WorldWideScience

Sample records for n-methyl-d-aspartate receptor-dependent activation

  1. N-methyl-D-aspartate receptor encephalitis mediates loss of intrinsic activity measured by functional MRI.

    Science.gov (United States)

    Brier, Matthew R; Day, Gregory S; Snyder, Abraham Z; Tanenbaum, Aaron B; Ances, Beau M

    2016-06-01

    Spontaneous brain activity is required for the development and maintenance of normal brain function. Many disease processes disrupt the organization of intrinsic brain activity, but few pervasively reduce the amplitude of resting state blood oxygen level dependent (BOLD) fMRI fluctuations. We report the case of a female with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, longitudinally studied during the course of her illness to determine the contribution of NMDAR signaling to spontaneous brain activity. Resting state BOLD fMRI was measured at the height of her illness and 18 weeks following discharge from hospital. Conventional resting state networks were defined using established methods. Correlation and covariance matrices were calculated by extracting the BOLD time series from regions of interest and calculating either the correlation or covariance quantity. The intrinsic activity was compared between visits, and to expected activity from 45 similarly aged healthy individuals. Near the height of the illness, the patient exhibited profound loss of consciousness, high-amplitude slowing of the electroencephalogram, and a severe reduction in the amplitude of spontaneous BOLD fMRI fluctuations. The patient's neurological status and measures of intrinsic activity improved following treatment. We conclude that NMDAR-mediated signaling plays a critical role in the mechanisms that give rise to organized spontaneous brain activity. Loss of intrinsic activity is associated with profound disruptions of consciousness and cognition.

  2. Involvement of mitogen-activated protein kinase pathways in N-methyl-D-aspartate-induced excitotoxicity

    Institute of Scientific and Technical Information of China (English)

    Xiaorong Yang; Ping Sun; Huaping Qin; Rui Wang; Ye Wang; Ruihong Shi; Xin Zhao; Ce Zhang

    2011-01-01

    Previous studies have shown that mitogen-activated protein kinase (MAPK) signaling pathways are involved in N-methyl-D-aspartate (NMDA)-mediated excitotoxicity. However, a systematic observation or analysis of the role of these various MAPK pathways in excitotoxicity processes does not exist. The present study further evaluated the role and contribution of three MAPK pathways extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK in an NMDA-mediated excitotoxicity model using MAPK-specific inhibitor. Results demonstrated that c-Jun N-terminal kinase inhibitor SP600125 and/or p38 MAPK inhibitor SB203580 inhibited NMDA-induced reduction in cell viability, as well as reduced NMDA-induced lactate dehydrogenase leakage and reactive oxygen species production. However, PD98059, an inhibitor of extracellular signal-regulated kinase, did not influence this model. Results demonstrated an involvement of c-Jun N-terminal kinase and p38 MAPK, but not extracellular signal-regulated kinase, in NMDA-mediated excitotoxicity in cortical neurons.

  3. N-methyl-D-aspartate antagonist activity of alpha- and beta-sulfallorphans.

    Science.gov (United States)

    Shukla, V K; Lemaire, S

    1997-01-01

    Resolved equatorial (alpha) and axial (beta) forms of S-allylmorphinans, alpha-sulfallorphan and beta-sulfallorphan, were tested for their ability to compete with the binding of phencyclidine and sigma receptor ligands to mouse brain membranes and to antagonize N-methyl-D-aspartate (NMDA)-induced convulsions in mice. alpha- and beta-sulfallorphans displayed distinct binding affinities for phencyclidine and sigma sites, inhibiting the binding of [3H]-(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten++ +-5, 10-imine ([3H]MK-801) with Ki values of 2.32 and 0.13 microM and that of [3H](+)-pentazocine with Ki values of 1.97 and 1.61 microM, respectively. Intracerebroventricular administration of these compounds in mice caused dose-dependent inhibitions of NMDA-induced convulsions, but did not affect convulsions induced by (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainic acid and bicuculline. alpha- and beta-sulfallorphans blocked the convulsive activity of NMDA (1 nmol/mouse; intracerebroventricular) with ED50 values of 0.48 and 0.015 nmol/mouse, as compared with 0.55, 0.039 and 0.013 nmol/mouse for dextrorphan, MK-801 and (+/-)3-(2-carboxypiperazine-4yl)propyl-1-proprionic acid, respectively. The structurally related compound, dextrallorphan, significantly but less potently blocked NMDA-induced convulsions (ED60, 2.68 nmol/mouse). At the protective doses, alpha- and beta-sulfallorphans markedly reduced NMDA- and AMPA-induced mortality without inducing locomotion and falling behavior. These results indicate that alpha- and beta-sulfallorphans are potent and selective NMDA antagonists devoid of motor side effects at protective doses.

