subunits in hippocampus were measured by ELISA. Finally, effects of memantine, a low-affinity uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, on postoperative cognitive performance were tested. Postoperative RGS was increased in Group IL, but not in other groups. The number of memory errors in Group I were comparable to that in Group C, whereas errors in Group IL were increased. Importantly, in Group IL+R and IL+M, cognitive impairment was not found. The memory errors were positively correlated with the levels of NMDA receptor 2 subunits in hippocampus. Prophylactic treatment with memantine could prevent the development of memory deficits observed in Group IL without an analgesic effect. Postoperative pain contributes to the development of memory deficits after anesthesia and surgery via up-regulation of hippocampal NMDA receptors. Our findings suggest that postoperative pain management may be important for the prevention of POCD in elderly patients. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Changes in cortical N-methyl-D-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide.

    Science.gov (United States)

    Dean, Brian; Gibbons, Andrew S; Boer, Simone; Uezato, Akihito; Meador-Woodruff, James; Scarr, Elizabeth; McCullumsmith, Robert E

    2016-03-01

    In humans, depending on dose, blocking the N-methyl-D-aspartate receptor (NMDAR) with ketamine can cause psychomimetic or antidepressant effects. The overall outcome for drugs such as ketamine depends on dose and the number of its available binding sites in the central nervous system, and to understand something of the latter variable we measure NMDAR in the frontal pole, dorsolateral prefrontal, anterior cingulate and parietal cortices from people with schizophrenia, bipolar disorder, major depressive disorders and age/sex matched controls. We measured levels of NMDARs (using [(3)H]MK-801 binding) and NMDAR sub-unit mRNAs (GRINs: using in situ hybridisation) as well as post-synaptic density protein 95 (anterior cingulate cortex only; not major depressive disorders: an NMDAR post-synaptic associated protein) in bipolar disorder, schizophrenia and controls. Compared to controls, levels of NMDAR were lower in the outer laminae of the dorsolateral prefrontal cortex (-17%, p = 0.01) in people with schizophrenia. In bipolar disorder, levels of NMDAR binding (laminae IV-VI; -19%, p disorders, levels of GRIN2D mRNA were higher in frontal pole (+22%, p suicide completers, levels of GRIN2B mRNA were higher in parietal cortex (+20%, p disorders and suicide completion and may contribute to different responses to ketamine. © The Royal Australian and New Zealand College of Psychiatrists 2015.

  14. Interactions of MK-801 with glutamate-, glutamine- and methamphetamine-evoked release of [3H]dopamine from striatal slices

    International Nuclear Information System (INIS)

    Bowyer, J.F.; Scallet, A.C.; Holson, R.R.; Lipe, G.W.; Slikker, W. Jr.; Ali, S.F.

    1991-01-01

    The interactions of MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine], glutamate and glutamine with methamphetamine (METH)-evoked release of [ 3 H]dopamine were assessed in vitro to determine whether MK-801 inhibition of METH neurotoxicity might be mediated presynaptically, and to evaluate the effects of glutamatergic stimulation on METH-evoked dopamine release. MK-801 inhibition of glutamate- or METH-evoked dopamine release might reduce synaptic dopamine levels during METH exposure and decrease the formation of 6-hydroxydopamine or other related neurotoxins. Without Mg 2+ present, 40 microM and 1 mM glutamate evoked a N-methyl-D-aspartate receptor-mediated [ 3 H]dopamine and [ 3 H]metabolite (tritium) release of 3 to 6 and 12 to 16% of total tritium stores, respectively, from striatal slices. With 1.50 mM Mg 2+ present, 10 mM glutamate alone or in combination with the dopamine uptake blocker nomifensine released only 2.1 or 4.2%, respectively, of total tritium stores, and release was only partially dependent on N-methyl-D-aspartate-type glutamate receptors. With or without 1.50 mM Mg 2+ present, 0.5 or 5 microM METH evoked a substantial release of tritium (5-8 or 12-21% of total stores, respectively). METH-evoked dopamine release was not affected by 5 microM MK-801 but METH-evoked release was additive with glutamate-evoked release. Without Mg 2+ present, 1 mM glutamine increased glutamate release and induced the release of [ 3 H]dopamine and metabolites. Both 0.5 and 5 microM METH also increased tritium release with 1 mM glutamine present. When striatal slices were exposed to 5 microM METH this glutamine-evoked release of glutamate was increased more than 50%

  15. Synthesis and pharmacology of 3-isoxazolol amino acids as selective antagonists at group I metabotropic glutamic acid receptors

    DEFF Research Database (Denmark)

    Madsen, U; Bräuner-Osborne, H; Frydenvang, Karla Andrea

    2001-01-01

    Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (i......GluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown...... to originate in (S)-11 (EC(50) = 395 microM, K(b) = 86 and 90 microM, respectively). Compound 9, administered icv, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments...

  16. Anti-N-methyl-d-aspartate receptor encephalitis in children of Central South China: Clinical features, treatment, influencing factors, and outcomes.

    Science.gov (United States)

    Wang, Ying; Zhang, Weixi; Yin, Jinghua; Lu, Qianjin; Yin, Fei; He, Fang; Peng, Jing

    2017-11-15

    We analyzed the clinical manifestations of children with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis in Central South China and the factors influencing the effectiveness of treatment. A retrospective study of children (0-14years old) with anti-NMDAR encephalitis in Central South China was carried out from March 2014 to November 2016. Demographics, clinical features, treatment, outcome, and the factors influencing the effectiveness of treatment were reviewed. Fifty-one patients with anti-NMDAR encephalitis were enrolled (age from 4months to 14years old; median age, 8years; 30 females). Forty-five patients (88%) presented with psychiatric symptoms, 40 (78%) with dyskinesia and movement disorders, 39 (77%) with sleep disturbances, 34 (67%) with seizures, 30 (59%) with a decreased level of consciousness (Glasgow scoreanti-NMDAR encephalitis in Central South China. Patients with decreased consciousness, PICU stay and autonomic instability were more likely to have no or limited response to first-line immunotherapy and to require second-line or even more aggressive immunotherapy. Children with anti-NMDAR encephalitis in China have a much lower incidence of tumors, lower mortality rates, and a lower proportion of lethal autonomic instability than adults. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Anti-N-Methyl-d-Aspartate Receptor Encephalitis as an Unusual Cause of Altered Mental Status in the Emergency Department.

    Science.gov (United States)

    Weaver, Michael; Griffey, Richard T

    2016-08-01

    Anti-N-methyl-d-aspartate (NMDA) receptor autoimmune encephalitis is a newly identified form of encephalitis whose incidence is on the rise. Awareness of this condition and symptom recognition are key to early diagnosis and prompt treatment, which may alter the course of the disease. A 35-year-old woman presented to our Emergency Department (ED) with lethargy, bizarre behavior, agitation, confusion, memory deficits, and word-finding difficulties. Her symptoms and evaluation were potentially consistent with a primary psychiatric disorder, but the absence of frank psychosis and presence of neurologic features related to memory and cognition prompted other considerations. In the ED we performed a lumbar puncture, and in addition to routine studies, ordered anti-NMDAR antibody screening. The screening studies returned positive, leading to treatment with glucocorticoids and intravenous immune globulin and resulting in improvement to near baseline function. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although anti-NMDAR encephalitis is relatively uncommon, reports of this previously unrecognized condition are increasing, with an unclear true incidence of disease. Emergency providers should consider this diagnosis in their differential for patients presenting with new neuropsychiatric symptoms, particularly in young women. Prompt treatment leads to near complete neurologic recovery in 75% of patients, whereas delays in diagnosis and treatment may be associated with worse outcomes including death. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Cephalopod vision involves dicarboxylic amino acids: D-aspartate, L-aspartate and L-glutamate.

    Science.gov (United States)

    D'Aniello, Salvatore; Spinelli, Patrizia; Ferrandino, Gabriele; Peterson, Kevin; Tsesarskia, Mara; Fisher, George; D'Aniello, Antimo

    2005-03-01

    In the present study, we report the finding of high concentrations of D-Asp (D-aspartate) in the retina of the cephalopods Sepia officinalis, Loligo vulgaris and Octopus vulgaris. D-Asp increases in concentration in the retina and optic lobes as the animal develops. In neonatal S. officinalis, the concentration of D-Asp in the retina is 1.8+/-0.2 micromol/g of tissue, and in the optic lobes it is 5.5+/-0.4 micromol/g of tissue. In adult animals, D-Asp is found at a concentration of 3.5+/-0.4 micromol/g in retina and 16.2+/-1.5 micromol/g in optic lobes (1.9-fold increased in the retina, and 2.9-fold increased in the optic lobes). In the retina and optic lobes of S. officinalis, the concentration of D-Asp, L-Asp (L-aspartate) and L-Glu (L-glutamate) is significantly influenced by the light/dark environment. In adult animals left in the dark, these three amino acids fall significantly in concentration in both retina (approx. 25% less) and optic lobes (approx. 20% less) compared with the control animals (animals left in a diurnal/nocturnal physiological cycle). The reduction in concentration is in all cases statistically significant (P=0.01-0.05). Experiments conducted in S. officinalis by using D-[2,3-3H]Asp have shown that D-Asp is synthesized in the optic lobes and is then transported actively into the retina. D-aspartate racemase, an enzyme which converts L-Asp into D-Asp, is also present in these tissues, and it is significantly decreased in concentration in animals left for 5 days in the dark compared with control animals. Our hypothesis is that the dicarboxylic amino acids, D-Asp, L-Asp and L-Glu, play important roles in vision.

  19. Prediction of N-Methyl-D-Aspartate Receptor GluN1-Ligand Binding Affinity by a Novel SVM-Pose/SVM-Score Combinatorial Ensemble Docking Scheme.

    Science.gov (United States)

    Leong, Max K; Syu, Ren-Guei; Ding, Yi-Lung; Weng, Ching-Feng

    2017-01-06

    The glycine-binding site of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN1 is a potential pharmacological target for neurodegenerative disorders. A novel combinatorial ensemble docking scheme using ligand and protein conformation ensembles and customized support vector machine (SVM)-based models to select the docked pose and to predict the docking score was generated for predicting the NMDAR GluN1-ligand binding affinity. The predicted root mean square deviation (RMSD) values in pose by SVM-Pose models were found to be in good agreement with the observed values (n = 30, r 2  = 0.928-0.988,  = 0.894-0.954, RMSE = 0.002-0.412, s = 0.001-0.214), and the predicted pK i values by SVM-Score were found to be in good agreement with the observed values for the training samples (n = 24, r 2  = 0.967,  = 0.899, RMSE = 0.295, s = 0.170) and test samples (n = 13, q 2  = 0.894, RMSE = 0.437, s = 0.202). When subjected to various statistical validations, the developed SVM-Pose and SVM-Score models consistently met the most stringent criteria. A mock test asserted the predictivity of this novel docking scheme. Collectively, this accurate novel combinatorial ensemble docking scheme can be used to predict the NMDAR GluN1-ligand binding affinity for facilitating drug discovery.

  20. N-methyl-D-aspartate improved social recognition potency in rats

    Czech Academy of Sciences Publication Activity Database

    Hliňák, Zdeněk; Krejčí, I.

    2002-01-01

    Roč. 330, č. 3 (2002), s. 227-230 ISSN 0304-3940 R&D Projects: GA ČR GA309/00/1644 Institutional research plan: CEZ:AV0Z5011922 Keywords : N-Metyl-D-aspartate * olfactory stimuly * short-term memory Subject RIV: FH - Neurology Impact factor: 2.100, year: 2002

  1. MS-377, a selective sigma receptor ligand, indirectly blocks the action of PCP in the N-methyl-D-aspartate receptor ion-channel complex in primary cultured rat neuronal cells.

    Science.gov (United States)

    Karasawa, Jun-ichi; Yamamoto, Hideko; Yamamoto, Toshifumi; Sagi, Naoki; Horikomi, Kazutoshi; Sora, Ichiro

    2002-02-22

    MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate) is a antipsychotic agent that binds to sigma-1 receptor. MS-377 showed anti-dopaminergic and anti-serotonergic activities and antagonistic action against phencyclidine (PCP)-induced behaviors in an animal model. These anti-psychotic activities of MS-377 are attributable to association with sigma-1 receptor. However, the mechanism by which the sigma-1 receptor ligands exact those numerous effects remains to be elucidated. In the present study, we evaluated the effect of MS-377 on N-methyl-D-aspartate (NMDA) receptor ion-channel complex in primary cultured rat neuronal cells. First, we examined the effect of MS-377 on NMDA-induced Ca2+ influx with fura-2/ AM loaded cells. MS-377 showed no effects on the basal Ca2+ concentration and NMDA-induced Ca2+ influx by itself PCP and SKF-10047 reduced the NMDA-induced increase in intracellular Ca2+ concentration. Pre-incubation of 1 microM MS-377 was found to significantly block the reduction by PCP or SKF-10047 of the NMDA-induced Ca2+ influx. Second, the effect of MS-377 on [3H]MK-801 intact cell binding was examined. PCP, haloperidol and (+)-pentazocine inhibited [3H]MK-801 binding, although MS-377 showed no effect by itself Pre-treatment of MS-377 markedly reversed the inhibition of [3H]MK-801 binding by PCP in a dose-dependent manner. These effects of MS-377 may depend on its affinity for the sigma-1 receptor, because MS-377 is a selective sigma-1 receptor ligand without any affinity for NMDA receptor ion-channel complex. These observations suggest that the MS-377 indirectly modulated the NMDA receptor ion-channel complex, and the anti-psychotic activities of MS-377, in part, are attributable to such on action via sigma-1 receptor.

  2. A comparison of N-methyl-D-aspartate-evoked release of adenosine and [3H]norepinephrine from rat cortical slices

    International Nuclear Information System (INIS)

    Hoehn, K.; Craig, C.G.; White, T.D.

    1990-01-01

    Tetrodotoxin reduced N-methyl-D-aspartate (NMDA)-evoked release of adenosine by 35% but virtually abolished [3H]norepinephrine release. Although [3H]norepinephrine release from rat cortical slices evoked by 500 microM NMDA was abolished by 1.2 mM Mg++, which produces a voltage-sensitive, uncompetitive block of NMDA-channels, adenosine release was increased in the presence of Mg++. Partial depolarization with 12 mM K+ relieved the Mg++ block of 500 microM NMDA-evoked [3H]norepinephrine release but did not affect adenosine release, indicating that a Mg++ requirement for the adenosine release process per se cannot account for this discrepancy. NMDA was 33 times more potent in releasing adenosine than [3H]norepinephrine. At submaximal concentrations of NMDA (10 and 20 microM), adenosine release was augmented in Mg+(+)-free medium. Although a high concentration of the uncompetitive NMDA antagonist MK-801 [(+)-5-methyl-10,11,dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine maleate] (3 microM) blocked NMDA-evoked release of [3H]norepinephrine and adenosine, a lower concentration (300 nM) decreased NMDA-evoked [3H]norepinephrine release by 66% without affecting adenosine release. These findings suggest that maximal adenosine release occurs when relatively few NMDA receptors are activated, raising the possibility that spare receptors exist for NMDA-evoked adenosine release. Rather than acting as a protectant against excessive NMDA excitation, released adenosine might provide an inhibitory threshold which must be overcome for NMDA-mediated neurotransmission to proceed

  3. D-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice.

    Science.gov (United States)

    Palazzo, Enza; Luongo, Livio; Guida, Francesca; Marabese, Ida; Romano, Rosaria; Iannotta, Monica; Rossi, Francesca; D'Aniello, Antimo; Stella, Luigi; Marmo, Federica; Usiello, Alessandro; de Bartolomeis, Andrea; Maione, Sabatino; de Novellis, Vito

    2016-07-01

    D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with D-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. D-Asp also restored the levels of extracellular D-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike D-Asp, was effective in reducing depression and anxiety-like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that D-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice.

  4. Characterization of depolarization-coupled release of glutamate from cultured mouse cerebellar granule cells using DL-threo-beta-benzyloxyaspartate (DL-TBOA) to distinguish between the vesicular and cytoplasmic pools

    DEFF Research Database (Denmark)

    Bak, Lasse K; Schousboe, Arne; Waagepetersen, Helle S

    2003-01-01

    Release of preloaded [3H]D-aspartate in response to depolarization induced by N-methyl-D-aspartate (NMDA) or the endogenous agonist glutamate was characterized using cultured glutamatergic cerebellar granule neurons. Release from the vesicular and the cytoplasmic glutamate pools, respectively, wa...

  5. (S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors

    DEFF Research Database (Denmark)

    Ahmadian, H; Nielsen, B; Bräuner-Osborne, Hans

    1997-01-01

    of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu1-7 were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu6 (EC50 = 58 +/- 11 microM) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3......Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu6 subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist...... microM). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu1-7, turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 microM)....

  6. Prevalence of elevated serum anti-N-methyl-D-aspartate receptor antibody titers in patients presenting exclusively with psychiatric symptoms: a comparative follow-up study.

    Science.gov (United States)

    Ando, Yoshihito; Shimazaki, Haruo; Shiota, Katsutoshi; Tetsuka, Syuichi; Nakao, Koichi; Shimada, Tatsuhiro; Kurata, Kazumi; Kuroda, Jinichi; Yamashita, Akihiro; Sato, Hayato; Sato, Mamoru; Eto, Shinkichi; Onishi, Yasunori; Tanaka, Keiko; Kato, Satoshi

    2016-07-08

    Increasing numbers of patients with elevated anti-N-methyl-D-aspartate (NMDA) receptor antibody titers presenting exclusively with psychiatric symptoms have been reported. The aim of the present study was to clarify the prevalence of elevated serum anti-NMDA receptor antibody titers in patients with new-onset or acute exacerbations of psychiatric symptoms. In addition, the present study aimed to investigate the association between elevated anti-NMDA receptor titers and psychiatric symptoms. The present collaborative study included 59 inpatients (23 male, 36 female) presenting with new-onset or exacerbations of schizophrenia-like symptoms at involved institutions from June 2012 to March 2014. Patient information was collected using questionnaires. Anti-NMDA receptor antibody titers were measured using NMDAR NR1 and NR2B co-transfected human embryonic kidney (HEK) 293 cells as an antigen (cell-based assay). Statistical analyses were performed for each questionnaire item. The mean age of participants was 42.0 ± 13.7 years. Six cases had elevated serum anti-NMDA antibody titers (10.2 %), four cases were first onset, and two cases with disease duration >10 years presented with third and fifth recurrences. No statistically significant difference in vital signs or major symptoms was observed between antibody-positive and antibody-negative groups. However, a trend toward an increased frequency of schizophrenia-like symptoms was observed in the antibody-positive group. Serum anti-NMDA receptor antibody titers may be associated with psychiatric conditions. However, an association with specific psychiatric symptoms was not observed in the present study. Further studies are required to validate the utility of serum anti-NMDA receptor antibody titer measurements at the time of symptom onset.

  7. Spinal Tolerance and Dependence: Some Observations on the Role of Spinal N-Methyl-D-Aspartate Receptors and Phosphorylation in the Loss of Opioid Analgesic Responses

    Directory of Open Access Journals (Sweden)

    Tony L Yaksh

    2000-01-01

    Full Text Available The continuous delivery of opiates can lead to a reduction in analgesic effects. In humans, as in other animals, some component of this change in sensitivity seems likely to have a strong pharmacodynamic component. Such loss of effect, deemed to be tolerance in the present article, can be readily demonstrated in animals with repeated bolus and continuous intrathecal infusion of mu and delta opioids and alpha-2 adrenergic agonists. Research has shown that this loss of effect can be diminished by concurrent treatment with N-methyl-D-aspartate (NMDA receptor antagonists and by the suppression of the activity of spinal protein kinase C (PKC. This suggests in part the probable role of PKC-mediated phosphorylation in the right shift in the dose-effect curves observed with continuous opiate or adrenergic exposure. Importantly, this right shift is seen to occur in parallel with an increase in the phosphorylating activity in the dorsal horn and in the expression of several PKC isozymes. The target of this phosphorylation is not certain. Phosphorylation of the NMDA receptor enhances its functionality, while phosphorylation of the opioid receptor or associated channels seems to diminish their activity or to enhance internalization. While the focus is on several specific components, the accumulating data emphasize the biological complexity of these changes in spinal drug reactivity.

  8. Neurosteroid-like Inhibitors of N-Methyl-D-aspartate Receptor: Substituted 2-Sulfates and 2-Hemisuccinates of Perhydrophenanthrene

    Czech Academy of Sciences Publication Activity Database

    Slavíková, Barbora; Chodounská, Hana; Nekardová, Michaela; Vyklický, Vojtěch; Ladislav, Marek; Hubálková, Pavla; Krausová, Barbora; Vyklický ml., Ladislav; Kudová, Eva

    2016-01-01

    Roč. 59, č. 10 (2016), s. 4724-4739 ISSN 0022-2623 R&D Projects: GA TA ČR(CZ) TE01020028; GA ČR(CZ) GAP303/12/1464; GA MŠk(CZ) LQ1604; GA ČR(CZ) GBP208/12/G016; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388963 ; RVO:67985823 Keywords : NMDA receptor * 3 alpha 5 beta-pregnanolone glutamate * noncovalent complexes Subject RIV: CC - Organic Chemistry ; ED - Physiology (FGU-C) Impact factor: 6.259, year: 2016

  9. Agmatine protects Müller cells from high-concentration glucose-induced cell damage via N-methyl-D-aspartic acid receptor inhibition.

    Science.gov (United States)

    Han, Ning; Yu, Li; Song, Zhidu; Luo, Lifu; Wu, Yazhen

    2015-07-01

    Neural injury is associated with the development of diabetic retinopathy. Müller cells provide structural and metabolic support for retinal neurons. High glucose concentrations are known to induce Müller cell activity. Agmatine is an endogenous polyamine, which is enzymatically formed in the mammalian brain and has exhibited neuroprotective effects in a number of experimental models. The aims of the present study were to investigate whether agmatine protects Müller cells from glucose-induced damage and to explore the mechanisms underlying this process. Lactate dehydrogenase activity and tumor necrosis factor-α mRNA expression were significantly reduced in Müller cells exposed to a high glucose concentration, following agmatine treatment, compared with cells not treated with agmatine. In addition, agmatine treatment inhibited glucose-induced Müller cell apoptosis, which was associated with the regulation of Bax and Bcl-2 expression. Agmatine treatment suppressed glucose-induced phosphorylation of mitogen-activated protein kinase (MAPK) protein in Müller cells. The present study demonstrated that the protective effects of agmatine on Müller cells were inhibited by N-methyl-D-aspartic acid (NMDA). The results of the present study suggested that agmatine treatment protects Müller cells from high-concentration glucose-induced cell damage. The underlying mechanisms may relate to the anti-inflammatory and antiapoptotic effects of agmatine, as well as to the inhibition of the MAPK pathway, via NMDA receptor suppression. Agmatine may be of use in the development of novel therapeutic approaches for patients with diabetic retinopathy.

  10. Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist-Induced Rat Models of Schizophrenia.

    Science.gov (United States)

    Nakashima, Masato; Imada, Haruka; Shiraishi, Eri; Ito, Yuki; Suzuki, Noriko; Miyamoto, Maki; Taniguchi, Takahiko; Iwashita, Hiroki

    2018-04-01

    The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including N -methyl-d-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain-penetrant PDE2A inhibitor, ( N -{(1 S )-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3- b ]pyrazine-4(1 H )-carboxamide) (TAK-915) as a novel treatment of schizophrenia. Oral administration of TAK-915 at 3 and 10 mg/kg significantly increased cGMP levels in the frontal cortex, hippocampus, and striatum of rats. TAK-915 at 10 mg/kg significantly upregulated the phosphorylation of α -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor subunit GluR1 in the rat hippocampus. TAK-915 at 3 and 10 mg/kg significantly attenuated episodic memory deficits induced by the NMDA receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in the rat passive avoidance test. TAK-915 at 10 mg/kg significantly attenuated working memory deficits induced by MK-801 in the rat radial arm maze test. Additionally, TAK-915 at 10 mg/kg prevented subchronic phencyclidine-induced social withdrawal in social interaction in rats. In contrast, TAK-915 did not produce antipsychotic-like activity; TAK-915 had little effect on MK-801- or methamphetamine-induced hyperlocomotion in rats. These results suggest that TAK-915 has a potential to ameliorate cognitive impairments and social withdrawal in schizophrenia. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  11. Evidence for a causative role of N-methyl-D-aspartate receptors in an in vitro model of alcohol withdrawal hyperexcitability.

    Science.gov (United States)

    Thomas, M P; Monaghan, D T; Morrisett, R A

    1998-10-01

    Synaptic mechanisms underlying hyperexcitability due to withdrawal from chronic ethanol exposure were investigated in a hippocampal explant model system using electrophysiological techniques. Whole-cell voltage clamp recordings from CA1 pyramidal cells demonstrated that acute ethanol exposure inhibited N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents by over 40%. Chronic ethanol exposure for 6 to 11 days at 35 or 75 mM induced no differences from control explants in the fast component of the population synaptic response (non-NMDAR-mediated). Prolonged field potential recordings (to 10 hr) were used to monitor the withdrawal process in vitro. Ethanol-exposed explants from both 35 and 75 mM groups displayed an increase (60% and 89%, respectively) in the NMDAR-mediated component of synaptic transmission on withdrawal from chronic exposure. Prolonged tonic-clonic electrographic seizure activity was consistently observed after ethanol withdrawal only after the increase in NMDAR function. This hyperexcitability was inhibited by the NMDAR antagonist D-2-amino-5-phosphonovaleric acid and returned once the NMDAR component was reestablished after antagonist washout. In situ hybridization studies suggest that expression of NR2B subunit mRNA may be enhanced in explants after chronic ethanol exposure. No lasting differences were observed in the NMDAR component after acute in vitro ethanol exposure and withdrawal. These data suggest that the occurance of ethanol withdrawal hyperexcitability in this system may be directly dependent on alterations in NMDAR function after chronic exposure. Since this region and others that contain ethanol sensitive NMDARs may serve as epileptic foci, long term alterations in NMDAR function may be expected to generate paroxysmal depolarizing shifts underlying ictal events after withdrawal from ethanol exposure.

  12. Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons

    Science.gov (United States)

    Zhou, Chengwen; Sun, Hongyu; Klein, Peter M.; Jensen, Frances E.

    2015-01-01

    Neonatal seizures are commonly caused by hypoxic and/or ischemic injury during birth and can lead to long-term epilepsy and cognitive deficits. In a rodent hypoxic seizure (HS) model, we have previously demonstrated a critical role for seizure-induced enhancement of the AMPA subtype of glutamate receptor (GluA) in epileptogenesis and cognitive consequences, in part due to GluA maturational upregulation of expression. Similarly, as the expression and function of the N-Methyl-D-aspartate (NMDA) subtype of glutamate receptor (GluN) is also developmentally controlled, we examined how early life seizures during the critical period of synaptogenesis could modify GluN development and function. In a postnatal day (P)10 rat model of neonatal seizures, we found that seizures could alter GluN2/3 subunit composition of GluNs and physiological function of synaptic GluNs. In hippocampal slices removed from rats within 48–96 h following seizures, the amplitudes of synaptic GluN-mediated evoked excitatory postsynaptic currents (eEPSCs) were elevated in CA1 pyramidal neurons. Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg2+ sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively. These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein. These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain. PMID:26441533

  13. Methylenetetrahydrofolate reductase deficiency alters levels of glutamate and γ-aminobutyric acid in brain tissue

    Directory of Open Access Journals (Sweden)

    N.M. Jadavji

    2015-06-01

    Full Text Available Methylenetetrahydrofolate reductase (MTHFR is an enzyme key regulator in folate metabolism. Deficiencies in MTHFR result in increased levels of homocysteine, which leads to reduced levels of S-adenosylmethionine (SAM. In the brain, SAM donates methyl groups to catechol-O-methyltransferase (COMT, which is involved in neurotransmitter analysis. Using the MTHFR-deficient mouse model the purpose of this study was to investigate levels of monoamine neurotransmitters and amino acid levels in brain tissue. MTHFR deficiency affected levels of both glutamate and γ-aminobutyric acid in within the cerebellum and hippocampus. Mthfr−/− mice had reduced levels of glutamate in the amygdala and γ-aminobutyric acid in the thalamus. The excitatory mechanisms of homocysteine through activation of the N-methyl-d-aspartate receptor in brain tissue might alter levels of glutamate and γ-aminobutyric acid.

  14. Observation of the side chain O-methylation of glutamic acid or aspartic acid containing model peptides by electrospray ionization-mass spectrometry.

    Science.gov (United States)

    Atik, A Emin; Guray, Melda Z; Yalcin, Talat

    2017-03-15

    O-methylation of the side chains of glutamic acid (E) and aspartic acid (D) residues is generally observed modification when an acidified methanol/water (MeOH/dH 2 O) mixture is used as a solvent system during sample preparation for proteomic research. This chemical modification may result misidentification with endogenous protein methylation; therefore, a special care should be taken during sample handling prior to mass spectrometric analysis. In the current study, we systematically examined the extent of E/D methylation and C-terminus carboxyl group of synthetic model peptides in terms of different incubation temperatures, storage times, and added acid types as well as its percentages. To monitor these effects, C-terminus amidated and free acid forms of synthetic model peptides comprised of E or D residue(s) have been analyzed by electrospray ionization-mass spectrometry (ESI-MS). Additionally, LC-MS/MS experiments were performed to confirm the formation of methylated peptide product. The results showed that the rate of methylation was increased as the temperature increases along with prolong incubation times. Moreover, the extent of methylation was remarkably high when formic acid (FA) used as a protonation agent instead of acetic acid (AA). In addition, it was found that the degree of methylation was significantly decreased by lowering acid percentages in ESI solution. More than one acidic residue containing model peptides have been also used to explore the extent of multiple methylation reaction. Lastly, the ethanol (EtOH) and isopropanol (iPrOH) have been substituted separately with MeOH in sample preparation step to investigate the extent of esterification reaction under the same experimental conditions. However, in the positive perspective of view, this method can be used as a simple, rapid and cheap method for methylation of acidic residues under normal laboratory conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Anatomical and pharmacological characterization of excitatory amino acid receptors

    International Nuclear Information System (INIS)

    Monaghan, D.T.

    1985-01-01

    The majority of the excitatory neurotransmission in the vertebrate Central Nervous System is thought to be mediated by acidic amino acid neurotransmitters. However, relatively little is known about the excitatory amino acid receptors and their distribution within the CNS. By analyzing radioligand binding to purified synaptic plasma membranes and to thin tissue sections processed for autoradiography, multiple distinct binding sites were found. These binding sites exhibited the pharmacological properties indicative of the excitatory amino acid receptors, which had been identified by electrophysiological techniques. Specifically, L-[ 3 H]-glutamate and D-[ 3 H]-amino-5-phosphonopentanoate appear to label N-methyl-D-aspartate receptors, L-[ 3 H]-glutamate and [ 3 H]-kainic acid appear to label kainic acid receptors, and L-[ 3 H]-glutamate and [ 3 H]-amino-3-hydroxy-5-methyl-4-isoxazolepropionate appear to label quisqualate receptors. Together, these results confirm the three receptor scheme proposed for excitatory amino acid neurotransmission. These results also show that these transmitter-receptor systems are differentially distributed in the brain, and that the total distribution is consistent with that found by other markers for excitatory amino acid-using neurons

  16. Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses.

    Directory of Open Access Journals (Sweden)

    Laurent Ladepeche

    Full Text Available Dopamine receptor potently modulates glutamate signalling, synaptic plasticity and neuronal network adaptations in various pathophysiological processes. Although key intracellular signalling cascades have been identified, the cellular mechanism by which dopamine and glutamate receptor-mediated signalling interplay at glutamate synapse remain poorly understood. Among the cellular mechanisms proposed to aggregate D1R in glutamate synapses, the direct interaction between D1R and the scaffold protein PSD95 or the direct interaction with the glutamate NMDA receptor (NMDAR have been proposed. To tackle this question we here used high-resolution single nanoparticle imaging since it provides a powerful way to investigate at the sub-micron resolution the dynamic interaction between these partners in live synapses. We demonstrate in hippocampal neuronal networks that dopamine D1 receptors (D1R laterally diffuse within glutamate synapses, in which their diffusion is reduced. Disrupting the interaction between D1R and PSD95, through genetical manipulation and competing peptide, did not affect D1R dynamics in glutamatergic synapses. However, preventing the physical interaction between D1R and the GluN1 subunit of NMDAR abolished the synaptic stabilization of diffusing D1R. Together, these data provide direct evidence that the interaction between D1R and NMDAR in synapses participate in the building of the dopamine-receptor-mediated signalling, and most likely to the glutamate-dopamine cross-talk.

  17. Involvement of N-methyl-D-aspartate receptor subunits in zinc-mediated modification of CA1 long-term potentiation in the developing hippocampus.

    Science.gov (United States)

    Takeda, Atsushi; Itagaki, Kosuke; Ando, Masaki; Oku, Naoto

    2012-03-01

    Zinc is an endogenous N-methyl-D-aspartate (NMDA) receptor blocker. It is possible that zinc-mediated modification of hippocampal CA1 long-term potentiation (LTP) is linked to the expression of NMDA receptor subunits, which varies with postnatal development. In the present study, the effect of ZnCl(2) and CaEDTA, a membrane-impermeable zinc chelator, on CA1 LTP induction was examined in hippocampal slices from immature (3-week-old) and young (6-week-old) rats. Tetanus (10-100 Hz, 1 sec)-induced CA1 LTP was more greatly enhanced in 3-week-old rats. CA1 LTP was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, and CaEDTA in 3-week-old rats, as in the case of 6-week-old rats reported previously. In 3-week-old rats, on the other hand, 5 μM ZnCl(2) attenuated NMDA receptor-mediated EPSPs more than in 6-week-old rats and significantly attenuated CA1 LTP. Moreover, 5 μM ZnCl(2) significantly attenuated CA1 LTP in the presence of (2R,4S)-4-(3-phosphonopropyl)-2-piperidinecarboxylic acid (PPPA), an NR2A antagonist, in 3-week-old rats, but not that in the presence of ifenprodil, an NR2B antagonist, suggesting that zinc-mediated attenuation of CA1 LTP is associated with the preferential expression of NR2B subunit in 3-week-old rats. In 6-week-old rats, however, 5 μM ZnCl(2) significantly potentiated CA1 LTP and also CA1 LTP in the presence of PPPA. The present study demonstrates that endogenous zinc may participate in the induction of CA1 LTP. It is likely that the changes in expression of NMDA receptor subunits are involved in the zinc-mediated modification of CA1 LTP in the developing hippocampus. Copyright © 2011 Wiley Periodicals, Inc.

  18. N-methyl-D-aspartate receptor antibody-mediated neurological disease: results of a UK-based surveillance study in children.

    Science.gov (United States)

    Wright, Sukhvir; Hacohen, Yael; Jacobson, Leslie; Agrawal, Shakti; Gupta, Rajat; Philip, Sunny; Smith, Martin; Lim, Ming; Wassmer, Evangeline; Vincent, Angela

    2015-06-01

    N-methyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis is a well-recognised clinico-immunological syndrome that presents with neuropsychiatric symptoms cognitive decline, movement disorder and seizures. This study reports the clinical features, management and neurological outcomes of paediatric NMDAR-Ab-mediated neurological disease in the UK. A prospective surveillance study. Children with NMDAR-Ab-mediated neurological diseases were voluntarily reported to the British Neurological Surveillance Unit (BPNSU) from November 2010 to December 2011. Initial and follow-up questionnaires were sent out to physicians. Thirty-one children fulfilled the criteria for the study. Eight presented during the study period giving an incidence of 0.85 per million children per year (95% CI 0.64 to 1.06); 23 cases were historical. Behavioural change and neuropsychiatric features were present in 90% of patients, and seizures and movement disorders both in 67%. Typical NMDAR-Ab encephalitis was reported in 24 children and partial phenotype without encephalopathy in seven, including predominantly psychiatric (four) and movement disorder (three). All patients received steroids, 22 (71%) received intravenous immunoglobulin, 9 (29%) received plasma exchange,and 10 (32%) received second-line immunotherapy. Of the 23 patients who were diagnosed early, 18 (78%) made a full recovery compared with only 1 of 8 (13%) of the late diagnosed patients (p=0.002, Fisher's exact test). Seven patients relapsed, with four needing additional second-line immunotherapy. Paediatric NMDAR-Ab-mediated neurological disease appears to be similar to adult NMDAR-Ab encephalitis, but some presented with a partial phenotype. Early treatment was associated with a quick and often full recovery. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  19. Case report of anti-N-methyl-D-aspartate receptor encephalitis in a middle-aged woman with a long history of major depressive disorder.

    Science.gov (United States)

    Rong, Xia; Xiong, Zhenzhen; Cao, Bingrong; Chen, Juan; Li, Mingli; Li, Zhe

    2017-08-31

    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease involving antibodies against the NR1 subunits of NMDARs. The disease shows variable clinical presentation, and involves new-onset acute psychotic symptoms, making it difficult to differentiate from major depressive disorder with psychotic symptoms. Potential associations between this autoimmune disorder and onset or progression of major depressive disorder remains unclear. We present a rare case of a patient who had both major depressive disorder and anti-NMDAR encephalitis and in whom the encephalitis initially went undetected. The patient had been suffering from depressive disorder for more than 6 years without any treatment, when she was hospitalized for new-onset psychotic symptoms. She was initially diagnosed only with major depressive disorder with psychotic symptoms, but antipsychotics did not alleviate symptoms and the patient's psychiatric course began to fluctuate rapidly. Anti-NR1 IgG autoantibodies were detected in cerebrospinal fluid, and the combination of immunotherapy and antipsychotics proved more effective than antipsychotics alone. The patient was then also diagnosed with anti-NMDAR encephalitis. Our case suggests that clinicians should consider anti-NMDAR encephalitis when a patient with depressive disorder shows sudden fluctuations in psychiatric symptoms. It also highlights the need for research into possible relationships between anti-NMDAR encephalitis and major depressive disorder.

  20. Cocaine modulates allosteric D2-σ1 receptor-receptor interactions on dopamine and glutamate nerve terminals from rat striatum.

    Science.gov (United States)

    Beggiato, Sarah; Borelli, Andrea Celeste; Borroto-Escuela, Dasiel; Corbucci, Ilaria; Tomasini, Maria Cristina; Marti, Matteo; Antonelli, Tiziana; Tanganelli, Sergio; Fuxe, Kjell; Ferraro, Luca

    2017-12-01

    The effects of nanomolar cocaine concentrations, possibly not blocking the dopamine transporter activity, on striatal D 2 -σ 1 heteroreceptor complexes and their inhibitory signaling over Gi/o, have been tested in rat striatal synaptosomes and HEK293T cells. Furthermore, the possible role of σ 1 receptors (σ 1 Rs) in the cocaine-provoked amplification of D 2 receptor (D 2 R)-induced reduction of K + -evoked [ 3 H]-DA and glutamate release from rat striatal synaptosomes, has also been investigated. The dopamine D 2 -likeR agonist quinpirole (10nM-1μM), concentration-dependently reduced K + -evoked [ 3 H]-DA and glutamate release from rat striatal synaptosomes. The σ 1 R antagonist BD1063 (100nM), amplified the effects of quinpirole (10 and 100nM) on K + -evoked [ 3 H]-DA, but not glutamate, release. Nanomolar cocaine concentrations significantly enhanced the quinpirole (100nM)-induced decrease of K + -evoked [ 3 H]-DA and glutamate release from rat striatal synaptosomes. In the presence of BD1063 (10nM), cocaine failed to amplify the quinpirole (100nM)-induced effects. In cotransfected σ 1 R and D 2L R HEK293T cells, quinpirole had a reduced potency to inhibit the CREB signal versus D 2L R singly transfected cells. In the presence of cocaine (100nM), the potency of quinpirole to inhibit the CREB signal was restored. In D 2L singly transfected cells cocaine (100nM and 10μM) exerted no modulatory effects on the inhibitory potency of quinpirole to bring down the CREB signal. These results led us to hypothesize the existence of functional D 2 -σ 1 R complexes on the rat striatal DA and glutamate nerve terminals and functional D 2 -σ 1 R-DA transporter complexes on the striatal DA terminals. Nanomolar cocaine concentrations appear to alter the allosteric receptor-receptor interactions in such complexes leading to enhancement of Gi/o mediated D 2 R signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Prion protein is a key determinant of alcohol sensitivity through the modulation of N-methyl-D-aspartate receptor (NMDAR activity.

    Directory of Open Access Journals (Sweden)

    Agnès Petit-Paitel

    Full Text Available The prion protein (PrP is absolutely required for the development of prion diseases; nevertheless, its physiological functions in the central nervous system remain elusive. Using a combination of behavioral, electrophysiological and biochemical approaches in transgenic mouse models, we provide strong evidence for a crucial role of PrP in alcohol sensitivity. Indeed, PrP knock out (PrP(-/- mice presented a greater sensitivity to the sedative effects of EtOH compared to wild-type (wt control mice. Conversely, compared to wt mice, those over-expressing mouse, human or hamster PrP genes presented a relative insensitivity to ethanol-induced sedation. An acute tolerance (i.e. reversion to ethanol inhibition of N-methyl-D-aspartate (NMDA receptor-mediated excitatory post-synaptic potentials in hippocampal slices developed slower in PrP(-/- mice than in wt mice. We show that PrP is required to induce acute tolerance to ethanol by activating a Src-protein tyrosine kinase-dependent intracellular signaling pathway. In an attempt to decipher the molecular mechanisms underlying PrP-dependent ethanol effect, we looked for changes in lipid raft features in hippocampus of ethanol-treated wt mice compared to PrP(-/- mice. Ethanol induced rapid and transient changes of buoyancy of lipid raft-associated proteins in hippocampus of wt but not PrP(-/- mice suggesting a possible mechanistic link for PrP-dependent signal transduction. Together, our results reveal a hitherto unknown physiological role of PrP on the regulation of NMDAR activity and highlight its crucial role in synaptic functions.

  2. Evidence that glutamate mediates axon-to-Schwann cell signaling in the squid.

    Science.gov (United States)

    Lieberman, E M; Abbott, N J; Hassan, S

    1989-01-01

    High-frequency stimulation (100 Hz) of isolated giant axons of the small squid Alloteuthis subulata and the large squid Loligo forbesi caused the periaxonal Schwann cell resting potential (Em = -40 mV) to hyperpolarize up to 11 mV in direct proportion to train duration and action potential amplitude. In both species, the Schwann cell also hyperpolarized up to 17 mV with the application of L-glutamate (10(-9) to 10(-6) M), in a dose-dependent manner. By contrast, in the presence of 10(-8) M d-tubocurarine (d-TC) to block the cholinergic component of the Schwann cell response, Schwann cells depolarized 8-9 mV during electrical stimulation of the axon or application of L-glutamate. In the presence of 10(-5) M 2-amino-4-phosphonobutyrate (2-APB), the hyperpolarization to glutamate and to axon stimulation was blocked, whereas the cholinergic (carbachol-induced) hyperpolarization was unaffected. In experiments with Alloteuthis, L-aspartate (10(-7) M) also caused a Schwann cell hyperpolarization, but this was not blocked by 2-APB. In tests with glutamate receptor agonists and antagonists, quisqualate (10(-5) M) produced a hyperpolarization blocked by 10(-4) M L-glutamic acid diethylester (GDEE), which also blocked the response to axonal stimulation. Kainic acid (10(-4) M) also caused a hyperpolarization, but n-methyl-D-aspartate (NMDA; 10(-4) M), ibotenate (10(-5) M), alpha-amino-3-hydroxy-5-methyl-isoxazole proprionate (AMPA; (10(-4) M), and isethionate (10(-5) M) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Changes in D-aspartic acid and D-glutamic acid levels in the tissues and physiological fluids of mice with various D-aspartate oxidase activities.

    Science.gov (United States)

    Han, Hai; Miyoshi, Yurika; Koga, Reiko; Mita, Masashi; Konno, Ryuichi; Hamase, Kenji

    2015-12-10

    D-Aspartic acid (D-Asp) and D-glutamic acid (D-Glu) are currently paid attention as modulators of neuronal transmission and hormonal secretion. These two D-amino acids are metabolized only by D-aspartate oxidase (DDO) in mammals. Therefore, in order to design and develop new drugs controlling the D-Asp and D-Glu amounts via regulation of the DDO activities, changes in these acidic D-amino acid amounts in various tissues are expected to be clarified in model animals having various DDO activities. In the present study, the amounts of Asp and Glu enantiomers in 6 brain tissues, 11 peripheral tissues and 2 physiological fluids of DDO(+/+), DDO(+/-) and DDO(-/-) mice were determined using a sensitive and selective two-dimensional HPLC system. As a result, the amounts of D-Asp were drastically increased with the decrease in the DDO activity in all the tested tissues and physiological fluids. On the other hand, the amounts of D-Glu were almost the same among the 3 strains of mice. The present results are useful for designing new drug candidates, such as DDO inhibitors, and further studies are expected. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Crystal structure and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site

    DEFF Research Database (Denmark)

    Kvist, Trine; Steffensen, Thomas Bielefeldt; Greenwood, Jeremy R

    2013-01-01

    NMDA receptors are ligand-gated ion channels that mediate excitatory neurotransmission in the brain. They are tetrameric complexes composed of glycine-binding GluN1 and GluN3 subunits together with glutamate-binding GluN2 subunits. Subunit-selective antagonists that discriminate between the glyci...... screening. Furthermore, the structure reveals that the imino acetamido group of TK40 acts as an α-amino acid bioisostere, which could be of importance in bioisosteric replacement strategies for future ligand design....

  5. The respective N-hydroxypyrazole analogues of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid

    DEFF Research Database (Denmark)

    Clausen, Rasmus P; Hansen, Kasper B; Calí, Patrizia

    2004-01-01

    We have determined the pharmacological activity of N-hydroxypyrazole analogues (3a and 4a) of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA), as well as substituted derivatives of these two compounds. The pharmacological...... partial agonism to antagonism with increasing substituent size, substitution abolishes affinity for mglu1 and mglu4 receptors. Ligand- and receptor-based modelling approaches assist in explaining these pharmacological trends among the metabotropic receptors and suggest a mechanism of partial agonism...

  6. The pharmacology of tacrine at N-methyl-D-aspartate receptors

    Czech Academy of Sciences Publication Activity Database

    Horák, Martin; Holubová, K.; Nepovímová, E.; Krůšek, Jan; Kaniaková, Martina; Korábečný, J.; Vyklický ml., Ladislav; Kuča, K.; Stuchlík, Aleš; Říčný, J.; Valeš, K.; Soukup, O.

    2017-01-01

    Roč. 75, Apr 3 (2017), s. 54-62 ISSN 0278-5846 R&D Projects: GA ČR(CZ) GA16-08554S Institutional support: RVO:67985823 Keywords : tacrine * NMDA receptors * long term potentiation * cognition * M1 activation * multi-target directed ligands Subject RIV: FH - Neurology OBOR OECD: Neurosciences (including psychophysiology Impact factor: 4.187, year: 2016

  7. Involvement of N-methyl-d-aspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test.

    Science.gov (United States)

    Kordjazy, Nastaran; Haj-Mirzaian, Arya; Amiri, Shayan; Ostadhadi, Sattar; Amini-Khoei, Hossein; Dehpour, Ahmad Reza

    2016-02-01

    Recent evidence indicates that 5-hydroxytryptamine 3 (5-HT3) antagonists such as ondansetron and tropisetron exert positive behavioral effects in animal models of depression. Due to the ionotropic nature of 5-HT3 and N-methyl-d-aspartate (NMDA) receptors, plus their contribution to the pathophysiology of depression, we investigated the possible role of NMDA receptors in the antidepressant-like effect of 5-HT3 receptor antagonists in male mice. In order to evaluate the animals' behavior in response to different treatments, we performed open-field test (OFT), forced swimming test (FST), and tail-suspension test (TST), which are considered as valid tasks for measuring locomotor activity and depressive-like behaviors in mice. Our data revealed that intraperitoneal (i.p.) administration of tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01, and 0.1μg/kg) significantly decreased the immobility time in FST and TST. Also, co-administration of subeffective doses of tropisetron (1mg/kg, i.p.) or ondansetron (0.001μg/kg, i.p.) with subeffective doses of NMDA receptor antagonists, ketamine (1mg/kg, i.p.), MK-801 (0.05mg/kg, i.p.) and magnesium sulfate (10mg/kg, i.p.) resulted in a reduced immobility time both in FST and TST. The subeffective dose of NMDA (NMDA receptor agonist, 75mg/kg, i.p.) abolished the effects of 5-HT3 antagonists in FST and TST, further supporting the presumed interaction between 5-HT3 and NMDA receptors. These treatments did not affect the locomotor behavior of animals in OFT. Finally, the results of our study suggest that the positive effects of 5-HT3 antagonists on the coping behavior of mice in FST and TST are at least partly mediated through NMDA receptors participation. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Modulation of [3H]-glutamate binding by serotonin in the rat hippocampus: An autoradiographic study

    International Nuclear Information System (INIS)

    Mennini, T.; Miari, A.

    1991-01-01

    Serotonin (5-HT) added in vitro increased [ 3 H]-glutamate specific binding in the rat hippocampus, reaching statistical significance in layers rich in N-Methyl-D-Aspartate sensitive glutamate receptors. This effect was explained by a significant increase in the apparent affinity of [ 3 H]-glutamate when 5-HT is added in vitro. Two days after lesion of serotonergic afferents to the hippocampus with 5,7- Dihydroxytryptamine [ 3 H]-glutamate binding was significantly decreased in the CA3 region and stratum lacunosum moleculare of the hippocampus, this reduction being reversed by in vitro addition of 10 μM 5-HT. The decrease observed is due to a significant reduction of quisqualate-insensitive (radiatum CA3) and kainate receptors (strata oriens, radiatum, pyramidal of CA3). Five days after lesion [ 3 H]-glutamate binding increased significantly in the CA3 region of the hippocampus but was not different from sham animals in the other hippocampal layers. Two weeks after lesion [ 3 H]-glutamate binding to quisqualate-insensitive receptors was increased in all the hippocampal layers, while kainate and quisqualate-sensitive receptors were not affected. These data are consistent with the possibility that 5-HT is a direct positive modulator of glutamate receptor subtypes

  9. Herpes simplex virus-induced anti-N-methyl-d-aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases.

    Science.gov (United States)

    Nosadini, Margherita; Mohammad, Shekeeb S; Corazza, Francesco; Ruga, Ezia Maria; Kothur, Kavitha; Perilongo, Giorgio; Frigo, Anna Chiara; Toldo, Irene; Dale, Russell C; Sartori, Stefano

    2017-08-01

    To conduct a systematic literature review on patients with biphasic disease with herpes simplex virus (HSV) encephalitis followed by anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. We conducted a case report and systematic literature review (up to 10 December 2016), focused on differences between herpes simplex encephalitis (HSE) and anti-NMDAR encephalitis phases, age-related characteristics of HSV-induced anti-NMDAR encephalitis, and therapy. For statistical analyses, McNemar's test, Fisher's test, and Wilcoxon rank sum test were used (two-tailed significance level set at 5%). Forty-three patients with biphasic disease were identified (31 children). Latency between HSE and anti-NMDAR encephalitis was significantly shorter in children than adults (median 24 vs 40.5d; p=0.006). Compared with HSE, anti-NMDAR encephalitis was characterized by significantly higher frequency of movement disorder (2.5% vs 75% respectively; panti-NMDAR encephalitis children had significantly more movement disorders (86.7% children vs 40% adults; p=0.006), fewer psychiatric symptoms (41.9% children vs 90.0% adults; p=0.025), and a slightly higher median modified Rankin Scale score (5 in children vs 4 in adults; p=0.015). During anti-NMDAR encephalitis, 84.6 per cent of patients received aciclovir (for ≤7d in 22.7%; long-term antivirals in 18.0% only), and 92.7 per cent immune therapy, but none had recurrence of HSE clinically or using cerebrospinal fluid HSV polymerase chain reaction (median follow-up 7mo). Our review suggests that movement disorder may help differentiate clinically an episode of HSV-induced anti-NMDAR encephalitis from HSE relapse. Compared with adults, children have shorter latency between HSE and anti-NMDAR encephalitis and, during anti-NMDAR encephalitis, more movement disorder, fewer psychiatric symptoms, and slightly more severe disease. According to our results, immune therapy given for HSV-induced anti-NMDAR encephalitis does not predispose patients to

  10. Selective stimulation of excitatory amino acid receptor subtypes and the survival of cerebellar granule cells in culture: effect of kainic acid

    DEFF Research Database (Denmark)

    Balázs, R; Hack, N; Jørgensen, Ole Steen

    1990-01-01

    Our previous studies showed that the survival of cerebellar granule cells in culture is promoted by treatment with N-methyl-D-aspartate. Here we report on the influence of another glutamate analogue, kainic acid, which, in contrast to N-methyl-D-aspartate, is believed to stimulate transmitter rec...

  11. Molecular Mechanisms Elicited by d-Aspartate in Leydig Cells and Spermatogonia

    Directory of Open Access Journals (Sweden)

    Maria Maddalena Di Fiore

    2016-07-01

    Full Text Available A bulk of evidence suggests that d-aspartate (d-Asp regulates steroidogenesis and spermatogenesis in vertebrate testes. This review article focuses on intracellular signaling mechanisms elicited by d-Asp possibly via binding to the N-methyl-d-aspartate receptor (NMDAR in both Leydig cells, and spermatogonia. In Leydig cells, the amino acid upregulates androgen production by eliciting the adenylate cyclase-cAMP and/or mitogen-activated protein kinase (MAPK pathways. d-Asp treatment enhances gene and protein expression of enzymes involved in the steroidogenic cascade. d-Asp also directly affects spermatogonial mitotic activity. In spermatogonial GC-1 cells, d-Asp induces phosphorylation of MAPK and AKT serine-threonine kinase proteins, and stimulates expression of proliferating cell nuclear antigen (PCNA and aurora kinase B (AURKB. Further stimulation of spermatogonial GC-1 cell proliferation might come from estradiol/estrogen receptor β (ESR2 interaction. d-Asp modulates androgen and estrogen levels as well as the expression of their receptors in the rat epididymis by acting on mRNA levels of Srd5a1 and Cyp19a1 enzymes, hence suggesting involvement in spermatozoa maturation.

  12. Cerebral (18)FluoroDeoxy-Glucose Positron Emission Tomography in paediatric anti N-methyl-D-aspartate receptor encephalitis: A case series.

    Science.gov (United States)

    Lagarde, Stanislas; Lepine, Anne; Caietta, Emilie; Pelletier, Florence; Boucraut, José; Chabrol, Brigitte; Milh, Mathieu; Guedj, Eric

    2016-05-01

    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a frequent and severe cause of encephalitis in children with potential efficient treatment (immunotherapy). Suggestive clinical features are behavioural troubles, seizures and movement disorders. Prompt diagnosis and treatment initiation are needed to guarantee favourable outcome. Nevertheless, diagnosis may be challenging because of the classical ancillary test (magnetic resonance imaging (MRI), electroencephalogram, standard cerebro-spinal fluid analysis) have limited sensitivity. Currently, immunological analyses are needed for the diagnostic confirmation. In adult patients, some studies suggested a potential role of cerebral (18)FluoroDeoxy-Glucose Positron Emission Tomography (FDG-PET) in the evaluation of anti-NMDAR encephalitis. Nevertheless, almost no data exist in paediatric population. We report retrospectively clinical, ancillary tests and cerebral FDG-PET data in 6 young patients (median age=10.5 years, 4 girls) with immunologically confirmed anti-NMDAR encephalitis. Our patients presented classical clinical features of anti-NMDAR encephalitis with severe course (notably four patients had normal MRI). Our series shows the feasibility and the good sensitivity of cerebral FDG-PET (6/6 patients with brain metabolism alteration) in paediatric population. We report some particular features in this population: extensive, symmetric cortical hypometabolism especially in posterior areas; asymmetric anterior focus of hypermetabolism; and basal ganglia hypermetabolism. We found also a good correlation between the clinical severity and the cerebral metabolism changes. Moreover, serial cerebral FDG-PET showed parallel brain metabolism and clinical improvement. Our study reveals the existence of specific patterns of brain metabolism alteration in anti-NMDAR encephalitis in paediatric population. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  13. Glutamate as a neurotransmitter in the brain: review of physiology and pathology.

    Science.gov (United States)

    Meldrum, B S

    2000-04-01

    Glutamate is the principal excitatory neurotransmitter in brain. Our knowledge of the glutamatergic synapse has advanced enormously in the last 10 years, primarily through application of molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic receptors with intrinsic cation permeable channels [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate]. There are three groups of metabotropic, G protein-coupled glutamate receptors (mGluR) that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain. Glutamate is the most abundant amino acid in the diet. There is no evidence for brain damage in humans resulting from dietary glutamate. A kainate analog, domoate, is sometimes ingested accidentally in blue mussels; this potent toxin causes limbic seizures, which can lead to hippocampal and related pathology and amnesia. Endogenous glutamate, by activating NMDA, AMPA or mGluR1 receptors, may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury. It may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington's chorea. In animal models of cerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damage and delayed behavioral deficits. Such compounds are undergoing testing in humans, but therapeutic efficacy has yet to be established. Other clinical conditions that may respond to drugs acting on glutamatergic transmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis.

  14. The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue

    DEFF Research Database (Denmark)

    Clausen, Rasmus Prætorius; Naur, Peter; Kristensen, Anders Skov

    2009-01-01

    The design, synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H......-cyclohepta[d]isoxazol-4-yl)propionic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (i......GluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)-glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously...

  15. Pharmacological characterization of LY233053: A structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action

    International Nuclear Information System (INIS)

    Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M.

    1990-01-01

    This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 [cis-(+-)-4-[(2H-tetrazol-5-yl)methyl]piperidine-2-carboxylic acid], the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of [3H] CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or [3H]kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity

  16. Prolonged ketamine exposure induces increased activity of the GluN2B-containing N-methyl-d-aspartate receptor in the anterior cingulate cortex of neonatal rats.

    Science.gov (United States)

    Kokane, Saurabh S; Gong, Kerui; Jin, Jianhui; Lin, Qing

    2017-09-01

    Ketamine is a commonly used anesthetic among pediatric patients due to its high efficacy. However, it has been demonstrated by several preclinical studies that, widespread accelerated programmed death of neurons (neuroapoptosis) occurs due to prolonged or repeated exposure to ketamine specifically in the neonatal brain. Therefore, an emphasis on understanding the molecular mechanisms underlying this selective vulnerability of the neonatal brain to ketamine-induced neuroapoptosis becomes important in order to identify potential therapeutic targets, which would help prevent or at least ameliorate this neuroapoptosis. In this study, we demonstrated that repeated ketamine administration (6 injections of 20mg/kg dose given over 12h time period) in neonatal (postnatal day 7; PND 7) Sprague-Dawley rats induced a progressive increase in N-methyl-d-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs) in the neurons of the anterior cingulate cortex (ACC) for up to 6h after the last ketamine dose. Specifically, we observed that the increased EPSCs were largely mediated by GluN2B-containing NMDARs in the neurons of the ACC. Along with increased synaptic transmission, there was also a significant increase in the expression of the GluN2B-containing NMDARs as well. Taken together, these results showed that after repeated exposure to ketamine, the synaptic transmission mediated by GluN2B-containing NMDARs was significantly increased in the neonatal brain. This was significant as it showed for the first time that ketamine had subunit-specific effects on GluN2B-containing NMDARs, potentially implicating the involvement of these subunits in the increased vulnerability of immature neurons of the neonatal brain to ketamine-induced neuroapoptosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Effects of the NMDA receptor antagonist, D-CPPene, on sensitization to the operant decrement produced by naloxone in morphine-treated rats.

    Science.gov (United States)

    Bespalov, A Y; Medvedev, I O; Sukhotina, I A; Zvartau, E E

    2001-04-01

    Sensitization to the rate-decreasing effects of opioid antagonists induced by acute pretreatment with opioid agonists has been suggested to reflect initial changes in opioid systems that underlie physical dependence. Glutamate receptors are implicated in the development and expression of opioid dependence, and antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown repeatedly to attenuate the severity of opioid withdrawal. The present study evaluated the ability of a competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), to affect morphine-induced sensitization to naloxone in rats trained to lever-press on a multiple-trial, fixed-ratio 10 schedule of food reinforcement. D-CPPene (0.3-3 mg/kg) was administered either 4 h or 30 min prior to the test session. Morphine (10 mg/kg) or its vehicle was administered 4 h before naloxone challenge (0.3-3 mg/kg). D-CPPene failed to prevent morphine-induced potentiation of the naloxone-produced decrement in operant performance. Thus, these results suggest that agonist-induced sensitization to behavioral effects of opioid antagonists may be insensitive to NMDA receptor blockade.

  18. NMDA Receptor Modulators in the Treatment of Drug Addiction.

    Science.gov (United States)

    Tomek, Seven E; Lacrosse, Amber L; Nemirovsky, Natali E; Olive, M Foster

    2013-02-06

    Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

  19. NMDA Receptor Modulators in the Treatment of Drug Addiction

    Directory of Open Access Journals (Sweden)

    M. Foster Olive

    2013-02-01

    Full Text Available Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

  20. Glutamate receptor ligands

    DEFF Research Database (Denmark)

    Guldbrandt, Mette; Johansen, Tommy N; Frydenvang, Karla Andrea

    2002-01-01

    Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA...

  1. Induced expression of hepatic N-methyl-D-aspartate receptor 2C subunit gene during liver enlargement induced by lead nitrate, a hepatocellular mitogen.

    Science.gov (United States)

    Nemoto, Kiyomitsu; Ikeda, Ayaka; Hikida, Tokihiro; Kojima, Misaki; Degawa, Masakuni

    2013-02-01

    We previously demonstrated the super-induced expression of the Grin2c gene encoding the N-methyl-D-aspartate receptor 2C subunit during the development of liver enlargement with hepatocellular hypertrophy induced by phenobarbital, clofibrate, or piperonyl butoxide. In the present study, we assessed whether or not Grin2c gene expression was induced during the development of chemically induced liver enlargement with hyperplasia. Male Sprague-Dawley (SD) rats, stroke-prone spontaneously hypertensive rats (SHRSPs), and SHRSP's normotensive control, Wistar-Kyoto (WKY) rats, were administered lead nitrate (LN) (0.1 mmol/kg, single i.v.), a direct inducer of liver hyperplasia, and changes in the level of Grin2c mRNA in the liver were assessed by real-time RT-PCR. The level of hepatic Grin2c mRNA was significantly higher 6-48 hr after the injection in SD rats (about 30~40- and 70-fold over the control at 6~24 hr and 48 hr, respectively) and in WKY rats (about 20-fold over the control only at 12 hr), but was not significantly higher in SHRSPs. Such differences in LN-induced levels of Grin2c mRNA among SD rats, WKY rats, and SHRSPs were closely correlated with those in the previously reported increase in liver weight 48 hr after LN administration. The present findings suggest that the increase in the level of hepatic Grin2c mRNA relates to development of chemically induced liver enlargement with hyperplasia.

  2. 7T Proton Magnetic Resonance Spectroscopy of Gamma-Aminobutyric Acid, Glutamate, and Glutamine Reveals Altered Concentrations in Patients With Schizophrenia and Healthy Siblings

    DEFF Research Database (Denmark)

    Thakkar, Katharine N; Rösler, Lara; Wijnen, Jannie P

    2017-01-01

    BACKGROUND: The N-methyl-D-aspartate receptor hypofunction model of schizophrenia predicts dysfunction in both glutamatergic and gamma-aminobutyric acidergic (GABAergic) transmission. We addressed this hypothesis by measuring GABA, glutamate, glutamine, and the sum of glutamine plus glutamate...... concentrations in vivo in patients with schizophrenia using proton magnetic resonance spectroscopy at 7T, which allows separation of metabolites that would otherwise overlap at lower field strengths. In addition, we investigated whether altered levels of GABA, glutamate, glutamine, and the sum of glutamine plus...... glutamate reflect genetic vulnerability to schizophrenia by including healthy first-degree relatives. METHODS: Proton magnetic resonance spectroscopy at 7T was performed in 21 patients with chronic schizophrenia who were taking medication, 23 healthy first-degree relatives of patients with schizophrenia...

  3. Mechanical stress activates NMDA receptors in the absence of agonists

    OpenAIRE

    Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.

    2017-01-01

    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 Ca2+ 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 i...

  4. Synthesis and receptor binding studies of (+/-)1-iodo-MK-801

    International Nuclear Information System (INIS)

    Yang, D.J.; Ciliax, B.J.; Van Dort, M.E.; Gildersleeve, D.; Pirat, J.L.; Young, A.B.; Wieland, D.M.

    1989-01-01

    The glutamate analogue N-methyl-D-aspartate (NMDA) binds to a subset of glutamate receptors that are coupled to a voltage-sensitive cation channel. This NMDA-linked channel is the likely binding locus of the potent anticonvulsant MK-801. To develop single-photon emission computed tomography (SPECT) probes of this brain channel, we synthesized (+/)1-iodo-MK-801 and (+/-)1-[ 125 I]iodo-MK-801. The effect of (+/-)1-iodo-MK-801 on ligand binding to the NMDA-linked glutamate receptor site was assessed using a rat brain homogenate assay. (+/-)1-Iodo-MK-801 displaced the dissociative anesthetic ligand [ 3 H]N-[1-(2-thienyl)cyclohexyl]piperidine ([ 3 H]TCP) binding with an IC50 of 1 microM, which is a 10-fold lower binding affinity than that of (+/-)MK-801. In in vivo autoradiographic studies, (+/-)MK-801 failed to block selective uptake of (+/-)1-iodo-MK-801 in rat brain. These results suggest that (+/-)1-iodo-MK-801 may not be a suitable ligand for mapping NMDA-linked glutamate receptor channels

  5. Alkaloid fraction of Uncaria rhynchophylla protects against N-methyl-D-aspartate-induced apoptosis in rat hippocampal slices.

    Science.gov (United States)

    Lee, Jongseok; Son, Dongwook; Lee, Pyeongjae; Kim, Sun-Yeou; Kim, Hocheol; Kim, Chang-Ju; Lim, Eunhee

    2003-09-04

    Uncaria rhynchophylla is a medicinal herb which has sedative and anticonvulsive effects and has been applied in the treatment of epilepsy in Oriental medicine. In this study, the effect of alkaloid fraction of U. rhynchophylla against N-methyl-D-aspartate (NMDA)-induced neuronal cell death was investigated. Pretreatment with an alkaloid fraction of U. rhynchophylla for 1 h decreased the degree of neuronal damage induced by NMDA exposure in cultured hippocampal slices and also inhibited NMDA-induced enhanced expressions of apoptosis-related genes such as c-jun, p53, and bax. In the present study, the alkaloid fraction of U. rhynchophylla was shown to have a protective property against NMDA-induced cytotoxicity by suppressing the NMDA-induced apoptosis in rat hippocampal slices.

  6. Clinical characteristics, treatments, and outcomes of patients with anti-N-methyl-d-aspartate receptor encephalitis: A systematic review of reported cases.

    Science.gov (United States)

    Zhang, Le; Wu, Meng-Qian; Hao, Zi-Long; Chiang, Siew Mun Vance; Shuang, Kun; Lin, Min-Tao; Chi, Xiao-Sa; Fang, Jia-Jia; Zhou, Dong; Li, Jin-Mei

    2017-03-01

    Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a recently recognized autoimmune disorder which is responsive to immunotherapy. However, the outcomes of different immunotherapies have not been defined and there have been few studies that carried out a comparison among them. To provide an overview of the clinical characteristics, treatments, and outcomes of anti-NMDAR encephalitis, we systematically reviewed the literature in the PubMed, Medline, Embase, Cochrane Library, BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), and Wan-fang databases. Eighty-three studies with a total of 432 patients were included. The median age was 22years. Two hundred ninety-three (68%) patients were female, 87 (21%) of 412 patients had a tumor, including 68 (78%) patients with ovarian teratoma. Pediatric patients had a higher ratio of seizures to psychiatric symptoms as the initial manifestation (p=0.0012), a lower proportion with a tumor (p<0.0001) and CSF pleocytosis (p=0.0163), and a better outcome (p=0.0064) than adults. Patients who died had a higher proportion of CSF pleocytosis than the patients who survived (p=0.0021). There were no significant differences among three first-line immunotherapy used alone (p=0.9172) or among combinations of every two of them (p=0.3059). With regard to the use of corticosteroid and IVIG, there were no significant differences between the outcomes of early combined treatment and sequential treatment (p=0.7277), or between using corticosteroid first and IVIG first (p=0.5422). Our findings suggest that the clinical characteristics and outcomes for pediatric patients were different from adult patients, and no significant differences were found among different immunotherapies. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Formation of N-acyl-phosphatidylethanolamine and N-acylethanolamine (including anandamide) during glutamate-induced neurotoxicity

    DEFF Research Database (Denmark)

    Hansen, Harald S.; Moesgaard, B.; Hansen, H.H.

    1999-01-01

    N-acyl-phosphatidylethanolamine (NAPE) is present in very small amounts in mammalian tissues (less than 0.1% of total phospholipids). However, NAPE as well as its degradation production, N-acylethanolamine (NAE), can be formed in certain neuronal tissues in response to increased [Ca ](i). A high...... activation of the N-methyl-D-aspartate-receptor. Both NAPE and, to a lesser extent, NAE accumulate in a linear fashion for many hours while at the same time the neurons are dying. Likewise, in neurons prelabeled with C-arachidonic acid, C-arachidonic acid-labeled NAPE, and anandamide (= N...

  8. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis.

    Science.gov (United States)

    Bien, Christian G; Vincent, Angela; Barnett, Michael H; Becker, Albert J; Blümcke, Ingmar; Graus, Francesc; Jellinger, Kurt A; Reuss, David E; Ribalta, Teresa; Schlegel, Jürgen; Sutton, Ian; Lassmann, Hans; Bauer, Jan

    2012-05-01

    Classical paraneoplastic encephalitis syndromes with 'onconeural' antibodies directed to intracellular antigens, and the recently described paraneoplastic or non-paraneoplastic encephalitides and antibodies against both neural surface antigens (voltage-gated potassium channel-complexes, N-methyl-d-aspartate receptors) and intracellular antigens (glutamic acid decarboxylase-65), constitute an increasingly recognized group of immune-mediated brain diseases. Evidence for specific immune mechanisms, however, is scarce. Here, we report qualitative and quantitative immunopathology in brain tissue (biopsy or autopsy material) of 17 cases with encephalitis and antibodies to either intracellular (Hu, Ma2, glutamic acid decarboxylase) or surface antigenic targets (voltage-gated potassium channel-complex or N-methyl-d-aspartate receptors). We hypothesized that the encephalitides with antibodies against intracellular antigens (intracellular antigen-onconeural and intracellular antigen-glutamic acid decarboxylase groups) would show neurodegeneration mediated by T cell cytotoxicity and the encephalitides with antibodies against surface antigens would be antibody-mediated and would show less T cell involvement. We found a higher CD8/CD3 ratio and more frequent appositions of granzyme-B(+) cytotoxic T cells to neurons, with associated neuronal loss, in the intracellular antigen-onconeural group (anti-Hu and anti-Ma2 cases) compared to the patients with surface antigens (anti-N-methyl-d-aspartate receptors and anti-voltage-gated potassium channel complex cases). One of the glutamic acid decarboxylase antibody encephalitis cases (intracellular antigen-glutamic acid decarboxylase group) showed multiple appositions of GrB-positive T cells to neurons. Generally, however, the glutamic acid decarboxylase antibody cases showed less intense inflammation and also had relatively low CD8/CD3 ratios compared with the intracellular antigen-onconeural cases. Conversely, we found complement C9neo

  9. Increased response to glutamate in small diameter dorsal root ganglion neurons after sciatic nerve injury.

    Directory of Open Access Journals (Sweden)

    Kerui Gong

    Full Text Available Glutamate in the peripheral nervous system is involved in neuropathic pain, yet we know little how nerve injury alters responses to this neurotransmitter in primary sensory neurons. We recorded neuronal responses from the ex-vivo preparations of the dorsal root ganglia (DRG one week following a chronic constriction injury (CCI of the sciatic nerve in adult rats. We found that small diameter DRG neurons (30 µm were unaffected. Puff application of either glutamate, or the selective ionotropic glutamate receptor agonists alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA and kainic acid (KA, or the group I metabotropic receptor (mGluR agonist (S-3,5-dihydroxyphenylglycine (DHPG, induced larger inward currents in CCI DRGs compared to those from uninjured rats. N-methyl-D-aspartate (NMDA-induced currents were unchanged. In addition to larger inward currents following CCI, a greater number of neurons responded to glutamate, AMPA, NMDA, and DHPG, but not to KA. Western blot analysis of the DRGs revealed that CCI resulted in a 35% increase in GluA1 and a 60% decrease in GluA2, the AMPA receptor subunits, compared to uninjured controls. mGluR1 receptor expression increased by 60% in the membrane fraction, whereas mGluR5 receptor subunit expression remained unchanged after CCI. These results show that following nerve injury, small diameter DRG neurons, many of which are nociceptive, have increased excitability and an increased response to glutamate that is associated with changes in receptor expression at the neuronal membrane. Our findings provide further evidence that glutamatergic transmission in the periphery plays a role in nociception.

  10. Development of calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in cultured neocortical neurons visualized by cobalt staining

    DEFF Research Database (Denmark)

    Jensen, J B; Schousboe, A; Pickering, D S

    1998-01-01

    The developmental expression of calcium (Ca2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in cultured neocortical neurons was evaluated by using cobalt uptake, a histochemical method that identifies cells expressing Ca2+-permeable, non-N-methyl-D-aspartate...

  11. Temperature dependence of N-methyl-d-aspartate receptor channels and N-methyl-d-aspartate receptor excitatory postsynaptic currents

    Czech Academy of Sciences Publication Activity Database

    Kořínek, Miroslav; Sedláček, Miloslav; Cais, Ondřej; Dittert, Ivan; Vyklický ml., Ladislav

    2010-01-01

    Roč. 165, č. 3 (2010), s. 736-748 ISSN 0306-4522 R&D Projects: GA MŠk(CZ) 1M0517; GA MŠk(CZ) LC554; GA ČR(CZ) GA309/07/0271 Grant - others:EC(XE) LSHM-CT-2007-037765 Institutional research plan: CEZ:AV0Z50110509 Keywords : hypothermia * patch-clamp recording Subject RIV: ED - Physiology Impact factor: 3.215, year: 2010

  12. Glutamate and GABA in lateral hypothalamic mechanisms controlling food intake.

    Science.gov (United States)

    Stanley, B G; Urstadt, K R; Charles, J R; Kee, T

    2011-07-25

    By the 1990s a convergence of evidence had accumulated to suggest that neurons within the lateral hypothalamus (LH) play important roles in the stimulation of feeding behavior. However, there was little direct evidence demonstrating that neurotransmitters in the LH could, like electrical stimulation, elicit feeding in satiated animals. The present paper is a brief review in honor of Bartley Hoebel's scientific contributions, emphasizing the evidence from my lab that the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter gamma aminobutyric acid (GABA) in the LH mediate feeding stimulation and feeding inhibition respectively. Specifically, we summarize evidence that LH injection of glutamate, or agonists of its N-methyl-D-aspartate (NMDA) and non-NMDA receptors, elicits feeding in satiated rats, that NMDA receptor antagonists block the eating elicited by NMDA and, more importantly, that NMDA blockade suppresses natural feeding and can reduce body weight. Conversely, GABA(A) agonists injected into the LH suppress feeding and can also reduce body weight, while GABA(A) receptor antagonists actually elicit eating when injected into the LH of satiated rats. It is suggested that natural feeding may reflect the moment-to-moment balance in the activity of glutamate and GABA within the LH. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Chronic intermittent hypoxia impairs heart rate responses to AMPA and NMDA and induces loss of glutamate receptor neurons in nucleus ambiguous of F344 rats.

    Science.gov (United States)

    Yan, Binbin; Li, Lihua; Harden, Scott W; Gozal, David; Lin, Ying; Wead, William B; Wurster, Robert D; Cheng, Zixi Jack

    2009-02-01

    Chronic intermittent hypoxia (CIH), as occurs in sleep apnea, impairs baroreflex-mediated reductions in heart rate (HR) and enhances HR responses to electrical stimulation of vagal efferent. We tested the hypotheses that HR responses to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the nucleus ambiguous (NA) are reduced in CIH-exposed rats and that this impairment is associated with degeneration of glutamate receptor (GluR)-immunoreactive NA neurons. Fischer 344 rats (3-4 mo) were exposed to room air (RA) or CIH for 35-50 days (n = 18/group). At the end of the exposures, AMPA (4 pmol, 20 nl) and NMDA (80 pmol, 20 nl) were microinjected into the same location of the left NA (-200 microm to +200 microm relative to caudal end of area postrema; n = 6/group), and HR and arterial blood pressure responses were measured. In addition, brain stem sections at the level of -800, -400, 0, +400, and +800 microm relative to obex were processed for AMPA and NMDA receptor immunohistochemistry. The number of NA neurons expressing AMPA receptors and NMDA receptors (NMDARs) was quantified. Compared with RA, we found that after CIH 1) HR responses to microinjection of AMPA into the left NA were reduced (RA -290 +/- 30 vs. CIH -227 +/- 15 beats/min, P neurons expressing GluRs contributes to impaired baroreflex control of HR in rats exposed to CIH.

  14. Selective increases of AMPA, NMDA and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics

    Directory of Open Access Journals (Sweden)

    Zhe eJin

    2014-01-01

    Full Text Available Glutamate is the main excitatory transmitter in the human brain. Drugs that affect the glutamatergic signaling will alter neuronal excitability. Ethanol inhibits glutamate receptors. We examined the expression level of glutamate receptor subunit mRNAs in human post-mortem samples from alcoholics and compared the results to brain samples from control subjects. RNA from hippocampal dentate gyrus (HP-DG, orbitofrontal cortex (OFC, and dorso-lateral prefrontal cortex (DL-PFC samples from 21 controls and 19 individuals with chronic alcohol dependence were included in the study. Total RNA was assayed using quantitative RT-PCR. Out of the 16 glutamate receptor subunits, mRNAs encoding two AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-ylpropanoic acid receptor subunits GluA2 and GluA3; three kainate receptor subunits GluK2, GluK3 and GluK5 and five NMDA (N-methyl-D-aspartate receptor subunits GluN1, GluN2A, GluN2C, GluN2D and GluN3A were significantly increased in the HP-DG region in alcoholics. In the OFC, mRNA encoding the NMDA receptor subunit GluN3A was increased, whereas in the DL-PFC, no differences in mRNA levels were observed. Our laboratory has previously shown that the expression of genes encoding inhibitory GABA-A receptors is altered in the HP-DG and OFC of alcoholics (Jin et al., 2011. Whether the changes in one neurotransmitter system drives changes in the other or if they change independently is currently not known. The results demonstrate that excessive long-term alcohol consumption is associated with altered expression of genes encoding glutamate receptors in a brain region-specific manner. It is an intriguing possibility that genetic predisposition to alcoholism may contribute to these gene expression changes.

  15. Loss of GluN2D subunit results in social recognition deficit, social stress, 5-HT2C receptor dysfunction, and anhedonia in mice.

    Science.gov (United States)

    Yamamoto, Hideko; Kamegaya, Etsuko; Hagino, Yoko; Takamatsu, Yukio; Sawada, Wakako; Matsuzawa, Maaya; Ide, Soichiro; Yamamoto, Toshifumi; Mishina, Masayoshi; Ikeda, Kazutaka

    2017-01-01

    The N-methyl-d-aspartate (NMDA) receptor channel is involved in various physiological functions, including learning and memory. The GluN2D subunit of the NMDA receptor has low expression in the mature brain, and its role is not fully understood. In the present study, the effects of GluN2D subunit deficiency on emotional and cognitive function were investigated in GluN2D knockout (KO) mice. We found a reduction of motility (i.e., a depressive-like state) in the tail suspension test and a reduction of sucrose preference (i.e., an anhedonic state) in GluN2D KO mice that were group-housed with littermates. Despite apparently normal olfactory function and social interaction, GluN2D KO mice exhibited a decrease in preference for social novelty, suggesting a deficit in social recognition or memory. Golgi-Cox staining revealed a reduction of the complexity of dendritic trees in the accessory olfactory bulb in GluN2D KO mice, suggesting a deficit in pheromone processing pathway activation, which modulates social recognition. The deficit in social recognition may result in social stress in GluN2D KO mice. Isolation housing is a procedure that has been shown to reduce stress in mice. Interestingly, 3-week isolation and treatment with agomelatine or the 5-hydroxytryptamine-2C (5-HT 2C ) receptor antagonist SB242084 reversed the anhedonic-like state in GluN2D KO mice. In contrast, treatment with the 5-HT 2C receptor agonist CP809101 induced depressive- and anhedonic-like states in isolated GluN2D KO mice. These results suggest that social stress that is caused by a deficit in social recognition desensitizes 5-HT 2c receptors, followed by an anhedonic- and depressive-like state, in GluN2D KO mice. The GluN2D subunit of the NMDA receptor appears to be important for the recognition of individuals and development of normal emotionality in mice. 5-HT 2C receptor antagonism may be a therapeutic target for treating social stress-induced anhedonia. This article is part of the Special

  16. role of heterogeneous astrocyte receptor expression in determining

    African Journals Online (AJOL)

    2018-02-28

    Feb 28, 2018 ... has been increasing (Denis et al, 1989; Lau and. Breteler, 2006). ... toxicity, the excess glutamate binds to N-Methyl-. D-aspartate ... absorption into the astrocyte (Lau and .... Heales JR, Lam AJ, Duncan AJ, Land JM. 2004.

  17. Retrieval Is Not Necessary to Trigger Reconsolidation of Object Recognition Memory in the Perirhinal Cortex

    Science.gov (United States)

    Santoyo-Zedillo, Marianela; Rodriguez-Ortiz, Carlos J.; Chavez-Marchetta, Gianfranco; Bermudez-Rattoni, Federico; Balderas, Israela

    2014-01-01

    Memory retrieval has been considered as requisite to initiate memory reconsolidation; however, some studies indicate that blocking retrieval does not prevent memory from undergoing reconsolidation. Since N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in the perirhinal cortex have…

  18. Anions mediate ligand binding in Adineta vaga glutamate receptor ion channels.

    Science.gov (United States)

    Lomash, Suvendu; Chittori, Sagar; Brown, Patrick; Mayer, Mark L

    2013-03-05

    AvGluR1, a glutamate receptor ion channel from the primitive eukaryote Adineta vaga, is activated by alanine, cysteine, methionine, and phenylalanine, which produce lectin-sensitive desensitizing responses like those to glutamate, aspartate, and serine. AvGluR1 LBD crystal structures reveal an unusual scheme for binding dissimilar ligands that may be utilized by distantly related odorant/chemosensory receptors. Arginine residues in domain 2 coordinate the γ-carboxyl group of glutamate, whereas in the alanine, methionine, and serine complexes a chloride ion acts as a surrogate ligand, replacing the γ-carboxyl group. Removal of Cl(-) lowers affinity for these ligands but not for glutamate or aspartate nor for phenylalanine, which occludes the anion binding site and binds with low affinity. AvGluR1 LBD crystal structures and sedimentation analysis also provide insights into the evolutionary link between prokaryotic and eukaryotic iGluRs and reveal features unique to both classes, emphasizing the need for additional structure-based studies on iGluR-ligand interactions. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Investigating altered nitric oxide signalling as an up-stream mediator of the antidepressant action of ketamine

    DEFF Research Database (Denmark)

    Liebenberg, N.; Muller, H. K.; Elfving, B.

    2012-01-01

    Background and Aim: Stress-induced excessive glutamate transmission at N-methyl-D-aspartate (NMDA) receptors may underlie a major mechanism in the pathophysiology that leads to depression, while ketamine, an NMDA receptor antagonist, has been shown to induce a rapid antidepressant effect in depre......Background and Aim: Stress-induced excessive glutamate transmission at N-methyl-D-aspartate (NMDA) receptors may underlie a major mechanism in the pathophysiology that leads to depression, while ketamine, an NMDA receptor antagonist, has been shown to induce a rapid antidepressant effect...... in depressed patients following a single intravenous administration that is sustained for (plus or minus) 7 days. A number of downstream cellular mechanisms appear to mediate the antidepressant action of ketamine, and the majority of evidence point to a rapid activation of protein translation leading...... to and activated by NMDA receptors, while the uncoupling of the nNOS-NMDA receptor complex prevents NMDA-induced excitotoxicity. Thus, it is possible that the inhibition of nitric oxide (NO) signalling underlies a key upstream mechanism in the antidepressant action of ketamine. Methods: We used a genetic rat model...

  20. Is nitric oxide signalling involved in the antidepressant action of ketamine?

    DEFF Research Database (Denmark)

    Liebenberg, Nico; Müller, Heidi Kaastrup; Elfving, Betina

    2012-01-01

    Background and Aim: Stress-induced excessive glutamate transmission at N-methyl-D-aspartate (NMDA) receptors may underlie a major mechanism in the pathophysiology that leads to depression, while ketamine, an NMDA receptor antagonist, has been shown to induce a rapid antidepressant effect in depre......Background and Aim: Stress-induced excessive glutamate transmission at N-methyl-D-aspartate (NMDA) receptors may underlie a major mechanism in the pathophysiology that leads to depression, while ketamine, an NMDA receptor antagonist, has been shown to induce a rapid antidepressant effect...... in depressed patients following a single intravenous administration that is sustained for ± 7 days. A number of downstream cellular mechanisms appear to mediate the antidepressant action of ketamine, and the majority of evidence point to a rapid activation of protein translation leading to increased synaptic...... receptors, while the uncoupling of the nNOS-NMDA receptor complex prevents NMDA-induced excitotoxicity. Thus, it is possible that the inhibition of nitric oxide (NO) signalling underlies a key upstream mechanism in the antidepressant action of ketamine. Methods: We used a genetic rat model of depression...

  1. Ionotropic glutamate receptors (iGluRs of the delta family (GluD1 and GluD2 and synaptogenesis

    Directory of Open Access Journals (Sweden)

    Muhammad Zahid Khan

    2017-08-01

    Full Text Available Glutamate delta-1 (GluD1 and glutamate delta-2 (GluD2 form the delta family of ionotropic glutamate receptors (iGluRs and are distinct from other (iGluRs in that they do not exhibit typical agonist-induced ion channel currents. Recent studies have demonstrated a crucial role of the delta receptors in synapse formation by interacting with presynaptic proteins such as Neurexin1. This review presents current knowledge regarding the expression, structure and function of Glu delta receptors (GluD1, GluD2 in brain, focusing on synapse formation, function and dysfunction.

  2. Role of NMDA receptor GluN2D subunit in the antidepressant effects of enantiomers of ketamine

    Directory of Open Access Journals (Sweden)

    Soichiro Ide

    2017-11-01

    Full Text Available We investigated the rapid and sustained antidepressant effects of enantiomers of ketamine in N-methyl-d-aspartate (NMDA receptor GluN2D subunit knockout (GluN2D-KO mice. Intraperitoneal administration of ketamine or its enantiomers 10 min before the tail-suspension test exerted significant antidepressant effects on restraint stress-induced depression in both wildtype and GluN2D-KO mice. The antidepressant effects of (RS-ketamine and (S-ketamine were sustained 96 h after the injection in both wildtype and GluN2D-KO mice, but such sustained antidepressant effects of (R-ketamine were only observed in wildtype mice. These data suggest that the GluN2D subunit is critical for the sustained antidepressant effects of (R-ketamine.

  3. Quinazolin-4-one derivatives

    DEFF Research Database (Denmark)

    Mosley, Cara A; Acker, Timothy M; Hansen, Kasper Bø

    2010-01-01

    We describe a new class of subunit-selective antagonists of N-methyl D-aspartate (NMDA)-selective ionotropic glutamate receptors that contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone. The inhibition of recombinant NMDA receptor function induced by these quinazolin-4-one derivatives...

  4. Expression analysis in a rat psychosis model identifies novel candidate genes validated in a large case–control sample of schizophrenia

    DEFF Research Database (Denmark)

    Ingason, Andrés; Giegling, Ina; Harmann, AM

    2015-01-01

    Antagonists of the N-methyl-D-aspartate (NMDA)-type glutamate receptor induce psychosis in healthy individuals and exacerbate schizophrenia symptoms in patients. In this study we have produced an animal model of NMDA receptor hypofunction by chronically treating rats with low doses of the NMDA re...

  5. Chemical lesioning and glutamate administration reveal a major role for the nucleus tractus solitarius in the cardiac-somatic reflex in rats.

    Science.gov (United States)

    Liu, X-H; Sun, N; Du, J-Q; Tang, J-S; Han, M; Zhu, J-X; Huo, F-Q

    2012-04-05

    Many patients suffer from secondary muscle hyperalgesia after experiencing angina pectoris. In this study, we examined the role of the nucleus tractus solitarius (NTS) and glutamate receptors in modulating cardiac-evoked muscle hyperalgesia induced by pericardial capsaicin, which was monitored by recording electromyogram (EMG) activity from the spinotrapezius muscle in the anesthetized rat. Unilateral chemical lesioning of the commissural NTS with the neurotoxin ibotenic acid significantly depressed the cardiac-somatic reflex; the EMG responses decreased to 56.4 ± 6.9% of that of the controls (5 of 5). Microinjection of the excitatory amino acid glutamate, at 10, 20, and 50 nmol, into the commissural NTS increased the EMG response, in a dose-dependent manner, to 116.9 ± 4.9%, 143.9 ± 10.2%, and 214.2 ± 15.8% (n=8), respectively, of that of the controls. In contrast, microinjection of the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-5-methyl-10, 11-dihydro-5H-dibenzo [a, d]-cyclohepten-5,10-imine maleate (MK-801) at 4 and 6 nmol, decreased the EMG response to 45.2 ± 10.6% and 36.8 ± 14.3%, respectively, of that of the controls (n=8 for each dose). Similarly, the metabotropic glutamate receptor (mGluR) antagonist (RS)-a-methyl-4-carboxyphenylglycine (MCPG), at 2.5 and 5 nmol, decreased the EMG response to 65.2 ± 16.3% and 57.0 ± 4.2%, respectively, of that of the controls. When a combination of MK-801 and MCPG was administrated, the EMG response further decreased to 22.5 ± 13.2% (n=6) of that of the controls. However, administration of a non-NMDA receptor antagonist 6, 7-dinitroquinoxaline-2, 3-dione (DNQX), at 2 and 5 nmol, had no effect on the EMG response. These results suggest that the NTS is involved in the facilitation of the cardiac-somatic reflex, and that the NMDA receptor and mGluRs play an important role in mediating this effect. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. High and low nightly running behavior associates with nucleus accumbens N-Methyl-d-aspartate receptor (NMDAR) NR1 subunit expression and NMDAR functional differences.

    Science.gov (United States)

    Grigsby, Kolter B; Kovarik, Cathleen M; Rottinghaus, George E; Booth, Frank W

    2018-04-03

    The extent to which N-Methyl-d-aspartate (NMDA) receptors facilitate the motivation to voluntarily wheel-run in rodents has yet to be determined. In so, we utilized female Wistar rats selectively bred to voluntarily run high (HVR) and low (LVR) nightly distances in order to examine if endogenous differences in nucleus accumbens (NAc) NMDA receptor expression and function underlies the propensity for high or low motivation to voluntarily wheel-run. 12-14 week old HVR and LVR females were used to examine: 1.) NAc mRNA and protein expression of NMDA subunits NR1, NR2A and NR2B; 2.) NMDA current responses in isolated medium spiny neurons (MSNs) and 3.) NMDA-evoked dopamine release in an ex vivo preparation of NAc punches. Expectedly, there was a large divergence in nightly running distance and time between HVR and LVR rats. We saw a significantly higher mRNA and protein expression of NR1 in HVR compared to LVR rats, while seeing no difference in the expression of NR2A or NR2B. There was a greater current response to a 500 ms application of 300 μM of NMDA in medium-spiny neurons isolated from the NAc HVR compared to LVR animals. On average, NMDA-evoked punches (50 μM of NMDA for 10 min) taken from HVR rats retained ∼54% of the dopamine content compared to their bilateral non-evoked sides, while evoked punches from LVR animals showed no statistical decrease in dopamine content compared to their non-evoked sides. Collectively, these data suggest a potential link between NAc NR1 subunit expression as well as NMDA function and the predisposition for nightly voluntary running behavior in rats. In light of the epidemic rise in physical inactivity, these findings have the potential to explain a neuro-molecular mechanism that regulates the motivation to be physically active. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Clinical presentation of anti-N-methyl-d-aspartate receptor and anti-voltage-gated potassium channel complex antibodies in children: A series of 24 cases.

    Science.gov (United States)

    Konuskan, Bahadir; Yildirim, Mirac; Topaloglu, Haluk; Erol, Ilknur; Oztoprak, Ulkuhan; Tan, Huseyin; Gocmen, Rahsan; Anlar, Banu

    2018-01-01

    The symptomatology and paraclinical findings of antibody-mediated encephalitis, a relatively novel disorder, are still being characterized in adults and children. A high index of suspicion is needed in order to identify these cases among children presenting with various neurological symptoms. The aim of this study is to examine the clinical, demographic and laboratory findings and outcome of children with anti-NMDAR and anti-VGKC encephalitis for any typical or distinctive features. Cases diagnosed with anti-N-Methyl d-aspartate receptor (NMDAR) and anti-voltage gated potassium channel (VGKC) antibody-mediated encephalopathy in four major child neurology centers are described. In four years, 16 children with NMDAR and 8 children with VGKC antibody-associated disease were identified in the participating centers. The most frequent initial manifestation consisted of generalized seizures and cognitive symptoms in both groups. Movement abnormalities were frequent in anti-NMDAR patients and autonomic symptoms, in anti-VGKC patients. Cerebrospinal fluid (CSF) protein, cell count and IgG index were normal in 9/15 anti-NMDAR and 5/8 anti-VGKC patients tested. EEG and MRI findings were usually nonspecific and non-contributory. The rate and time of recovery was not related to age, sex, acute or subacute onset, antibody type, MRI, EEG or CSF results. Treatment within 3 months of onset was associated with normal neurological outcome. Our results suggest anti-NMDAR and VGKC encephalopathies mostly present with non-focal neurological symptoms longer than 3 weeks. In contrast with adult cases, routine CSF testing, MRI and EEG did not contribute to the diagnosis in this series. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  8. Association of Progressive Cerebellar Atrophy With Long-term Outcome in Patients With Anti-N-Methyl-d-Aspartate Receptor Encephalitis.

    Science.gov (United States)

    Iizuka, Takahiro; Kaneko, Juntaro; Tominaga, Naomi; Someko, Hidehiro; Nakamura, Masaaki; Ishima, Daisuke; Kitamura, Eiji; Masuda, Ray; Oguni, Eiichi; Yanagisawa, Toshiyuki; Kanazawa, Naomi; Dalmau, Josep; Nishiyama, Kazutoshi

    2016-06-01

    Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder that occurs with IgG antibodies against the GluN1 subunit of NMDAR. Some patients develop reversible diffuse cerebral atrophy (DCA), but the long-term clinical significance of progressive brain and cerebellar atrophy is unknown. To report the long-term clinical implications of DCA and cerebellar atrophy in anti-NMDAR encephalitis. A retrospective observational study and long-term imaging investigation was conducted in the Department of Neurology at Kitasato University. Fifteen patients with anti-NMDAR encephalitis admitted to Kitasato University Hospital between January 1, 1999, and December 31, 2014, were included; data analysis was conducted between July 15, 2015, and January 18, 2016. Neurologic examination, immunotherapy, and magnetic resonance imaging (MRI) studies were performed. Long-term MRI changes in association with disease severity, serious complications (eg, pulmonary embolism, septic shock, and rhabdomyolysis), treatment, and outcome. The clinical outcome of 15 patients (median age, 21 years, [range, 14-46 years]; 10 [67%] female) was evaluated after a median follow-up of 68 months (range, 10-179 months). Thirteen patients (87%) received first-line immunotherapy (intravenous high-dose methylprednisolone, intravenous immunoglobulin, and plasma exchange alone or combined), and 4 individuals (27%) also received cyclophosphamide; 2 patients (13%) did not receive immunotherapy. In 5 patients (33%), ovarian teratoma was found and removed. Serious complications developed in 4 patients (27%). Follow-up MRI revealed DCA in 5 patients (33%) that, in 2 individuals (13%), was associated with progressive cerebellar atrophy. Long-term outcome was good in 13 patients (87%) and poor in the other 2 individuals (13%). Although cerebellar atrophy was associated with poor long-term outcome (2 of 2 vs 0 of 13 patients; P = .01), other features, such as DCA without cerebellar atrophy

  9. Solubilities of magnesium-L-ascorbate, calcium-L-ascorbate, magnesium-L-glutamate, magnesium-D-gluconate, calcium-D-gluconate, calcium-D-heptagluconate, L-aspartic acid, and 3-nitrobenzoic acid in water

    Energy Technology Data Exchange (ETDEWEB)

    Mishelevich, Alexander [Department of Chemical Engineering, Ben Gurion University of the Negev, Beer Sheva 84105 (Israel); Apelblat, Alexander [Department of Chemical Engineering, Ben Gurion University of the Negev, Beer Sheva 84105 (Israel)], E-mail: apelblat@bgu.ac.il

    2008-05-15

    The solubility in water of magnesium-L-ascorbate, calcium-L-ascorbate, magnesium-L-glutamate, magnesium-D-gluconate, calcium-D-gluconate, calcium-D-heptagluconate, L-aspartic acid, and 3-nitrobenzoic acid was determined in the 278.15 K to 343.15 K temperature range. The solubility of these compounds served to permit the evaluation of the apparent molar enthalpies of solution.

  10. Solubilities of magnesium-L-ascorbate, calcium-L-ascorbate, magnesium-L-glutamate, magnesium-D-gluconate, calcium-D-gluconate, calcium-D-heptagluconate, L-aspartic acid, and 3-nitrobenzoic acid in water

    International Nuclear Information System (INIS)

    Mishelevich, Alexander; Apelblat, Alexander

    2008-01-01

    The solubility in water of magnesium-L-ascorbate, calcium-L-ascorbate, magnesium-L-glutamate, magnesium-D-gluconate, calcium-D-gluconate, calcium-D-heptagluconate, L-aspartic acid, and 3-nitrobenzoic acid was determined in the 278.15 K to 343.15 K temperature range. The solubility of these compounds served to permit the evaluation of the apparent molar enthalpies of solution

  11. Brain glutamine synthesis requires neuronal-born aspartate as amino donor for glial glutamate formation.

    Science.gov (United States)

    Pardo, Beatriz; Rodrigues, Tiago B; Contreras, Laura; Garzón, Miguel; Llorente-Folch, Irene; Kobayashi, Keiko; Saheki, Takeyori; Cerdan, Sebastian; Satrústegui, Jorgina

    2011-01-01

    The glutamate-glutamine cycle faces a drain of glutamate by oxidation, which is balanced by the anaplerotic synthesis of glutamate and glutamine in astrocytes. De novo synthesis of glutamate by astrocytes requires an amino group whose origin is unknown. The deficiency in Aralar/AGC1, the main mitochondrial carrier for aspartate-glutamate expressed in brain, results in a drastic fall in brain glutamine production but a modest decrease in brain glutamate levels, which is not due to decreases in neuronal or synaptosomal glutamate content. In vivo (13)C nuclear magnetic resonance labeling with (13)C(2)acetate or (1-(13)C) glucose showed that the drop in brain glutamine is due to a failure in glial glutamate synthesis. Aralar deficiency induces a decrease in aspartate content, an increase in lactate production, and lactate-to-pyruvate ratio in cultured neurons but not in cultured astrocytes, indicating that Aralar is only functional in neurons. We find that aspartate, but not other amino acids, increases glutamate synthesis in both control and aralar-deficient astrocytes, mainly by serving as amino donor. These findings suggest the existence of a neuron-to-astrocyte aspartate transcellular pathway required for astrocyte glutamate synthesis and subsequent glutamine formation. This pathway may provide a mechanism to transfer neuronal-born redox equivalents to mitochondria in astrocytes.

  12. IgE binding to peanut allergens is inhibited by combined D-aspartic and D-glutamic acids.

    Science.gov (United States)

    Chung, Si-Yin; Reed, Shawndrika

    2015-01-01

    The objective of this study was to determine if D-amino acids (D-aas) bind and inhibit immunoglobulin E (IgE) binding to peanut allergens. D-aas such as D-Asp (aspartic acid), D-Glu (glutamic acid), combined D-[Asp/Glu] and others were each prepared in a cocktail of 9 other D-aas, along with L-amino acids (L-aas) and controls. Each sample was mixed with a pooled plasma from peanut-allergic donors, and tested by ELISA (enzyme-linked immunosorbent assay) and Western blots for IgE binding to peanut allergens. Results showed that D-[Asp/Glu] (4 mg/ml) inhibited IgE binding (75%) while D-Glu, D-Asp and other D-aas had no inhibitory effect. A higher inhibition was seen with D-[Asp/Glu] than with L-[Asp/Glu]. We concluded that IgE was specific for D-[Asp/Glu], not D-Asp or D-Glu, and that D-[Asp/Glu] was more reactive than was L-[Asp/Glu] in IgE inhibition. The finding indicates that D-[Asp/Glu] may have the potential for removing IgE or reducing IgE binding to peanut allergens in vitro. Published by Elsevier Ltd.

  13. De-coupling of blood flow and metabolism in the rat brain induced by glutamate

    International Nuclear Information System (INIS)

    Hirose, Shinichiro; Momosaki, Sotaro; Sasaki, Kazunari; Hosoi, Rie; Abe, Kohji; Inoue, Osamu; Gee, A.

    2009-01-01

    Glutamate plays an essential role in neuronal cell death in many neurological disorders. In this study, we examined both glucose metabolism and cerebral blood flow in the same rat following infusion of glutamate or ibotenic acid using the dual-tracer technique. The effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-kainate receptor antagonist, on the changes in the glucose metabolism and cerebral blood flow induced by glutamate were also examined. The rats were microinjected with glutamate (1 μmol/μl, 2 μl) or ibotenic acid (10 μg/μl, 1 μl) into the right striatum, and dual-tracer autoradiograms of [ 18 F]fluorodeoxyglucose (FDG) and [ 14 C]iofetamine (IMP) were obtained. MK-801 and NBQX were injected intravenously about 45 and 30 min, respectively, after the infusion of glutamate. De-coupling of blood flow and metabolism was noted in the glutamate-infused hemisphere (as assessed by no alteration of [ 18 F]FDG uptake and significant decrease of [ 14 C]IMP uptake). Pretreatments with MK-801, NBQX, or combined use of MK-801 and NBQX did not affect the de-coupling of the blood flow and metabolism induced by glutamate. A histochemical study revealed that about 20% neuronal cell death had occurred in the striatum at 105 min after the infusion of glutamate. In addition, a significant increase of the [ 18 F]FDG uptake and decrease of [ 14 C]IMP uptake were also seen in the rat brain infused with ibotenic acid. These results indicate that glutamate and ibotenic acid caused a significant de-coupling of blood flow and glucose metabolism in the intact rat brain during the early phase of neurodegeneration. It is necessary to evaluate the relation between metabotropic glutamate receptors and de-coupling of blood flow and metabolism. (author)

  14. Role of NMDA receptor GluN2D subunit in the antidepressant effects of enantiomers of ketamine.

    Science.gov (United States)

    Ide, Soichiro; Ikekubo, Yuiko; Mishina, Masayoshi; Hashimoto, Kenji; Ikeda, Kazutaka

    2017-11-01

    We investigated the rapid and sustained antidepressant effects of enantiomers of ketamine in N-methyl-d-aspartate (NMDA) receptor GluN2D subunit knockout (GluN2D-KO) mice. Intraperitoneal administration of ketamine or its enantiomers 10 min before the tail-suspension test exerted significant antidepressant effects on restraint stress-induced depression in both wildtype and GluN2D-KO mice. The antidepressant effects of (RS)-ketamine and (S)-ketamine were sustained 96 h after the injection in both wildtype and GluN2D-KO mice, but such sustained antidepressant effects of (R)-ketamine were only observed in wildtype mice. These data suggest that the GluN2D subunit is critical for the sustained antidepressant effects of (R)-ketamine. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  15. Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type

    International Nuclear Information System (INIS)

    Chalmers, D.T.; Dewar, D.; Graham, D.I.; Brooks, D.N.; McCulloch, J.

    1990-01-01

    Involvement of cortical glutamatergic mechanisms in senile dementia of the Alzheimer type (SDAT) has been investigated with quantitative ligand-binding autoradiography. The distribution and density of Na(+)-dependent glutamate uptake sites and glutamate receptor subtypes--kainate, quisqualate, and N-methyl-D-aspartate--were measured in adjacent sections of frontal cortex obtained postmortem from six patients with SDAT and six age-matched controls. The number of senile plaques was determined in the same brain region. Binding of D-[3H]aspartate to Na(+)-dependent uptake sites was reduced by approximately 40% throughout SDAT frontal cortex relative to controls, indicating a general loss of glutamatergic presynaptic terminals. [3H]Kainate receptor binding was significantly increased by approximately 70% in deep layers of SDAT frontal cortex compared with controls, whereas this binding was unaltered in superficial laminae. There was a positive correlation (r = 0.914) between kainate binding and senile plaque number in deep cortical layers. Quisqualate receptors, as assessed by 2-amino-3-hydroxy-5-[3H]methylisoxazole-4-propionic acid binding, were unaltered in SDAT frontal cortex compared with controls. There was a small reduction (25%) in N-methyl-D-aspartate-sensitive [3H]glutamate binding only in superficial cortical layers of SDAT brains relative to control subjects. [3H]Glutamate binding in SDAT subjects was unrelated to senile plaque number in superficial cortical layers (r = 0.104). These results indicate that in the presence of cortical glutamatergic terminal loss in SDAT plastic alterations occur in some glutamate receptor subtypes but not in others

  16. Decreased levels of free D-aspartic acid in the forebrain of serine racemase (Srr) knock-out mice.

    Science.gov (United States)

    Horio, Mao; Ishima, Tamaki; Fujita, Yuko; Inoue, Ran; Mori, Hisashi; Hashimoto, Kenji

    2013-05-01

    d-Serine, an endogenous co-agonist of the N-methyl-d-aspartate (NMDA) receptor is synthesized from l-serine by serine racemase (SRR). A previous study of Srr knockout (Srr-KO) mice showed that levels of d-serine in forebrain regions, such as frontal cortex, hippocampus, and striatum, but not cerebellum, of mutant mice are significantly lower than those of wild-type (WT) mice, suggesting that SRR is responsible for d-serine production in the forebrain. In this study, we attempted to determine whether SRR affects the level of other amino acids in brain tissue. We found that tissue levels of d-aspartic acid in the forebrains (frontal cortex, hippocampus and striatum) of Srr-KO mice were significantly lower than in WT mice, whereas levels of d-aspartic acid in the cerebellum were not altered. Levels of d-alanine, l-alanine, l-aspartic acid, taurine, asparagine, arginine, threonine, γ-amino butyric acid (GABA) and methionine, remained the same in frontal cortex, hippocampus, striatum and cerebellum of WT and mutant mice. Furthermore, no differences in d-aspartate oxidase (DDO) activity were detected in the forebrains of WT and Srr-KO mice. These results suggest that SRR and/or d-serine may be involved in the production of d-aspartic acid in mouse forebrains, although further detailed studies will be necessary to confirm this finding. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD.

    Science.gov (United States)

    Han, Jing; Kesner, Philip; Metna-Laurent, Mathilde; Duan, Tingting; Xu, Lin; Georges, Francois; Koehl, Muriel; Abrous, Djoher Nora; Mendizabal-Zubiaga, Juan; Grandes, Pedro; Liu, Qingsong; Bai, Guang; Wang, Wei; Xiong, Lize; Ren, Wei; Marsicano, Giovanni; Zhang, Xia

    2012-03-02

    Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction

    DEFF Research Database (Denmark)

    Bach, Anders; Chi, Celestine N.; Olsen, Thomas B.

    2008-01-01

    and unnatural amino acids, which disclosed a tripeptide with micromolar affinity and N-methylated tetrapeptides with improved affinities. Molecular modeling studies guided further N-terminal modifications and introduction of a range of N-terminal substitutions dramatically improved affinity. The best compound...

  19. Aspartate and glutamate mimetic structures in biologically active compounds.

    Science.gov (United States)

    Stefanic, Peter; Dolenc, Marija Sollner

    2004-04-01

    Glutamate and aspartate are frequently recognized as key structural elements for the biological activity of natural peptides and synthetic compounds. The acidic side-chain functionality of both the amino acids provides the basis for the ionic interaction and subsequent molecular recognition by specific receptor sites that results in the regulation of physiological or pathophysiological processes in the organism. In the development of new biologically active compounds that possess the ability to modulate these processes, compounds offering the same type of interactions are being designed. Thus, using a peptidomimetic design approach, glutamate and aspartate mimetics are incorporated into the structure of final biologically active compounds. This review covers different bioisosteric replacements of carboxylic acid alone, as well as mimetics of the whole amino acid structure. Amino acid analogs presented include those with different distances between anionic moieties, and analogs with additional functional groups that result in conformational restriction or alternative interaction sites. The article also provides an overview of different cyclic structures, including various cycloalkane, bicyclic and heterocyclic analogs, that lead to conformational restriction. Higher di- and tripeptide mimetics in which carboxylic acid functionality is incorporated into larger molecules are also reviewed. In addition to the mimetic structures presented, emphasis in this article is placed on their steric and electronic properties. These mimetics constitute a useful pool of fragments in the design of new biologically active compounds, particularly in the field of RGD mimetics and excitatory amino acid agonists and antagonists.

  20. Synthesis and preclinical evaluation of carbon-11 labelled N-((5-(4-fluoro-2-[11C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine as a PET tracer for NR2B subunit-containing NMDA receptors

    International Nuclear Information System (INIS)

    Christiaans, Johannes A.M.; Klein, Pieter J.; Metaxas, Athanasios; Kooijman, Esther J.M.; Schuit, Robert C.; Leysen, Josée E.; Lammertsma, Adriaan A.; Berckel, Bart N.M. van; Windhorst, Albert D.

    2014-01-01

    Introduction: The N-methyl-D-Aspartate (NMDA) receptor plays an important role in learning and memory. Overactivation is thought to play an important role in neurodegenerative disorders such as Alzheimer's disease. Currently, it is not possible to assess N-methyl-D-aspartate receptor (NMDAr) bio-availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NR2B binding site of the NMDA receptor. Methods: N-((5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was radiolabelled with carbon-11 in the phenyl moiety. Biodistribution and blocking studies were carried out in anaesthetized mice and in non-anaesthetized rats. Results: N-((5-(4-fluoro-2-[ 11 C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was prepared in 49 ± 3% (decay-corrected) yield, affording 4.1 ± 0.3 GBq of formulated product at the end of synthesis with a radiochemical purity of > 99% and with a specific activity of 78 ± 10 GBq/μmol. Conclusion: A new NR2B PET ligand was developed in high yield. [ 11 C]4 readily enters the brain and binds to the NR2B subunit-containing NMDAr in the rodent brain. High sigma-1 receptor binding may, however, limit its future application as a PET probe for imaging the NR2B subunit-containing NMDAr. Anaesthesia has an effect on NMDAr function and therefore can complicate interpretation of preclinical in vivo results. In addition, effects of endogenous compounds cannot be excluded. Despite these potential limitations, further studies are warranted to investigate the values of [ 11 C]4 as an NR2B PET ligand

  1. DEVELOPMENTAL LEAD (PB) EXPOSURE REDUCES THE ABILITY OF THE NNDA ANTAGONIST MK801 TO SUPPRESS LONG-TERM POTENTIATION (LTP) IN THE RAT DENTATE GYRUS, IN VIVO

    Science.gov (United States)

    Chronic developmental lead (Pb) exposure increases the threshold and enhances decay of long-term potentiation (LTP) in the dentate gyrus of the hippocampal formation. MK-801 and other antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype impair induction of LT...

  2. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression : a pilot randomized, placebo-controlled continuation trial

    NARCIS (Netherlands)

    Mathew, S.J.; Murrough, J.W.; Aan het Rot, M.; Collins, K.A.; Reich, D.L.; Charney, D.S.

    2010-01-01

    The N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine may have rapid, albeit transient, antidepressant properties. This study in patients with treatment-resistant major depression (TRD) aimed to (1) replicate the acute efficacy of single-close intravenous (i.v.) ketamine; (2) test

  3. Neuromodulatory Effect of Thymoquinone in Attenuating Glutamate-Mediated Neurotoxicity Targeting the Amyloidogenic and Apoptotic Pathways

    Directory of Open Access Journals (Sweden)

    Ibram Amin Fouad

    2018-04-01

    Full Text Available Overexposure of the glutamatergic N-methyl-d-aspartate (NMDA receptor to the excitatory neurotransmitter l-glutamic acid leads to neuronal cell death by excitotoxicity as a result of increased intracellular Ca2+, mitochondrial dysfunction, and apoptosis. Moreover, it was previously reported that prolonged activation of the NMDA receptor increased beta-amyloid (Aβ levels in the brain. Thymoquinone (TQ, the active constituent of Nigella sativa seeds, has been shown to have potent antioxidant and antiapoptotic effects. The aim of the present study was to explore the neuromodulatory effects of different doses of TQ (2.5 and 10 mg/kg against apoptotic cell death and Aβ formation resulting from glutamate administration in rats using vitamin E as a positive control. Behavioral changes were assessed using Y-maze and Morris water maze tests for evaluating spatial memory and cognitive functions. Caspase-3, Lactate dehydrogenase, Aβ-42, and cytochrome c gene expression were determined. TQ-treated groups showed significant decreases in the levels of all tested biochemical and behavioral parameters compared with the glutamate-treated group. These findings demonstrated that TQ has a promising neuroprotective activity against glutamate-induced neurotoxicity and this effect is mediated through its anti-amyloidogenic, antioxidant, and antiapoptotic activities.

  4. Effect of the non-NMDA receptor antagonist GYKI 52466 on the microdialysate and tissue concentrations of amino acids following transient forebrain ischaemia.

    Science.gov (United States)

    Arvin, B; Lekieffre, D; Graham, J L; Moncada, C; Chapman, A G; Meldrum, B S

    1994-04-01

    The effect of the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) on ischaemia-induced changes in the microdialysate and tissue concentrations of glutamate, aspartate, and gamma-aminobutyric acid (GABA) was studied in rats. Twenty minutes of four-vessel occlusion resulted in a transient increase in microdialysate levels of glutamate, aspartate, and GABA in striatum, cortex, and hippocampus. Administration of GYKI 52466 (10 mg/kg bolus + 10 mg/kg/60 min intravenously starting 20 min before onset of ischaemia) inhibited ischaemia-induced increases in microdialysate glutamate and GABA in striatum without affecting the increases in hippocampus or cortex. Twenty minutes of four-vessel occlusion resulted in immediate small decreases and larger delayed (72 h) decreases in tissue levels of glutamate and aspartate. Transient increases in tissue levels of GABA were shown in all three structures at the end of the ischaemic period. At 72 h, after the ischaemic period, significantly reduced GABA levels were observed in striatum and hippocampus. GYKI 52466, given under identical conditions as above, augmented the ischaemia-induced decrease in striatal tissue levels of glutamate and aspartate, without significantly affecting the decreases in hippocampus and cortex. Twenty minutes of ischaemia resulted in a large increase in microdialysate dopamine in striatum. GYKI 52466 failed to inhibit this increase. Kainic acid (500 microM infused through the probe for 20 min) caused increases in microdialysate glutamate and aspartate in the striatum. GYKI 52466 (10 mg/kg bolus + 10 mg/kg/60 min) completely inhibited the kainic acid-induced glutamate release. In conclusion, the action of the non-NMDA antagonist, GYKI 52466, in the striatum is different from that in the cortex and hippocampus. The inhibition by GYKI 52466 of ischaemia-induced and kainate-induced increases in microdialysate

  5. The effect of the mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear.

    Science.gov (United States)

    Handford, Charlotte E; Tan, Shawn; Lawrence, Andrew J; Kim, Jee Hyun

    2014-09-01

    The metabotropic glutamate receptor 5 (mGlu5) and N-methyl-D-aspartate (NMDA) receptor are critical for processes underlying synaptic plasticity, such as long-term potentiation. mGlu5 signaling increases neuronal excitability and potentiates NMDA receptor currents in the amygdala and the hippocampus. The present study examined the involvement of mGlu5 in the acquisition and consolidation of conditioned fear to a tone and context in mice, and explored the functional relationship between mGlu5 and NMDA receptors in this regard. Experiment 1 showed that systemic administration of the mGlu5 negative allosteric modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning significantly attenuated cue-elicited freezing during fear conditioning, which suggests that mGlu5 is necessary for the formation of a tone-shock association. This effect was dose-related (Experiment 2) and not due to any effects of MTEP on shock sensitivity or state-dependency (Experiment 3). Post-conditioning injection of MTEP had no effects (Experiment 4). Although post-conditioning injection of the NMDA receptor partial agonist D-cycloserine (DCS) alone facilitated consolidation of conditioned fear (Experiment 6), it was not able to rescue the acquisition deficit caused by MTEP (Experiment 5). Taken together, these findings indicate a crucial role for mGlu5 signaling in acquisition and NMDA receptor signaling in consolidation of conditioned fear.

  6. Evidence for increased cellular uptake of glutamate and aspartate in the rat hippocampus during kainic acid seizures. A microdialysis study using the "indicator diffusion' method

    DEFF Research Database (Denmark)

    Bruhn, T; Christensen, Thomas; Diemer, Nils Henrik

    1997-01-01

    Using a newly developed technique, based on microdialysis, which allows cellular uptake of glutamate and aspartate to be studied in awake animals, we investigated uptake of glutamate and aspartate in the hippocampal formation of rats during limbic seizures induced by systemical administration of ....... The results indicate that during KA-induced seizures, uptake of glutamate and aspartate is increased, possibly aimed at maintaining the extracellular homeostasis of these two excitatory amino acids.......Using a newly developed technique, based on microdialysis, which allows cellular uptake of glutamate and aspartate to be studied in awake animals, we investigated uptake of glutamate and aspartate in the hippocampal formation of rats during limbic seizures induced by systemical administration...... of kainic acid (KA). With [14C]mannitol as an extracellular reference substance, the cellular extraction of the test substance [3H]D-aspartate was measured at different stages of seizure-activity. The results were compared to those obtained in a sham operated control group. During severe generalized clonic...

  7. Effects of 17beta-estradiol on glutamate synaptic transmission and neuronal excitability in the rat medial vestibular nuclei.

    Science.gov (United States)

    Grassi, S; Frondaroli, A; Scarduzio, M; Dutia, M B; Dieni, C; Pettorossi, V E

    2010-02-17

    We investigated the effects of the neurosteroid 17beta-estradiol (E(2)) on the evoked and spontaneous activity of rat medial vestibular nucleus (MVN) neurons in brainstem slices. E(2) enhances the synaptic response to vestibular nerve stimulation in type B neurons and depresses the spontaneous discharge in both type A and B neurons. The amplitude of the field potential, as well as the excitatory post-synaptic potential (EPSP) and current (EPSC), in type B neurons, are enhanced by E(2). Both effects are long-term phenomena since they outlast the drug washout. The enhancement of synaptic response is mainly due to facilitation of glutamate release mediated by pre-synaptic N-methyl-D-aspartate receptors (NMDARs), since the reduction of paired pulse ratio (PPR) and the increase of miniature EPSC frequency after E(2) are abolished under D-(-)-2-amino-5-phosphonopentanoic acid (AP-5). E(2) also facilitates post-synaptic NMDARs, but it does not affect directly alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and group I-metabotropic glutamate receptors (mGluRs-I). In contrast, the depression of the spontaneous discharge of type A and type B neurons appears to depend on E(2) modulation of intrinsic ion conductances, as the effect remains after blockade of glutamate, GABA and glycine receptors (GlyRs). The net effect of E(2) is to enhance the signal-to-noise ratio of the synaptic response in type B neurons, relative to resting activity of all MVN neurons. These findings provide evidence for a novel potential mechanism to modulate the responsiveness of vestibular neurons to afferent inputs, and so regulate vestibular function in vivo.

  8. Central N-acetyl aspartylglutamate deficit: a possible pathogenesis of schizophrenia.

    Science.gov (United States)

    Tsai, Shih-Jen

    2005-09-01

    The "glutamate hypothesis" of schizophrenia has emerged from the finding that phencyclidine (PCP) induces psychotic-like behaviors in rodents, possibly by blocking the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, thereby causing increased glutamate release. N-acetyl aspartylglutamate (NAAG), an endogenous peptide abundant in mammalian nervous systems, is localized in certain brain cells, including cortical and hippocampal pyramidal neurons. NAAG is synthesized from N-acetylaspartate (NAA) and glutamate, and NAA availability may limit the rate of NAAG synthesis. Although NAAG is known to have some neurotransmitter-like functions, NAA does not. NAAG is a highly selective agonist of the type 3 metabotropic glutamate receptor (mGluR3, a presynaptic autoreceptor) and can inhibit glutamate release. In addition, at low levels, NAAG is an NMDA receptor antagonist, and blocking of NMDA receptors may increase glutamate release. Taken together, low central NAAG levels may antagonize the effect of glutamate at NMDA receptors and decrease its agonistic effect on presynaptic mGluR3; both activities could increase glutamate release, similar to the increase demonstrated in the PCP model of schizophrenia. In this report, it is suggested that the central NAAG deficit, possibly through decreased synthesis or increased degradation of NAAG, may play a role in the pathogenesis of schizophrenia. Evidence is presented and discussed from magnetic resonance, postmortem, animal model, schizophrenia treatment, and genetic studies. The central NAAG deficit model of schizophrenia could explain the disease process, from the perspectives of both neurodevelopment and neurodegeneration, and may point to potential treatments for schizophrenia.

  9. Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus

    Directory of Open Access Journals (Sweden)

    F. A. Zeiler

    2015-01-01

    Full Text Available Refractory status epilepticus (RSE and superrefractory status epilepticus (SRSE pose a difficult clinical challenge. Multiple cerebral receptor and transporter changes occur with prolonged status epilepticus leading to pharmacoresistance patterns unfavorable for conventional antiepileptics. In particular, n-methyl-d-aspartate (NMDA receptor upregulation leads to glutamate mediated excitotoxicity. Targeting these NMDA receptors may provide a novel approach to otherwise refractory seizures. Ketamine has been utilized in RSE. Recent systematic review indicates 56.5% and 63.5% cessation in seizures in adults and pediatrics, respectively. No complications were described. We should consider earlier implementation of ketamine or other NMDA receptor antagonists, for RSE. Prospective study of early implementation of ketamine should shed light on the role of such medications in RSE.

  10. Subchronic administration of LY354740 does not modify ketamine-evoked behavior and neuronal activity in rats

    NARCIS (Netherlands)

    Imre, Gabor; Fokkema, Dirk S.; Ter Horst, Gert J.

    2006-01-01

    Acute treatment with LY354740 {1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate}, a potent and selective agonist for group 11 metabotropic glutamate receptors (mGlu2/3), has previously been shown to block some schizophrenia-like effects of N-methyl-D-aspartate (NMDA) receptor

  11. Distribution of radiolabeled L-glutamate and D-aspartate from blood into peripheral tissues in naive rats: Significance for brain neuroprotection

    International Nuclear Information System (INIS)

    Klin, Yael; Zlotnik, Alexander; Boyko, Matthew; Ohayon, Sharon; Shapira, Yoram; Teichberg, Vivian I.

    2010-01-01

    Research highlights: → Blood glutamate has a half-life time of 2-3 min. → Blood glutamate is submitted to rapid decarboxylation. → Blood glutamate and its metabolites are mainly absorbed in skeletal muscle and liver. → The skeletal muscle and liver are now targets for potential drugs affording brain neuroprotection. -- Abstract: Excess L-glutamate (glutamate) levels in brain interstitial and cerebrospinal fluids (ISF and CSF, respectively) are the hallmark of several neurodegenerative conditions such as stroke, traumatic brain injury or amyotrophic lateral sclerosis. Its removal could prevent the glutamate excitotoxicity that causes long-lasting neurological deficits. As in previous studies, we have established the role of blood glutamate levels in brain neuroprotection, we have now investigated the contribution of the peripheral organs to the homeostasis of glutamate in blood. We have administered naive rats with intravenous injections of either L-[1- 14 C] Glutamic acid (L-[1- 14 C] Glu), L-[G- 3 H] Glutamic acid (L-[G- 3 H] Glu) or D-[2,3- 3 H] Aspartic acid (D-[2,3- 3 H] Asp), a non-metabolized analog of glutamate, and have followed their distribution into peripheral organs. We have observed that the decay of the radioactivity associated with L-[1- 14 C] Glu and L-[G- 3 H] Glu was faster than that associated with glutamate non-metabolized analog, D-[2,3- 3 H] Asp. L-[1- 14 C] Glu was subjected in blood to a rapid decarboxylation with the loss of 14 CO 2 . The three major sequestrating organs, serving as depots for the eliminated glutamate and/or its metabolites were skeletal muscle, liver and gut, contributing together 92% or 87% of total L-[U- 14 C] Glu or D-[2,3- 3 H] Asp radioactivity capture. L-[U- 14 C] Glu and D-[2,3- 3 H] Asp showed a different organ sequestration pattern. We conclude that glutamate is rapidly eliminated from the blood into peripheral tissues, mainly in non-metabolized form. The liver plays a central role in glutamate metabolism

  12. Distribution of radiolabeled L-glutamate and D-aspartate from blood into peripheral tissues in naive rats: Significance for brain neuroprotection

    Energy Technology Data Exchange (ETDEWEB)

    Klin, Yael [Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100 (Israel); Zlotnik, Alexander; Boyko, Matthew; Ohayon, Sharon; Shapira, Yoram [The Division of Anesthesiology, Soroka Medical Center and Ben Gurion University of the Negev, Beer-Sheva (Israel); Teichberg, Vivian I., E-mail: Vivian.teichberg@weizmann.ac.il [Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100 (Israel)

    2010-09-03

    Research highlights: {yields} Blood glutamate has a half-life time of 2-3 min. {yields} Blood glutamate is submitted to rapid decarboxylation. {yields} Blood glutamate and its metabolites are mainly absorbed in skeletal muscle and liver. {yields} The skeletal muscle and liver are now targets for potential drugs affording brain neuroprotection. -- Abstract: Excess L-glutamate (glutamate) levels in brain interstitial and cerebrospinal fluids (ISF and CSF, respectively) are the hallmark of several neurodegenerative conditions such as stroke, traumatic brain injury or amyotrophic lateral sclerosis. Its removal could prevent the glutamate excitotoxicity that causes long-lasting neurological deficits. As in previous studies, we have established the role of blood glutamate levels in brain neuroprotection, we have now investigated the contribution of the peripheral organs to the homeostasis of glutamate in blood. We have administered naive rats with intravenous injections of either L-[1-{sup 14}C] Glutamic acid (L-[1-{sup 14}C] Glu), L-[G-{sup 3}H] Glutamic acid (L-[G-{sup 3}H] Glu) or D-[2,3-{sup 3}H] Aspartic acid (D-[2,3-{sup 3}H] Asp), a non-metabolized analog of glutamate, and have followed their distribution into peripheral organs. We have observed that the decay of the radioactivity associated with L-[1-{sup 14}C] Glu and L-[G-{sup 3}H] Glu was faster than that associated with glutamate non-metabolized analog, D-[2,3-{sup 3}H] Asp. L-[1-{sup 14}C] Glu was subjected in blood to a rapid decarboxylation with the loss of {sup 14}CO{sub 2}. The three major sequestrating organs, serving as depots for the eliminated glutamate and/or its metabolites were skeletal muscle, liver and gut, contributing together 92% or 87% of total L-[U-{sup 14}C] Glu or D-[2,3-{sup 3}H] Asp radioactivity capture. L-[U-{sup 14}C] Glu and D-[2,3-{sup 3}H] Asp showed a different organ sequestration pattern. We conclude that glutamate is rapidly eliminated from the blood into peripheral tissues

  13. Simultaneous determination of D-aspartic acid and D-glutamic acid in rat tissues and physiological fluids using a multi-loop two-dimensional HPLC procedure.

    Science.gov (United States)

    Han, Hai; Miyoshi, Yurika; Ueno, Kyoko; Okamura, Chieko; Tojo, Yosuke; Mita, Masashi; Lindner, Wolfgang; Zaitsu, Kiyoshi; Hamase, Kenji

    2011-11-01

    For a metabolomics study focusing on the analysis of aspartic and glutamic acid enantiomers, a fully automated two-dimensional HPLC system employing a microbore-ODS column and a narrowbore-enantioselective column was developed. By using this system, a detailed distribution of D-Asp and D-Glu besides L-Asp and L-Glu in mammals was elucidated. For the total analysis concept, the amino acids were first pre-column derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) to be sensitively and fluorometrically detected. For the non-stereoselective separation of the analytes in the first dimension a monolithic ODS column (750 mm × 0.53 mm i.d.) was adopted, and a self-packed narrowbore-Pirkle type enantioselective column (Sumichiral OA-2500S, 250 mm × 1.5 mm i.d.) was selected for the second dimension. In the rat plasma, RSD values for intra-day and inter-day precision were less than 6.8%, and the accuracy ranged between 96.1% and 105.8%. The values of LOQ of D-Asp and D-Glu were 5 fmol/injection (0.625 nmol/g tissue). The present method was successfully applied to the simultaneous determination of free aspartic acid and glutamic acid enantiomers in 7 brain areas, 11 peripheral tissues, plasma and urine of Wistar rats. Biologically significant D-Asp values were found in various tissue samples whereas for D-Glu the values were very low possibly indicating less significance. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons

    Science.gov (United States)

    Wang, Wei-Ping; Iyo, Abiye H.; Miguel-Hidalgo, Javier; Regunathan, Soundar; Zhu, Meng-Yang

    2010-01-01

    Agmatine is a polyamine and has been considered as a novel neurotransmitter or neuromodulator in the central nervous system. In the present study, the neuroprotective effect of agmatine against cell damage caused by N-methyl-d-aspartate (NMDA) and glutamate was investigated in cultured rat hippocampal neurons. Lactate dehydrogenase (LDH) activity assay, β-tubulin III immunocytochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay were conducted to detect cell damage. Exposure of 12-day neuronal cultures of rat hippocampus to NMDA or glutamate for 1 h caused a concentration-dependent neurotoxicity, as indicated by the significant increase in released LDH activities. Addition of 100 µM agmatine into media ablated the neurotoxicity induced by NMDA or glutamate, an effect also produced by the specific NMDA receptor antagonist dizocilpine hydrogen maleate (MK801). Arcaine, an analog of agmatine with similar structure as agmatine, fully prevented the NMDA- or glutamate-induced neuronal damage. Spermine and putrescine, the endogenous polyamine and metabolic products of agmatine without the guanidine moiety of agmatine, failed to show this effect, indicating a structural relevance for this neuroprotection. Immunocytochemical staining and TUNEL assay confirmed the findings in the LDH measurement. That is, agmatine and MK801 markedly attenuated NMDA-induced neuronal death and significantly reduced TUNEL-positive cell numbers induced by exposure of cultured hippocampal neurons to NMDA. Taken together, these results demonstrate that agmatine can protect cultured hippocampal neurons from NMDA- or glutamate-induced excitotoxicity, through a possible blockade of the NMDA receptor channels or a potential anti-apoptotic property. PMID:16546145

  15. The role of NMDA receptor and nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like effect of dextromethorphan in mice forced swimming test and tail suspension test.

    Science.gov (United States)

    Sakhaee, Ehsan; Ostadhadi, Sattar; Khan, Muhammad Imran; Yousefi, Farbod; Norouzi-Javidan, Abbas; Akbarian, Reyhaneh; Chamanara, Mohsen; Zolfaghari, Samira; Dehpour, Ahmad-Reza

    2017-01-01

    Depression is a devastating disorder which has a high impact on the wellbeing of overall society. As such, need for innovative therapeutic agents are always there. Most of the researchers focused on N-methyl-d-aspartate receptor to explore the antidepressant like activity of new therapeutic agents. Dextromethorphan is a cough suppressant agent with potential antidepressant activity reported in mouse force swimming test. Considering N-methyl-d-aspartate as a forefront in exploring antidepressant agents, here we focused to unpin the antidepressant mechanism of dextromethorphan targeting N-methyl-d-aspartate receptor induced nitric oxide-cyclic guanosine monophosphate signaling. Dextromethorphan administered at a dose of 10 and 30mg/kg i.p significantly reduced the immobility time. Interestingly, this effect of drug (30mg/kg) was inhibited when the animals were pretreated either with N-methyl-d-aspartate (75mg/kg), or l-arginine (750mg/kg) as a nitric oxide precursor and/or sildenafil (5mg/kg) as a phosphodiesterase 5 inhibitor. However, the antidepressant effect of Dextromethorphan subeffective dose (3mg/kg) was augmented when the animals were administered with either L-NG-Nitroarginine methyl ester (10mg/kg) non-specific nitric oxide synthase inhibitor, 7-Nitroindazole (30mg/kg) specific neural nitric oxide synthase inhibitor, MK-801 (0.05mg/kg) an N-methyl-d-aspartate receptor antagonist but not aminoguanidine (50mg/kg) which is specific inducible nitric oxide synthase inhibitor as compared to the drugs when administered alone. No remarkable effect on locomotor activity was observed during open field test when the drugs were administered at the above mentioned doses. Therefore, it is evident that the antidepressant like effect of Dextromethorphan is owed due to its inhibitory effect on N-methyl-d-aspartate receptor and NO- Cyclic guanosine monophosphate pathway. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d-aspartate (NMDA) Receptor Antagonist

    DEFF Research Database (Denmark)

    Gynther, Mikko; Proietti Silvestri, Ilaria; Hansen, Jacob C

    2017-01-01

    -acting ionotropic glutamate receptor antagonist 1a. Subsequently, we demonstrate that 1l augments the cytotoxic action of sorafenib in murine hepatocellular carcinoma cells. The underlying biological mechanism was shown to be interference with the lipid signaling pathway, leading to reduced expression of MDR...

  17. Combination of aspartic acid and glutamic acid inhibits tumor cell proliferation.

    Science.gov (United States)

    Yamaguchi, Yoshie; Yamamoto, Katsunori; Sato, Yoshinori; Inoue, Shinjiro; Morinaga, Tetsuo; Hirano, Eiichi

    2016-01-01

    Placental extract contains several biologically active compounds, and pharmacological induction of placental extract has therapeutic effects, such as improving liver function in patients with hepatitis or cirrhosis. Here, we searched for novel molecules with an anti-tumor activity in placental extracts. Active molecules were separated by chromatographic analysis, and their antiproliferative activities were determined by a colorimetric assay. We identified aspartic acid and glutamic acid to possess the antiproliferative activity against human hepatoma cells. Furthermore, we showed that the combination of aspartic acid and glutamic acid exhibited enhanced antiproliferative activity, and inhibited Akt phosphorylation. We also examined in vivo tumor inhibition activity using the rabbit VX2 liver tumor model. The treatment mixture (emulsion of the amino acids with Lipiodol) administered by hepatic artery injection inhibited tumor cell growth of the rabbit VX2 liver. These results suggest that the combination of aspartic acid and glutamic acid may be useful for induction of tumor cell death, and has the potential for clinical use as a cancer therapeutic agent.

  18. Anti-N-methyl-D-aspartate receptor(NMDAR) antibody encephalitis presents in atypical types and coexists with neuromyelitis optica spectrum disorder or neurosyphilis.

    Science.gov (United States)

    Qin, Kaiyu; Wu, Wenqing; Huang, Yuming; Xu, Dongmei; Zhang, Lei; Zheng, Bowen; Jiang, Meijuan; Kou, Cheng; Gao, Junhua; Li, Wurong; Zhang, Jinglin; Wang, Sumei; Luan, Yanfei; Yan, Chaoling; Xu, Dan; Zheng, Xinmei

    2017-01-05

    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a clinically heterogeneous disorder characterized by epileptic seizures, psychosis, dyskinesia, consciousness impairments, and autonomic instability. Symptoms are always various. Sometimes it presents in milder or incomplete forms. We report 4 cases of anti-NMDAR encephalitis with incomplete forms, 3 cases of which were accompanied by neuromyelitis optica spectrum disorder or neurosyphilis respectively. A 33-year-old man presented with dysarthria, movement disorder and occasional seizures. He had 6 relapses in 28 years. When suffered from upper respiratory tract syndrome, he developed behavioral and consciousness impairment. Cranial MRI was normal. Viral PCR studies and oncologic work-up were negative. Anti-NMDAR antibody was detected in CSF and serum. A 21-year-old female manifested dizziness and diplopia ten months and six months before, respectively. Both responded to steroid therapy and improved completely. This time she presented with progressive left limb and facial anesthesia, walking and holding unsteadily. Spinal cord MRI follow-up showed abnormality of medulla oblongata and cervical cord(C1). Anti-AQP4 and anti-NMDAR were positive in CSF. Steroid-pulse therapy ameliorated her symptoms. A 37-year-old male experienced worsening vision. He was confirmed neurosyphilis since the CSF tests for syphilis were positive. Protein was elevated and the oligoclonal IgG bands(OB) and anti-NMDAR was positive in CSF. Anti-aquaporin 4(AQP4) antibodies and NMO-IgG were negative. Cranial MRI showed high FLAIR signal on frontal lobe and low T2 signal adjacent to the right cornu posterious ventriculi lateralis. Treatment for neurosyphlis was commenced with gradual improvement. A 39-year-old male, developed serious behavioral and psychiatric symptoms. Examination showed abnormal pupils and unsteady gait. He was confirmed neurosyphilis according to the CSF tests for syphilis. Anti-NMDAR was positive in CSF and serum

  19. Mapping of the human NMDA receptor subunit (NMDAR1) and the proposed NMDA receptor glutamate-binding subunit (NMDARA1) to chromosomes 9q34.3 and chromosome 8, respectively

    DEFF Research Database (Denmark)

    Collins, C; Duff, C; Duncan, A M

    1993-01-01

    to human chromosome 8 using a somatic cell hybrid panel. Because the gene causing HD has been localized to chromosome 4p16.3, the chromosome assignments reported here are inconsistent with either of these genes playing a causative role in the molecular pathology of HD. However, it is noteworthy......A role for the N-methyl-D-aspartate (NMDA) receptor in the molecular pathology underlying Huntington disease (HD) has been proposed on the basis of neurochemical studies in HD and the ability of the NMDA receptor to mediate neuronal cell death. The molecular cloning of the human NMDA receptor...

  20. Synthesis and structure-activity studies on acidic amino acids and related diacids as NMDA receptor ligands

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1994-01-01

    The 3-isoxazolol amino acids (S)-2-amino-3-(3-hydroxy-5-methyl-4- isoxazolyl)propionic acid [(S)-AMPA, 2] and (R,S)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA, 5a) (Figure 1) are potent and specific agonists at the AMPA and N-methyl-D-aspartic acid (NMDA) subtypes, respectively......, of (S)-glutamic acid (1) receptors. A number of amino acids and diacids structurally related to AMAA were synthesized and tested electrophysiologically and in receptor-binding assays. The hydroxymethyl analogue 7c of AMAA was an NMDA agonist approximately equipotent with AMAA in the [3H...... by molecular mechanics calculations. Compound 7a possesses extra steric bulk and shows significant restriction of conformational flexibility compared to AMAA and 7c, which may be determining factors for the observed differences in biological activity. Although the nitrogen atom of quinolinic acid (6) has very...

  1. Valine but not leucine or isoleucine supports neurotransmitter glutamate synthesis during synaptic activity in cultured cerebellar neurons

    DEFF Research Database (Denmark)

    Bak, Lasse Kristoffer; Johansen, Maja L.; Schousboe, Arne

    2012-01-01

    Synthesis of neuronal glutamate from a-ketoglutarate for neurotransmission necessitates an amino group nitrogen donor; however, it is not clear which amino acid(s) serves this role. Thus, the ability of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, to act as amino...... group nitrogen donors for synthesis of vesicular neurotransmitter glutamate was investigated in cultured mouse cerebellar (primarily glutamatergic) neurons. The cultures were superfused in the presence of (15) N-labeled BCAAs, and synaptic activity was induced by pulses of N-methyl-D-aspartate (300 µ......]valine was able to maintain the amount of vesicular glutamate during synaptic activity. This indicates that, among the BCAAs, only valine supports the increased need for synthesis of vesicular glutamate. © 2012 Wiley Periodicals, Inc....

  2. Regulation of Arterial Pressure By The Paraventricular Nucleus in Conscious Rats: Interactions Among Glutamate, GABA, and Nitric Oxide

    Directory of Open Access Journals (Sweden)

    Marli Cardoso Martins-Pinge

    2013-01-01

    Full Text Available The paraventricular nucleus (PVN of the hypothalamus is an important site for autonomic and neuroendocrine regulation. Experiments in anesthetized animals and in vitro indicate an interaction among gamma-aminobutyric acid (GABA, nitric oxide (NO and glutamate in the PVN. The cardiovascular role of the PVN and interactions of these neurotransmitters in conscious animals have not been evaluated fully. In chronically instrumented conscious rats, mean arterial pressure (MAP and heart rate (HR responses to microinjections (100 nl in the region of the PVN were tested. Bilateral blockade of ionotropic excitatory amino acid (EAA receptors (kynurenic acid, Kyn in the PVN produced small but significant decreases in MAP and HR. GABAA receptor blockade (bicuculline, Bic, and inhibition of NO synthase (N-(G-monomethyl-L-arginine, L-NMMA each increased MAP and HR. The NO donor sodium nitroprusside (SNP produced depressor responses that were attenuated by Bic. NO synthase inhibition potentiated both pressor responses to the selective EAA agonist, N-methyl-D-aspartic acid (NMDA, and depressor responses to Kyn. Increases in MAP and HR due to Bic were blunted by prior blockade of EAA receptors. Thus, pressor responses to GABA blockade require EAA receptors and GABA neurotransmission contributes to NO inhibition. Tonic excitatory effects of glutamate in the PVN are tonically attenuated by NO. These data demonstrate that, in the PVN of conscious rats, GABA, glutamate and NO interact in a complex fashion to regulate arterial pressure and heart rate under normal conditions.

  3. Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Lara Hwa

    2017-03-01

    Full Text Available Glutamate signaling in the brain is one of the most studied targets in the alcohol research field. Here, we report the current understanding of how the excitatory neurotransmitter glutamate, its receptors, and its transporters are involved in low, episodic, and heavy alcohol use. Specific animal behavior protocols can be used to assess these different drinking levels, including two-bottle choice, operant self-administration, drinking in the dark, the alcohol deprivation effect, intermittent access to alcohol, and chronic intermittent ethanol vapor inhalation. Importantly, these methods are not limited to a specific category, since they can be interchanged to assess different states in the development from low to heavy drinking. We encourage a circuit-based perspective beyond the classic mesolimbic-centric view, as multiple structures are dynamically engaged during the transition from positive- to negative-related reinforcement to drive alcohol drinking. During this shift from lower-level alcohol drinking to heavy alcohol use, there appears to be a shift from metabotropic glutamate receptor-dependent behaviors to N-methyl-D-aspartate receptor-related processes. Despite high efficacy of the glutamate-related pharmaceutical acamprosate in animal models of drinking, it is ineffective as treatment in the clinic. Therefore, research needs to focus on other promising glutamatergic compounds to reduce heavy drinking or mediate withdrawal symptoms or both.

  4. Adaptation Mechanism of the Aspartate Receptor: Electrostatics of the Adaptation Subdomain Play a Key Role in Modulating Kinase Activity†

    Science.gov (United States)

    Starrett, Diane J.; Falke, Joseph J.

    2010-01-01

    The aspartate receptor of the Escherichia coli and Salmonella typhimurium chemotaxis pathway generates a transmembrane signal that regulates the activity of the cytoplasmic kinase CheA. Previous studies have identified a region of the cytoplasmic domain that is critical to receptor adaptation and kinase regulation. This region, termed the adaptation subdomain, contains a high density of acidic residues, including specific glutamate residues that serve as receptor adaptation sites. However, the mechanism of signal propagation through this region remains poorly understood. This study uses site-directed mutagenesis to neutralize each acidic residue within the subdomain to probe the hypothesis that electrostatics in this region play a significant role in the mechanism of kinase activation and modulation. Each point mutant was tested for its ability to regulate chemotaxis in vivo and kinase activity in vitro. Four point mutants (D273N, E281Q, D288N, and E477Q) were found to superactivate the kinase relative to the wild-type receptor, and all four of these kinase-activating substitutions are located along the same intersubunit interface as the adaptation sites. These activating substitutions retained the wild-type ability of the attractant-occupied receptor to inhibit kinase activity. When combined in a quadruple mutant (D273N/E281Q/D288N/E477Q), the four charge-neutralizing substitutions locked the receptor in a kinase-superactivating state that could not be fully inactivated by the attractant. Similar lock-on character was observed for a charge reversal substitution, D273R. Together, these results implicate the electrostatic interactions at the intersubunit interface as a major player in signal transduction and kinase regulation. The negative charge in this region destabilizes the local structure in a way that enhances conformational dynamics, as detected by disulfide trapping, and this effect is reversed by charge neutralization of the adaptation sites. Finally, two

  5. Curcumin Protects against Monosodium Glutamate Neurotoxicity and Decreasing NMDA2B and mGluR5 Expression in Rat Hippocampus

    Directory of Open Access Journals (Sweden)

    Rania M. Khalil

    2016-08-01

    Full Text Available Background: Monosodium glutamate (MSG is a flavor enhancer used in food industries. MSG is well documented to induce neurotoxicity. Curcumin (CUR reportedly possesses beneficial effects against various neurotoxic insults. Hence, this present study has been designed to evaluate the neuroprotective effect of curcumin on MSG-induced neurotoxicity in rats. Methods: Thirty-two male Wister rats were divided into four groups (n=8: Control group, MSG group, CUR group and MSG + CUR group. CUR (Curcumin 150 mg/kg, orally was given day after day for four weeks along with MSG (4 mg/kg, orally. After 4 weeks, rats were sacrificed and brain hippocampus was isolated immediately on ice. Inflammatory marker TNFα and acetylcholinesterase (AChE activity (marker for cholinergic function were estimated. Gene expressions of metabotropic glutamate receptor 5 (mGluR5 and N-methyl-D-aspartate receptor 2B (NMDA2B along with glutamate concentration were assessed. Results: Treatment with CUR significantly attenuated AChE activity and TNFα in MSG-treated animals. The anti-inflammatory properties of CUR may be responsible for this observed neuroprotective action. A possible role of CUR to attenuate both glutamate level and gene expression of NMDA2B and mGLUR5 in brain hippocampus was established when compared to MSG group. Conclusion: We concluded that CUR as flavor enhancer protects against MSG-induced neurotoxicity in rats.

  6. Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats.

    Science.gov (United States)

    Wang, Xiao-Fei; Zhao, Tai-Yun; Su, Rui-Bin; Wu, Ning; Li, Jin

    2016-12-01

    Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

  7. Calix[4]arene-Based Enantioselective Fluorescent Sensors for the Recognition of N-Acetyl-aspartate

    Institute of Scientific and Technical Information of China (English)

    QING Guang-Yan; CHEN Zhi-Hong; WANG Feng; YANG Xi; MENG Ling-Zhi; HE Yong-Bing

    2008-01-01

    Two-armed chiral anion receptors (1 and 2), calix[4]arenes bearing dansyl fluorophore and (1R,2R)- or(1S,2S)-1,2-diphenylethylenediamine binding sites, were prepared and examined for their chiral amino acid anion binding abilities by the fluorescence spectra in dimethylsulfoxide (DMSO). The results of non-linear curve fitting indicate that 1 or 2 forms a 1 : 1 stoichiometry complex with N-acetyl-L-or D-aspartate by multiple hydrogen bonding interactions, exhibiting good enantioselective fluorescent recognition for the enantiomers of N-acetyl-as-partate, [receptor 1: Kass(D)/Kass(L)=6.74; receptor 2: Kass(L)/Kass(D)=6.48]. The clear fluorescent response difference indicates that receptors 1 and 2 could be used as a fluorescent chemosensor for N-Acetyl-aspartate.

  8. Neuroprotection of rat retinal ganglion cells mediated through alpha7 nicotinic acetylcholine receptors.

    Science.gov (United States)

    Iwamoto, K; Mata, D; Linn, D M; Linn, C L

    2013-05-01

    Glutamate-induced excitotoxicity is thought to play an important role in several neurodegenerative diseases in the central nervous system (CNS). In this study, neuroprotection against glutamate-induced excitotoxicity was analyzed using acetylcholine (ACh), nicotine and the α7 specific nicotinic acetylcholine receptor (α7 nAChR) agonist, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-282987), in cultured adult rat retinal neurons. Adult Long Evans rat retinas were dissociated and retinal ganglion cells (RGCs) were isolated from all other retinal tissue using a two-step panning technique. Once isolated, RGCs were cultured under various pharmacological conditions to demonstrate excitotoxicity and neuroprotection against excitotoxicity. After 3 days, RGCs were immunostained with antibodies against the glycoprotein, Thy 1.1, counted and cell survival was assessed relative to control untreated conditions. 500 μM glutamate induced excitotoxicity in large and small RGCs in an adult rat dissociated culture. After 3 days in culture with glutamate, the cell survival of large RGCs decreased by an average of 48.16% while the cell survival of small RGCs decreased by an average of 42.03%. Using specific glutamate receptor agonists and antagonists, we provide evidence that the excitotoxic response was mediated through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainic acid (KA) and N-methyl-d-aspartate (NMDA) glutamate receptors through an apoptotic mechanism. However, the excitotoxic effect of glutamate on all RGCs was eliminated if cells were cultured for an hour with 10 μM ACh, 100 μM nicotine or 100 nM of the α7 nAChR agonist, PNU-282987, before the glutamate insult. Inhibition studies using 10nM methyllycaconitine (MLA) or α-bungarotoxin (α-Bgt) supported the hypothesis that neuroprotection against glutamate-induced excitotoxicity on rat RGCs was mediated through α7 nAChRs. In immunocytochemical studies, double

  9. Studies of the pH dependence of 13C shifts and carbon-carbon coupling constants of [U-13C]aspartic and -glutamic acids

    International Nuclear Information System (INIS)

    London, R.E.; Walker, T.E.; Kollman, V.H.; Matwiyoff, N.A.

    1978-01-01

    13 C NMR studies of the chemical shifts and carbon--carbon spin--spin coupling constants of 90% [U- 13 C]aspartic and -glutamic acids are reported. Effects of titration of the two carboxyl groups are separated computationally and the results compared with those for asparagine and glutamine, aspartate and glutamate containing peptides, and a series of amino-n-butyric acids. The results indicate that the carboxyl carbon shift resulting from titration of the carboxyl group is strongly dependent on its distance (number of bonds) from an amino group. Alternatively, remote methyl groups exhibit a much smaller titration induced shift than carboxyl groups in the corresponding position. Significant remote effects of pH titration on the one-bond carbon-carbon coupling are also observed, particularly for couplings involving the side-chain carboxyl carbons. These results are discussed in terms of polarization of the C--O bonds in response to titration of a remote carboxyl group. Values of 3 J/sub CC/ in asparate and glutamate indicate a strong conformational dependence. Rotamer populations predicted on the basis of the observed couplings and theoretical INDO calculations are in good agreement with values based on analysis of the 3 J/sub HH/ and 3 J/sub CH/ couplings. For a given conformation of glutamic acid, it is found that 3 J 14 is considerably smaller than 3 J 25 . This result is consistent with obsrvations on a number of other 13 C-labeled amino acids. 5 figures, 4 tables

  10. LOCALIZATION OF NMDA AND AMPA RECEPTORS IN RAT BARREL FIELD

    NARCIS (Netherlands)

    JAARSMA, D; SEBENS, JB; KORF, J

    1991-01-01

    The aim of this study was to asses the distribution of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-S-methyl-4-isoxazole propionic acid (AMPA) receptors in the barrel field of rat primary somatosensory (SI) cortex using light-microscopic in vitro autoradiography. NMDA receptors were labeled

  11. Neurological effects of inorganic arsenic exposure: altered cysteine/glutamate transport, NMDA expression and spatial memory impairment.

    Directory of Open Access Journals (Sweden)

    Lucio A Ramos-Chávez

    2015-02-01

    Full Text Available Inorganic arsenic (iAs is an important natural pollutant. Millions of individuals worldwide drink water with high levels of iAs. Chronic exposure to iAs has been associated with lower IQ and learning disabilities as well as memory impairment. iAs is methylated in tissues such as the brain generating mono and dimethylated species. iAs methylation requires cellular glutathione (GSH, which is the main antioxidant in the central nervous system. In humans, As species cross the placenta and are found in cord blood. A CD1 mouse model was used to investigate effects of gestational iAs exposure which can lead to oxidative damage, disrupted cysteine/glutamate transport and its putative impact in learning and memory. On postnatal days (PNDs 1, 15 and 90, the expression of membrane transporters related to GSH synthesis and glutamate transport and toxicity, such as xCT, EAAC1, GLAST and GLT1, as well as LAT1, were analyzed. Also, the expression of the glutamate receptor N-methyl-D-aspartate (NMDAR subunits NR2A and B as well as the presence of As species in cortex and hippocampus were investigated. On PND 90, an object location task was performed to associate exposure with memory impairment. Gestational exposure to iAs affected the expression of cysteine/glutamate transporters in cortex and hippocampus and induced a negative modulation of NMDAR NR2B subunit in the hippocampus. Behavioral tasks showed significant spatial memory impairment in males while the effect was marginal in females.

  12. Enhancing NMDA Receptor Function: Recent Progress on Allosteric Modulators

    Directory of Open Access Journals (Sweden)

    Lulu Yao

    2017-01-01

    Full Text Available The N-methyl-D-aspartate receptors (NMDARs are subtype glutamate receptors that play important roles in excitatory neurotransmission and synaptic plasticity. Their hypo- or hyperactivation are proposed to contribute to the genesis or progression of various brain diseases, including stroke, schizophrenia, depression, and Alzheimer’s disease. Past efforts in targeting NMDARs for therapeutic intervention have largely been on inhibitors of NMDARs. In light of the discovery of NMDAR hypofunction in psychiatric disorders and perhaps Alzheimer’s disease, efforts in boosting NMDAR activity/functions have surged in recent years. In this review, we will focus on enhancing NMDAR functions, especially on the recent progress in the generation of subunit-selective, allosteric positive modulators (PAMs of NMDARs. We shall also discuss the usefulness of these newly developed NMDAR-PAMs.

  13. Activity of the lactate-alanine shuttle is independent of glutamate-glutamine cycle activity in cerebellar neuronal-astrocytic cultures

    DEFF Research Database (Denmark)

    Bak, Lasse K; Sickmann, Helle M; Schousboe, Arne

    2004-01-01

    The glutamate-glutamine cycle describes the neuronal release of glutamate into the synaptic cleft, astrocytic uptake, and conversion into glutamine, followed by release for use as a neuronal glutamate precursor. This only explains the fate of the carbon atoms, however, and not that of the ammonia....... Recently, a role for alanine has been proposed in transfer of ammonia between glutamatergic neurons and astrocytes, denoted the lactate-alanine shuttle (Waagepetersen et al. [ 2000] J. Neurochem. 75:471-479). The role of alanine in this context has been studied further using cerebellar neuronal cultures...... and corresponding neuronal-astrocytic cocultures. A superfusion paradigm was used to induce repetitively vesicular glutamate release by N-methyl-D-aspartate (NMDA) in the neurons, allowing the relative activity dependency of the lactate-alanine shuttle to be assessed. [(15)N]Alanine (0.2 mM), [2-(15)N]/[5-(15)N...

  14. Changes in Glutamate/NMDA Receptor Subunit 1 Expression in Rat Brain after Acute and Subacute Exposure to Methamphetamine

    Directory of Open Access Journals (Sweden)

    Walailuk Kerdsan

    2009-01-01

    Full Text Available Methamphetamine (METH is a psychostimulant drug of abuse that produces long-term behavioral changes including behavioral sensitization, tolerance, and dependence. METH has been reported to induce neurotoxic effects in several areas of the brain via the dopaminergic system. Changes of dopamine function can induce malfunction of the glutamatergic system. Therefore, the aim of the present study was to examine the effects of METH administration on the expression of glutamate N-methyl-D-aspartate receptor subunit 1 (NMDAR1 in frontal cortex, striatum, and hippocampal formation after acute and subacute exposure to METH by western blotting. Male Sprague-Dawley rats were injected intraperitoneally with a single dose of 8 mg/kg METH, 4 mg/kg/day METH for 14 days and saline in acute, subacute, and control groups, respectively. A significant increase in NMDAR1 immunoreactive protein was found in frontal cortex in the subacute group (P=.036 but not in the acute group (P=.580. Moreover, a significant increase in NMDAR1 was also observed in striatum in both acute (P=.025 and subacute groups (P=.023. However, no significant differences in NMDAR1 in hippocampal formation were observed in either acute or subacute group. The results suggest that an upregulation of NMDA receptor expression may be a consequence of glutamatergic dysfunction induced by METH.

  15. Site-specific and synergistic stimulation of methylation on the bacterial chemotaxis receptor Tsr by serine and CheW

    Directory of Open Access Journals (Sweden)

    Weis Robert M

    2005-03-01

    Full Text Available Abstract Background Specific glutamates in the methyl-accepting chemotaxis proteins (MCPs of Escherichia coli are modified during sensory adaptation. Attractants that bind to MCPs are known to increase the rate of receptor modification, as with serine and the serine receptor (Tsr, which contributes to an increase in the steady-state (adapted methylation level. However, MCPs form ternary complexes with two cytoplasmic signaling proteins, the kinase (CheA and an adaptor protein (CheW, but their influences on receptor methylation are unknown. Here, the influence of CheW on the rate of Tsr methylation has been studied to identify contributions to the process of adaptation. Results Methyl group incorporation was measured in a series of membrane samples in which the Tsr molecules were engineered to have one available methyl-accepting glutamate residue (297, 304, 311 or 493. The relative rates at these sites (0.14, 0.05, 0.05 and 1, respectively differed from those found previously for the aspartate receptor (Tar, which was in part due to sequence differences between Tar and Tsr near site four. The addition of CheW generated unexpectedly large and site-specific rate increases, equal to or larger than the increases produced by serine. The increases produced by serine and CheW (added separately were the largest at site one, ~3 and 6-fold, respectively, and the least at site four, no change and ~2-fold, respectively. The rate increases were even larger when serine and CheW were added together, larger than the sums of the increases produced by serine and CheW added separately (except site four. This resulted in substantially larger serine-stimulated increases when CheW was present. Also, CheW enhanced methylation rates when either two or all four sites were available. Conclusion The increase in the rate of receptor methylation upon CheW binding contributes significantly to the ligand specificity and kinetics of sensory adaptation. The synergistic effect of

  16. Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity

    Directory of Open Access Journals (Sweden)

    Douglas Bledsoe

    2017-05-01

    Full Text Available N-methyl D-aspartate receptors (NMDAR play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A–D and two GluN3 (A–B subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD and ligand binding domain (LBD, transmembrane domain (TMD and an intracellular C-terminal domain (CTD. Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics.

  17. Evaluation of the role of NMDA receptor function in antidepressant-like activity. A new study with citalopram and fluoxetine in the forced swim test in mice.

    Science.gov (United States)

    Wolak, Małgorzata; Siwek, Agata; Szewczyk, Bernadeta; Poleszak, Ewa; Bystrowska, Beata; Moniczewski, Andrzej; Rutkowska, Anita; Młyniec, Katarzyna; Nowak, Gabriel

    2015-06-01

    The NMDA/glutamate receptors are involved in the mechanism of antidepressant activity. The present study was designed to investigate the effect of NMDA receptor ligands (agonists and antagonists of glutamate sites) on the antidepressant-like activity of selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, in the forced swim test in mice. The antidepressant activity (reduction in immobility time) of citalopram but not of fluoxetine was antagonized by N-methyl-D-aspartate acid and enhanced by CGP37849 (antagonist of the NMDA receptor). The present literature data indicate that the antidepressant-like activity of conventional antidepressants is generally affected by the NMDA receptor, although by modulation from different sites of the complex. Thus, it supports the issue of the ability of NMDA receptor antagonists to enhance the antidepressant action in human depression. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  18. Meta-analysis of the association between N-methyl-d-aspartate receptor antibodies and schizophrenia, schizoaffective disorder, bipolar disorder, and major depressive disorder.

    Science.gov (United States)

    Pearlman, Daniel M; Najjar, Souhel

    2014-08-01

    N-methyl-d-aspartate receptor (NMDAR) antibodies have been documented in the serum of individuals with primary psychiatric disorders from several independent cohorts, but these findings have not been systematically assessed in aggregate or in relation to methodological covariates. We searched MEDLINE, EMBASE, and PsycINFO for studies in any language that provided data on NMDAR antibody seropositivity or absolute serum titers in schizophrenia or schizoaffective, bipolar, or major depressive disorders. We used a random effects model to pool estimates across studies. Nine studies met the eligibility criteria. Five studies (3387 participants) provided data on NMDAR antibody seropositivity in psychiatric versus control groups based on high-specificity seropositivity thresholds (cell-based assays [CBAs]: 1:320 dilution, 1:200 dilution, visual score>1; enzyme-linked immunosorbent assay [ELISA]: 90(th) percentile of control titers). Meta-analysis showed significantly higher odds of NMDAR antibody seropositivity among those with schizophrenia or schizoaffective, bipolar, or major depressive disorders compared with healthy controls (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.04-9.27; P=.043; I(2)=68%). Four studies (3194 participants) provided outcome data for these groups based on low-specificity seropositivity thresholds (CBAs 1:10 dilution; ELISA: 75(th) percentile of control titers). Meta-analysis showed greater heterogeneity and no significant between-group difference (OR, 2.31; 95% CI, 0.55-9.73; P=.25; I(2)=90%). Seropositive participants in psychiatric groups had various combinations of IgG, IgM, and IgA class antibodies against NR1, NR1/NR2B, and NR2A/NR2B subunits. Subgroup analysis revealed significantly higher odds of seropositivity among all participants based on 1:10 versus 1:320 dilution seropositivity thresholds (OR, 4.56; 95% CI, 2.41-8.62; Pschizoaffective disorder (OR, 1.15; 95% CI, 0.19-7.24; P=.88, I(2)=43%, studies=2, n=1108). Average NR2A

  19. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  20. Acute D2/D3 dopaminergic agonism but chronic D2/D3 antagonism prevents NMDA antagonist neurotoxicity.

    Science.gov (United States)

    Farber, Nuri B; Nemmers, Brian; Noguchi, Kevin K

    2006-09-15

    Antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor, most likely by producing disinhibtion in complex circuits, acutely produce psychosis and cognitive disturbances in humans, and neurotoxicity in rodents. Studies examining NMDA Receptor Hypofunction (NRHypo) neurotoxicity in animals, therefore, may provide insights into the pathophysiology of psychotic disorders. Dopaminergic D2 and/or D3 agents can modify psychosis over days to weeks, suggesting involvement of these transmitter system(s). We studied the ability of D2/D3 agonists and antagonists to modify NRHypo neurotoxicity both after a one-time acute exposure and after chronic daily exposure. Here we report that D2/D3 dopamine agonists, probably via D3 receptors, prevent NRHypo neurotoxicity when given acutely. The protective effect with D2/D3 agonists is not seen after chronic daily dosing. In contrast, the antipsychotic haloperidol does not affect NRHypo neurotoxicity when given acutely at D2/D3 doses. However, after chronic daily dosing of 1, 3, or 5 weeks, haloperidol does prevent NRHypo neurotoxicity with longer durations producing greater protection. Understanding the changes that occur in the NRHypo circuit after chronic exposure to dopaminergic agents could provide important clues into the pathophysiology of psychotic disorders.

  1. Synthesis and binding characteristics of N-(1-naphthyl)-N'-(3-[125I]-iodophenyl)-N'-methylguanidine ([125I]-CNS 1261): a potential SPECT agent for imaging NMDA receptor activation

    International Nuclear Information System (INIS)

    Owens, Jonathan; Tebbutt, Andrew A.; McGregor, Ailsa L.; Kodama, K.; Magar, Sharad S.; Perlman, Michael E.; Robins, David J.; Durant, Graham J.; McCulloch, James

    2000-01-01

    N-(1-Naphthyl)-N'-(3-[ 125 I]-iodophenyl)-N'-methylguanidine ([ 125 I]-CNS 1261) was synthesized as a potential radioligand to image N-methyl-D-aspartate (NMDA) receptor activation. [ 125 I]-CNS 1261 was prepared by radioiodination of N-(1-naphthyl)-N'-(3-tributylstannylphenyl)-N'-methylguanidine using Na 125 I and peracetic acid. [ 125 I]-CNS 1261 uptake in vivo reflected NMDA receptor distribution in normal rat brain, whereas in ischemic rat brain, uptake was markedly increased in areas of NMDA receptor activation. Radiolabeled CNS 1261 appears to be a good candidate for further development as a single photon emission computed tomography tracer in the investigation of NMDA receptor activation in cerebral ischemia

  2. Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring

    OpenAIRE

    Khalil, Omari S; Pisar, Mazura; Forrest, Caroline M; Vincenten, Maria C J; Darlington, L Gail; Stone, Trevor W

    2014-01-01

    Glutamate receptors for N-methyl-d-aspartate (NMDA) are involved in early brain development. The kynurenine pathway of tryptophan metabolism includes the NMDA receptor agonist quinolinic acid and the antagonist kynurenic acid. We now report that prenatal inhibition of the pathway in rats with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulphonamide (Ro61-8048) produces marked changes in hippocampal neuron morphology, spine density and the immunocytochemical localisation of developme...

  3. PET/CT in the evaluation of anti-NMDA-receptor encephalitis: what we need to know as a NM physician

    International Nuclear Information System (INIS)

    Padma, S.; Shanmuga Sundaram, P.; Marmattom, Bobby Varkey

    2011-01-01

    Anti N-methyl-D-aspartate receptor encephalitis (ANMDARE), also known as limbic encephalitis (LE), is a treatable rare disorder characterized by personality changes, irritability, depression, seizures, memory loss and sometimes dementia. It is classified under paraneoplastic syndrome (PNS) and produces antibodies against NR1 and NR2 subunits of glutamate aspartate receptor. It is thought to be closely related with malignancies like small cell lung cancer, ovarian teratoma and Hodgkin's lymphoma, apart from testis, breast and rarely gastric malignancies. Non-paraneoplastic encephalitis cases are the ones with no detectable malignancy and may be triggered by severe infection. As nuclear medicine physicians, we must be aware of the diverse presentation of ANMDARE or LE and should include a whole body positron emission tomography/computed tomography (PET/CT) and not just brain PET/CT during imaging. We describe the first case of PET/CT in an idiopathic ANMDARE Indian adolescent girl. (author)

  4. Pregnanolone Glutamate, a Novel Use-Dependent NMDA Receptor Inhibitor, Exerts Antidepressant-Like Properties in Animal Models.

    Science.gov (United States)

    Holubova, Kristina; Nekovarova, Tereza; Pistovcakova, Jana; Sulcova, Alexandra; Stuchlík, Ales; Vales, Karel

    2014-01-01

    A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders. -3α5

  5. Spermine modulation of the glutamateNMDA receptors is differentially responsive to conantokins in normal and alzheimer disease human cortex

    International Nuclear Information System (INIS)

    Ragnarsson, L.; Dodd, P.R.; Lewis, R.; University of Queensland, QLD

    1998-01-01

    Full text: The pharmacological characteristics of human N-methyl-D-aspartate (NMDA) receptors were examined in 12 control and 6 pathologically confirmed Alzheimer disease (AD) cases in six different brain areas, by studying their responses to MK-801, glutamate, spermine, and the NMDA receptor antagonists Ala(7)-conantokinG and Lys(7)-conantokinG. [ 3 H]MK801 binding assays performed by standard protocols on well-washed synoptic plasma membranes showed little variation in k D in all six brain areas, including comparisons between control and matched AD cases. b MAX values showed regional differences within control and AD cases, but there was no significant difference between groups in any of the brain regions. Maximal glutamate-enhanced [ 3 H]MK801 binding did not vary much between the brain regions or between control and AD cases, whereas maximal spermine-enhanced [ 3 H]MK-801 binding differed significantly between certain brain regions and between control and AD cases. In absolute terms in the control cases, the activation values were much lower in the spared regions, occipital and motor cortex, than in other areas; further, areas which are susceptible to damage showed reduced spermine activation in AD cases. These regional differences in the efficacy of spermine activation might be the result of local variations in the subunit composition of the NMDA receptor. Ala(7)-conantokinG and Lys(7)-conantokinG showed slight differences in potency, with the Ala(7) compound as the more potent. Both peptides produced 100% inhibition of spermine-enhanced [ 3 H]MK-801 binding in all brain areas, ana both gave lower IC 50 values in AD cases than in control cases. The significant differences in the inhibition of spermine-enhanced [ 3 H]MK-801 binding by the peptides between control and AD cases suggest that AD cases have a particular receptor subunit composition that is responsive to polyamines and which might make them more susceptible to excitotoxic damage. The spermine site

  6. Rapid synthesis and metabolism of glutamate in N2-fixing bacteroids

    International Nuclear Information System (INIS)

    Salminen, S.O.; Streeter, J.G.

    1987-01-01

    Symbiotic nodule bacteroids are thought to support N 2 fixation mainly by metabolizing dicarboxylic acids to CO 2 , generating reductant and ATP required by nitrogenase. Bradyrhizobium japonicum bacteroids were isolated anaerobically and incubated at 2% O 2 with 14 C-labeled succinate, malate, glutamate, or aspartate. 14 CO 2 was collected, and the bacteroid contents separated into neutral, organic acid, and amino acid fractions. The respiration of substrates, relative to their uptake, was malate > glutamate > succinate > aspartate. Analysis of the fractions revealed that will all substrates the radioactivity was found mostly in the amino acid fraction. The labeling of the neutral fraction was negligible and only a small amount of label was found in the organic acid fraction indicating a small pool size. TLC of the amino acid fraction showed the label to be principally in glutamate. Glutamate contained 67, 80, 97, and 88% of the 14 C in the amino acid fraction in bacteroids fed with succinate, malate, glutamate and aspartate, respectively. The data suggest that glutamate may play an important role in the bacteroid function

  7. Atypical cleavage of protonated N-fatty acyl amino acids derived from aspartic acid evidenced by sequential MS3 experiments.

    Science.gov (United States)

    Boukerche, Toufik Taalibi; Alves, Sandra; Le Faouder, Pauline; Warnet, Anna; Bertrand-Michel, Justine; Bouchekara, Mohamed; Belbachir, Mohammed; Tabet, Jean-Claude

    2016-12-01

    Lipidomics calls for information on detected lipids and conjugates whose structural elucidation by mass spectrometry requires to rationalization of their gas phase dissociations toward collision-induced dissociation (CID) processes. This study focused on activated dissociations of two lipoamino acid (LAA) systems composed of N-palmitoyl acyl coupled with aspartic and glutamic acid mono ethyl esters (as LAA (*D) and LAA (*E) ). Although in MS/MS, their CID spectra show similar trends, e.g., release of water and ethanol, the [(LAA (*D/*E) +H)-C 2 H 5 OH] + product ions dissociate via distinct pathways in sequential MS 3 experiments. The formation of all the product ions is rationalized by charge-promoted cleavages often involving stepwise processes with ion isomerization into ion-dipole prior to dissociation. The latter explains the maleic anhydride or ketene neutral losses from N-palmitoyl acyl aspartate and glutamate anhydride fragment ions, respectively. Consequently, protonated palmitoyl acid amide is generated from LAA (*D), whereas LAA (*E) leads to the [*E+H-H 2 O] + anhydride. The former releases ammonia to provide acylium, which gives the C n H (2n-1) and C n H (2n-3) carbenium series. This should offer structural information, e.g., to locate either unsaturation(s) or alkyl group branching present on the various fatty acyl moieties of lipo-aspartic acid in further studies based on MS n experiments.

  8. Two N-glycosylation Sites in the GluN1 Subunit Are Essential for Releasing N-methyl-D-aspartate (NMDA) Receptors from the Endoplasmic Reticulum

    Czech Academy of Sciences Publication Activity Database

    Lichnerová, Katarina; Kaniaková, Martina; Park, S. P.; Skřenková, Kristýna; Wang, Y.- X.; Petralia, R. S.; Suh, Y. H.; Horák, Martin

    2015-01-01

    Roč. 290, č. 30 (2015), s. 18379-18390 ISSN 0021-9258 R&D Projects: GA ČR(CZ) GA14-02219S; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : peptide-N-glycosidase * NMDAR * NMDA receptor * endoplasmic reticulum Subject RIV: FH - Neurology Impact factor: 4.258, year: 2015

  9. Dissociation of thirst and sodium appetite in the furo/cap model of extracellular dehydration and a role for N-methyl-D-aspartate receptors in the sensitization of sodium appetite

    Science.gov (United States)

    Hurley, Seth. W.; Johnson, Alan Kim

    2015-01-01

    Depletion of extracellular fluids motivates many animals to seek out and ingest water and sodium. Animals with a history of extracellular dehydration display enhanced sodium appetite and in some cases thirst. The progressive increase in sodium intake induced by repeated sodium depletions is known as sensitization of sodium appetite. Administration of the diuretic and natriuretic drug, furosemide, along with a low dose of captopril (furo/cap), elicits thirst and a rapid onset of sodium appetite. In the present studies the furo/cap model was used to explore the physiological mechanisms of sensitization of sodium appetite. However, when thirst and sodium appetite were measured concurrently in the furo/cap model, individual rats exhibited sensitization of either thirst or sodium appetite. In subsequent studies, thirst and sodium appetite were dissociated by offering either water prior to sodium or sodium before water. When water and sodium intake were dissociated in time, the furo/cap model reliably produced sensitization of sodium appetite. It is likely that neuroplasticity mediates this sensitization. Glutamatergic N-methyl-d-aspartate receptor (NMDA-R) activation is critical for the development of most forms of neuroplasticity. Therefore, we hypothesized that integrity of NMDA-R function is necessary for the sensitization of sodium appetite. Pharmacological blockade of NMDA-Rs with systemic administration of MK-801 (0.15mg/kg) prevented the sensitization of fluid intake in general when water and sodium were offered concurrently, and prevented sensitization of sodium intake specifically when water and sodium intake were dissociated. The involvement of NMDA-Rs provides support for the possibility that sensitization of sodium appetite is mediated by neuroplasticity. PMID:24341713

  10. The effects of an intraperitoneal single low dose of ketamine in attenuating the postoperative skin/muscle incision and retraction-induced pain related to the inhibition of N-methyl-D-aspartate receptors in the spinal cord.

    Science.gov (United States)

    Shen, Yu; Xu, Li; Liu, Ming; Lei, Yishan; Gu, Xiaoping; Ma, Zhengliang

    2016-03-11

    Chronic postoperative pain (CPOP) is a common clinical problem which might be related to central sensitization. It has been widely accepted that NMDA (N-methyl-D-aspartate) receptors are among the triggers of central sensitization. Ketamine is a non-competitive NMDA receptor antagonist that is widely used in alleviating postoperative pain, but its effect on CPOP has been rarely reported. In the present study, the skin/muscle incision and retraction (SMIR) model was used to investigate the role of NMDARs in chronic postoperative pain and the effect of an intraperitoneal single low dose ketamine (10mg/kg) of attenuating SMIR-induced CPOP. We assessed pain behaviours after a SMIR operation by paw withdrawal threshold (PWMT) and paw withdrawal latency (PWMTL). Western blotting were performed to examine the role of NMDARs in SMIR-induced CPOP and the effect of ketamine on the expression and phosphorylation of NMDARs. The SMIR operation induced long-lasting mechanical hyperalgesia, and the up-regulation of phosphorylated NMDARs and total NMDARs at the spinal level. A single intraperitoneal administration of low dose ketamine (10mg/kg) during surgery alleviated pain behaviors and inhibited the up-regulation of phosphorylated NMDARs and total NMDARs. Our datas suggested that NMDARs play important roles in SMIR-induced CPOP. A single intraperitoneal low dose of ketamine could attenuate SMIR-induced CPOP, which might be associated with the inhibition of NMDARs. Our finding might provide a new, simple method of addressing CPOP. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.

    Directory of Open Access Journals (Sweden)

    Cecilia Gonzalez Campo

    Full Text Available BACKGROUND: Reelin is a large secreted protein of the extracellular matrix that has been proposed to participate to the etiology of schizophrenia. During development, reelin is crucial for the correct cytoarchitecture of laminated brain structures and is produced by a subset of neurons named Cajal-Retzius. After birth, most of these cells degenerate and reelin expression persists in postnatal and adult brain. The phenotype of neurons that bind secreted reelin and whether the continuous secretion of reelin is required for physiological functions at postnatal stages remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Combining immunocytochemical and pharmacological approaches, we first report that two distinct patterns of reelin expression are present in cultured hippocampal neurons. We show that in hippocampal cultures, reelin is secreted by GABAergic neurons displaying an intense reelin immunoreactivity (IR. We demonstrate that secreted reelin binds to receptors of the lipoprotein family on neurons with a punctate reelin IR. Secondly, using calcium imaging techniques, we examined the physiological consequences of reelin secretion blockade. Blocking protein secretion rapidly and reversibly changes the subunit composition of N-methyl-D-aspartate glutamate receptors (NMDARs to a predominance of NR2B-containing NMDARs. Addition of recombinant or endogenously secreted reelin rescues the effects of protein secretion blockade and reverts the fraction of NR2B-containing NMDARs to control levels. Therefore, the continuous secretion of reelin is necessary to control the subunit composition of NMDARs in hippocampal neurons. CONCLUSIONS/SIGNIFICANCE: Our data show that the heterogeneity of reelin immunoreactivity correlates with distinct functional populations: neurons synthesizing and secreting reelin and/or neurons binding reelin. Furthermore, we show that continuous reelin secretion is a strict requirement to maintain the composition of NMDARs. We propose

  12. Modulation of NMDA receptor function by ketamine and magnesium: Part I

    NARCIS (Netherlands)

    Liu, H. T.; Hollmann, M. W.; Liu, W. H.; Hoenemann, C. W.; Durieux, M. E.

    2001-01-01

    N-methyl-D-aspartate (NMDA) receptors are important components of pain processing. Ketamine and Mg2+ block NMDA receptors and might therefore be useful analgesics, and combinations of Mg2+ and ketamine provide more effective analgesia. We investigated their interactions at NMDA receptors. Xenopus

  13. The ratio of N-acetyl aspartate to glutamate correlates with disease duration of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Sako, Wataru; Abe, Takashi; Izumi, Yuishin; Harada, Masafumi; Kaji, Ryuji

    2016-05-01

    Glutamate (Glu)-induced excitotoxicity has been implicated in the neuronal loss of amyotrophic lateral sclerosis. To test the hypothesis that Glu in the primary motor cortex contributes to disease severity and/or duration, the Glu level was investigated using MR spectroscopy. Seventeen patients with amyotrophic lateral sclerosis were diagnosed according to the El Escorial criteria for suspected, possible, probable or definite amyotrophic lateral sclerosis, and enrolled in this cross-sectional study. We measured metabolite concentrations, including N-acetyl aspartate (NAA), creatine, choline, inositol, Glu and glutamine, and performed partial correlation between each metabolite concentration or NAA/Glu ratio and disease severity or duration using age as a covariate. Considering our hypothesis that Glu is associated with neuronal cell death in amyotrophic lateral sclerosis, we investigated the ratio of NAA to Glu, and found a significant correlation between NAA/Glu and disease duration (r=-0.574, p=0.02). The "suspected" amyotrophic lateral sclerosis patients showed the same tendency as possible, probable and definite amyotrophic lateral sclerosis patients in regard to correlation of NAA/Glu ratio with disease duration. The other metabolites showed no significant correlation. Our findings suggested that glutamatergic neurons are less vulnerable compared to other neurons and this may be because inhibitory receptors are mainly located presynaptically, which supports the notion of Glu-induced excitotoxicity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence?

    Directory of Open Access Journals (Sweden)

    Pamela eMaher

    2015-12-01

    Full Text Available Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors and a class of G-protein coupled receptors (metabotropic glutamate receptors. Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer’s disease and Huntington’s disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.

  15. Sodium and potassium ions and accumulation of labelled D-aspartate and GABA in crude synaptosomal fraction from rat cerebral cortex

    International Nuclear Information System (INIS)

    Takagaki, G.

    1978-01-01

    The accumulation of labelled D-aspartate into crude synaptosomal fraction (P 2 ) prepared from the rat cerebral cortex proceeded by a 'high affinity' system (Ksub(m) = 15.1 μM). The maximal velocity of D-aspartate uptake was higher than that of the 'high affinity' component of L-aspartate uptake and almost equal to that of L-glutamate under the same incubation conditions. Negligible metabolism of labelled D-aspartate was observed in the P 2 fraction. These findings are in accord with those which have been reported for rat cerebral cortical slices. The following observations were made on D-aspartate uptake into rat cerebral P 2 fraction. The requirement of sodium were almost absolute and obligatory. The affinity of the carrier for the substrate was increased by increasing sodium concentration in the medium, but the maximal velocity was not altered. It is suggested that sodium ion is co-transported mole for mole with the substrate molecule. Omission of potassium from the medium inhibited the uptake competitively. Ouabain was a competitive inhibitor on the uptake. Whereas thallium, rubidium and ammonium were efficient substitutes for potassium in exhibiting Na-K ATPase activity of the P 2 fraction, the uptake was activated only by rubidium in the absence of potassium. These observations were in common with the uptake of L-aspartate as well as of L- and D-glutamate, but not with GABA uptake. The requirement of sodium for the uptake of D-glutamate was indicated to be higher than that in the uptake of the other amino acids. Mutual inhibitions of the uptake among L- and D-isomers of glutamate and aspartate suggested that a common carrier is involved in the transport. Mechanisms of the transport of these amino acids in the crude synaptosomal fraction were discussed. (author)

  16. Glutamatergic receptor dysfunction in spinal cord contributes to the exaggerated exercise pressor reflex in heart failure.

    Science.gov (United States)

    Wang, Han-Jun; Cahoon, Rebecca; Cahoon, Edgar B; Zheng, Hong; Patel, Kaushik P; Zucker, Irving H

    2015-03-01

    Excitatory amino acids (e.g., glutamate) released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR) in physiological conditions. However, the role of glutamate and glutamate receptors in mediating the exaggerated EPR in the chronic heart failure (CHF) state remains to be determined. In the present study, we performed microinjection of glutamate receptor antagonists into ipisilateral L4/L5 dorsal horns to investigate their effects on the pressor response to static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots in decerebrate sham-operated (sham) and CHF rats. Microinjection of glutamate (10 mM, 100 nl) into the L4 or L5 dorsal horn caused a greater pressor response in CHF rats compared with sham rats. Furthermore, microinjection of either the broad-spectrum glutamate receptor antagonist kynurenate (10 mM, 100 nl) or the N-methyl-d-aspartate (NMDA) receptor antagonist dl-2-amino-5-phosphonovalerate (50 mM, 100 nl) or the non-NMDA-sensitive receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (5 mM, 100 nl) into L4/5 dorsal horns decreased the pressor response to static contraction in CHF rats to a greater extent than in sham rats. Molecular evidence showed that the protein expression of glutamate receptors (both non-NMDA and NMDA) was elevated in the dorsal horn of the lumbar spinal cord in CHF rats. In addition, data from microdialysis experiments demonstrated that although basal glutamate release at the dorsal horn at rest was similar between sham and CHF rats (225 ± 50 vs. 260 ± 63 nM in sham vs. CHF rats, n = 4, P > 0.05), CHF rats exhibit greater glutamate release into the dorsal horn during muscle contraction compared with sham rats (549 ± 60 vs. 980 ± 65 nM in sham vs. CHF rats, n = 4, P < 0.01). These data indicate that the spinal glutamate system contributes to the exaggerated EPR in the CHF state. Copyright

  17. Altered astrocyte glutamate transporter regulation of hypothalamic neurosecretory neurons in heart failure rats.

    Science.gov (United States)

    Potapenko, Evgeniy S; Biancardi, Vinicia C; Zhou, Yiqiang; Stern, Javier E

    2012-08-01

    Neurohumoral activation, which includes augmented plasma levels of the neurohormone vasopressin (VP), is a common finding in heart failure (HF) that contributes to morbidity and mortality in this disease. While an increased activation of magnocellular neurosecretory cells (MNCs) and enhanced glutamate function in HF is well documented, the precise underlying mechanisms remain to be elucidated. Here, we combined electrophysiology and protein measurements to determine whether altered glial glutamate transporter function and/or expression occurs in the hypothalamic supraoptic nucleus (SON) during HF. Patch-clamp recordings obtained from MNCs in brain slices show that pharmacological blockade of astrocyte glutamate transporter 1 (GLT1) function [500 μM dihydrokainate (DHK)], resulted in a persistent N-methyl-D-aspartate receptor (NMDAR)-mediated inward current (tonic I(NMDA)) in sham rats, an effect that was significantly smaller in MNCs from HF rats. In addition, we found a diminished GLT1 protein content in plasma membrane (but not cytosolic) fractions of SON punches in HF rats. Conversely, astrocyte GLAST expression was significantly higher in the SON of HF rats, while nonselective blockade of glutamate transport activity (100 μM TBOA) evoked an enhanced tonic I(NMDA) activation in HF rats. Steady-state activation of NMDARs by extracellular glutamate levels was diminished during HF. Taken together, these results support a shift in the relative expression and function of two major glial glutamate transporters (from GLT1 to GLAST predominance) during HF. This shift may act as a compensatory mechanism to preserve an adequate basal glutamate uptake level in the face of an enhanced glutamatergic afferent activity in HF rats.

  18. Mechanisms of glycine release, which build up synaptic and extrasynaptic glycine levels: the role of synaptic and non-synaptic glycine transporters.

    Science.gov (United States)

    Harsing, Laszlo G; Matyus, Peter

    2013-04-01

    Glycine is an amino acid neurotransmitter that is involved in both inhibitory and excitatory neurochemical transmission in the central nervous system. The role of glycine in excitatory neurotransmission is related to its coagonist action at glutamatergic N-methyl-D-aspartate receptors. The glycine levels in the synaptic cleft rise many times higher during synaptic activation assuring that glycine spills over into the extrasynaptic space. Another possible origin of extrasynaptic glycine is the efflux of glycine occurring from astrocytes associated with glutamatergic synapses. The release of glycine from neuronal or glial origins exhibits several differences compared to that of biogenic amines or other amino acid neurotransmitters. These differences appear in an external Ca(2+)- and temperature-dependent manner, conferring unique characteristics on glycine as a neurotransmitter. Glycine transporter type-1 at synapses may exhibit neural and glial forms and plays a role in controlling synaptic glycine levels and the spill over rate of glycine from the synaptic cleft into the extrasynaptic biophase. Non-synaptic glycine transporter type-1 regulates extrasynaptic glycine concentrations, either increasing or decreasing them depending on the reverse or normal mode operation of the carrier molecule. While we can, at best, only estimate synaptic glycine levels at rest and during synaptic activation, glycine concentrations are readily measurable via brain microdialysis technique applied in the extrasynaptic space. The non-synaptic N-methyl-D-aspartate receptor may obtain glycine for activation following its spill over from highly active synapses or from its release mediated by the reverse operation of non-synaptic glycine transporter-1. The sensitivity of non-synaptic N-methyl-D-aspartate receptors to glutamate and glycine is many times higher than that of synaptic N-methyl-D-aspartate receptors making the former type of receptor the primary target for drug action. Synaptic

  19. Displacement of DL-[3H]-2-amino-4-phosphonobutanoic acid ( [3H]APB) binding with methyl-substituted APB analogues and glutamate agonists

    International Nuclear Information System (INIS)

    Robinson, M.B.; Crooks, S.L.; Johnson, R.L.; Koerner, J.F.

    1985-01-01

    The binding of the excitatory amino acid antagonist DL-2-amino-4-phosphonobutanoic acid (DL-APB) to rat brain synaptic plasma membranes was characterized. As determined by Scatchard analysis, the binding was saturable and homogeneous with a Kd = 6.0 microM and Bmax = 380 pmol/mg of protein. The binding was dependent on the presence of Ca 2+ and Cl - ions and was diminished upon freezing. The association rate constant was 6.8 X 10(-3) microM -1 min -1 , and the dissociation rate constant was 2.0 X 10(-2) min -1 . The L isomers of APB, glutamate, and aspartate were more potent as displacers of APB binding than the D isomers. With the exception of kynurenic acid, all compounds examined in both systems were more potent as displacers of APB binding than as inhibitors of synaptic transmission. This difference in potency was most pronounced for agonists at dentate granule cells. L-Glutamate, D-glutamate, and L-glutamate tetrazole were between 140- and 7500-fold more potent as displacers of DL-APB binding than as inhibitors of synaptic transmission. D-2-Amino-5-phosphonopentanoic acid and alpha-methyl-APB were between 10- and 20-fold more potent as displacers of binding

  20. NMDA receptor antagonists for the treatment of neuropathic pain

    NARCIS (Netherlands)

    Collins, S.; Sigtermans, M.J.; Dahan, A.; Zuurmond, W.W.A.; Perez, R.S.G.M.

    2010-01-01

    Objective. The N-methyl-D-Aspartate (NMDA) receptor has been proposed as a primary target for the treatment of neuropathic pain. The aim of the present study was to perform a meta-analysis evaluating the effects of (individual) NMDA receptor antagonists on neuropathic pain, and the response

  1. On the mechanism of aluminum ion-induced neurotoxicity: The effects of aluminum species on G-protein-mediated processes and on drug interactions with the N-methyl-D-aspartate modulated ionophore

    International Nuclear Information System (INIS)

    Hubbard, C.M.

    1989-01-01

    To establish what effects Al 3+ may have on G-protein mediate signal transduction, the effects of Al 3+ on the signal-coupling G-protein from retinal rod outer segments (G t or transducin) have been investigated as a model for the effects of Al 3+ on signal transduction by G-proteins in general. In this investigation, we have studied the effects of Al 3+ on the isolated, light-dependent rhodopsin catalyzed GTP-GDP exchange on G t ; the light-dependent GTPase activity of G t ; the light-independent cGMP hydrolysis by PDE; and the light activated, rhodopsin catalyzed, cGMP hydrolysis by PDE in vitro. To determine the effects of two defined species of aluminum on N-methyl-D-aspartic acid (NMDA) receptor-channel modulation we utilized a specific radioligand binding assay. This allowed us to compare the effects of aluminum to other metal ions on specific [ 3 H]MK-801 binding to the NMDA receptor-channel complex. This complex is involved in long-term potentiation, which is currently being investigated as the mechanism by which learning and memory occur and has been implicated in the pathology of Alzheimer's disease. We have investigated the effects of two different species of aluminum, as well as Ca 2+ , Zn 2+ , Mg 2+ , and Li + on the specific binding of [ 3 H]MK-801 to the NMDA receptor-channel complex under depolarized conditions

  2. The Role of Canonical Transient Receptor Potential Channels in Seizure and Excitotoxicity

    Directory of Open Access Journals (Sweden)

    Fang Zheng

    2014-04-01

    Full Text Available Canonical transient receptor potential (TRPC channels are a family of polymodal cation channels with some degree of Ca2+ permeability. Although initially thought to be channels mediating store-operated Ca2+ influx, TRPC channels can be activated by stimulation of Gq-coupled G-protein coupled receptors, or by an increase in intracellular free Ca2+ concentration. Thus, activation of TRPC channels could be a common downstream event of many signaling pathways that contribute to seizure and excitotoxicity, such as N-methyl-D-aspartate (NMDA receptor-mediated Ca2+ influx, or metabotropic glutamate receptor activation. Recent studies with genetic ablation of various TRPC family members have demonstrated that TRPC channels, in particular heteromeric TRPC1/4 channels and homomeric TRPC5 channels, play a critical role in both pilocarpine-induced acute seizures and neuronal cell death. However, exact underlying mechanisms remain to be fully elucidated, and selective TRPC modulators and antibodies with better specificity are urgently needed for future research.

  3. Temporal alteration of spreading depression by the glycine transporter type-1 inhibitors NFPS and Org-24461 in chicken retina.

    Science.gov (United States)

    Kertesz, Szabolcs; Szabo, Geza; Udvari, Szabolcs; Levay, Gyorgy; Matyus, Peter; Harsing, Laszlo G

    2013-01-25

    We used isolated chicken retina to induce spreading depression by the glutamate receptor agonist N-methyl-d-aspartate. The N-methyl-d-aspartate-induced latency time of spreading depression was extended by the glycine(B) binding site competitive antagonist 7-chlorokynurenic acid. Addition of the glycine transporter type-1 inhibitors NFPS and Org-24461 reversed the inhibitory effect of 7-chlorokynurenic acid on N-methyl-d-aspartate-evoked spreading depression. The glycine uptake inhibitory activity of Org-24461, NFPS, and some newly synthesized analogs of NFPS was determined in CHO cells stably expressing human glycine transporter type-1b isoform. Compounds, which failed to inhibit glycine transporter type-1, also did not have effect on retinal spreading depression. These experiments indicate that the spreading depression model in chicken retina is a useful in vitro test to determine activity of glycine transporter type-1 inhibitors. In addition, our data serve further evidence for the role of glycine transporter type-1 in retinal neurotransmission and light processing. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Tegaserod Mimics the Neurostimulatory Glycan Polysialic Acid and Promotes Nervous System Repair

    Science.gov (United States)

    2014-01-01

    syndrome and constipation (Muller-Lissner et al., 2001) by stimu- lating 5-HT4 receptors on enteric neurons (Liu et al., 2005, 2009). The present study...and kept under standard laboratory conditions with food and water supply ad libitum and with an artificial 12 h light/dark cycle. Twelve-week-old...Neural cell adhesion molecule-associated polysialic acid inhibits NR2B-containing N-methyl-D-aspartate receptors and prevents glutamate-induced cell

  5. Creatine affords protection against glutamate-induced nitrosative and oxidative stress.

    Science.gov (United States)

    Cunha, Mauricio P; Lieberknecht, Vicente; Ramos-Hryb, Ana Belén; Olescowicz, Gislaine; Ludka, Fabiana K; Tasca, Carla I; Gabilan, Nelson H; Rodrigues, Ana Lúcia S

    2016-05-01

    Creatine has been reported to exert beneficial effects in several neurodegenerative diseases in which glutamatergic excitotoxicity and oxidative stress play an etiological role. The purpose of this study was to investigate the protective effects of creatine, as compared to the N-Methyl-d-Aspartate (NMDA) receptor antagonist dizocilpine (MK-801), against glutamate or hydrogen peroxide (H2O2)-induced injury in human neuroblastoma SH-SY5Y cells. Exposure of cells to glutamate (60-80 mM) or H2O2 (200-300 μM) for 24 h decreased cellular viability and increased dichlorofluorescein (DCF) fluorescence (indicative of increased reactive oxygen species, ROS) and nitric oxide (NO) production (assessed by mono-nitrogen oxides, NOx, levels). Creatine (1-10 mM) or MK-801 (0.1-10 μM) reduced glutamate- and H2O2-induced toxicity. The protective effect of creatine against glutamate-induced toxicity involves its antioxidant effect, since creatine, similar to MK-801, prevented the increase on DCF fluorescence induced by glutamate or H2O2. Furthermore, creatine or MK-801 blocked glutamate- and H2O2-induced increases in NOx levels. In another set of experiments, the repeated, but not acute, administration of creatine (300 mg/kg, po) in mice prevented the decreases on cellular viability and mitochondrial membrane potential (assessed by tetramethylrhodamine ethyl ester, TMRE, probe) of hippocampal slices incubated with glutamate (10 mM). Creatine concentration-dependent decreased the amount of nitrite formed in the reaction of oxygen with NO produced from sodium nitroprusside solution, suggesting that its protective effect against glutamate or H2O2-induced toxicity might be due to its scavenger activity. Overall, the results suggest that creatine may be useful as adjuvant therapy for neurodegenerative disease treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Negative modulation of NMDA receptor channel function by DREAM/calsenilin/KChIP3 provides neuroprotection?

    Science.gov (United States)

    Wang, KeWei; Wang, Yun

    2012-01-01

    N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels highly permeable to calcium and essential to excitatory neurotransmission. The NMDARs have attracted much attention because of their role in synaptic plasticity and excitotoxicity. Evidence has recently accumulated that NMDARs are negatively regulated by intracellular calcium binding proteins. The calcium-dependent suppression of NMDAR function serves as a feedback mechanism capable of regulating subsequent Ca2+ entry into the postsynaptic cell, and may offer an alternative approach to treating NMDAR-mediated excitotoxic injury. This short review summarizes the recent progress made in understanding the negative modulation of NMDAR function by DREAM/calsenilin/KChIP3, a neuronal calcium sensor (NCS) protein. PMID:22518099

  7. The glutamate aspartate transporter (GLAST) mediates L-glutamate-stimulated ascorbate-release via swelling-activated anion channels in cultured neonatal rodent astrocytes.

    Science.gov (United States)

    Lane, Darius J R; Lawen, Alfons

    2013-03-01

    Vitamin C (ascorbate) plays important neuroprotective and neuromodulatory roles in the mammalian brain. Astrocytes are crucially involved in brain ascorbate homeostasis and may assist in regenerating extracellular ascorbate from its oxidised forms. Ascorbate accumulated by astrocytes can be released rapidly by a process that is stimulated by the excitatory amino acid, L-glutamate. This process is thought to be neuroprotective against excitotoxicity. Although of potential clinical interest, the mechanism of this stimulated ascorbate-release remains unknown. Here, we report that primary cultures of mouse and rat astrocytes release ascorbate following initial uptake of dehydroascorbate and accumulation of intracellular ascorbate. Ascorbate-release was not due to cellular lysis, as assessed by cellular release of the cytosolic enzyme lactate dehydrogenase, and was stimulated by L-glutamate and L-aspartate, but not the non-excitatory amino acid L-glutamine. This stimulation was due to glutamate-induced cellular swelling, as it was both attenuated by hypertonic and emulated by hypotonic media. Glutamate-stimulated ascorbate-release was also sensitive to inhibitors of volume-sensitive anion channels, suggesting that the latter may provide the conduit for ascorbate efflux. Glutamate-stimulated ascorbate-release was not recapitulated by selective agonists of either ionotropic or group I metabotropic glutamate receptors, but was completely blocked by either of two compounds, TFB-TBOA and UCPH-101, which non-selectively and selectively inhibit the glial Na(+)-dependent excitatory amino acid transporter, GLAST, respectively. These results suggest that an impairment of astrocytic ascorbate-release may exacerbate neuronal dysfunction in neurodegenerative disorders and acute brain injury in which excitotoxicity and/or GLAST deregulation have been implicated.

  8. Glutamate regulation of non-quantal release of acetylcholine in the rat neuromuscular junction

    Czech Academy of Sciences Publication Activity Database

    Malomouzh, A. I.; Mukhtarov, M. R.; Nikolsky, E. E.; Vyskočil, František; Lieberman, E. M.; Urazaev, A. K.

    2003-01-01

    Roč. 85, č. 1 (2003), s. 206-213 ISSN 0022-3042 R&D Projects: GA AV ČR IAA7011902; GA ČR GA305/02/1333; GA ČR GA202/02/1213 Institutional research plan: CEZ:AV0Z5011922; CEZ:MSM 113100003 Keywords : muscle endplate * nitric oxide * N-methyl-D-aspartate receptor Subject RIV: CG - Electrochemistry Impact factor: 4.825, year: 2003

  9. Synthesis and binding characteristics of N-(1-naphthyl)-N'-(3-[{sup 125}I]-iodophenyl)-N'-methylguanidine ([{sup 125}I]-CNS 1261): a potential SPECT agent for imaging NMDA receptor activation

    Energy Technology Data Exchange (ETDEWEB)

    Owens, Jonathan E-mail: j.owens@clinmed.gla.ac.uk; Tebbutt, Andrew A.; McGregor, Ailsa L.; Kodama, K.; Magar, Sharad S.; Perlman, Michael E.; Robins, David J.; Durant, Graham J.; McCulloch, James

    2000-06-01

    N-(1-Naphthyl)-N'-(3-[{sup 125}I]-iodophenyl)-N'-methylguanidine ([{sup 125}I]-CNS 1261) was synthesized as a potential radioligand to image N-methyl-D-aspartate (NMDA) receptor activation. [{sup 125}I]-CNS 1261 was prepared by radioiodination of N-(1-naphthyl)-N'-(3-tributylstannylphenyl)-N'-methylguanidine using Na{sup 125}I and peracetic acid. [{sup 125}I]-CNS 1261 uptake in vivo reflected NMDA receptor distribution in normal rat brain, whereas in ischemic rat brain, uptake was markedly increased in areas of NMDA receptor activation. Radiolabeled CNS 1261 appears to be a good candidate for further development as a single photon emission computed tomography tracer in the investigation of NMDA receptor activation in cerebral ischemia.

  10. Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

    Science.gov (United States)

    Ducrot, Charles; Fortier, Emmanuel; Bouchard, Claude; Rompré, Pierre-Paul

    2013-01-01

    Previous studies have shown that blockade of ventral tegmental area (VTA) glutamate N-Methyl-D-Aspartate (NMDA) receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VTA neurons, a fast and short lasting depolarization mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VTA neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VTA neuronal activity, we studied the effects of VTA AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for 2 h after bilateral VTA microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5 μl/side) and of a single dose (0.825 nmol/0.5 μl/side) of the NMDA antagonist, PPPA (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid). NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VTA sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected, respectively, into the anterior and posterior VTA. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VTA neurons, to

  11. Opposite modulation of brain stimulation reward by NMDA and AMPA receptors in the ventral tegmental area.

    Directory of Open Access Journals (Sweden)

    Charles eDucrot

    2013-10-01

    Full Text Available Previous studies have shown that blockade of ventral midbrain (VM glutamate N-Methyl-D-Aspartate (NMDA receptors induces reward, stimulates forward locomotion and enhances brain stimulation reward. Glutamate induces two types of excitatory response on VM neurons, a fast and short lasting depolarisation mediated by a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA receptors and a longer lasting depolarization mediated by NMDA receptors. A role for the two glutamate receptors in modulation of VM neuronal activity is evidenced by the functional change in AMPA and NMDA synaptic responses that result from repeated exposure to reward. Since both receptors contribute to the action of glutamate on VM neuronal activity, we studied the effects of VM AMPA and NMDA receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer electrical pulses in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and for two hours after bilateral VM microinjections of the AMPA antagonist, NBQX (2,3,-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(fquinoxaline-7-sulfonamide, 0, 80, and 800 pmol/0.5ul/side and of a single dose (0.825 nmol/0.5ul/side of the NMDA antagonist, PPPA (2R,4S-4-(3-Phosphonopropyl-2-piperidinecarboxylic acid. NBQX produced a dose-dependent increase in reward threshold with no significant change in maximum rate of responding. Whereas PPPA injected at the same VM sites produced a significant time dependent decrease in reward threshold and increase in maximum rate of responding. We found a negative correlation between the magnitude of the attenuation effect of NBQX and the enhancement effect of PPPA; moreover, NBQX and PPPA were most effective when injected respectively into the anterior and posterior VM. These results suggest that glutamate acts on different receptor sub-types, most likely located on different VM neurons, to modulate

  12. NMDA receptor function during senescence: implication on cognitive performance

    Directory of Open Access Journals (Sweden)

    Ashok eKumar

    2015-12-01

    Full Text Available N-methyl-D-aspartate (NMDA receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. These receptors are tetrameric ion channels composed of a family of related subunits. One of the hallmarks of the aging human population is a decline in cognitive function; studies in the past couple of years have demonstrated deterioration in NMDA receptor subunit expression and function with advancing age. However, a direct relationship between impaired memory function and a decline in NMDA receptors is still ambiguous. Recent studies indicate a link between an age-associated NMDA receptor hypofunction and memory impairment and provide evidence that age-associated enhanced oxidative stress might be contributing to the alterations associated with senescence. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between age-associated impaired cognitive faculties and NMDA receptor hypofunction. The current review intends to present an overview of the research findings regarding changes in expression of various NMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function.

  13. Intercellular signal communication among odontoblasts and trigeminal ganglion neurons via glutamate.

    Science.gov (United States)

    Nishiyama, A; Sato, M; Kimura, M; Katakura, A; Tazaki, M; Shibukawa, Y

    2016-11-01

    extracellular Mg 2+ , indicating that N-methyl-d-aspartic acid receptor does not contribute to inter-odontoblast signal communication. The results suggest that a mechanically stimulated odontoblast is capable of releasing glutamate into the extracellular space via glutamate-permeable anion channels. The released glutamate activates mGluRs on the odontoblasts in an autocrine/paracrine manner, forming an inter-odontoblasts communication, which drives dentin formation via odontoblast-odontoblast signal communication. Glutamate and mGluRs also mediate neurotransmission between the odontoblasts and neurons in the dental pulp to modulate sensory signal transmission for dentinal sensitivity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Essential role of NMDA receptor channel ε4 subunit (GluN2D in the effects of phencyclidine, but not methamphetamine.

    Directory of Open Access Journals (Sweden)

    Yoko Hagino

    Full Text Available Phencyclidine (PCP, a noncompetitive N-methyl-D-aspartate (NMDA receptor antagonist, increases locomotor activity in rodents and causes schizophrenia-like symptoms in humans. Although activation of the dopamine (DA pathway is hypothesized to mediate these effects of PCP, the precise mechanisms by which PCP induces its effects remain to be elucidated. The present study investigated the effect of PCP on extracellular levels of DA (DA(ex in the striatum and prefrontal cortex (PFC using in vivo microdialysis in mice lacking the NMDA receptor channel ε1 or ε4 subunit (GluRε1 [GluN2A] or GluRε4 [GluN2D] and locomotor activity. PCP significantly increased DA(ex in wildtype and GluRε1 knockout mice, but not in GluRε4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluRε4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluRε4.

  15. The role of striatal NMDA receptors in drug addiction.

    Science.gov (United States)

    Ma, Yao-Ying; Cepeda, Carlos; Cui, Cai-Lian

    2009-01-01

    The past decade has witnessed an impressive accumulation of evidence indicating that the excitatory amino acid glutamate and its receptors, in particular the N-methyl-D-aspartate (NMDA) receptor subtype, play an important role in drug addiction. Various lines of research using animal models of drug addiction have demonstrated that drug-induced craving is accompanied by significant upregulation of NR2B subunit expression. Furthermore, selective blockade of NR2B-containing NMDA receptors in the striatum, especially in the nucleus accumbens (NAc) can inhibit drug craving and reinstatement. The purpose of this review is to examine the role of striatal NMDA receptors in drug addiction. After a brief description of glutamatergic innervation and NMDA receptor subunit distribution in the striatum, we discuss potential mechanisms to explain the role of striatal NMDA receptors in drug addiction by elucidating signaling cascades involved in the regulation of subunit expression and redistribution, phosphorylation of receptor subunits, as well as activation of intracellular signals triggered by drug experience. Understanding the mechanisms regulating striatal NMDA receptor changes in drug addiction will provide more specific and rational targets to counteract the deleterious effects of drug addiction.

  16. Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation.

    Science.gov (United States)

    Delle Donne, K T; Sonsalla, P K

    1994-12-01

    Methamphetamine (METH)-induced neurotoxicity to nigrostriatal dopaminergic neurons in experimental animals appears to have a glutamatergic component because blockade of N-methyl-D-aspartate receptors prevents the neuropathologic consequences. Because adenosine affords neuroprotection against various forms of glutamate-mediated neuronal damage, the present studies were performed to investigate whether adenosine plays a protective role in METH-induced toxicity. METH-induced decrements in neostriatal dopamine content and tyrosine hydroxylase activity in mice were potentiated by concurrent treatment with caffeine, a nonselective adenosine antagonist that blocks both A1 and A2 adenosine receptors. In contrast, chronic treatment of mice with caffeine through their drinking water for 4 weeks, which increased the number of adenosine A1 receptors in the neostriatum and frontal cortex, followed by drug washout, prevented the neurochemical changes produced by the treatment of mice with METH treatment. In contrast, this treatment did not prevent 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced dopaminergic neurotoxicity. Furthermore, concurrent administration of cyclopentyladenosine, an adenosine A1 receptor agonist, attenuated the METH-induced neurochemical changes. This protection by cyclopentyladenosine was blocked by cyclopentyltheophylline, an A1 receptor antagonist. These results indicate that activation of A1 receptors can protect against METH-induced neurotoxicity in mice.

  17. Involvement of NMDA receptor in low-frequency magnetic field-induced anxiety in mice.

    Science.gov (United States)

    Salunke, Balwant P; Umathe, Sudhir N; Chavan, Jagatpalsingh G

    2014-12-01

    It had been reported that exposure to extremely low-frequency magnetic field (ELFMF) induces anxiety in human and rodents. Anxiety mediates via the activation of N-methyl-d-aspartate (NMDA) receptor, whereas activation of γ-aminobutyric acid (GABA) receptor attenuates the same. Hence, the present study was carried out to understand the contribution of NMDA and/or GABA receptors modulation in ELFMF-induced anxiety for which Swiss albino mice were exposed to ELFMF (50 Hz, 10 G) by subjecting them to Helmholtz coils. The exposure was for 8 h/day for 7, 30, 60, 90 and 120 days. Anxiety level was assessed in elevated plus maze, open field test and social interaction test, on 7th, 30th, 60th, 90th and 120th exposure day, respectively. Moreover, the role of GABA and glutamate in ELFMF-induced anxiety was assessed by treating mice with muscimol [0.25 mg/kg intraperitoneally (i.p.)], bicuculline (1.0 mg/kg i.p.), NMDA (15 mg/kg i.p.) and MK-801 (0.03 mg/kg i.p.), as a GABAA and NMDA receptor agonist and antagonist, respectively. Glutamate receptor agonist exacerbated while inhibitor attenuated the ELFMF-induced anxiety. In addition, levels of GABA and glutamate were determined in regions of the brain viz, cortex, striatum, hippocampus and hypothalamus. Experiments demonstrated significant elevation of GABA and glutamate levels in the hippocampus and hypothalamus. However, GABA receptor modulators did not produce significant effect on ELFMF-induced anxiety and elevated levels of GABA at tested dose. Together, these findings suggest that ELFMF significantly induced anxiety behavior, and indicated the involvement of NMDA receptor in its effect.

  18. Interactions of neurotoxins with non-NMDA glutamate receptors: an autoradiographic study

    International Nuclear Information System (INIS)

    Kuenig, G.; Niedermeyer, B.; Krause, F.; Hartmann, J.; Deckert, J.; Heinsen, H.; Beckmann, H.; Riederer, P.; Ransmayr, G.

    1994-01-01

    Neurotoxic substances are discussed to cause neurode-generation by acting as excitotoxins on glutamate receptors. We investigated the properties of L-beta-oxalyl-amino-alanine (L-BOAA) and 3,4,6-trihydroxyphenlyalanine (6-OH-Dopa) at the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) glutamate receptor and that of L-BOAA and domoic acid at the kainate glutamate receptor in human hippocampus. (3 H)AMPA binding in hippocampal subfields was inhibited by L-BOAA and 6-OH-Dopa with mean IC50-values in the low micromolar range. (3H)Kainate binding was inhibited by L-BOAA with similar potency as (3H)AMPA binding and by domoic acid with mean IC50-values in the low nanomolar range. These results support the notion that symptoms like anterograde amnesia and epileptic seizures seen in domoic acid intoxication and limbic symptoms, e.g. cognitive and mood impairment observed in neurolathyrism may be caused by excitotoxic action on non-NMDA receptors. The potent interaction of 6-OH-Dopa with the AMPA-receptor may point to a possible dopaminergic-glutamatergic interaction in the development of neurodegenerative diseases like Parkinson's and Huntington's disease. (author)

  19. Central transport and distribution of labelled glutamic and aspartic acids to the cochlear nucleus in cats

    International Nuclear Information System (INIS)

    Kane, E.S.

    1979-01-01

    Tritiated L-glutamic acid or L-aspartic acid was injected unilaterally into the cochleas of adult cats, and 4 h-7 days later the localization of label was studied by light-microscopic autoradiography in sections of the brain stem. Consistent differences in labelling after glutamate and after aspartate suggest differences in their uptake, metabolic conversion and/or transport to the cochlear nucleus by cochlear fibers. The morphological differences shown here agree with the distribution of those two amino acids in the cat cochlear nucleus as shown by microchemical analyses. (author)

  20. FBXO22 Protein Is Required for Optimal Synthesis of the N-Methyl-d-Aspartate (NMDA) Receptor Coagonist d-Serine

    DEFF Research Database (Denmark)

    Dikopoltsev, Elena; Foltyn, Veronika N; Zehl, Martin

    2014-01-01

    d-Serine is a physiological activator of NMDA receptors (NMDARs) in the nervous system that mediates several NMDAR-mediated processes ranging from normal neurotransmission to neurodegeneration. d-Serine is synthesized from l-serine by serine racemase (SR), a brain-enriched enzyme. However, little......, SR interacts preferentially with free FBXO22 species. In vivo ubiquitination and SR half-life determination indicate that FBXO22 does not target SR to the proteasome system. FBXO22 primarily affects SR subcellular localization and seems to increase d-serine synthesis by preventing the association...... is known about the regulation of d-serine synthesis. We now demonstrate that the F-box only protein 22 (FBXO22) interacts with SR and is required for optimal d-serine synthesis in cells. Although FBXO22 is classically associated with the ubiquitin system and is recruited to the Skip1-Cul1-F-box E3 complex...

  1. Subcellular fractionation on Percoll gradient of mossy fiber synaptosomes: evoked release of glutamate, GABA, aspartate and glutamate decarboxylase activity in control and degranulated rat hippocampus.

    Science.gov (United States)

    Taupin, P; Ben-Ari, Y; Roisin, M P

    1994-05-02

    Using discontinuous density gradient centrifugation in isotonic Percoll sucrose, we have characterized two subcellular fractions (PII and PIII) enriched in mossy fiber synaptosomes and two others (SII and SIII) enriched in small synaptosomes. These synaptosomal fractions were compared with those obtained from adult hippocampus irradiated at neonatal stage to destroy granule cells and their mossy fibers. Synaptosomes were viable as judged by their ability to release aspartate, glutamate and GABA upon K+ depolarization. After irradiation, compared to the control values, the release of glutamate and GABA was decreased by 57 and 74% in the PIII fraction, but not in the other fractions and the content of glutamate, aspartate and GABA was also decreased in PIII fraction by 62, 44 and 52% respectively. These results suggest that mossy fiber (MF) synaptosomes contain and release glutamate and GABA. Measurement of the GABA synthesizing enzyme, glutamate decarboxylase, exhibited no significant difference after irradiation, suggesting that GABA is not synthesized by this enzyme in mossy fibers.

  2. Resolution, configurational assignment, and enantiopharmacology at glutamate receptors of 2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) and demethyl-ACPA

    DEFF Research Database (Denmark)

    Johansen, T N; Stensbøl, T B; Nielsen, B

    2001-01-01

    We have previously described (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) as a potent agonist at the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of (S)-glutamic acid (Glu) receptors. We now report the chromatographic resolution...... of ACPA and (RS)-2-amino-3-(3-carboxy-4-isoxazolyl)propionic acid (demethyl-ACPA) using a Sumichiral OA-5000 column. The configuration of the enantiomers of both compounds have been assigned based on X-ray crystallographic analyses, supported by circular dichroism spectra and elution orders on chiral HPLC...... columns. Furthermore, the enantiopharmacology of ACPA and demethyl-ACPA was investigated using radioligand binding and cortical wedge electrophysiological assay systems and cloned metabotropic Glu receptors. (S)-ACPA showed high affinity in AMPA binding (IC(50) = 0.025 microM), low affinity in kainic acid...

  3. A New Class of Potent N-Methyl-D-Aspartate Receptor Inhibitors: Sulfated Neuroactive Steroids with Lipophilic D-Ring Modifications

    Czech Academy of Sciences Publication Activity Database

    Kudová, Eva; Chodounská, Hana; Slavíková, Barbora; Buděšínský, Miloš; Nekardová, Michaela; Vyklický, Vojtěch; Krausová, Barbora; Švehla, Pavel; Vyklický ml., Ladislav

    2015-01-01

    Roč. 58, č. 15 (2015), s. 5950-5966 ISSN 0022-2623 R&D Projects: GA TA ČR(CZ) TE01020028; GA ČR(CZ) GAP303/12/1464; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388963 ; RVO:67985823 Keywords : NMDA receptor * noncovalent complexes * neurosteroids Subject RIV: CC - Organic Chemistry Impact factor: 5.589, year: 2015

  4. D-serine : The right or wrong isoform?

    NARCIS (Netherlands)

    Fuchs, Sabine A; Berger, Ruud; de Koning, Tom J

    2011-01-01

    Only recently, d-amino acids have been identified in mammals. Of these, d-serine has been most extensively studied. d-Serine was found to play an important role as a neurotransmitter in the human central nervous system (CNS) by binding to the N-methyl-d-aspartate receptor (NMDAr), similar to

  5. Prenatal chronic mild stress induces depression-like behavior and sex-specific changes in regional glutamate receptor expression patterns in adult rats.

    Science.gov (United States)

    Wang, Y; Ma, Y; Hu, J; Cheng, W; Jiang, H; Zhang, X; Li, M; Ren, J; Li, X

    2015-08-20

    Chronic stress during critical periods of human fetal brain development is associated with cognitive, behavioral, and mood disorders in later life. Altered glutamate receptor (GluR) expression has been implicated in the pathogenesis of stress-dependent disorders. To test whether prenatal chronic mild stress (PCMS) enhances offspring's vulnerability to stress-induced behavioral and neurobiological abnormalities and if this enhanced vulnerability is sex-dependent, we measured depression-like behavior in the forced swimming test (FST) and regional changes in GluR subunit expression in PCMS-exposed adult male and female rats. Both male and female PCMS-exposed rats exhibited stronger depression-like behavior than controls. Males and females exhibited unique regional changes in GluR expression in response to PCMS alone, FST alone (CON-FST), and PCMS with FST (PCMS-FST). In females, PCMS alone did not alter N-methyl-d-aspartate receptor (NMDAR) or metabotropic glutamate receptor (mGluR) expression, while in PCMS males, higher mGluR2/3, mGluR5, and NR1 expression levels were observed in the prefrontal cortex. In addition, PCMS altered the change in GluR expression induced by acute stress (the FST test), and this too was sex-specific. Male PCMS-FST rats expressed significantly lower mGluR5 levels in the hippocampus, lower mGluR5, NR1, postsynaptic density protein (PSD)95, and higher mGluR2/3 in the prefrontal cortex, and higher mGluR5 and PSD95 in the amygdala than male CON-FST rats. Female PCMS-FST rats expressed lower NR1 in the hippocampus, lower NR2B and PSD95 in the prefrontal cortex, lower mGluR2/3 in the amygdala, and higher PSD95 in the amygdala than female CON-FST rats. PCMS may increase the offspring's vulnerability to depression by altering sex-specific stress-induced changes in glutamatergic signaling. Copyright © 2015. Published by Elsevier Ltd.

  6. The low binding affinity of D-serine at the ionotropic glutamate receptor GluD2 can be attributed to the hinge region

    DEFF Research Database (Denmark)

    Tapken, Daniel; Steffensen, Thomas Bielefeldt; Leth, Rasmus

    2017-01-01

    Ionotropic glutamate receptors (iGluRs) are responsible for most of the fast excitatory communication between neurons in our brain. The GluD2 receptor is a puzzling member of the iGluR family: It is involved in synaptic plasticity, plays a role in human diseases, e.g. ataxia, binds glycine and D...

  7. Glutamate Receptors within the Mesolimbic Dopamine System Mediate Alcohol Relapse Behavior.

    Science.gov (United States)

    Eisenhardt, Manuela; Leixner, Sarah; Luján, Rafael; Spanagel, Rainer; Bilbao, Ainhoa

    2015-11-25

    Glutamatergic input within the mesolimbic dopamine (DA) pathway plays a critical role in the development of addictive behavior. Although this is well established for some drugs of abuse, it is not known whether glutamate receptors within the mesolimbic system are involved in mediating the addictive properties of chronic alcohol use. Here we evaluated the contribution of mesolimbic NMDARs and AMPARs in mediating alcohol-seeking responses induced by environmental stimuli and relapse behavior using four inducible mutant mouse lines lacking the glutamate receptor genes Grin1 or Gria1 in either DA transporter (DAT) or D1R-expressing neurons. We first demonstrate the lack of GluN1 or GluA1 in either DAT- or D1R-expressing neurons in our mutant mouse lines by colocalization studies. We then show that GluN1 and GluA1 receptor subunits within these neuronal subpopulations mediate the alcohol deprivation effect, while having no impact on context- plus cue-induced reinstatement of alcohol-seeking behavior. We further validated these results pharmacologically by demonstrating similar reductions in the alcohol deprivation effect after infusion of the NMDAR antagonist memantine into the nucleus accumbens and ventral tegmental area of control mice, and a rescue of the mutant phenotype via pharmacological potentiation of AMPAR activity using aniracetam. In conclusion, dopamine neurons as well as D1R-expressing medium spiny neurons and their glutamatergic inputs via NMDARs and AMPARs act in concert to influence relapse responses. These results provide a neuroanatomical and molecular substrate for relapse behavior and emphasize the importance of glutamatergic drugs in modulating relapse behavior. Here we provide genetic and pharmacological evidence that glutamate receptors within the mesolimbic dopamine system play an essential role in alcohol relapse. Using various inducible and site-specific transgenic mouse models and pharmacological validation experiments, we show that critical

  8. Meeting overview: Sensory perception and schizophrenia, Lausanne, Switzerland June 31–July 1, 2014

    Directory of Open Access Journals (Sweden)

    Daniel C. Javitt, M.D., Ph.D.

    2015-06-01

    Third, several visual measures were found to correlate highly with symptoms and/or neurocognitive processing. Deficits in contour integration, for example, correlated highly with conceptual disorganization, whereas perceptual instability correlated with delusion formation. These findings highlight links between perceptual-level disturbance and clinical manifestation. Finally, the potential involvement of specific neurotransmitter receptors, including N-methyl-D-aspartate (NMDA-type glutamate receptors and alpha7 nicotinic receptors were discussed as potential etiological mechanisms. Overall, the meeting highlighted the contributions of visual pathway dysfunction to the etiopathogenesis of neurocognitive dysfunction in schizophrenia.

  9. NMDA Receptor-Dependent Synaptic Activity in Dorsal Motor Nucleus of Vagus Mediates the Enhancement of Gastric Motility by Stimulating ST36

    Directory of Open Access Journals (Sweden)

    Xinyan Gao

    2012-01-01

    Full Text Available Previous studies have demonstrated the efficacy of electroacupuncture at ST36 for patients with gastrointestinal motility disorders. While several lines of evidence suggest that the effect may involve vagal reflex, the precise molecular mechanism underlying this process still remains unclear. Here we report that the intragastric pressure increase induced by low frequency electric stimulation at ST36 was blocked by AP-5, an antagonist of N-methyl-D-aspartate receptors (NMDARs. Indeed, stimulating ST36 enhanced NMDAR-mediated, but not 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-ylpropanoic-acid-(AMPA- receptor-(AMPAR- mediated synaptic transmission in gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV. We also identified that suppression of presynaptic μ-opioid receptors may contribute to upregulation of NMDAR-mediated synaptic transmission induced by electroacupuncture at ST36. Furthermore, we determined that the glutamate-receptor-2a-(NR2A- containing NMDARs are essential for NMDAR-mediated enhancement of gastric motility caused by stimulating ST36. Taken together, our results reveal an important role of NMDA receptors in mediating enhancement of gastric motility induced by stimulating ST36.

  10. Heterogeneity of D-Serine Distribution in the Human Central Nervous System

    Science.gov (United States)

    Suzuki, Masataka; Imanishi, Nobuaki; Mita, Masashi; Hamase, Kenji; Aiso, Sadakazu

    2017-01-01

    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. There is heterogeneity in its distribution in the cerebrum and even within the cerebral neocortex. The neocortical heterogeneity is associated with Brodmann or functional areas but is unrelated to basic patterns of cortical layer structure or regional expressional variation of metabolic enzymes for D-serine. Such D-serine distribution may reflect functional diversity of glutamatergic neurons in the human CNS, which may serve as a basis for clinical and pharmacological studies on D-serine modulation. PMID:28604057

  11. In vitro evidence for the brain glutamate efflux hypothesis

    DEFF Research Database (Denmark)

    Helms, Hans Christian; Madelung, Rasmus; Waagepetersen, Helle Sønderby

    2012-01-01

    resistance values of 1014 ± 70 O cm(2) , and (14) C-D-mannitol permeability values of 0.88 ± 0.13 × 10(-6) cm s(-1) . Unidirectional flux studies showed that L-aspartate and L-glutamate, but not D-aspartate, displayed polarized transport in the brain-to-blood direction, however, all three amino acids......The concentration of the excitotoxic amino acid, L-glutamate, in brain interstitial fluid is tightly regulated by uptake transporters and metabolism in astrocytes and neurons. The aim of this study was to investigate the possible role of the blood-brain barrier endothelium in brain L......-glutamate homeostasis. Transendothelial transport- and accumulation studies of (3) H-L-glutamate, (3) H-L-aspartate, and (3) H-D-aspartate in an electrically tight bovine endothelial/rat astrocyte blood-brain barrier coculture model were performed. After 6 days in culture, the endothelium displayed transendothelial...

  12. DNA methyltransferase homologue TRDMT1 in Plasmodium falciparum specifically methylates endogenous aspartic acid tRNA.

    Science.gov (United States)

    Govindaraju, Gayathri; Jabeena, C A; Sethumadhavan, Devadathan Valiyamangalath; Rajaram, Nivethika; Rajavelu, Arumugam

    2017-10-01

    In eukaryotes, cytosine methylation regulates diverse biological processes such as gene expression, development and maintenance of genomic integrity. However, cytosine methylation and its functions in pathogenic apicomplexan protozoans remain enigmatic. To address this, here we investigated the presence of cytosine methylation in the nucleic acids of the protozoan Plasmodium falciparum. Interestingly, P. falciparum has TRDMT1, a conserved homologue of DNA methyltransferase DNMT2. However, we found that TRDMT1 did not methylate DNA, in vitro. We demonstrate that TRDMT1 methylates cytosine in the endogenous aspartic acid tRNA of P. falciparum. Through RNA bisulfite sequencing, we mapped the position of 5-methyl cytosine in aspartic acid tRNA and found methylation only at C38 position. P. falciparum proteome has significantly higher aspartic acid content and a higher proportion of proteins with poly aspartic acid repeats than other apicomplexan pathogenic protozoans. Proteins with such repeats are functionally important, with significant roles in host-pathogen interactions. Therefore, TRDMT1 mediated C38 methylation of aspartic acid tRNA might play a critical role by translational regulation of important proteins and modulate the pathogenicity of the malarial parasite. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Radial symmetry in a chimeric glutamate receptor pore

    Science.gov (United States)

    Wilding, Timothy J.; Lopez, Melany N.; Huettner, James E.

    2014-02-01

    Ionotropic glutamate receptors comprise two conformationally different A/C and B/D subunit pairs. Closed channels exhibit fourfold radial symmetry in the transmembrane domain (TMD) but transition to twofold dimer-of-dimers symmetry for extracellular ligand binding and N-terminal domains. Here, to evaluate symmetry in open pores we analysed interaction between the Q/R editing site near the pore loop apex and the transmembrane M3 helix of kainate receptor subunit GluK2. Chimeric subunits that combined the GluK2 TMD with extracellular segments from NMDA receptors, which are obligate heteromers, yielded channels made up of A/C and B/D subunit pairs with distinct substitutions along M3 and/or Q/R site editing status, in an otherwise identical homotetrameric TMD. Our results indicate that Q/R site interaction with M3 occurs within individual subunits and is essentially the same for both A/C and B/D subunit conformations, suggesting that fourfold pore symmetry persists in the open state.

  14. Neuroprotective effects of the novel glutamate transporter inhibitor (-)-3-hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]-isoxazole-4-carboxylic acid, which preferentially inhibits reverse transport (glutamate release) compared with glutamate reuptake

    DEFF Research Database (Denmark)

    Colleoni, Simona; Jensen, Anders Asbjørn; Landucci, Elisa

    2008-01-01

    on the three hEAAT subtypes. (-)-HIP-A maintained the remarkable property, previously reported with the racemates, of inhibiting synaptosomal glutamate-induced [3H]D-aspartate release (reverse transport) at concentrations significantly lower than those inhibiting [3H]L-glutamate uptake. New data suggest...

  15. Ketamine appears associated with better word recall than etomidate after a course of 6 electroconvulsive therapies.

    Science.gov (United States)

    McDaniel, William W; Sahota, Anupinder K; Vyas, Barin V; Laguerta, Nena; Hategan, Liana; Oswald, Jessica

    2006-06-01

    Ten patients treated with electroconvulsive therapy (ECT) for depressive illness received anesthesia with either etomidate or ketamine. Three patients received both etomidate and ketamine anesthesia for ECT during separate episodes of depression. Patients anesthetized with ketamine for ECT had significantly less impairment of short-term memory function than did patients who received ECT with etomidate anesthesia. All patients who received both anesthetics for ECT during 2 different episodes had less memory loss during ECT with ketamine than with etomidate. These results show the importance of studying the effects of all anesthetic agents used during ECT on cognitive functions. The results imply that the effect of ECT on memory may be largely caused by effects mediated by glutamate at N-methyl-d-aspartate receptors and suggest that N-methyl-d-aspartate antagonists may offer protection from memory dysfunction during ECT.

  16. Alteration of Depressive-like Behaviors by Psilocybe cubensis Alkaloid Extract in Mice: the Role of Glutamate Pathway

    Directory of Open Access Journals (Sweden)

    Elaheh Mahmoudi

    2018-03-01

    Full Text Available Background and objectives: Considering the increasing prevalence of depression, many studies are launched to investigate new antidepressant treatments. The present research has shown how psilocybin as an active compound of Psilocybe cubensis (Earle Singer extract (PCE can change the parameters related to depression and anxiety in animal models. Both serotonin (5-hydroxytryptamine: 5-HT and glutamate modulate depressive-like behaviors and, therefore, we examined the possible interaction of psilocybin as 5-HT1 agonist with glutamate receptor N-methyl-D-aspartate (NMDA. Methods: Psilocybe cubensis extract of this mushroom was prepared by ethyl acetate. NMRI mice involved in all experiments and were treated with the vehicle, extract, or standard drug intraperitoneally. Open field (OFT, forced swimming (FST and tail suspension tests (TST were applied to measure the intended parameters. OFT was performed to verify the applied doses for measuring the following antidepressant activity.  Results: PCE at the doses of 100 mg/kg significantly changed the locomotion, time spent in center and velocity of the animals in OFT. While treatment of the animals with PCE 10 and 40 mg/kg or ketamine 1 mg/kg did not alter the locomotor activity, co-administration of these subeffective amounts significantly reduced the immobility time in both FST and TST. Conclusion: These effects may indicate possible implication of psilocybin with NMDA receptor which consequently produces the antidepressant effects.

  17. D-cycloserine enhances spatial learning performances of rats ...

    African Journals Online (AJOL)

    Chronic developmental lead (Pb) exposure has long been associated with cognitive dysfunction in children and animals. N-methyl-D-aspartate (NMDA) receptors, important in the synaptic mechanisms involved in learning and memory, are key target of lead toxicity. D-cycloserine (DCS), a partial agonist of the ...

  18. NMDA receptor antagonist ketamine impairs feature integration in visual perception

    NARCIS (Netherlands)

    Meuwese, Julia D I; van Loon, Anouk M; Scholte, H Steven; Lirk, Philipp B; Vulink, Nienke C C; Hollmann, Markus W; Lamme, Victor A F

    2013-01-01

    Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground

  19. Alteration of glutamate/GABA balance during acute alcohol intoxication in rats: effect of Xingnaojing injection.

    Science.gov (United States)

    Wei, Jingjing; Yao, Limei; Yang, Lei; Zhao, Wei; Shi, Si; Cai, Qingyan; Chen, Dingsheng; Li, Weirong; Wang, Qi

    2015-05-26

    Xingnaojing Injection (XNJI) is a modern Chinese formula came from famous Chinese medicine An Gong Niu Huang Pill. XNJI has been used for treatment of cerebral diseases and stroke in China, and is approved by the State Food and Drug Administration of China for the treatment of acute alcohol intoxication (AAI). XNJI belongs to the ethnopharmacological family of medicines. In this study, we investigated the mechanisms of the XNJI effect on AAI. To investigate the effects of XNJI on glutamate, gamma-aminobutyric acid (GABA) and related receptor in lateral hypothalamic area (LHA) of AAI rat. Adult male Sprague-Dawley rats were implanted with microdialysis probes in LHA. Rats were randomly divided into control, model, 1.36mg/kg XNJI, 0.68mg/kg XNJI and 0.34mg/kg XNJI groups. During microdialysis, baseline samples were collected from 1h to 2.5h; thereafter, the rats were given an intraperitoneal injection of 52% ethanol, 5.2g/kg, or saline for control group. Twenty minutes later, three doses of XNJI was given by unilateral injection respectively, while saline for control and model groups, and samples were collected for the next 4h. The extracellular glutamate and GABA levels were measured in the LHA by a high performance liquid chromatography coupled with fluorescence detector (HPLC-FLU). The expression levels of related receptors N-methyl-d-aspartate receptor (NR) subunit NR2A, NR2B and GABAA were analyzed by reverse transcription polymerase chain reaction (RT-PCR). Ethanol (5.2g/kg) significantly decreased the extracellular levels of glutamate and increased extracellular GABA in LHA. On the other hand ethanol significantly decreased NR2A and NR2B mRNAs expression, and increase GABAA mRNA expression. XNJI could increase the extracellular level of glutamate and decrease that of GABA; moreover, induced an increase in NR2A and NR2B mRNA expression, and a decrease in GABAA mRNA expression in LHA. The current changes in glutamate, GABA and mRNA expressions of related

  20. GluN2C/GluN2D subunit-selective NMDA receptor potentiator CIQ reverses MK-801-induced impairment in prepulse inhibition and working memory in Y-maze test in mice

    Science.gov (United States)

    Suryavanshi, P S; Ugale, R R; Yilmazer-Hanke, D; Stairs, D J; Dravid, S M

    2014-01-01

    Background and Purpose Despite ample evidence supporting the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (d-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.). Experimental Approach The effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test. Key Results We found that systemic administration of CIQ (20 mg·kg−1, i.p.) in mice reversed MK-801 (0.15 mg·kg−1, i.p.)-induced, but not methamphetamine (3 mg·kg−1, i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801- and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze. Conclusion and Implications Together, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia. PMID:24236947

  1. D-serine increases adult hippocampal neurogenesis

    Directory of Open Access Journals (Sweden)

    Sebastien eSultan

    2013-08-01

    Full Text Available Adult hippocampal neurogenesis results in the continuous formation of new neurons and is a process of brain plasticity involved in learning and memory. The neurogenic niche regulates the stem cell proliferation and the differentiation and survival of new neurons and a major contributor to the neurogenic niche are astrocytes. Among the molecules secreted by astrocytes, D-serine is an important gliotransmitter and is a co-agonist of the glutamate, N-methyl-D-aspartate (NMDA receptor. D-serine has been shown to enhance the proliferation of neural stem cells in vitro, but its effect on adult neurogenesis in vivo is unknown. Here, we tested the effect of exogenous administration of D-serine on adult neurogenesis in the mouse dentate gyrus. We found that 1 week of treatment with D-serine increased cell proliferation in vivo and in vitro and increased the density of neural stem cells and transit amplifying progenitors. Furthermore, D-serine increased the survival of newborn neurons. Together, these results indicate that D-serine treatment resulted in the improvement of several steps of adult neurogenesis in vivo.

  2. Stereocontrolled dopamine receptor binding and subtype selectivity of clebopride analogues synthesized from aspartic acid.

    Science.gov (United States)

    Einsiedel, Jürgen; Weber, Klaus; Thomas, Christoph; Lehmann, Thomas; Hübner, Harald; Gmeiner, Peter

    2003-10-06

    Employing the achiral 4-aminopiperidine derivative clebopride as a lead compound, chiral analogues were developed displaying dopamine receptor binding profiles that proved to be strongly dependent on the stereochemistry. Compared to the D1 receptor, the test compounds showed high selectivity for the D2-like subtypes including D2(long), D2(short), D3 and D4. The highest D4 and D3 affinities were observed for the cis-3-amino-4-methylpyrrolidines 3e and the enantiomer ent3e resulting in K(i) values of 0.23 and 1.8 nM, respectively. The benzamides of type 3 and 5 were synthesized in enantiopure form starting from (S)-aspartic acid and its unnatural optical antipode.

  3. High-Frequency Stimulation of the Subthalamic Nucleus Activates Motor Cortex Pyramidal Tract Neurons by a Process Involving Local Glutamate, GABA and Dopamine Receptors in Hemi-Parkinsonian Rats.

    Science.gov (United States)

    Chuang, Chi-Fen; Wu, Chen-Wei; Weng, Ying; Hu, Pei-San; Yeh, Shin-Rung; Chang, Yen-Chung

    2018-04-30

    Deep brain stimulation (DBS) is widely used to treat advanced Parkinson’s disease (PD). Here, we investigated how DBS applied on the subthalamic nucleus (STN) influenced the neural activity in the motor cortex. Rats, which had the midbrain dopaminergic neurons partially depleted unilaterally, called the hemi-Parkinsonian rats, were used as a study model. c-Fos expression in the neurons was used as an indicator of neural activity. Application of high-frequency stimulation (HFS) upon the STN was used to mimic the DBS treatment. The motor cortices in the two hemispheres of hemi-Parkinsonian rats were found to contain unequal densities of c-Fos-positive (Fos+) cells, and STN-HFS rectified this bilateral imbalance. In addition, STN-HFS led to the intense c-Fos expression in a group of motor cortical neurons which exhibited biochemical and anatomical characteristics resembling those of the pyramidal tract (PT) neurons sending efferent projections to the STN. The number of PT neurons expressing high levels of c-Fos was significantly reduced by local application of the antagonists of non-N-methyl-D-aspartate (non-NMDA) glutamate receptors, gammaaminobutyric acid A (GABAA) receptors and dopamine receptors in the upper layers of the motor cortex. The results indicate that the coincident activations of synapses and dopamine receptors in the motor cortex during STN-HFS trigger the intense expression of c-Fos of the PT neurons. The implications of the results on the cellular mechanism underlying the therapeutic effects of STN-DBS on the movement disorders of PD are also discussed.

  4. NMDA receptor activation upstream of methyl farnesoate signaling for short day-induced male offspring production in the water flea, Daphnia pulex.

    Science.gov (United States)

    Toyota, Kenji; Miyakawa, Hitoshi; Yamaguchi, Katsushi; Shigenobu, Shuji; Ogino, Yukiko; Tatarazako, Norihisa; Miyagawa, Shinichi; Iguchi, Taisen

    2015-03-14

    The cladoceran crustacean Daphnia pulex produces female offspring by parthenogenesis under favorable conditions, but in response to various unfavorable external stimuli, it produces male offspring (environmental sex determination: ESD). We recently established an innovative system for ESD studies using D. pulex WTN6 strain, in which the sex of the offspring can be controlled simply by changes in the photoperiod: the long-day and short-day conditions can induce female and male offspring, respectively. Taking advantage of this system, we demonstrated that de novo methyl farnesoate (MF) synthesis is necessary for male offspring production. These results indicate the key role of innate MF signaling as a conductor between external environmental stimuli and the endogenous male developmental pathway. Despite these findings, the molecular mechanisms underlying up- and downstream signaling of MF have not yet been well elucidated in D. pulex. To elucidate up- and downstream events of MF signaling during sex determination processes, we compared the transcriptomes of daphnids reared under the long-day (female) condition with short-day (male) and MF-treated (male) conditions. We found that genes involved in ionotropic glutamate receptors, known to mediate the vast majority of excitatory neurotransmitting processes in various organisms, were significantly activated in daphnids by the short-day condition but not by MF treatment. Administration of specific agonists and antagonists, especially for the N-methyl-D-aspartic acid (NMDA) receptor, strongly increased or decreased, respectively, the proportion of male-producing mothers. Moreover, we also identified genes responsible for male production (e.g., protein kinase C pathway-related genes). Such genes were generally shared between the short-day reared and MF-treated daphnids. We identified several candidate genes regulating ESD which strongly suggests that these genes may be essential factors for male offspring production as an

  5. EPR study of gamma-irradiated N-methyl-L-alanine, DL-2-methyl glutamic acid hemihydrate and Di-leucine hydrochloride in solid state

    Science.gov (United States)

    Sütçü, Kerem; Osmanoğlu, Y. Emre

    2017-12-01

    In this study, it was aimed to investigate ɣ-irradiated powders of N-methyl-L-alanine (NMLA), DL-2-methyl glutamic acid hemihydrate (DL2MGAH), and Di-leucine hydrochloride (DLHCl) at room temperature by electron paramagnetic resonance spectroscopy. After the γ-irradiation the samples indicated the existence of the CH3ĊNHCH3COOH, HOOCCH3NH2CĊHCH2COOH·1/2H2O and (CH3)2ĊCH2CH NHCOOHCOCH (NH2HCl) CH2CH (CH3)2 radicals, respectively. The spectral parameters of the radicals were determined. The results were compared with the earlier studies and discussed accordingly.

  6. Effects of systemic glutamatergic manipulations on conditioned eyeblink responses and hyperarousal in a rabbit model of post-traumatic stress disorder.

    Science.gov (United States)

    Burhans, Lauren B; Smith-Bell, Carrie A; Schreurs, Bernard G

    2017-10-01

    Glutamatergic dysfunction is implicated in many neuropsychiatric conditions, including post-traumatic stress disorder (PTSD). Glutamate antagonists have shown some utility in treating PTSD symptoms, whereas glutamate agonists may facilitate cognitive behavioral therapy outcomes. We have developed an animal model of PTSD, based on conditioning of the rabbit's eyeblink response, that addresses two key features: conditioned responses (CRs) to cues associated with an aversive event and a form of conditioned hyperarousal referred to as conditioning-specific reflex modification (CRM). The optimal treatment to reduce both CRs and CRM is unpaired extinction. The goals of the study were to examine whether treatment with the N-methyl-D-aspartate glutamate receptor antagonist ketamine could reduce CRs and CRM, and whether the N-methyl-D-aspartate agonist D-cycloserine combined with unpaired extinction treatment could enhance the extinction of both. Administration of a single dose of subanesthetic ketamine had no significant immediate or delayed effect on CRs or CRM. Combining D-cycloserine with a single day of unpaired extinction facilitated extinction of CRs in the short term while having no impact on CRM. These results caution that treatments may improve one aspect of the PTSD symptomology while having no significant effects on other symptoms, stressing the importance of a multiple-treatment approach to PTSD and of animal models that address multiple symptoms.

  7. pH-Responsive chromogenic-sensing molecule based on bis(indolylmethene for the highly selective recognition of aspartate and glutamate

    Directory of Open Access Journals (Sweden)

    Shijun Shao

    2011-02-01

    Full Text Available Bis(indolylmethene displays high selectivity and sensitivity for aspartate and glutamate in water-containing medium based on the proton transfer signaling mode. The presence of acid can easily induce proton transfer to the basic H-bond acceptor moiety, which modulates the internal charge transfer state of the bis(indolylmethene skeleton and gives rise to dramatic change in color. The detection limits for aspartate and glutamate were 0.80 ppm and 1.12 ppm, respectively.

  8. Mechanical stress activates NMDA receptors in the absence of agonists.

    Science.gov (United States)

    Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K; Sachs, Frederick; Hua, Susan Z

    2017-01-03

    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. Extracellular Mg 2+ at 2 mM did not significantly affect the shear induced Ca 2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI.

  9. D-Serine and Glycine Differentially Control Neurotransmission during Visual Cortex Critical Period.

    Directory of Open Access Journals (Sweden)

    Claire N J Meunier

    Full Text Available N-methyl-D-aspartate receptors (NMDARs play a central role in synaptic plasticity. Their activation requires the binding of both glutamate and d-serine or glycine as co-agonist. The prevalence of either co-agonist on NMDA-receptor function differs between brain regions and remains undetermined in the visual cortex (VC at the critical period of postnatal development. Here, we therefore investigated the regulatory role that d-serine and/or glycine may exert on NMDARs function and on synaptic plasticity in the rat VC layer 5 pyramidal neurons of young rats. Using selective enzymatic depletion of d-serine or glycine, we demonstrate that d-serine and not glycine is the endogenous co-agonist of synaptic NMDARs required for the induction and expression of Long Term Potentiation (LTP at both excitatory and inhibitory synapses. Glycine on the other hand is not involved in synaptic efficacy per se but regulates excitatory and inhibitory neurotransmission by activating strychnine-sensitive glycine receptors, then producing a shunting inhibition that controls neuronal gain and results in a depression of synaptic inputs at the somatic level after dendritic integration. In conclusion, we describe for the first time that in the VC both D-serine and glycine differentially regulate somatic depolarization through the activation of distinct synaptic and extrasynaptic receptors.

  10. Peptidyl prolyl isomerase Pin1-inhibitory activity of D-glutamic and D-aspartic acid derivatives bearing a cyclic aliphatic amine moiety.

    Science.gov (United States)

    Nakagawa, Hidehiko; Seike, Suguru; Sugimoto, Masatoshi; Ieda, Naoya; Kawaguchi, Mitsuyasu; Suzuki, Takayoshi; Miyata, Naoki

    2015-12-01

    Pin1 is a peptidyl prolyl isomerase that specifically catalyzes cis-trans isomerization of phosphorylated Thr/Ser-Pro peptide bonds in substrate proteins and peptides. Pin1 is involved in many important cellular processes, including cancer progression, so it is a potential target of cancer therapy. We designed and synthesized a novel series of Pin1 inhibitors based on a glutamic acid or aspartic acid scaffold bearing an aromatic moiety to provide a hydrophobic surface and a cyclic aliphatic amine moiety with affinity for the proline-binding site of Pin1. Glutamic acid derivatives bearing cycloalkylamino and phenylthiazole groups showed potent Pin1-inhibitory activity comparable with that of known inhibitor VER-1. The results indicate that steric interaction of the cyclic alkyl amine moiety with binding site residues plays a key role in enhancing Pin1-inhibitory activity. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in β-cell glutamate signaling for incretin-induced insulin secretion.

    Directory of Open Access Journals (Sweden)

    Naoya Murao

    Full Text Available Incretins (GLP-1 and GIP potentiate insulin secretion through cAMP signaling in pancreatic β-cells in a glucose-dependent manner. We recently proposed a mechanistic model of incretin-induced insulin secretion (IIIS that requires two critical processes: 1 generation of cytosolic glutamate through the malate-aspartate (MA shuttle in glucose metabolism and 2 glutamate transport into insulin granules by cAMP signaling to promote insulin granule exocytosis. To directly prove the model, we have established and characterized CRISPR/Cas9-engineered clonal mouse β-cell lines deficient for the genes critical in these two processes: aspartate aminotransferase 1 (AST1, gene symbol Got1, a key enzyme in the MA shuttle, which generates cytosolic glutamate, and the vesicular glutamate transporters (VGLUT1, VGLUT2, and VGLUT3, gene symbol Slc17a7, Slc17a6, and Slc17a8, respectively, which participate in glutamate transport into secretory vesicles. Got1 knockout (KO β-cell lines were defective in cytosolic glutamate production from glucose and showed impaired IIIS. Unexpectedly, different from the previous finding that global Slc17a7 KO mice exhibited impaired IIIS from pancreatic islets, β-cell specific Slc17a7 KO mice showed no significant impairment in IIIS, as assessed by pancreas perfusion experiment. Single Slc17a7 KO β-cell lines also retained IIIS, probably due to compensatory upregulation of Slc17a6. Interestingly, triple KO of Slc17a7, Slc17a6, and Slc17a8 diminished IIIS, which was rescued by exogenously introduced wild-type Slc17a7 or Slc17a6 genes. The present study provides direct evidence for the essential roles of AST1 and VGLUTs in β-cell glutamate signaling for IIIS and also shows the usefulness of the CRISPR/Cas9 system for studying β-cells by simultaneous disruption of multiple genes.

  12. Synthesis of novel N1-substituted bicyclic pyrazole amino acids and evaluation of their interaction with glutamate receptors

    DEFF Research Database (Denmark)

    Conti, Paola; Grazioso, Giovanni; di Ventimiglia, Samuele Joppolo

    2005-01-01

    N1-substituted bicyclic pyrazole amino acids (S)-9a-9c and (R)-9a-9c, which are conformationally constrained analogues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested for activity at ionotropic and metabotropic glutamate receptors...

  13. Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity

    Directory of Open Access Journals (Sweden)

    Dickenson Anthony H

    2009-02-01

    Full Text Available Abstract Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavα2δ1 has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavα2δ1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA and α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavα2δ1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavα2δ1 transgenic mice. Our data indicated that overexpression of Cavα2δ1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavα2δ1-mediated spinal sensitization in which elevated Cavα2δ1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal

  14. Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity

    Science.gov (United States)

    Nguyen, David; Deng, Ping; Matthews, Elizabeth A; Kim, Doo-Sik; Feng, Guoping; Dickenson, Anthony H; Xu, Zao C; Luo, Z David

    2009-01-01

    Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavα2δ1) has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavα2δ1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia) similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavα2δ1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR) neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavα2δ1 transgenic mice. Our data indicated that overexpression of Cavα2δ1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavα2δ1-mediated spinal sensitization in which elevated Cavα2δ1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal horn neurons to innocuous

  15. Coping with dehydration: sympathetic activation and regulation of glutamatergic transmission in the hypothalamic PVN

    Science.gov (United States)

    Bardgett, Megan E.; Chen, Qing-Hui; Guo, Qing; Calderon, Alfredo S.; Andrade, Mary Ann

    2014-01-01

    Autonomic and endocrine profiles of chronic hypertension and heart failure resemble those of acute dehydration. Importantly, all of these conditions are associated with exaggerated sympathetic nerve activity (SNA) driven by glutamatergic activation of the hypothalamic paraventricular nucleus (PVN). Here, studies sought to gain insight into mechanisms of disease by determining the role of PVN ionotropic glutamate receptors in supporting SNA and mean arterial pressure (MAP) during dehydration and by elucidating mechanisms regulating receptor activity. Blockade of PVN N-methyl-d-aspartate (NMDA) receptors reduced (P dehydrated (DH) (48 h water deprivation) rats, but had no effect in euhydrated (EH) controls. Blockade of PVN α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors had no effect in either group. NMDA in PVN caused dose-dependent increases of renal SNA and MAP in both groups, but the maximum agonist evoked response (Emax) of the renal SNA response was greater (P dehydration increases excitatory NMDA receptor tone in PVN. Reduced glial-mediated glutamate uptake was identified as a key contributing factor. Defective glutamate uptake in PVN could therefore be an important, but as yet unexplored, mechanism driving sympathetic hyperactivity in chronic cardiovascular diseases. PMID:24671240

  16. Amino acid neurotransmitters and new approaches to anticonvulsant drug action.

    Science.gov (United States)

    Meldrum, B

    1984-01-01

    Amino acids provide the most universal and important inhibitory (gamma-aminobutyric acid (GABA), glycine) and excitatory (glutamate, aspartate, cysteic acid, cysteine sulphinic acid) neurotransmitters in the brain. An anticonvulsant action may be produced (1) by enhancing inhibitory (GABAergic) processes, and (2) by diminishing excitatory transmission. Possible pharmacological mechanisms for enhancing GABA-mediated inhibition include (1) GABA agonist action, (2) GABA prodrugs, (3) drugs facilitating GABA release from terminals, (4) inhibition of GABA-transaminase, (5) allosteric enhancement of the efficacy of GABA at the receptor complex, (6) direction action on the chloride ionophore, and (7) inhibition of GABA reuptake. Examples of these approaches include the use of irreversible GABA-transaminase inhibitors, such as gamma-vinyl GABA, and the development of anticonvulsant beta-carbolines that interact with the "benzodiazepine receptor." Pharmacological mechanisms for diminishing excitatory transmission include (1) enzyme inhibitors that decrease the maximal rate of synthesis of glutamate or aspartate, (2) drugs that decrease the synaptic release of glutamate or aspartate, and (3) drugs that block the post-synaptic action of excitatory amino acids. Compounds that selectively antagonise excitation due to dicarboxylic amino acids have recently been developed. Those that selectively block excitation produced by N-methyl-D-aspartate (and aspartate) have proved to be potent anticonvulsants in many animal models of epilepsy. This provides a novel approach to the design of anticonvulsant drugs.

  17. ATP induces NO production in hippocampal neurons by P2X(7 receptor activation independent of glutamate signaling.

    Directory of Open Access Journals (Sweden)

    Juan Francisco Codocedo

    Full Text Available To assess the putative role of adenosine triphosphate (ATP upon nitric oxide (NO production in the hippocampus, we used as a model both rat hippocampal slices and isolated hippocampal neurons in culture, lacking glial cells. In hippocampal slices, additions of exogenous ATP or 2'(3'-O-(4-Benzoylbenzoyl ATP (Bz-ATP elicited concentration-dependent NO production, which increased linearly within the first 15 min and plateaued thereafter; agonist EC50 values were 50 and 15 µM, respectively. The NO increase evoked by ATP was antagonized in a concentration-dependent manner by Coomassie brilliant blue G (BBG or by N(ω-propyl-L-arginine, suggesting the involvement of P2X7Rs and neuronal NOS, respectively. The ATP induced NO production was independent of N-methyl-D-aspartic acid (NMDA receptor activity as effects were not alleviated by DL-2-Amino-5-phosphonopentanoic acid (APV, but antagonized by BBG. In sum, exogenous ATP elicited NO production in hippocampal neurons independently of NMDA receptor activity.

  18. The HIV-1 viral protein Tat increases glutamate and decreases GABA exocytosis from human and mouse neocortical nerve endings.

    Science.gov (United States)

    Musante, Veronica; Summa, Maria; Neri, Elisa; Puliti, Aldamaria; Godowicz, Tomasz T; Severi, Paolo; Battaglia, Giuseppe; Raiteri, Maurizio; Pittaluga, Anna

    2010-08-01

    Human immunodeficiency virus-1 (HIV-1)-encoded transactivator of transcription (Tat) potentiated the depolarization-evoked exocytosis of [(3)H]D-aspartate ([(3)H]D-ASP) from human neocortical terminals. The metabotropic glutamate (mGlu) 1 receptor antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) prevented this effect, whereas the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) was ineffective. Western blot analysis showed that human neocortex synaptosomes possess mGlu1 and mGlu5 receptors. Tat potentiated the K(+)-evoked release of [(3)H]D-ASP or of endogenous glutamate from mouse neocortical synaptosomes in a CPCCOEt-sensitive and MPEP-insensitive manner. Deletion of mGlu1 receptors (crv4/crv4 mice) or mGlu5 receptors (mGlu5(-/-)mouse) silenced Tat effects. Tat enhanced inositol 1,4,5-trisphosphate production in human and mouse neocortical synaptosomes, consistent with the involvement of group I mGlu receptors. Tat inhibited the K(+)-evoked release of [(3)H]gamma-aminobutyric acid ([(3)H]GABA) from human synaptosomes and that of endogenous GABA or [(3)H]GABA from mouse nerve terminals; the inhibition was insensitive to CPCCOEt or MPEP. Tat-induced effects were retained by Tat(37-72) but not by Tat(48-85). In mouse neocortical slices, Tat facilitated the K(+)- and the veratridine-induced release of [(3)H]D-ASP in a CPCCOEt-sensitive manner and was ineffective in crv4/crv4 mouse slices. These observations are relevant to the comprehension of the pathophysiological effects of Tat in central nervous system and may suggest new potential therapeutic approaches to the cure of HIV-1-associated dementia.

  19. Effects of hypoxia-ischemia and MK-801 treatment on the binding of a phencyclidine analogue in the developing rat brain

    International Nuclear Information System (INIS)

    Silverstein, F.S.; McDonald, J.W. III; Bommarito, M.; Johnston, M.V.

    1990-01-01

    The phencyclidine analogue [ 3 H](1-[2-thienyl]cyclohexyl)piperidine ( 3 H-TCP) binds to the ion channel associated with the N-methyl-D-aspartate receptor channel complex. In vitro autoradiography indicates that the distribution of 3 H-TCP binding in brain closely parallels that of [ 3 H]glutamate binding to the N-methyl-D-aspartate receptor. In nine 7-day-old rats, an acute focal hypoxic-ischemic insult produced by unilateral carotid artery ligation and subsequent exposure to 8% oxygen acutely reduced 3 H-TCP binding ipsilateral to the ligation by 30% in the CA1, by 27% in the CA3, by 26% in the dentate gyrus, and by 17% in the striatum compared with values from the contralateral hemisphere. In 10 littermates that received 1 mg/kg of the neuroprotective noncompetitive N-methyl-D-aspartate antagonist MK-801 immediately before hypoxic exposure, the regional distribution of 3 H-TCP binding in hypoxic-ischemic brain was relatively preserved and there were no interhemispheric asymmetries in 3 H-TCP binding densities. In addition, in three unoperated rats decapitated 24 hours after MK-801 treatment, 3 H-TCP binding was reduced by 15-35%; similar bilateral suppression of 3 H-TCP binding was detected in MK-801-treated ligates. Our data indicate that 3 H-TCP autoradiography can be used to assay the efficacy of neuroprotective agents in this experimental model of perinatal stroke

  20. Anti-neuronal anti-bodies in patients with early psychosis.

    Science.gov (United States)

    Mantere, O; Saarela, M; Kieseppä, T; Raij, T; Mäntylä, T; Lindgren, M; Rikandi, E; Stoecker, W; Teegen, B; Suvisaari, J

    2018-02-01

    It may be challenging to distinguish autoimmune encephalitis associated with anti-neuronal autoantibodies from primary psychiatric disorders. Here, serum was drawn from patients with a first-episode psychosis (n=70) or a clinical high-risk for psychosis (n=6) and controls (n=34). We investigated the serum prevalence of 24 anti-neuronal autoantibodies: IgG antibodies for anti-N-methyl-d-aspartate-type glutamate receptor (anti-NMDAR), glutamate and γ-aminobutyric acid alpha and beta receptors (GABA-a, GABA-b), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), glycine receptor (GlyR), metabotropic glutamate receptor 1 and 5 (mGluR1, mGluR5), anti-Tr/Delta/notch-like epidermal growth factor-related receptor (DNER), contactin-associated protein-like 2 (CASPR2), myelin oligodendrocyte glycoprotein (MOG), glutamic acid decarboxylase-65 (GAD65), collapsin response mediator protein 5/crossveinless-2 (CV2), aquaporin-4 (AQP4), anti-dipeptidyl-peptidase-like protein-6 (DPPX), type 1 anti-neuronal nuclear antibody (ANNA-1, Hu), Ri, Yo, IgLON5, Ma2, zinc finger protein 4 (ZIC4), Rho GTPase-activating protein 26, amphiphysin, and recoverin, as well as IgA and IgM for dopamine-2-receptor (DRD2). Anti-NMDA IgG antibodies were positive with serum titer 1:320 in one patient with a clinical high risk for psychosis. He did not receive a diagnosis of encephalitis after comprehensive neurological evaluation. All other antineuronal autoantibodies were negative and there were no additional findings with immunohistochemistry of brain issues. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats.

    Science.gov (United States)

    Stern, Javier E; Potapenko, Evgeniy S

    2013-08-15

    An enhanced glutamate excitatory function within the hypothalamic supraoptic and paraventricluar nuclei is known to contribute to increased neurosecretory and presympathetic neuronal activity, and hence, neurohumoral activation, during heart failure (HF). Still, the precise mechanisms underlying enhanced glutamate-driven neuronal activity in HF remain to be elucidated. Here, we performed simultaneous electrophysiology and fast confocal Ca²⁺ imaging to determine whether altered N-methyl-d-aspartate (NMDA) receptor-mediated changes in intracellular Ca²⁺ levels (NMDA-ΔCa²⁺) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in HF rats. We found that activation of NMDA receptors resulted in a larger ΔCa²⁺ in MNCs from HF when compared with sham rats. The enhanced NMDA-ΔCa²⁺ was neither dependent on the magnitude of the NMDA-mediated current (voltage clamp) nor on the degree of membrane depolarization or firing activity evoked by NMDA (current clamp). Differently from NMDA receptor activation, firing activity evoked by direct membrane depolarization resulted in similar changes in intracellular Ca²⁺ in sham and HF rats. Taken together, our results support a relatively selective alteration of intracellular Ca²⁺ homeostasis and signaling following activation of NMDA receptors in MNCs during HF. The downstream functional consequences of such altered ΔCa²⁺ signaling during HF are discussed.

  2. D-Amino Acid Aberrations in Cerebrospinal Fluid and Plasma of Smokers

    NARCIS (Netherlands)

    Luykx, Jurjen J.; Bakker, Steven C.; van Boxmeer, Loes; Vinkers, Christiaan H.; Smeenk, Hanne E.; Visser, Wouter F.; Verhoeven-Duif, Nanda M.; Strengman, Eric; Buizer-Voskamp, Jacobine E.; de Groene, Lizzy; van Dongen, Eric P. A.; Borgdorff, Paul; Bruins, Peter; de Koning, Tom J.; Kahn, Rene S.; Ophoff, Roel A.

    The glutamatergic neurotransmission system and the N-methyl-D-aspartate receptor (NMDAR) have been implicated in smoking and alcohol consumption behavior. Preclinical studies have demonstrated that nicotine and ethanol influence NMDAR functionality, which may have a role in tendencies to consume

  3. Effects of ketamine and N-methyl-D-aspartate on fluoxetine-induced antidepressant-related behavior using the forced swimming test.

    Science.gov (United States)

    Owolabi, Rotimi Adegbenga; Akanmu, Moses Atanda; Adeyemi, Oluwole Isaac

    2014-04-30

    This study investigated the effects of ketamine on fluoxetine-induced antidepressant behavior using the forced swimming test (FST) in mice. In order to understand the possible role of N-methyl-d-aspartate (NMDA) neurotransmission in the antidepressant effect of fluoxetine, different groups of mice (n=10) were administered with acute ketamine (3mg/kg, i.p.), acute NMDA (75mg/kg and 150mg/kg, i.p.) and a 21-day chronic ketamine (15mg/kg, i.p./day) were administered prior to the administration of fluoxetine (20mg/kg, i.p.) in the mice. Antidepressant related behavior (immobility score) was measured using the forced swimming test. The results showed that the acute ketamine and fluoxetine alone treatments elicited a significant (pfluoxetine-induced decrease in immobility score. In contrast, pre-treatment with NMDA (150mg/kg) significantly (pfluoxetine-induced decrease in immobility score. On the other hand, chronic administration of ketamine significantly elicited an increase in immobility score as well as reversed the reduction induced by fluoxetine. Similarly, NMDA administration at both 75mg/kg and 150mg/kg increased immobility score in chronically administered ketamine groups. Furthermore, chronic administration of ketamine, followed by NMDA (75mg/kg) and fluoxetine significantly elevated the immobility score when compared with the group that received NMDA and fluoxetine but not chronically treated with ketamine. It can be suggested) that facilitation of NMDA transmission blocked fluoxetine-induced reduction in immobility score, while down-regulation of NMDA transmission is associated with increase in fluoxetine-induced antidepressant-related behavior in mice. Down-regulation of the NMDA transmission is proposed as an essential component of mechanism of suppression of depression related behaviors by fluoxetine. Modulation of NMDA transmission is suggested to be relevant in the mechanism of action of fluoxetine. Copyright © 2014 Elsevier Ireland Ltd. All rights

  4. Central transport and distribution of labelled glutamic and aspartic acids to the cochlear nucleus in cats. An autoradiographic study

    Energy Technology Data Exchange (ETDEWEB)

    Kane, E S [University of Massachusetts Medical School, Worcester, MA (USA). Dept. of Anatomy

    1979-01-01

    Tritiated L-glutamic acid or L-aspartic acid was injected unilaterally into the cochleas of adult cats, and 4 h-7 days later the localization of label was studied by light-microscopic autoradiography in sections of the brain stem. Consistent differences in labelling after glutamate and after aspartate suggest differences in their uptake, metabolic conversion and/or transport to the cochlear nucleus by cochlear fibers. The morphological differences shown here agree with the distribution of those two amino acids in the cat cochlear nucleus as shown by microchemical analyses.

  5. Aggression and increased glutamate in the mPFC during withdrawal from intermittent alcohol in outbred mice.

    Science.gov (United States)

    Hwa, Lara S; Nathanson, Anna J; Shimamoto, Akiko; Tayeh, Jillian K; Wilens, Allison R; Holly, Elizabeth N; Newman, Emily L; DeBold, Joseph F; Miczek, Klaus A

    2015-08-01

    Disrupted social behavior, including occasional aggressive outbursts, is characteristic of withdrawal from long-term alcohol (EtOH) use. Heavy EtOH use and exaggerated responses during withdrawal may be treated using glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonists. The current experiments explore aggression and medial prefrontal cortex (mPFC) glutamate as consequences of withdrawal from intermittent access to EtOH and changes in aggression and mPFC glutamate caused by NMDAR antagonists memantine and ketamine. Swiss male mice underwent withdrawal following 1-8 weeks of intermittent access to 20 % EtOH. Aggressive and nonaggressive behaviors with a conspecific were measured 6-8 h into EtOH withdrawal after memantine or ketamine (0-30 mg/kg, i.p.) administration. In separate mice, extracellular mPFC glutamate after memantine was measured during withdrawal using in vivo microdialysis. At 6-8 h withdrawal from EtOH, mice exhibited more convulsions and aggression and decreased social contact compared to age-matched water controls. Memantine, but not ketamine, increased withdrawal aggression at the 5-mg/kg dose in mice with a history of 8 weeks of EtOH but not 1 or 4 weeks of EtOH or in water drinkers. Tonic mPFC glutamate was higher during withdrawal after 8 weeks of EtOH compared to 1 week of EtOH or 8 weeks of water. Five milligrams per kilogram of memantine increased glutamate in 8-week EtOH mice, but also in 1-week EtOH and water drinkers. These studies reveal aggressive behavior as a novel symptom of EtOH withdrawal in outbred mice and confirm a role of NMDARs during withdrawal aggression and for disrupted social behavior.

  6. N-fluoroalkylated and N-alkylated analogues of the dopaminergic D-2 receptor antagonist raclopride

    International Nuclear Information System (INIS)

    Lannoye, G.S.; Moerlein, S.M.; Parkinson, D.; Welch, M.J.

    1990-01-01

    A series of raclopride [(S)-2-[(3,5-dichloro-6-methoxy-2- hydroxybenzamido)methyl]-1-ethylpyrrolidine] derivatives bearing pyrrolidino N-fluoroalkyl or -alkyl substituents were synthesized and evaluated as potential dopaminergic receptor-based positron tomography radiopharmaceuticals. Radiosynthetic procedures for producing the corresponding N-[18F]fluoroalkylated analogues of raclopride from 18F- (beta+, t1/2 = 110 min) in high specific activity were also developed. In vitro binding assays using competitive displacement of [3H]spiperone from primate caudate tissue indicated that the N-alkylated analogues of raclopride had Ki values of 5-40 nM, whereas the corresponding values for analogous N-fluoroalkylated derivatives ranged from 90-160 nM. The relatively low D-2 binding affinity of these fluorinated salicylamides was corroborated by in vivo tissue biodistribution results in rodents. On the basis of structure-binding correlations, the impact of intramolecular hydrogen bonding, ligand basicity, and steric bulk on the affinity of the benzamides for D-2 receptor binding are discussed. Strategies are presented for the development of alternative fluorinated salicylamides that are both receptor active and metabolically stable

  7. Proteomic analysis of adrenocorticotropic hormone treatment of an infantile spasm model induced by N-methyl-D-aspartic acid and prenatal stress.

    Directory of Open Access Journals (Sweden)

    Jing Wang

    Full Text Available Infantile spasms is an age-specific epileptic syndrome associated with poor developmental outcomes and poor response to nearly all traditional antiepileptic drugs except adrenocorticotropic hormone (ACTH. We investigated the protective mechanism of ACTH against brain damage. An infantile spasm rat model induced by N-methyl-D-aspartate (NMDA in neonate rats was used. Pregnant rats were randomly divided into the stress-exposed and the non-stress exposed groups, and their offspring were randomly divided into ACTH-treated spasm model, untreated spasm model, and control groups. A proteomics-based approach was used to detect the proteome differences between ACTH-treated and untreated groups. Gel image analysis was followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometric protein identification and bioinformatics analysis. Prenatal stress exposure resulted in more severe seizures, and ACTH treatment reduced and delayed the onset of seizures. The most significantly up-regulated proteins included isoform 1 of tubulin β-5 chain, cofilin-1 (CFL1, synaptosomal-associated protein 25, malate dehydrogenase, N(G,N(G-dimethylarginine dimethylaminohydrolase 1, annexin A3 (ANXA3, and rho GDP-dissociation inhibitor 1 (ARHGDIA. In contrast, tubulin α-1A chain was down-regulated. Three of the identified proteins, ARHGDIA, ANXA3, and CFL1, were validated using western blot analysis. ARHGDIA expression was assayed in the brain samples of five infantile spasm patients. These proteins are involved in the cytoskeleton, synapses, energy metabolism, vascular regulation, signal transduction, and acetylation. The mechanism underlying the effects of ACTH involves the molecular events affected by these proteins, and protein acetylation is the mechanism of action of the drug treatment.

  8. Unusual differences in the reactivity of glutamic and aspartic acid in oxidative decarboxylation reactions

    NARCIS (Netherlands)

    But, Andrada; Wijst, van der Evie; Notre, le Jerome; Wever, Ron; Sanders, Johan P.M.; Bitter, Johannes H.; Scott, Elinor L.

    2017-01-01

    Amino acids are potential substrates to replace fossil feedstocks for the synthesis of nitriles via oxidative decarboxylation using vanadium chloroperoxidase (VCPO), H2O2 and bromide. Here the conversion of glutamic acid (Glu) and aspartic acid (Asp) was investigated. It was

  9. D-Cycloserine Administered Directly to Infralimbic Medial Prefrontal Cortex Enhances Extinction Memory in Sucrose-Seeking Animals

    NARCIS (Netherlands)

    Peters, J.; de Vries, T.J.

    2013-01-01

    d-Cycloserine (DCS), a co-agonist at the N-methyl-D-aspartate (NMDA) receptor, has proven to be an effective adjunct to cognitive behavioral therapies that utilize extinction. This pharmacological-based enhancement of extinction memory has been primarily demonstrated in neuropsychiatric disorders

  10. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats

    NARCIS (Netherlands)

    Vogels, B. A.; Maas, M. A.; Daalhuisen, J.; Quack, G.; Chamuleau, R. A.

    1997-01-01

    The aim of this study was to investigate the possible role of N-methyl-D-aspartate (NMDA)-receptor overactivity in two different experimental rat models of encephalopathy: subacute encephalopathy caused by severe hyperammonemia in portacaval-shunted rats (AI-PCS rats) and acute hepatic

  11. Gentiopicroside attenuates morphine rewarding effect through downregulation of GluN2B receptors in nucleus accumbens.

    Science.gov (United States)

    Liu, Shui-Bing; Ma, Lan; Guo, Hong-Ju; Feng, Bin; Guo, Yan-Yan; Li, Xiao-Qiang; Sun, Wen-Ji; Zheng, Lian-He; Zhao, Ming-Gao

    2012-08-01

    Gentiopicroside (Gent) is one of the secoiridoid compound isolated from Gentiana lutea. This compound exhibits analgesic activities and inhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the anterior cingulate cortex in mice. Nucleus accumbens (NAc) is a forebrain structure known for its role in drug addiction. However, little is known about the role of Gent on morphine dependence and synaptic transmission changes in the NAc. Conditioned place preference (CPP) test and behavioral sensitization of locomotor activity were used to investigate drug-seeking related behaviors. Brain slices containing NAc were prepared, and whole-cell patch-clamp recordings were performed to record the excitatory postsynaptic currents (EPSCs). Expression of proteins was detected by Western blot analysis. Systemic administration of Gent attenuated the CPP effect induced by morphine, but had no effect on morphine-induced behavioral sensitization. Gent significantly reversed overexpression of GluN2B-containing NMDA receptors and dopamine D2 receptors in NAc during the first week of morphine withdrawal. However, the compound did not affect the overexpression of GluN2A-containing NMDA receptors, GluA1, and dopamine D1 receptors. Lastly, Gent significantly reduced NMDA receptors-mediated EPSCs in the NAc. Our study provides strong evidence that Gent inhibits morphine dependence through downregulation of GluN2B-containing NMDA receptors in the NAc. © 2012 Blackwell Publishing Ltd.

  12. In vitro evidence for the brain glutamate efflux hypothesis: brain endothelial cells cocultured with astrocytes display a polarized brain-to-blood transport of glutamate.

    Science.gov (United States)

    Helms, Hans Christian; Madelung, Rasmus; Waagepetersen, Helle Sønderby; Nielsen, Carsten Uhd; Brodin, Birger

    2012-05-01

    The concentration of the excitotoxic amino acid, L-glutamate, in brain interstitial fluid is tightly regulated by uptake transporters and metabolism in astrocytes and neurons. The aim of this study was to investigate the possible role of the blood-brain barrier endothelium in brain L-glutamate homeostasis. Transendothelial transport- and accumulation studies of (3) H-L-glutamate, (3) H-L-aspartate, and (3) H-D-aspartate in an electrically tight bovine endothelial/rat astrocyte blood-brain barrier coculture model were performed. After 6 days in culture, the endothelium displayed transendothelial resistance values of 1014 ± 70 Ω cm(2) , and (14) C-D-mannitol permeability values of 0.88 ± 0.13 × 10(-6) cm s(-1) . Unidirectional flux studies showed that L-aspartate and L-glutamate, but not D-aspartate, displayed polarized transport in the brain-to-blood direction, however, all three amino acids accumulated in the cocultures when applied from the abluminal side. The transcellular transport kinetics were characterized with a K(m) of 69 ± 15 μM and a J(max) of 44 ± 3.1 pmol min(-1) cm(-2) for L-aspartate and a K(m) of 138 ± 49 μM and J(max) of 28 ± 3.1 pmol min(-1) cm(-2) for L-glutamate. The EAAT inhibitor, DL-threo-ß-Benzyloxyaspartate, inhibited transendothelial brain-to-blood fluxes of L-glutamate and L-aspartate. Expression of EAAT-1 (Slc1a3), -2 (Slc1a2), and -3 (Slc1a1) mRNA in the endothelial cells was confirmed by conventional PCR and localization of EAAT-1 and -3 in endothelial cells was shown with immunofluorescence. Overall, the findings suggest that the blood-brain barrier itself may participate in regulating brain L-glutamate concentrations. Copyright © 2012 Wiley Periodicals, Inc.

  13. EEG with extreme delta brush in young female with methotrexate neurotoxicity supports NMDA receptor involvement

    DEFF Research Database (Denmark)

    Schmidt, Lisbeth Samsø; Kjær, Troels W; Schmiegelow, Kjeld

    2017-01-01

    Sub-acute neurotoxicity is a well-known complication to high-dose and intrathecal methotrexate (MTX) treatment of children with leukemia. Symptoms can be treated safely by dextromethorphan, a non-competitive antagonist to N-methyl-D-aspartic acid receptor (NMDAR). In a female with subacute MTX...

  14. Posttranslational Modification Biology of Glutamate Receptors and Drug Addiction

    Directory of Open Access Journals (Sweden)

    Li-Min eMao

    2011-03-01

    Full Text Available Posttranslational covalent modifications of glutamate receptors remain a hot topic. Early studies have established that this family of receptors, including almost all ionotropic and metabotropic glutamate receptor subtypes, undergoes active phosphorylation at serine, threonine, or tyrosine residues on their intracellular domains. Recent evidence identifies several glutamate receptor subtypes to be direct substrates for palmitoylation at cysteine residues. Other modifications such as ubiquitination and sumoylation at lysine residues also occur to certain glutamate receptors. These modifications are dynamic and reversible in nature and are regulatable by changing synaptic inputs. The regulated modifications significantly impact the receptor in many ways, including interrelated changes in biochemistry (synthesis, subunit assembling and protein-protein interactions, subcellular redistribution (trafficking, endocytosis, synaptic delivery and clustering, and physiology, usually associated with changes in synaptic plasticity. Glutamate receptors are enriched in the striatum and cooperate closely with dopamine to regulate striatal signaling. Emerging evidence shows that modification processes of striatal glutamate receptors are sensitive to addictive drugs, such as psychostimulants (cocaine and amphetamines. Altered modifications are believed to be directly linked to enduring receptor/synaptic plasticity and drug-seeking. This review summarizes several major types of modifications of glutamate receptors and analyzes the role of these modifications in striatal signaling and in the pathogenesis of psychostimulant addiction.

  15. Differential Modulation of GABAA and NMDA Receptors by an α7-nicotinic Acetylcholine Receptor Agonist in Chronic Glaucoma

    Directory of Open Access Journals (Sweden)

    Xujiao Zhou

    2017-12-01

    Full Text Available Presynaptic modulation of γ-aminobutyric acid (GABA release by an alpha7 nicotinic acetylcholine receptor (α7-nAChR agonist promotes retinal ganglion cell (RGC survival and function, as suggested by a previous study on a chronic glaucomatous model from our laboratory. However, the role of excitatory and inhibitory amino acid receptors and their interaction with α7-nAChR in physiological and glaucomatous events remains unknown. In this study, we investigated GABAA and N-methyl-D-aspartate (NMDA receptor activity in control and glaucomatous retinal slices and the regulation of amino acid receptor expression and function by α7-nAChR. Whole-cell patch-clamp recordings from RGCs revealed that the α7-nAChR specific agonist PNU-282987 enhanced the amplitude of currents elicited by GABA and reduced the amplitude of currents elicited by NMDA. The positive modulation of GABAA receptor and the negative modulation of NMDA receptor (NMDAR by PNU-282987-evoked were prevented by pre-administration of the α7-nAChR antagonist methyllycaconitine (MLA. The frequency and the amplitude of glutamate receptor-mediated miniature glutamatergic excitatory postsynaptic currents (mEPSCs were not significantly different between the control and glaucomatous RGCs. Additionally, PNU-282987-treated slices showed no alteration in the frequency or amplitude of mEPSCs relative to control RGCs. Moreover, we showed that expression of the α1 subunit of the GABAA receptor was downregulated and the expression of the NMDAR NR2B subunit was upregulated by intraocular pressure (IOP elevation, and the changes of high IOP were blocked by PNU-282987. In conclusion, retina GABAA and NMDARs are modulated positively and negatively, respectively, by activation of α7-nAChR in in vivo chronic glaucomatous models.

  16. Dopamine D1-D2 receptor heteromer in dual phenotype GABA/glutamate-coexpressing striatal medium spiny neurons: regulation of BDNF, GAD67 and VGLUT1/2.

    Directory of Open Access Journals (Sweden)

    Melissa L Perreault

    Full Text Available In basal ganglia a significant subset of GABAergic medium spiny neurons (MSNs coexpress D1 and D2 receptors (D1R and D2R along with the neuropeptides dynorphin (DYN and enkephalin (ENK. These coexpressing neurons have been recently shown to have a region-specific distribution throughout the mesolimbic and basal ganglia circuits. While the functional relevance of these MSNs remains relatively unexplored, they have been shown to exhibit the unique property of expressing the dopamine D1-D2 receptor heteromer, a novel receptor complex with distinct pharmacology and cell signaling properties. Here we showed that MSNs coexpressing the D1R and D2R also exhibited a dual GABA/glutamate phenotype. Activation of the D1R-D2R heteromer in these neurons resulted in the simultaneous, but differential regulation of proteins involved in GABA and glutamate production or vesicular uptake in the nucleus accumbens (NAc, ventral tegmental area (VTA, caudate putamen and substantia nigra (SN. Additionally, activation of the D1R-D2R heteromer in NAc shell, but not NAc core, differentially altered protein expression in VTA and SN, regions rich in dopamine cell bodies. The identification of a MSN with dual inhibitory and excitatory intrinsic functions provides new insights into the neuroanatomy of the basal ganglia and demonstrates a novel source of glutamate in this circuit. Furthermore, the demonstration of a dopamine receptor complex with the potential to differentially regulate the expression of proteins directly involved in GABAergic inhibitory or glutamatergic excitatory activation in VTA and SN may potentially provide new insights into the regulation of dopamine neuron activity. This could have broad implications in understanding how dysregulation of neurotransmission within basal ganglia contributes to dopamine neuronal dysfunction.

  17. GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists.

    Science.gov (United States)

    Moskal, Joseph R; Burch, Ronald; Burgdorf, Jeffrey S; Kroes, Roger A; Stanton, Patric K; Disterhoft, John F; Leander, J David

    2014-02-01

    The N-methyl-d-aspartate receptor-ionophore complex plays a key role in learning and memory and has efficacy in animals and humans with affective disorders. GLYX-13 is an N-methyl-d-aspartate receptor (NMDAR) glycine-site functional partial agonist and cognitive enhancer that also shows rapid antidepressant activity without psychotomimetic side effects. The authors review the mechanism of action of GLYX-13 that was investigated in preclinical studies and evaluated in clinical studies. Specifically, the authors review its pharmacology, pharmacokinetics, and drug safety that were demonstrated in clinical studies. NMDAR full antagonists can produce rapid antidepressant effects in treatment-resistant subjects; however, they are often accompanied by psychotomimetic effects that make chronic use outside of a clinical trial inpatient setting problematic. GLYX-13 appears to exert its antidepressant effects in the frontal cortex via NMDAR-triggered synaptic plasticity. Understanding the mechanistic underpinning of GLYX-13's antidepressant action should provide both novel insights into the role of the glutamatergic system in depression and identify new targets for therapeutic development.

  18. Preliminary studies of 99mTc-memantine derivatives for NMDA receptor imaging

    International Nuclear Information System (INIS)

    Zhou Xingqin; Zhang Jiankang; Yan Chenglong; Cao Guoxian; Zhang Rongjun; Cai Gangming; Jiang Mengjun; Wang Songpei

    2012-01-01

    Introduction: Novel technetium-labeled ligands, 99m Tc-NCAM and 99m Tc-NHAM were developed from the N-methyl-D-aspartate (NMDA) receptor agonist memantine as a lead compound by coupling with N 2 S 2 . This study evaluated the binding affinity and specificity of the ligands for the NMDA receptor. Methods: Ligand biodistribution and uptake specificity in the brain were investigated in mice. Binding affinity and specificity were determined by radioligand receptor binding assay. Three antagonists were used for competitive binding analysis. In addition, uptake of the complexes into SH-SY5Y nerve cells was evaluated. Results: The radiochemical purity of 99m Tc-labeled ligands was more than 95%. Analysis of brain regional uptake showed higher concentration in the frontal lobe and specific uptake in the hippocampus. 99m Tc-NCAM reached a higher target to nontarget ratio than 99m Tc-NHAM. The results indicated that 99m Tc-NCAM bound to a single site on the NMDA receptor with a K d of 701.21 nmol/l and a B max of 62.47 nmol/mg. Specific inhibitors of the NMDA receptor, ketamine and dizocilpine, but not the dopamine D 2 and 5HT 1A receptor partial agonist aripiprazole, inhibited specific binding of 99m Tc-NCAM to the NMDA receptor. Cell physiology experiments showed that NCAM can increase the viability of SH-SY5Y cells after glutamate-induced injury. Conclusions: The new radioligand 99m Tc-NCAM has good affinity for and specific binding to the NMDA receptor, and easily crosses the blood–brain barrier; suggesting that it might be a potentially useful tracer for NMDA receptor expression.

  19. Glutamate and GABA in schizophrenia

    NARCIS (Netherlands)

    Marsman, A.

    2013-01-01

    Schizophrenia is characterized by a loss of brain tissue, which may represent an ongoing pathophysiological process. Possible mechanisms that may be involved are the glutamatergic and GABAergic (gamma-aminobutyric acid) systems. Particularly hypofunction of the N-methyl-D-aspartate (NMDA) type of

  20. NMDA Receptors in Glial Cells: Pending Questions.

    Science.gov (United States)

    Dzamba, David; Honsa, Pavel; Anderova, Miroslava

    2013-05-01

    Glutamate receptors of the N-methyl-D-aspartate (NMDA) type are involved in many cognitive processes, including behavior, learning and synaptic plasticity. For a long time NMDA receptors were thought to be the privileged domain of neurons; however, discoveries of the last 25 years have demonstrated their active role in glial cells as well. Despite the large number of studies in the field, there are many unresolved questions connected with NMDA receptors in glia that are still a matter of debate. The main objective of this review is to shed light on these controversies by summarizing results from all relevant works concerning astrocytes, oligodendrocytes and polydendrocytes (also known as NG2 glial cells) in experimental animals, further extended by studies performed on human glia. The results are divided according to the study approach to enable a better comparison of how findings obtained at the mRNA level correspond with protein expression or functionality. Furthermore, special attention is focused on the NMDA receptor subunits present in the particular glial cell types, which give them special characteristics different from those of neurons - for example, the absence of Mg(2+) block and decreased Ca(2+) permeability. Since glial cells are implicated in important physiological and pathophysiological roles in the central nervous system (CNS), the last part of this review provides an overview of glial NMDA receptors with respect to ischemic brain injury.

  1. No Effects of D-Cycloserine Enhancement in Exposure with Response Prevention Therapy in Panic Disorder with Agoraphobia : A Double-Blind, Randomized Controlled Trial

    NARCIS (Netherlands)

    Hofmeijer-Sevink, Mieke Klein; Duits, Puck; Rijkeboer, Marleen M.; Hoogendoorn, Adriaan W; Van Megen, Harold J.; Vulink, Nienke C.; Denys, Damiaan A.; Van Den Hout, Marcel A.; van Balkom, Anton J L M; Cath, Danielle C.

    2017-01-01

    Purpose/Background D-cycloserine (DCS) is a partial N-methyl-D-aspartate receptor agonist that potentially augments response to exposure therapy in anxiety disorders by enhancing extinction learning. This randomized, double-blinded, placebo-controlled augmentation trial examined (1) the

  2. No Effects of D-Cycloserine Enhancement in Exposure With Response Prevention Therapy in Panic Disorder With Agoraphobia : A Double-Blind, Randomized Controlled Trial

    NARCIS (Netherlands)

    Hofmeijer-Sevink, Mieke Klein; Duits, Puck; Rijkeboer, Marleen M; Hoogendoorn, Adriaan W; van Megen, Harold J; Vulink, Nienke C; Denys, D.; van den Hout, Marcel A; van Balkom, Anton J L M; Cath, Danielle C

    2017-01-01

    PURPOSE/BACKGROUND: D-cycloserine (DCS) is a partial N-methyl-D-aspartate receptor agonist that potentially augments response to exposure therapy in anxiety disorders by enhancing extinction learning. This randomized, double-blinded, placebo-controlled augmentation trial examined (1) the

  3. In vivo high-affinity uptake and axonal transport of D-(2,3-/sup 3/H)aspartate in excitatory neurons

    Energy Technology Data Exchange (ETDEWEB)

    Storm-Mathisen, J.; Wold, J.E. (Oslo Univ. (Norway))

    1981-12-28

    D-(2,3-/sup 3/H)aspartate ((/sup 3/H)D-Asp) at ..mu..M concentrations in Krebs' solution was infused intracerebrally in rats, mice and hamsters. Neuropil sites in the hippocampal formation, septum and neostriatum, known to receive excitatory nerve inputs with glutamate and aspartate as putative transmitters, showed strong autoradiographic labeling after intraventricular infusions. There was evidence for retrograde axonal transport to pyramidal cell bodies in hippocampus CA3 and neocortex. Infusions into the hilus fasciae dentatae led to anterograde axonal transport of (/sup 3/H)D-Asp in the mossy fibers.

  4. Early continuous white noise exposure alters auditory spatial sensitivity and expression of GAD65 and GABAA receptor subunits in rat auditory cortex.

    Science.gov (United States)

    Xu, Jinghong; Yu, Liping; Cai, Rui; Zhang, Jiping; Sun, Xinde

    2010-04-01

    Sensory experiences have important roles in the functional development of the mammalian auditory cortex. Here, we show how early continuous noise rearing influences spatial sensitivity in the rat primary auditory cortex (A1) and its underlying mechanisms. By rearing infant rat pups under conditions of continuous, moderate level white noise, we found that noise rearing markedly attenuated the spatial sensitivity of A1 neurons. Compared with rats reared under normal conditions, spike counts of A1 neurons were more poorly modulated by changes in stimulus location, and their preferred locations were distributed over a larger area. We further show that early continuous noise rearing induced significant decreases in glutamic acid decarboxylase 65 and gamma-aminobutyric acid (GABA)(A) receptor alpha1 subunit expression, and an increase in GABA(A) receptor alpha3 expression, which indicates a returned to the juvenile form of GABA(A) receptor, with no effect on the expression of N-methyl-D-aspartate receptors. These observations indicate that noise rearing has powerful adverse effects on the maturation of cortical GABAergic inhibition, which might be responsible for the reduced spatial sensitivity.

  5. Double Dissociation of Spike Timing-Dependent Potentiation and Depression by Subunit-Preferring NMDA Receptor Antagonists in Mouse Barrel Cortex

    NARCIS (Netherlands)

    Banerjee, A.; Meredith, R.M.; Rodriguez-Moreno, A.; Mierau, S.B.; Auberson, Y.P.; Paulsen, O.

    2009-01-01

    Spike timing-dependent plasticity (STDP) is a strong candidate for an N-methyl-D-aspartate (NMDA) receptor-dependent form of synaptic plasticity that could underlie the development of receptive field properties in sensory neocortices. Whilst induction of timing-dependent long-term potentiation

  6. D-Cycloserine for Treatment Nonresponders with Obsessive-Compulsive Disorder: A Case Report

    Science.gov (United States)

    Norberg, Melissa M.; Gilliam, Christina M.; Villavicencio, Anna; Pearlson, Godfrey D.; Tolin, David F.

    2012-01-01

    Despite being the most effective treatment available, as many as one third of patients who receive exposure and response prevention (ERP) for obsessive-compulsive disorder (OCD) do not initially respond to treatment. Recent research suggests that the n-methyl d-aspartate (NMDA) receptor partial agonist D-Cycloserine (DCS) may speed up the course…

  7. Retrograde transport of [3H]-D-aspartate label by cochlear and vestibular efferent neurons

    International Nuclear Information System (INIS)

    Schwarz, D.W.; Schwarz, I.E.

    1988-01-01

    [ 3 H]-D-aspartic acid was injected into the inner ear of rats. After a six hour survival time, labeled cells were found at all locations known to contain efferent cochlear or vestibular neurons. Most labeled neurons were found in the ipsilateral lateral superior olivary nucleus (LSO), although both ventral nuclei of the trapezoid body (VTB), group E, and the caudal pontine reticular nucleus (CPR) just adjacent to the ascending limb of the facial nerve also contained labeled cells. Because not all efferent neurons in the rat could be previously shown to be cholinergic, aspartate and glutamate are efferent transmitter candidates

  8. Anti-Hebbian long-term potentiation in the hippocampal feedback inhibitory circuit.

    Science.gov (United States)

    Lamsa, Karri P; Heeroma, Joost H; Somogyi, Peter; Rusakov, Dmitri A; Kullmann, Dimitri M

    2007-03-02

    Long-term potentiation (LTP), which approximates Hebb's postulate of associative learning, typically requires depolarization-dependent glutamate receptors of the NMDA (N-methyl-D-aspartate) subtype. However, in some neurons, LTP depends instead on calcium-permeable AMPA-type receptors. This is paradoxical because intracellular polyamines block such receptors during depolarization. We report that LTP at synapses on hippocampal interneurons mediating feedback inhibition is "anti-Hebbian":Itis induced by presynaptic activity but prevented by postsynaptic depolarization. Anti-Hebbian LTP may occur in interneurons that are silent during periods of intense pyramidal cell firing, such as sharp waves, and lead to their altered activation during theta activity.

  9. L-glutamate Receptor In Paramecium

    Science.gov (United States)

    Bernal-Martínez, Juan; Ortega-Soto, Arturo

    2004-09-01

    Behavioral, electrophysiological and biochemical experiments were performed in order to establish the presence of a glutamate receptor in the ciliate Paramecium. It was found that an AMPA/KA receptor is functionally expressed in Paramecium and that this receptor is immunologically and fillogenetically related to the AMPA/KA receptor present in vertebrates.

  10. Peri-adolescent drinking of ethanol and/or nicotine modulates astroglial glutamate transporters and metabotropic glutamate receptor-1 in female alcohol-preferring rats.

    Science.gov (United States)

    Alasmari, Fawaz; Bell, Richard L; Rao, P S S; Hammad, Alaa M; Sari, Youssef

    2018-07-01

    Impairment in glutamate neurotransmission mediates the development of dependence upon nicotine (NIC) and ethanol (EtOH). Previous work indicates that continuous access to EtOH or phasic exposure to NIC reduces expression of the glutamate transporter-1 (GLT-1) and cystine/glutamate antiporter (xCT) but not the glutamate/aspartate transporter (GLAST). Additionally, metabotropic glutamate receptors (mGluRs) expression was affected following exposure to EtOH or NIC. However, little is known about the effects of EtOH and NIC co-consumption on GLT-1, xCT, GLAST, and mGluR1 expression. In this study, peri-adolescent female alcohol preferring (P) rats were given binge-like access to water, sucrose (SUC), SUC-NIC, EtOH, or EtOH-NIC for four weeks. The present study determined the effects of these reinforcers on GLT-1, xCT, GLAST, and mGluR1 expression in the nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC). GLT-1 and xCT expression were decreased in the NAc following both SUC-NIC and EtOH-NIC. In addition, only xCT expression was downregulated in the HIP in both of these latter groups. Also, glutathione peroxidase (GPx) activity in the HIP was reduced following SUC, SUC-NIC, EtOH, and EtOH-NIC consumption. Similar to previous work, GLAST expression was not altered in any brain region by any of the reinforcers. However, mGluR1 expression was increased in the NAc in the SUC-NIC, EtOH, and EtOH-NIC groups. These results indicate that peri-adolescent binge-like drinking of EtOH or SUC with or without NIC may exert differential effects on astroglial glutamate transporters and receptors. Our data further parallel some of the previous findings observed in adult rats. Copyright © 2018. Published by Elsevier Inc.

  11. Multiple D2 heteroreceptor complexes: new targets for treatment of schizophrenia

    Science.gov (United States)

    Borroto-Escuela, Dasiel O.; Pintsuk, Julia; Schäfer, Thorsten; Friedland, Kristina; Ferraro, Luca; Tanganelli, Sergio; Liu, Fang; Fuxe, Kjell

    2016-01-01

    The dopamine (DA) neuron system most relevant for schizophrenia is the meso-limbic-cortical DA system inter alia densely innervating subcortical limbic regions. The field of dopamine D2 receptors and schizophrenia changed markedly with the discovery of many types of D2 heteroreceptor complexes in subcortical limbic areas as well as the dorsal striatum. The results indicate that the D2 is a hub receptor which interacts not only with many other G protein-coupled receptors (GPCRs) including DA isoreceptors but also with ion-channel receptors, receptor tyrosine kinases, scaffolding proteins and DA transporters. Disturbances in several of these D2 heteroreceptor complexes may contribute to the development of schizophrenia through changes in the balance of diverse D2 homo- and heteroreceptor complexes mediating the DA signal, especially to the ventral striato-pallidal γ-aminobutyric acid (GABA) pathway. This will have consequences for the control of this pathway of the glutamate drive to the prefrontal cortex via the mediodorsal thalamic nucleus which can contribute to psychotic processes. Agonist activation of the A2A protomer in the A2A–D2 heteroreceptor complex inhibits D2 Gi/o mediated signaling but increases the D2 β-arrestin2 mediated signaling. Through this allosteric receptor–receptor interaction, the A2A agonist becomes a biased inhibitory modulator of the Gi/o mediated D2 signaling, which may the main mechanism for its atypical antipsychotic properties especially linked to the limbic A2A–D2 heterocomplexes. The DA and glutamate hypotheses of schizophrenia come together in the signal integration in D2–N-methyl-d-aspartate (NMDA) and A2A–D2–metabotropic glutamate receptor 5 (mGlu5) heteroreceptor complexes, especially in the ventral striatum. 5-Hydroxytryptamine 2A (5-HT2A)–D2 heteroreceptor complexes are special targets for atypical antipsychotics with high potency to block their 5-HT2A protomer signaling in view of the potential development of

  12. Intracellular synthesis of glutamic acid in Bacillus methylotrophicus SK19.001, a glutamate-independent poly(γ-glutamic acid)-producing strain.

    Science.gov (United States)

    Peng, Yingyun; Zhang, Tao; Mu, Wanmeng; Miao, Ming; Jiang, Bo

    2016-01-15

    Bacillus methylotrophicus SK19.001 is a glutamate-independent strain that produces poly(γ-glutamic acid) (γ-PGA), a polymer of D- and L-glutamic acids that possesses applications in food, the environment, agriculture, etc. This study was undertaken to explore the synthetic pathway of intracellular L- and D-glutamic acid in SK19.001 by investigating the effects of tricarboxylic acid cycle intermediates and different amino acids as metabolic precursors on the production of γ-PGA and analyzing the activities of the enzymes involved in the synthesis of L- and D-glutamate. Tricarboxylic acid cycle intermediates and amino acids could participate in the synthesis of γ-PGA via independent pathways in SK19.001. L-Aspartate aminotransferase, L-glutaminase and L-glutamate synthase were the enzymatic sources of L-glutamate. Glutamate racemase was responsible for the formation of D-glutamate for the synthesis of γ-PGA, and the synthetase had stereoselectivity for glutamate substrate. The enzymatic sources of L-glutamate were investigated for the first time in the glutamate-independent γ-PGA-producing strain, and multiple enzymatic sources of L-glutamate were verified in SK19.001, which will benefit efforts to improve production of γ-PGA with metabolic engineering strategies. © 2015 Society of Chemical Industry.

  13. In SilicoModel-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology.

    Science.gov (United States)

    Agrawal, Rimjhim; Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan

    2017-05-31

    Deficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA. Using CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)- Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and β-catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm. Study observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network. The study presents in silico quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and neuroplasticity that are consistent with current

  14. CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis.

    Science.gov (United States)

    Wang, Rui; Guan, Hong-Zhi; Ren, Hai-Tao; Wang, Wei; Hong, Zhen; Zhou, Dong

    2015-07-01

    Anti-NMDAR-encephalitis is a recently described form of autoimmune encephalitis. Here, we characterize CSF changes in Chinese patients with anti-NMDAR encephalitis, and explore the relationship between CSF findings and disease outcome. The presence of NMDAR antibodies in serum or CSF samples was evaluated in patients diagnosed with encephalitis between October 1, 2010 and August 1, 2014 at the West China Hospital. All patients fulfilling our diagnostic criteria were included and CSF findings were analyzed. Patient outcome was assessed after 4, 8, 12, 16, 20, and 24 months using the modified Rankin scale (mRS). Out of 3000 people with encephalitis screened, 43 patients were anti-NMDAR antibody positive in CSF or serum and included in this study. 62.8% of the patients identified with positive CSFs had positive serum anti-NMDAR samples, while 100% patients with positive serum had positive CSF samples. In the CSF white cell counts were elevated in 58.1% of cases; protein was increased in 18.6%; QAlb>Qlim(Alb) of the blood-CSF barrier was found in 29.3%; intrathecal immunoglobulin synthesis was detected in 17.1%, and 39.5% patients exhibited increased CSF pressures. A longer follow-up period was associated with better outcomes. There was no relationship between changes in CSF findings and outcome. The sensitivity of NMDA receptor antibody testing is higher in CSF compared to serum. Other CSF abnormalities are present in some patients with Anti-NMDAR-encephalitis, however these changes do not appear to affect prognosis. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  15. Two grams of sarcosine in schizophrenia – is it too much? A potential role of glutamate- serotonin interaction

    Directory of Open Access Journals (Sweden)

    Strzelecki D

    2014-02-01

    Full Text Available Dominik Strzelecki, Justyna Szyburska, Jolanta Rabe-JabłońskaDepartment of Affective and Psychotic Disorders, Central Clinical Hospital, Medical University of Lódz, Lódz, PolandAbstract: Glutamate is the main excitatory neurotransmitter in the central nervous system. Dysfunction of the glutamatergic system plays an important role in the pathogenesis of schizophrenia. Therefore, glutamatergic agents such as N-methyl-D-aspartate receptor co-agonists (ie, glycine, D-cycloserine and glycine transporter type 1 inhibitors (eg, sarcosine are studied for their efficacy in ameliorating negative and cognitive symptomatology in patients with schizophrenia. We report the case of a 23-year-old schizophrenic patient treated with quetiapine and citalopram, who was offered concomitant sarcosine treatment. After obtaining an informed consent, we started administration of 2 g of sarcosine per day to treat persistent negative and cognitive symptoms. The patient's activity and mood improved within 2 weeks, but in the following 2 weeks the patient reported increased drive, activity, libido, unpleasant inner tension, and irritability. We ruled out hypomania and decided to decrease the daily dose of sarcosine to 1 g, which resulted in reduction of drive and irritability. Activity and mood improved compared with his state before adding sarcosine. We suggest a sarcosine dose between 1 g and 2 g per day with an initial dose of 2 g, but if side effects occur, the dose should be decreased to 1 g per day. We would like to emphasize the clinically important glutamate-serotonin interaction during concomitant use of sarcosine, citalopram, and quetiapine in our patient, which may lead to serious discomfort.Keywords: schizophrenia, glutamatergic system, serotoninergic system, sarcosine, NMDA receptor, dose finding

  16. Metabolic regulation in Streptomyces parvulus during actinomycin D synthesis, studied with 13C- and 15N-labeled precursors by 13C and 15N nuclear magnetic resonance spectroscopy and by gas chromatography-mass spectrometry

    International Nuclear Information System (INIS)

    Inbar, L.; Lapidot, A.

    1988-01-01

    Recent studies have suggested that the onset of synthesis of actinomycin D in Streptomyces is due to a release from L-glutamate catabolic repression. In the present investigation we showed that S. parvulus has the capacity to maintain high levels of intracellular glutamate during the synthesis of actinomycin D. The results seem contradictory, since actinomycin D synthesis cannot start before a release from L-glutamate catabolic repression, but a relatively high intracellular pool of glutamate is needed for the synthesis of actinomycin D. Utilizing different labeled precursors, D-[U- 13 C]fructose and 13 C- and 15 N-labeled L-glutamate, and nuclear magnetic resonance techniques, we showed that carbon atoms of an intracellular glutamate pool of S. parvulus were not derived biosynthetically from the culture medium glutamte source but rather from D-fructose catabolism. A new intracellular pyrimidine derivative whose nitrogen and carbon skeletons were derived from exogenous L-glutamate was obtained as the main glutamate metabolite. Another new pyrimidine derivative that had a significantly reduced intracellular mobility and that was derived from D-fructose catabolism was identified in the cell extracts of S. parvulus during actinomycin D synthesis. These pyrimidine derivatives may serve as a nitrogen store for actinomycin D synthesis. In the present study, the N-trimethyl group of a choline derivative was observed by 13 C nuclear magnetic resonance spectroscopy in growing S. parvulus cells. The choline group, as well as the N-methyl groups of sarcosine, N-methyl-valine, and the methyl groups of an actinomycin D chromophore, arose from D-fructose catabolism. The 13 C enrichments found in the peptide moieties of actinomycin D were in accordance with a mechanism of actinomycin D synthesis from L-glutamate and D-fructose

  17. Circadian and developmental regulation of N-methyl-d-aspartate-receptor 1 mRNA splice variants and N-methyl-d-aspartate-receptor 3 subunit expression within the rat suprachiasmatic nucleus

    Czech Academy of Sciences Publication Activity Database

    Bendová, Zdeňka; Sumová, Alena; Mikkelsen, J. D.

    2009-01-01

    Roč. 159, č. 2 (2009), s. 599-609 ISSN 0306-4522 R&D Projects: GA MŠk(CZ) LC554; GA ČR(CZ) GA309/08/0503 Grant - others:EC(XE) LSH-2004-115-4-018741 Institutional research plan: CEZ:AV0Z50110509 Keywords : circadian clock * ontogenesis * photic entrainment Subject RIV: FH - Neuro logy Impact factor: 3.292, year: 2009

  18. Methylation of hemoglobin to enhance flocculant performance

    Science.gov (United States)

    An inexpensive bioflocculant, bovine hemoglobin (Hb), has been covalently modified through methylation of the side chain carboxyl groups of aspartic and glutamic acid residues to improve its flocculation activity. Potentiometric titration of the recovered products showed approximately 28% degree of ...

  19. Pregnenolone sulfate modulation of N-methyl-d-aspartate receptors is phosphorylation dependent

    Czech Academy of Sciences Publication Activity Database

    Petrovič, Miloš; Sedláček, Miloslav; Cais, Ondřej; Horák, Martin; Chodounská, Hana; Vyklický ml., Ladislav

    2009-01-01

    Roč. 160, č. 3 (2009), s. 616-628 ISSN 0306-4522 R&D Projects: GA ČR(CZ) GA309/07/0271; GA ČR(CZ) GA203/08/1498; GA MŠk(CZ) LC554; GA MŠk(CZ) 1M0517 Grant - others:EC(XE) LSHM-CT-2007-037765 Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z40550506 Keywords : NMDA * patch-clamp * phosphorylation Subject RIV: ED - Physiology Impact factor: 3.292, year: 2009

  20. "Light switch" mental status changes and irritable insomnia are two particularly salient features of anti-NMDA receptor antibody encephalitis.

    Science.gov (United States)

    DeSena, Allen D; Greenberg, Benjamin M; Graves, Donna

    2014-07-01

    Anti-N-methyl-D-aspartate antibody encephalitis is becoming increasingly recognized as a cause of acute and subacute encephalopathy in both adults and children. The typical features of this disorder include some degree of encephalopathy, seizures, and often a movement disorder component. However, there is wide variability in its presentation, and diagnosis based on clinical features alone is often delayed. We report a series of four of 12 patients observed at our children's hospital between 2011 and 2013 that we chose as particularly representative examples of two distinct clinical features. In these individuals with anti-N-methyl-D-aspartate receptor antibody encephalitis, we note a very rapid on-off state between responsiveness and nonresponsiveness and/or insomnia accompanied by extreme irritability. We describe the abrupt mental status shift as "light switch" because the patients can awaken in seconds from a completely nonresponsive state. The insomnia noted in our patients was also impressive and often present early in the patients' courses. Light switch mental status changes and irritable insomnia are important early features of anti-N-methyl-D-aspartate receptor antibody encephalitis that can signal the presence of this disorder. The exact pathophysiology of these two symptoms has not been fully elucidated, and we feel that presence of one or both of these symptoms early in the disease course should prompt immediate concern for this disorder. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Structure-based discovery of antagonists for GluN3-containing N-methyl-D-aspartate receptors

    DEFF Research Database (Denmark)

    Kvist, Trine; Greenwood, Jeremy R; Hansen, Kasper B

    2013-01-01

    . In the subsequent pharmacological evaluation of 99 selected compounds, we identified 6-hydroxy-[1,2,5]oxadiazolo[3,4-b]pyrazin-5(4H)-one (TK80) a novel competitive antagonist with preference for the GluN3B subunit. Serendipitously, we also identified [2-hydroxy-5-((4-(pyridin-3-yl)thiazol-2-yl)amino]benzoic acid...... (TK13) and 4-(2,4-dichlorobenzoyl)-1H-pyrrole-2-carboxylic acid (TK30), two novel non-competitive GluN3 antagonists. These findings demonstrate that structural differences between the orthosteric binding site of GluN3 and GluN1 can be exploited to generate selective ligands....

  2. Blockade of NMDA receptor subtype NR2B prevents seizures but not apoptosis of dentate gyrus neurons in bacterial meningitis in infant rats

    Directory of Open Access Journals (Sweden)

    Täuber Martin G

    2003-09-01

    Full Text Available Abstract Background Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S-alpha-(4-hydroxyphenyl-beta-methyl-4-(phenylmethyl-1-piperid inepropanol (RO 25-6981. Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28 or 3.75 mg (150 mg/kg; n = 15 every 3 h or an equal volume of sterile saline (250 μl; n = 40 starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus. Results Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P Conclusions Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures.

  3. Novel Functional Properties of Drosophila CNS Glutamate Receptors

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yan; Dharkar, Poorva; Han, Tae-Hee; Serpe, Mihaela; Lee, Chi-Hon; Mayer, Mark L.

    2016-12-01

    Phylogenetic analysis reveals AMPA, kainate, and NMDA receptor families in insect genomes, suggesting conserved functional properties corresponding to their vertebrate counterparts. However, heterologous expression of the Drosophila kainate receptor DKaiR1D and the AMPA receptor DGluR1A revealed novel ligand selectivity at odds with the classification used for vertebrate glutamate receptor ion channels (iGluRs). DKaiR1D forms a rapidly activating and desensitizing receptor that is inhibited by both NMDA and the NMDA receptor antagonist AP5; crystallization of the KaiR1D ligand-binding domain reveals that these ligands stabilize open cleft conformations, explaining their action as antagonists. Surprisingly, the AMPA receptor DGluR1A shows weak activation by its namesake agonist AMPA and also by quisqualate. Crystallization of the DGluR1A ligand-binding domain reveals amino acid exchanges that interfere with binding of these ligands. The unexpected ligand-binding profiles of insect iGluRs allows classical tools to be used in novel approaches for the study of synaptic regulation.

  4. Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia.

    Science.gov (United States)

    Rowland, Laura M; Summerfelt, Ann; Wijtenburg, S Andrea; Du, Xiaoming; Chiappelli, Joshua J; Krishna, Nithin; West, Jeffrey; Muellerklein, Florian; Kochunov, Peter; Hong, L Elliot

    2016-02-01

    Auditory mismatch negativity (MMN) is a biomarker for schizophrenia thought to reflect glutamatergic N-methyl-d-aspartate receptor function and excitatory-inhibitory neurotransmission balance. However, the association of glutamate level with MMN has not been directly examined in patients with schizophrenia, to our knowledge. To investigate the contributions of glutamate and γ-aminobutyric acid (GABA) to MMN and digit sequencing task (DST) performance, an assessment of verbal working memory, in schizophrenia. Fifty-three control participants from the community and 45 persons with schizophrenia from outpatient clinics completed an electroencephalographic session for MMN, magnetic resonance spectroscopy for glutamate and GABA, and a DST. The study dates were July 2011 to May 2014, and the dates of our analysis were May 2014 to August 2015. Glutamate, GABA, the ratio of glutamine to glutamate, MMN amplitude, and DST. Structural equation modeling was used to test the effects of neurochemistry and MMN amplitude on DST performance. The 45 persons with schizophrenia were a mean (SD) of 37.7 (12.8) years and the control participants were 37.1 (13.1) years. The schizophrenia group had a mean (SD) of 14.7 (12.1) years of illness. Mismatch negativity amplitude (F = 4.39, P = .04) and glutamate (F = 9.69, P = .002) were reduced in the schizophrenia group. Smaller MMN amplitude was significantly associated with lower GABA level (P = .008), lower glutamate level (P = .05), and higher ratio of glutamine to glutamate (P = .003). Reduced MMN amplitude was linked to poor verbal working memory in schizophrenia (P = .002). Modeling revealed that a proxy of glutamatergic function, indexed by the ratio of glutamine to glutamate, influenced a path from the ratio of glutamine to glutamate to MMN to verbal working memory (P = .38 [root-mean-square error of approximation, P GABA in MMN and verbal working memory deficits in schizophrenia has been

  5. MK-801, but not drugs acting at strychnine-insensitive glycine receptors, attenuate methamphetamine nigrostriatal toxicity.

    Science.gov (United States)

    Layer, R T; Bland, L R; Skolnick, P

    1993-10-15

    Repeated administration of methamphetamine (METH) results in damage to nigrostriatal dopaminergic neurons. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists and use-dependent cation channel blockers attenuate METH-induced damage. The objectives of the present study were to examine whether comparable reductions in METH-induced damage could be obtained by compounds acting at strychnine-insensitive glycine receptors on the NMDA receptor complex. Four injections of METH (5 mg/kg i.p.) resulted in a approximately 70.9% depletion of striatal dopamine (DA) and approximately 62.7% depletion of dihydroxyphenylacetic acid (DOPAC) content, respectively. A significant protection against METH-induced DA and DOPAC depletion was afforded by the use-dependent channel blocker, MK-801. The competitive glycine antagonist 7-chlorokynurenic acid (7-Cl-KA), the low efficacy glycine partial agonist (+)-3-amino-1-hydroxy-2-pyrrolidone ((+)-HA-966), and the high efficacy partial glycine agonist 1-aminocyclopropane-carboxylic acid (ACPC) were ineffective against METH-induced toxicity despite their abilities to attenuate glutamate-induced neurotoxicity under both in vivo and in vitro conditions. These results indicate that glycinergic ligands do not possess the same broad neuroprotective spectrum as other classes of NMDA antagonists.

  6. 4,4-Dimethyl- and diastereomeric 4-hydroxy-4-methyl-(2S)-glutamate analogues display distinct pharmacological profiles at ionotropic glutamate receptors and excitatory amino acid transporters

    DEFF Research Database (Denmark)

    Bunch, Lennart; Pickering, Darryl S; Gefflaut, Thierry

    2009-01-01

    this approach has provided important insight into the structure-activity relationships (SAR) for ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs), as well as the excitatory amino acid transporters (EAATs). In this work, three 4,4-disubstituted Glu analogues 1-3, which are hybrid structures......Subtype-selective ligands are of great interest to the scientific community, as they provide a tool for investigating the function of one receptor or transporter subtype when functioning in its native environment. Several 4-substituted (S)-glutamate (Glu) analogues were synthesized, and altogether...

  7. Oxytocin induces penile erection and yawning when injected into the bed nucleus of the stria terminalis: Involvement of glutamic acid, dopamine, and nitric oxide.

    Science.gov (United States)

    Sanna, Fabrizio; Bratzu, Jessica; Argiolas, Antonio; Melis, Maria Rosaria

    2017-11-01

    Oxytocin (5-100ng), but not Arg 8 -vasopressin (100ng), injected unilaterally into the bed nucleus of the stria terminalis (BNST) induces penile erection and yawning in a dose-dependent manner in male rats. The minimal effective dose was 20ng for penile erection and 5ng for yawning. Oxytocin responses were abolished not only by the oxytocin receptor antagonist d(CH 2 ) 5 Tyr(Me) 2 -Orn 8 -vasotocin (1μg), but also by (+) MK-801 (1μg), an excitatory amino acid receptor antagonist of the N-methyl-d-aspartic acid (NMDA) subtype, SCH 23390 (1μg), a D1 receptor antagonist, but not haloperidol (1μg), a D2 receptor antagonist, and SMTC (40μg), an inhibitor of neuronal nitric oxide synthase, injected into the BNST 15min before oxytocin. Oxytocin-induced penile erection, but not yawning, was also abolished by CNQX (1μg), an excitatory amino acid receptor antagonist of the AMPA subtype. In contrast, oxytocin responses were not reduced by bicuculline (20ng), a GABA A receptor antagonist, phaclofen (5μg), a GABA B receptor antagonist, CP 376395, a CRF receptor-1 antagonist (5μg), or astressin 2B, a CRF receptor-2 antagonist (150ng). Considering the ability of NMDA (100ng) to induce penile erection and yawning when injected into the BNST and the available evidence showing possible interaction among oxytocin, glutamic acid, and dopamine in the BNST, oxytocin possibly activates glutamatergic neurotransmission in the BNST. This in turn leads to the activation of neural pathways projecting back to the paraventricular nucleus, medial preoptic area, ventral tegmental area, and/or ventral subiculum/amygdala, thereby inducing penile erection and yawning. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Differential Involvement of Amygdala and Cortical NMDA Receptors Activation upon Encoding in Odor Fear Memory

    Science.gov (United States)

    Hegoburu, Chloé; Parrot, Sandrine; Ferreira, Guilaume; Mouly, Anne-Marie

    2014-01-01

    Although the basolateral amygdala (BLA) plays a crucial role for the acquisition of fear memories, sensory cortices are involved in their long-term storage in rats. However, the time course of their respective involvement has received little investigation. Here we assessed the role of the glutamatergic N-methyl-D-aspartate (NMDA) receptors in the…

  9. Different effects of two N-methyl-d-aspartate receptor antagonists on seizures, spontaneous behavior, and motor performance in immature rats

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel; Mikulecká, Anna

    2009-01-01

    Roč. 14, č. 1 (2009), s. 32-39 ISSN 1525-5050 R&D Projects: GA MŠk(CZ) LC554; GA ČR(CZ) GA305/06/1188; GA MŠk(CZ) LN00B122 Institutional research plan: CEZ:AV0Z50110509 Keywords : NMDA receptors * antagonists * developing rat Subject RIV: FH - Neuro logy Impact factor: 2.610, year: 2009

  10. Effects of chronic inhalation of electronic cigarettes containing nicotine on glial glutamate transporters and α-7 nicotinic acetylcholine receptor in female CD-1 mice.

    Science.gov (United States)

    Alasmari, Fawaz; Crotty Alexander, Laura E; Nelson, Jessica A; Schiefer, Isaac T; Breen, Ellen; Drummond, Christopher A; Sari, Youssef

    2017-07-03

    Alteration in glutamate neurotransmission has been found to mediate the development of drug dependence, including nicotine. We and others, through using western blotting, have reported that exposure to drugs of abuse reduced the expression of glutamate transporter-1 (GLT-1) as well as cystine/glutamate antiporter (xCT), which consequently increased extracellular glutamate concentrations in the mesocorticolimbic area. However, our previous studies did not reveal any changes in glutamate/aspartate transporter (GLAST) following exposure to drugs of abuse. In the present study, for the first time, we investigated the effect of chronic exposure to electronic (e)-cigarette vapor containing nicotine, for one hour daily for six months, on GLT-1, xCT, and GLAST expression in frontal cortex (FC), striatum (STR), and hippocampus (HIP) in outbred female CD1 mice. In this study, we also investigated the expression of alpha-7 nicotinic acetylcholine receptor (α-7 nAChR), a major pre-synaptic nicotinic receptor in the glutamatergic neurons, which regulates glutamate release. We found that inhalation of e-cigarette vapor for six months increased α-7 nAChR expression in both FC and STR, but not in the HIP. In addition, chronic e-cigarette exposure reduced GLT-1 expression only in STR. Moreover, e-cigarette vapor inhalation induced downregulation of xCT in both the STR and HIP. We did not find any significant changes in GLAST expression in any brain region. Finally, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques, we detected high concentrations of nicotine and cotinine, a major metabolite of nicotine, in the FC tissues of e-cigarette exposed mice. These data provide novel evidence about the effects of chronic nicotine inhalation on the expression of key glial glutamate transporters as well as α-7 nAChR. Our work may suggest that nicotine exposure via chronic inhalation of e-cigarette vapor may be mediated in part by alterations in the glutamatergic

  11. Acute psychosis in a pregnant patient with Graves' hyperthyroidism and anti-NMDA receptor encephalitis.

    Science.gov (United States)

    Lu, Jesslyn; Samson, Susan; Kass, Joseph; Ram, Nalini

    2015-04-22

    A previously healthy 36-year-old woman presented with visual hallucinations and acute psychosis manifested predominantly as hypersexuality. Laboratory testing demonstrated elevated free thyroxine levels, suppressed thyroid-stimulating hormone levels and presence of thyroid-stimulating immunoglobulin and thyroid peroxidase (TPO) antibodies consistent with Graves' disease. Despite achieving biochemical euthyroidism, she remained profoundly hypersexual. She did not respond to additional treatment with antipsychotics and corticosteroids, prompting further evaluation. Cerebrospinal fluid analysis detected pleocytosis, elevated IgG, and presence of antibodies against anti-N-methyl-D-aspartate receptor (NMDAR), glutamic acid decarboxylase 65 and TPO. These results suggested a diagnosis of anti-NMDAR encephalitis. Prior to initiation of immunomodulator therapy, she was discovered to be pregnant with date of conception around the time of her original presentation. She received plasmapheresis with resolution of psychosis and decrease in free thyroxine levels. Graves' disease remitted during the remainder of the pregnancy but relapsed 5 months post partum. She has not had further neuropsychiatric symptoms. 2015 BMJ Publishing Group Ltd.

  12. The combination of glutamate receptor antagonist MK-801 with tamoxifen and its active metabolites potentiates their antiproliferative activity in mouse melanoma K1735-M2 cells

    International Nuclear Information System (INIS)

    Ribeiro, Mariana P.C.; Nunes-Correia, Isabel; Santos, Armanda E.; Custódio, José B.A.

    2014-01-01

    Recent reports suggest that N-methyl-D-aspartate receptor (NMDAR) blockade by MK-801 decreases tumor growth. Thus, we investigated whether other ionotropic glutamate receptor (iGluR) antagonists were also able to modulate the proliferation of melanoma cells. On the other hand, the antiestrogen tamoxifen (TAM) decreases the proliferation of melanoma cells, and is included in combined therapies for melanoma. As the efficacy of TAM is limited by its metabolism, we investigated the effects of the NMDAR antagonist MK-801 in combination with TAM and its active metabolites, 4-hydroxytamoxifen (OHTAM) and endoxifen (EDX). The NMDAR blockers MK-801 and memantine decreased mouse melanoma K1735-M2 cell proliferation. In contrast, the NMDAR competitive antagonist APV and the AMPA and kainate receptor antagonist NBQX did not affect cell proliferation, suggesting that among the iGluR antagonists only the NMDAR channel blockers inhibit melanoma cell proliferation. The combination of antiestrogens with MK-801 potentiated their individual effects on cell biomass due to diminished cell proliferation, since it decreased the cell number and DNA synthesis without increasing cell death. Importantly, TAM metabolites combined with MK-801 promoted cell cycle arrest in G1. Therefore, the data obtained suggest that the activity of MK-801 and antiestrogens in K1735-M2 cells is greatly enhanced when used in combination. - Highlights: • MK-801 and memantine decrease melanoma cell proliferation. • The combination of MK-801 with antiestrogens inhibits melanoma cell proliferation. • These combinations greatly enhance the effects of the compounds individually. • MK-801 combined with tamoxifen active metabolites induces cell cycle arrest in G1. • The combination of MK-801 and antiestrogens is an innovative strategy for melanoma

  13. Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway

    Directory of Open Access Journals (Sweden)

    Freeman Robert S

    2011-02-01

    Full Text Available Abstract Background Thrombolytic therapy with tissue plasminogen activator (tPA benefits patients with acute ischemic stroke. However, tPA increases the risk for intracerebral bleeding and enhances post-ischemic neuronal injury if administered 3-4 hours after stroke. Therefore, combination therapies with tPA and neuroprotective agents have been considered to increase tPA's therapeutic window and reduce toxicity. The anticoagulant factor protein S (PS protects neurons from hypoxic/ischemic injury. PS also inhibits N-methyl-D-aspartate (NMDA excitotoxicity by phosphorylating Bad and Mdm2 which blocks the downstream steps in the intrinsic apoptotic cascade. To test whether PS can protect neurons from tPA toxicity we studied its effects on tPA/NMDA combined injury which in contrast to NMDA alone kills neurons by activating the extrinsic apoptotic pathway. Neither Bad nor Mdm2 which are PS's targets and control the intrinsic apoptotic pathway can influence the extrinsic cascade. Thus, based on published data one cannot predict whether PS can protect neurons from tPA/NMDA injury by blocking the extrinsic pathway. Neurons express all three TAM (Tyro3, Axl, Mer receptors that can potentially interact with PS. Therefore, we studied whether PS can activate TAM receptors during a tPA/NMDA insult. Results We show that PS protects neurons from tPA/NMDA-induced apoptosis by suppressing Fas-ligand (FasL production and FasL-dependent caspase-8 activation within the extrinsic apoptotic pathway. By transducing neurons with adenoviral vectors expressing the kinase-deficient Akt mutant AktK179A and a triple FKHRL1 Akt phosphorylation site mutant (FKHRL1-TM, we show that Akt activation and Akt-mediated phosphorylation of FKHRL1, a member of the Forkhead family of transcription factors, are critical for FasL down-regulation and caspase-8 inhibition. Using cultured neurons from Tyro3, Axl and Mer mutants, we show that Tyro3, but not Axl and Mer, mediates

  14. Effect of Jian-Pi-Zhi-Dong Decoction on striatal glutamate and γ-aminobutyric acid levels detected using microdialysis in a rat model of Tourette syndrome

    Directory of Open Access Journals (Sweden)

    Zhang W

    2016-05-01

    Full Text Available Wen Zhang,1,* Li Wei,2,* Wenjing Yu,1 Xia Cui,1 Xiaofang Liu,2 Qian Wang,1 Sumei Wang2 1Department of Pediatrics, The Third Affiliated Hospital, 2Department of Pediatrics, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China *These authors contributed equally to this work Background: Jian-Pi-Zhi-Dong Decoction (JPZDD is a dedicated treatment of Tourette syndrome (TS. The balance of neurotransmitters in the cortico-striato-pallido-thalamo-cortical network is crucial to the occurrence of TS and related to its severity. This study evaluated the effect of JPZDD on glutamate (Glu and γ-aminobutyric acid (GABA and their receptors in a TS rat model.Materials and methods: Rats were divided into four groups (n=12 each. TS was induced in three of the groups by injecting them with 3,3'-iminodipropionitrile for 7 consecutive days. Two model groups were treated with tiapride (Tia or JPZDD, while the control and the remaining model group were gavaged with saline. Behavior was assessed by stereotypic score and autonomic activity. Striatal Glu and GABA contents were detected using microdialysis. Expressions of N-methyl-D-aspartate receptor 1 and GABAA receptor (GABAAR were observed using Western blot and real-time polymerase chain reaction.Results: Tia and JPZDD groups had decreased stereotypy compared with model rats; however, the JPZDD group showed a larger decrease in stereotypy than the Tia group at a 4-week time point. In a spontaneous activity test, the total distance of the JPZDD and Tia groups was significantly decreased compared with the model group. The Glu levels of the model group were higher than the control group and decreased with Tia or JPZDD treatment. The GABA level was higher in the model group than the control group. Expressions of GABAAR protein in the model group were higher than in the control group. Treatment with Tia or JPZDD reduced the expression of GABAAR protein. In the case of the m

  15. Modulation of gene expression of adenosine and metabotropic glutamate receptors in rat's neuronal cells exposed to L-glutamate and [60]fullerene.

    Science.gov (United States)

    Giust, Davide; Da Ros, Tatiana; Martín, Mairena; Albasanz, José Luis

    2014-08-01

    L-Glutamate (L-Glu) has been often associated not only to fundamental physiological roles, as learning and memory, but also to neuronal cell death and the genesis and development of important neurodegenerative diseases. Herein we studied the variation in the adenosine and metabotropic glutamate receptors expression induced by L-Glu treatment in rat's cortical neurons. The possibility to have structural alteration of the cells induced by L-Glu (100 nM, 1 and 10 microM) has been addressed, studying the modulation of microtubule associated protein-2 (MAP-2) and neurofilament heavy polypeptide (NEFH), natively associated proteins to the dendritic shape maintenance. Results showed that the proposed treatments were not destabilizing the cells, so the L-Glu concentrations were acceptable to investigate fluctuation in receptors expression, which were studied by RT-PCR. Interestingly, C60 fullerene derivative t3ss elicited a protective effect against glutamate toxicity, as demonstrated by MTT assay. In addition, t3ss compound exerted a different effect on the adenosine and metabotropic glutamate receptors analyzed. Interestingly, A(2A) and mGlu1 mRNAs were significantly decreased in conditions were t3ss neuroprotected cortical neurons from L-Glu toxicity. In summary, t3ss protects neurons from glutamate toxicity in a process that appears to be associated with the modulation of the gene expression of adenosine and metabotropic glutamate receptors.

  16. Mechanistic study of competitive releases of H2O, NH3 and CO2 from deprotonated aspartic and glutamic acids: Role of conformation.

    Science.gov (United States)

    Barbier Saint Hilaire, Pierre; Warnet, Anna; Gimbert, Yves; Hohenester, Ulli Martin; Giorgi, Gianluca; Olivier, Marie-Françoise; Fenaille, François; Colsch, Benoît; Junot, Christophe; Tabet, Jean-Claude

    2017-03-15

    energy and at lower excitation conditions, respectively. The latter takes place by stabilization of the deaminated aspartate solvated with two residual molecules of water (present in the collision cell). This desolvated anion formed is an α lactone substituted by a methylene carboxylate group. The vibrational excitation acquired by [(D-H)-NH 3 ] - during its isolation is enough to allow its prompt decarboxylation with a barrier lower than 8.4kJ/mol. In addition, study of glutamic acid-like diastereomers constituted by a cyclopropane, hindering any side chain rotation, confirms the impact of the three-dimensional geometry on fragmentation pathways. A significant specific loss of water is only observed for one of these diastereomers. Other experiments, such as stable isotope labeling, need to be performed to elucidate all the observed losses from activated aspartate and glutamate anions. These first mechanistic interpretations enhance understanding of this dissociative pathway and underline the necessity of studying fragmentation of a large number of various compounds to implement properly new algorithms for de novo elucidation of unknown metabolites. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. 7T Proton Magnetic Resonance Spectroscopy of Gamma-Aminobutyric Acid, Glutamate, and Glutamine Reveals Altered Concentrations in Patients With Schizophrenia and Healthy Siblings.

    Science.gov (United States)

    Thakkar, Katharine N; Rösler, Lara; Wijnen, Jannie P; Boer, Vincent O; Klomp, Dennis W J; Cahn, Wiepke; Kahn, René S; Neggers, Sebastiaan F W

    2017-03-15

    The N-methyl-D-aspartate receptor hypofunction model of schizophrenia predicts dysfunction in both glutamatergic and gamma-aminobutyric acidergic (GABAergic) transmission. We addressed this hypothesis by measuring GABA, glutamate, glutamine, and the sum of glutamine plus glutamate concentrations in vivo in patients with schizophrenia using proton magnetic resonance spectroscopy at 7T, which allows separation of metabolites that would otherwise overlap at lower field strengths. In addition, we investigated whether altered levels of GABA, glutamate, glutamine, and the sum of glutamine plus glutamate reflect genetic vulnerability to schizophrenia by including healthy first-degree relatives. Proton magnetic resonance spectroscopy at 7T was performed in 21 patients with chronic schizophrenia who were taking medication, 23 healthy first-degree relatives of patients with schizophrenia, and 24 healthy nonrelatives. Glutamate, glutamine, and GABA were measured cortically and subcortically in bilateral basal ganglia and occipital cortex. Patients with schizophrenia had reduced cortical GABA compared with healthy relatives and the combined sample of healthy relatives and healthy nonrelatives, suggesting that altered GABAergic systems in schizophrenia are associated with either disease state or medication effects. Reduced cortical glutamine relative to healthy control subjects was observed in patients with schizophrenia and the combined sample of healthy relatives and patients with schizophrenia, suggesting that altered glutamatergic metabolite levels are associated with illness liability. No group differences were found in the basal ganglia. Taken together, these findings are consistent with alterations in GABAergic and glutamatergic systems in patients with schizophrenia and provide novel insights into these systems in healthy relatives. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  18. Effects of phosphoenolpyruvate carboxylase desensitization on glutamic acid production in Corynebacterium glutamicum ATCC 13032.

    Science.gov (United States)

    Wada, Masaru; Sawada, Kazunori; Ogura, Kotaro; Shimono, Yuta; Hagiwara, Takuya; Sugimoto, Masakazu; Onuki, Akiko; Yokota, Atsushi

    2016-02-01

    Phosphoenolpyruvate carboxylase (PEPC) in Corynebacterium glutamicum ATCC13032, a glutamic-acid producing actinobacterium, is subject to feedback inhibition by metabolic intermediates such as aspartic acid and 2-oxoglutaric acid, which implies the importance of PEPC in replenishing oxaloacetic acid into the TCA cycle. Here, we investigated the effects of feedback-insensitive PEPC on glutamic acid production. A single amino-acid substitution in PEPC, D299N, was found to relieve the feedback control by aspartic acid, but not by 2-oxoglutaric acid. A simple mutant, strain R1, having the D299N substitution in PEPC was constructed from ATCC 13032 using the double-crossover chromosome replacement technique. Strain R1 produced glutamic acid at a concentration of 31.0 g/L from 100 g/L glucose in a jar fermentor culture under biotin-limited conditions, which was significantly higher than that of the parent, 26.0 g/L (1.19-fold), indicative of the positive effect of desensitized PEPC on glutamic acid production. Another mutant, strain DR1, having both desensitized PEPC and PYK-gene deleted mutations, was constructed in a similar manner using strain D1 with a PYK-gene deleted mutation as the parent. This mutation had been shown to enhance glutamic acid production in our previous study. Although marginal, strain D1 produced higher glutamic acid, 28.8 g/L, than ATCC13032 (1.11-fold). In contrast, glutamic acid production by strain DR-1 was elevated up to 36.9 g/L, which was 1.42-fold higher than ATCC13032 and significantly higher than the other three strains. The results showed a synergistic effect of these two mutations on glutamic acid production in C. glutamicum. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  19. Potentiation of glycine-gated NR1/NR3A NMDA receptors relieves Ca2+-dependent outward rectification

    Directory of Open Access Journals (Sweden)

    Christian Madry

    2010-03-01

    Full Text Available Glycine has diverse functions within the mammalian central nervous system. It inhibits postsynaptic neurons via strychnine-sensitive glycine receptors (GlyRs and enhances neuronal excitation through co-activation of N-methyl-D-aspartate (NMDA receptors. Classical Ca2+-permeable NMDA receptors are composed of glycine-binding NR1 and glutamate-binding NR2 subunits, and hence require both glutamate and glycine for efficient activation. In contrast, recombinant receptors composed of NR1 and the glycine binding NR3A and/or NR3B subunits lack glutamate binding sites and can be activated by glycine alone. Therefore these receptors are also named excitatory glycine receptors. Co-application of antagonists of the NR1 glycine-binding site or of the divalent cation Zn2+ markedly enhances the glycine responses of these receptors. To gain further insight into the properties of these glycine-gated NMDA receptors, we investigated their current-voltage (I-V dependence. Whole-cell current-voltage relations of glycine currents recorded from NR1/NR3B and NR1/NR3A/NR3B expressing oocytes were found to be linear under our recording conditions. In contrast, NR1/NR3A receptors displayed a strong outwardly rectifying I-V relation. Interestingly, the voltage-dependent inward current block was abolished in the presence of NR1 antagonists, Zn2+ or a combination of both. Further analysis revealed that Ca2+ (1.8 mM present in our recording solutions was responsible for the voltage-dependent inhibition of ion flux through NR1/NR3A receptors. Since physiological concentrations of the divalent cation Mg2+ did not affect the I-V dependence, our data suggest that relief of the voltage-dependent Ca2+ block of NR1/NR3A receptors by Zn2+ may be important for the regulation of excitatory glycinergic transmission, according to the Mg2+-block of conventional NR1/NR2 NMDA receptors.

  20. Glutamatergic induction of CREB phosphorylation and Fos expression in primary cultures of the suprachiasmatic hypothalamus in vitro is mediated by co-ordinate activity of NMDA and non-NMDA receptors.

    Science.gov (United States)

    Schurov, I L; McNulty, S; Best, J D; Sloper, P J; Hastings, M H

    1999-01-01

    Exposure of Syrian hamsters to light 1 h after lights-off rapidly (10 min) induced nuclear immunoreactivity (-ir) to the phospho-Ser133 form of the Ca2+/cAMP response element (CRE) binding protein (pCREB) in the retinorecipient zone of the suprachiasmatic nuclei (SCN). Light also induced nuclear Fos-ir in the same region of the SCN after 1 h. The glutamatergic N-methyl-D-aspartate (NMDA) receptor blocker MK801 attenuated the photic induction of both factors. To investigate glutamatergic regulation of pCREB and Fos further, tissue blocks and primary cultures of neonatal hamster SCN were examined by Western blotting and immunocytochemistry in vitro. On Western blots of SCN tissue, the pCREB-ir signal at 45 kDa was enhanced by glutamate or a mixture of glutamatergic agonists (NMDA, amino-methyl proprionic acid (AMPA), and Kainate (KA)), whereas total CREB did not change. Glutamate or the mixture of agonists also induced a 56 kDa band identified as Fos protein in SCN tissue. In dissociated cultures of SCN, glutamate caused a rapid (15 min) induction of nuclear pCREB-ir and Fos-ir (after 60 min) exclusively in neurones, both GABA-ir and others. Treatment with NMDA alone had no effect on pCREB-ir. AMPA alone caused a slight increase in pCREB-ir. However, kainate alone or in combination with NMDA and AMPA induced nuclear pCREB-ir equal to that induced by glutamate. The effects of glutamate on pCREB-ir and Fos-ir were blocked by antagonists of both NMDA (MK801) and AMPA/KA (NBQX) receptors. In the absence of extracellular Mg2+, MK801 blocked glutamatergic induction of Fos-ir. However, the AMPA/KA receptor antagonist was no longer effective at blocking glutamatergic induction of either Fos-ir or pCREB-ir, consistent with the model that glutamate regulates gene expression in the SCN by a co-ordinate action through both NMDA and AMPA/KA receptors. Glutamatergic induction of nuclear pCREB-ir in GABA-ir neurones was blocked by KN-62 an inhibitor of Ca2+/Calmodulin (Ca

  1. Molecular pharmacology of the AMPA agonist, (S)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(S)-APPA] and the AMPA antagonist, (R)-APPA

    DEFF Research Database (Denmark)

    Ebert, B; Madsen, U; Lund, Trine Meldgaard

    1994-01-01

    )-APPA, whereas (R)-APPA is a non-N-methyl-D-aspartic acid (non-NMDA) receptor antagonist showing preferential AMPA blocking effects. In agreement with classical theories for competitive interaction between agonists and antagonists, the efficacy of depolarizations produced by (S)-APPA in the rat cortical wedge......The heterocyclic analogue of (S)-glutamic acid, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [(S)-AMPA] is a potent and selective AMPA receptor agonist, whereas the enantiomeric compound, (R)-AMPA, is virtually inactive. We have previously characterized (RS)-2-amino-3-(3-hydroxy-5......-phenyl-4-isoxazolyl)propionic acid [(RS)-APPA] as a partial AMPA receptor agonist showing about 60% of the efficacy of (RS)-AMPA. This partial agonism produced by (RS)-APPA is, however, only apparent, since resolution of (RS)-APPA has now been shown to provide the full AMPA receptor agonist, (S...

  2. Phosphorylation of mouse serine racemase regulates D-serine synthesis

    DEFF Research Database (Denmark)

    Foltyn, Veronika N; Zehl, Martin; Dikopoltsev, Elena

    2010-01-01

    Serine racemase (SR) catalyses the synthesis of the transmitter/neuromodulator D-serine, which plays a major role in synaptic plasticity and N-methyl D-aspartate receptor neurotoxicity. We now report that SR is phosphorylated at Thr71 and Thr227 as revealed by mass spectrometric analysis and in v...... with a phosphorylation-deficient SR mutant indicate that Thr71 phosphorylation increases SR activity, suggesting a novel mechanism for regulating D-serine production....

  3. A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes.

    Science.gov (United States)

    Cervetto, Chiara; Venturini, Arianna; Passalacqua, Mario; Guidolin, Diego; Genedani, Susanna; Fuxe, Kjell; Borroto-Esquela, Dasiel O; Cortelli, Pietro; Woods, Amina; Maura, Guido; Marcoli, Manuela; Agnati, Luigi F

    2017-01-01

    Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes' participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were co-expressed on the same astrocyte processes. Evidence for A2A-D2 receptor-receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A-D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor-mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A-D2 receptors that via allosteric receptor-receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders. © 2016 International Society for Neurochemistry.

  4. Glutamate metabotropic receptors as targets for drug therapy in epilepsy.

    Science.gov (United States)

    Moldrich, Randal X; Chapman, Astrid G; De Sarro, Giovambattista; Meldrum, Brian S

    2003-08-22

    Metabotropic glutamate (mGlu) receptors have multiple actions on neuronal excitability through G-protein-linked modifications of enzymes and ion channels. They act presynaptically to modify glutamatergic and gamma-aminobutyric acid (GABA)-ergic transmission and can contribute to long-term changes in synaptic function. The recent identification of subtype-selective agonists and antagonists has permitted evaluation of mGlu receptors as potential targets in the treatment of epilepsy. Agonists acting on group I mGlu receptors (mGlu1 and mGlu5) are convulsant. Antagonists acting on mGlu1 or mGlu5 receptors are anticonvulsant against 3,5-dihydroxyphenylglycine (DHPG)-induced seizures and in mouse models of generalized motor seizures and absence seizures. The competitive, phenylglycine mGlu1/5 receptor antagonists generally require intracerebroventricular administration for potent anticonvulsant efficacy but noncompetitive antagonists, e.g., (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydrocyclopenta[c]furan-1-on (BAY36-7620), 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893) block generalized seizures with systemic administration. Agonists acting on group II mGlu receptors (mGlu2, mGlu3) to reduce glutamate release are anticonvulsant, e.g., 2R,4R-aminopyrrolidine-2,4-dicarboxylate [(2R,4R)-APDC], (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268). The classical agonists acting on group III mGlu receptors such as L-(+)-2-amino-4-phosphonobutyric acid, and L-serine-O-phosphate are acutely proconvulsant with some anticonvulsant activity. The more recently identified agonists (R,S)-4-phosphonophenylglycine [(R,S)-PPG] and (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG] and (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid [ACPT-1] are all anticonvulsant without proconvulsant effects. Studies in animal models of kindling

  5. Immune labeling and purification of a 71-kDa glutamate-binding protein from brain synaptic membranes

    International Nuclear Information System (INIS)

    Chen, J.W.; Cunningham, M.D.; Galton, N.; Michaelis, E.K.

    1988-01-01

    Immunoblot studies of synaptic membranes isolated from rat brain using antibodies raised against a previously purified glutamate-binding protein (GBP) indicated labeling of an ∼ 70-kDa protein band. Since the antibodies used were raised against a 14-kDa GBP, the present studies were undertaken to explore the possibility that the 14-kDa protein may have been a proteolytic fragment of a larger M/sub r/ protein in synaptic membranes. The major protein enriched in the most highly purified fractions was a 71-kDa glycoprotein, but a 63-kDa protein was co-purified during most steps of the isolation procedure. The glutamate-binding characteristics of these isolated protein fractions were very similar to those previously described for the 14-kDa GBP, including estimated dissociation constants for L-glutamate binding of 0.25 and 1 + M, inhibition of glutamate binding by azide and cyanide, and a selectivity of the ligand binding site for L-glutamate and L-aspartate. The neuroexcitatory analogs of L-glutamate and L-aspartate, ibotenate, quisqualate, and D-glutamate, inhibited L[ 3 H]glutamate binding to the isolated proteins, as did the antagonist of L-glutamate-induced neuronal excitation, L-glutamate diethylester. On the basis of the lack of any detectable glutamate-related enzyme activity associated with the isolated proteins and the presence of distinguishing sensitivities to analogs that inhibit glutamate transport carriers in synaptic membranes, it is proposed that the 71-kDa protein may be a component of a physiologic glutamate receptor complex in neuronal membranes

  6. Olanzapine Reverses MK-801-Induced Cognitive Deficits and Region-Specific Alterations of NMDA Receptor Subunits

    Science.gov (United States)

    Liu, Xiao; Li, Jitao; Guo, Chunmei; Wang, Hongli; Sun, Yaxin; Wang, Han; Su, Yun-Ai; Li, Keqing; Si, Tianmei

    2018-01-01

    Cognitive dysfunction constitutes an essential component in schizophrenia for its early presence in the pathophysiology of the disease and close relatedness to life quality of patients. To develop effective treatment of cognitive deficits, it is important to understand their neurobiological causes and to identify potential therapeutic targets. In this study, adopting repeated MK-801 treatment as an animal model of schizophrenia, we investigated whether antipsychotic drugs, olanzapine and haloperidol, can reverse MK-801-induced cognitive deficits and how the reversal processes recruited proteins involved in glutamate neurotransmission in rat medial prefrontal cortex (mPFC) and hippocampus. We found that low-dose chronic MK-801 treatment impaired object-in-context recognition memory and reversal learning in the Morris water maze, leaving reference memory relatively unaffected, and that these cognitive deficits can be partially reversed by olanzapine, not haloperidol, treatment. At the molecular level, chronic MK-801 treatment resulted in the reduction of multiple N-methyl-D-aspartate (NMDA) receptor subunits in rat mPFC and olanzapine, not haloperidol, treatment restored the levels of GluN1 and phosphorylated GluN2B in this region. Taken together, MK-801-induced cognitive deficits may be associated with region-specific changes in NMDA receptor subunits and the reversal of specific NMDA receptor subunits may underlie the cognition-enhancing effects of olanzapine. PMID:29375333

  7. Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test.

    Science.gov (United States)

    Li, Yan; Zhu, Zhuo R; Ou, Bao C; Wang, Ya Q; Tan, Zhou B; Deng, Chang M; Gao, Yi Y; Tang, Ming; So, Ji H; Mu, Yang L; Zhang, Lan Q

    2015-02-15

    Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses. The traditional antidepressants often take several weeks, even months, to obtain clinical effects. However, recent clinical studies have shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects within 2h and are long-lasting. The aim of the present study was to investigate whether dopaminergic system was involved in the rapid antidepressant effects of ketamine. The acute administration of ketamine (20 mg/kg) significantly reduced the immobility time in the forced swim test. MK-801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not significantly reduced the immobility time in the forced swim test after 30 min administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a selective dopamine D1 receptor antagonist), significantly prevented the effects of ketamine or MK-801. Moreover, the administration of sub-effective dose of ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3 receptor agonist) exerted antidepressant-like effects compared with each drug alone. In conclusion, our results indicated that the dopamine D2/D3 receptors, but not D1 receptors, are involved in the rapid antidepressant-like effects of ketamine. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Debler, Erik W.; Jain, Kanishk; Warmack, Rebeccah A.; Feng, You; Clarke, Steven G.; Blobel, Günter; Stavropoulos, Pete

    2016-02-08

    Trypanosoma brucei PRMT7 (TbPRMT7) is a protein arginine methyltransferase (PRMT) that strictly monomethylates various substrates, thus classifying it as a type III PRMT. However, the molecular basis of its unique product specificity has remained elusive. Here, we present the structure of TbPRMT7 in complex with its cofactor product S-adenosyl-L-homocysteine (AdoHcy) at 2.8 Å resolution and identify a glutamate residue critical for its monomethylation behavior. TbPRMT7 comprises the conserved methyltransferase and β-barrel domains, an N-terminal extension, and a dimerization arm. The active site at the interface of the N-terminal extension, methyltransferase, and β-barrel domains is stabilized by the dimerization arm of the neighboring protomer, providing a structural basis for dimerization as a prerequisite for catalytic activity. Mutagenesis of active-site residues highlights the importance of Glu181, the second of the two invariant glutamate residues of the double E loop that coordinate the target arginine in substrate peptides/proteins and that increase its nucleophilicity. Strikingly, mutation of Glu181 to aspartate converts TbPRMT7 into a type I PRMT, producing asymmetric dimethylarginine (ADMA). Isothermal titration calorimetry (ITC) using a histone H4 peptide showed that the Glu181Asp mutant has markedly increased affinity for monomethylated peptide with respect to the WT, suggesting that the enlarged active site can favorably accommodate monomethylated peptide and provide sufficient space for ADMA formation. In conclusion, these findings yield valuable insights into the product specificity and the catalytic mechanism of protein arginine methyltransferases and have important implications for the rational (re)design of PRMTs.

  9. Rescue of Na+ and H+ binding in Na+,K+-ATPase M8 aspartate mutants by secondary mutation

    DEFF Research Database (Denmark)

    Holm, Rikke; Einholm, Anja P.; Andersen, Jens Peter

    A mutation replacing the aspartate in transmembrane segment M8 in the a3-isoform of Na,K-ATPase with asparagine has been found in patients with rapid-onset dystonia parkinsonism or alternating hemiplegia of childhood. This aspartate may be a critical Na+ coordinating residue, but the crystal......-isoforms of Na,K-ATPase, and much smaller effects were seen for other mutations to the M8 aspartate, which were less disruptive of Na+ binding than mutations to other residues related to Na+ site III. The D928 (rat a1 numbering) mutations strongly diminished the cooperativity of Na+ binding. Moreover the p......H optimum of Na,K-ATPase activity was left-shifted, again with D928N being most disruptive. The reduced affinity for activating Na+ and for inhibitory protons, caused by D928N and D928A mutations, could be rescued by introduction of an additional mutation of a glutamate located far away from D928....

  10. Relationship between methylation status of vitamin D-related genes, vitamin D levels, and methyl-donor biochemistry

    Directory of Open Access Journals (Sweden)

    Emma Louise Beckett

    2016-12-01

    Full Text Available Vitamin D is known for its role in the regulation of gene expression via the vitamin D receptor, a nuclear transcription factor. More recently, a role for vitamin D in regulating DNA methylation has been identified as an additional mechanism of modulation of gene expression. How methylation status influences vitamin D metabolism and response pathways is not yet clear. Therefore, we aimed to assess the relationship between plasma 25-hydroxycholecalciferol (25(OHD and the methylation status of vitamin D metabolism enzyme genes (CYP2R1, CYP27B1 and CYP24A1 and the vitamin D receptor gene (VDR. This analysis was conducted in the context of dietary vitamin D, and background methyl donor related biochemistry, with adjustment for several dietary and lifestyle variables. Percentage methylation at CpG sites was assessed in peripheral blood cells using methylation sensitive and dependent enzymes and qPCR. Standard analytical techniques were used to determine plasma 25(OHD and homocysteine, and serum folate and B12, with the relationship to methylation status assessed using multi-variable regression analysis. CYP2R1 and VDR methylation were found to be independent predictors of plasma 25(OHD, when adjusted for vitamin D intake and other lifestyle variables. CYP24A1 was related to plasma 25(OHD directly, but not in the context of vitamin D intake. Methyl-group donor biochemistry was associated with the methylation status of some genes, but did not alter the relationship between methylation and plasma 25(OHD. Modulation of methylation status of CYP2R1, CYP24A1 and VDR in response to plasma 25(OHD may be part of feedback loops involved in maintaining vitamin D homeostasis, and may explain a portion of the variance in plasma 25(OHD levels in response to intake and sun exposure. Methyl-group donor biochemistry, while a potential independent modulator, did not alter this effect.

  11. Kinetics of reactions of aquacobalamin with aspartic and glutamic acids and their amides in water solutions

    Science.gov (United States)

    Bui, T. T. T.; Sal'nikov, D. S.; Dereven'kov, I. A.; Makarov, S. V.

    2017-04-01

    The kinetics of aquacobalamin reaction with aspartic and glutamic acids, and with their amides in water solutions, is studied via spectrophotometry. The kinetic and activation parameters of the process are determined. It is shown that the reaction product is cobalamin-amino acid complex. The data are compared to results on the reaction between aquacobalamin and primary amines.

  12. Bidirectional modulation of windup by NMDA receptors in the rat spinal trigeminal nucleus.

    Science.gov (United States)

    Woda, Alain; Blanc, Olivier; Voisin, Daniel L; Coste, Jérôme; Molat, Jean-Louis; Luccarini, Philippe

    2004-04-01

    Activation of afferent nociceptive pathways is subject to activity-dependent plasticity, which may manifest as windup, a progressive increase in the response of dorsal horn nociceptive neurons to repeated stimuli. At the cellular level, N-methyl-d-aspartate (NMDA) receptor activation by glutamate released from nociceptive C-afferent terminals is currently thought to generate windup. Most of the wide dynamic range nociceptive neurons that display windup, however, do not receive direct C-fibre input. It is thus unknown where the NMDA mechanisms for windup operate. Here, using the Sprague-Dawley rat trigeminal system as a model, we anatomically identify a subpopulation of interneurons that relay nociceptive information from the superficial dorsal horn where C-fibres terminate, to downstream wide dynamic range nociceptive neurons. Using in vivo electrophysiological recordings, we show that at the end of this pathway, windup was reduced (24 +/- 6%, n = 7) by the NMDA receptor antagonist AP-5 (2.0 fmol) and enhanced (62 +/- 19%, n = 12) by NMDA (1 nmol). In contrast, microinjections of AP-5 (1.0 fmol) within the superficial laminae increased windup (83 +/- 44%, n = 9), whereas NMDA dose dependently decreased windup (n = 19). These results indicate that NMDA receptor function at the segmental level depends on their precise location in nociceptive neural networks. While some NMDA receptors actually amplify pain information, the new evidence for NMDA dependent inhibition of windup we show here indicates that, simultaneously, others act in the opposite direction. Working together, the two mechanisms may provide a fine tuning of gain in pain.

  13. Kinetic isotope effect studies on aspartate aminotransferase: Evidence for a concerted 1,3 prototropic shift mechanism for the cytoplasmic isozyme and L-aspartate and dichotomy in mechanism

    International Nuclear Information System (INIS)

    Julin, D.A.; Kirsch, J.F.

    1989-01-01

    The C alpha primary hydrogen kinetic isotope effects (C alpha-KIEs) for the reaction of the cytoplasmic isozyme of aspartate aminotransferase (cAATase) with [alpha-2H]-L-aspartate are small and only slightly affected by deuterium oxide solvent (DV = 1.43 +/- 0.03 and DV/KAsp = 1.36 +/- 0.04 in H 2 O; DV = 1.44 +/- 0.01 and DV/KAsp = 1.61 +/- 0.06 in D 2 O). The D 2 O solvent KIEs (SKIEs) are somewhat larger and are essentially independent of deuterium at C alpha (D 2 OV = 2.21 +/- 0.07 and D 2 OV/KAsp = 1.70 +/- 0.03 with [α-1H]-L-aspartate; D 2 OV = 2.34 +/- 0.12 and D 2 OV/KAsp = 1.82 +/- 0.06 with [α-2H]-L- aspartate). The C alpha-KIEs on V and on V/KAsp are independent of pH from pH 5.0 to pH 10.0. These results support a rate-determining concerted 1,3 prototropic shift mechanism by the multiple KIE criteria. The large C alpha-KIEs for the reaction of mitochondrial AATase (mAATase) with L-glutamate (DV = 1.88 +/- 0.13 and DV/KGlu = 3.80 +/- 0.43 in H 2 O; DV = 1.57 +/- 0.05 and DV/KGlu = 4.21 +/- 0.19 in D 2 O) coupled with the relatively small SKIEs (D 2 OV = 1.58 +/- 0.04 and D 2 OV/KGlu = 1.25 +/- 0.05 with [α-1H]-L-glutamate; D 2 OV = 1.46 +/- 0.06 and D 2 OV/KGlu = 1.16 +/- 0.05 with [alpha-2H]-L-glutamate) are most consistent with a two-step mechanism for the 1,3 prototropic shift for this isozyme-substrate pair

  14. Influence of Pharmacological Manipulations of NMDA and Cholinergic Receptors on Working versus Reference Memory in a Dual Component Odor Span Task

    Science.gov (United States)

    MacQueen, David A.; Dalrymple, Savannah R.; Drobes, David J.; Diamond, David M.

    2016-01-01

    Developed as a tool to assess working memory capacity in rodents, the odor span task (OST) has significant potential to advance drug discovery in animal models of psychiatric disorders. Prior investigations indicate OST performance is impaired by systemic administration of N-methyl-D-aspartate receptor (NMDA-r) antagonists and is sensitive to…

  15. Gestational methylazoxymethanol exposure leads to NMDAR dysfunction in hippocampus during early development and lasting deficits in learning.

    Science.gov (United States)

    Snyder, Melissa A; Adelman, Alicia E; Gao, Wen-Jun

    2013-01-01

    The N-methyl-D-aspartate (NMDA) receptor has long been associated with learning and memory processes as well as diseased states, particularly in schizophrenia (SZ). Additionally, SZ is increasingly recognized as a neurodevelopmental disorder with cognitive impairments often preceding the onset of psychosis. However, the cause of these cognitive deficits and what initiates the pathological process is unknown. Growing evidence has implicated the glutamate system and, in particular, N-methyl-D-aspartate receptor (NMDAR) dysfunction in the pathophysiology of SZ. Yet, the vast majority of SZ-related research has focused on NMDAR function in adults leaving the role of NMDARs durin