  4. Sensitization of rat facial cutaneous mechanoreceptors by activation of peripheral N-methyl-d-aspartate receptors.

    Science.gov (United States)

    Gazerani, Parisa; Dong, Xudong; Wang, Mianwei; Kumar, Ujendra; Cairns, Brian E

    2010-03-10

    The effect of subcutaneous injection of glutamate on the mechanical sensitivity of rat facial cutaneous mechanoreceptors was examined. Individual facial mechanoreceptors were recorded in the trigeminal ganglion of anesthetized Sprague-Dawley rats. An electronic von Frey hair was used to measure the mechanical threshold (MT) of the afferent fibers at baseline and following subcutaneous injection of glutamate (0, 0.01, 0.1, 1M; 10microl) or glutamate (0, 0.1M) plus the competitive N-methyl-d-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (APV; 0.01M). Subcutaneous injections were randomized and the investigator was unaware of their content. Changes in MT were assessed with a repeated measure ANOVA with time, sex and treatment as factors. Immunohistochemistry was used to confirm NMDA receptor expression by cutaneous nerve fibers. A total of 100 (50 per sex) facial mechanoreceptors were recorded from 61 (32 females, 29 males) rats in two separate experiments. Subcutaneous injections of higher concentrations of glutamate (1, 0.1M) induced a significant mechanical sensitization of skin afferent fibers (compared to 0 and 0.01M). Females (EC(50)=16.2mM) were more sensitive to glutamate than males (EC(50)=73.0mM). Facial cutaneous nerve fibers in both sexes expressed NMDA receptors. APV blocked the mechanical sensitization of the afferent fibers treated by glutamate 0.1M in both sexes with a lower effect in females at a 10-20minute post-injection. Subcutaneous injection of glutamate mechanically sensitizes rat facial cutaneous mechanoreceptors through activation of peripheral NMDA receptors. Peripheral NMDA receptor antagonists may be considered for craniofacial pain.

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

    Science.gov (United States)

    Chay, Andrew; Zamparo, Ilaria; Koschinski, Andreas; Zaccolo, Manuela; Blackwell, Kim T

    2016-02-01

    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.

  6. 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.

  7. 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.

  8. Multiple signaling pathways involved in stimulation of osteoblast differentiation by N-methyl-D-aspartate receptors activation in vitro

    Institute of Scientific and Technical Information of China (English)

    Jie-li LI; Lin ZHAO; Bin CUI; Lian-fu DENG; Guang NING; Jian-min LIU

    2011-01-01

    Aim: Glutamate receptors are expressed in osteoblastic cells. The present study was undertaken to investigate the mechanisms underlying the stimulation of osteoblast differentiation by N-methyl-D-aspartate (NMDA) receptor activation in vitro.Methods: Primary culture of osteoblasts was prepared from SD rats. Microarray was used to detect the changes of gene expression.The effect of NMDA receptor agonist or antagonist on individual gene was examined using RT-PCR. The activity of alkaloid phosphotase (ALP) was assessed using a commercial ALP staining kit.Results: Microarray analyses revealed that 10 genes were up-regulated by NMDA (0.5 mmol/L) and down-regulated by MK801 (100μmol/L), while 13 genes down-regulated by NMDA (0.5 mmol/L) and up-regulated by MK801 (100 μmol/L). Pretreatment of osteoblasts with the specific PKC inhibitor Calphostin C (0.05 μmol/L), the PKA inhibitor H-89 (20 nmol/L), or the PI3K inhibitor wortmannin (100 nmol/L) blocked the ALP activity increase caused by NMDA (0.5 mmol/L). Furthermore, NMDA (0.5 mmol/L) rapidly increased PI3K phosphorylation, which could be blocked by pretreatment of wortmannin (100 nmol/L).Conclusion: The results suggest that activation of NMDA receptors stimulates osteoblasts differentiation through PKA, PKC, and PI3K signaling pathways, which is a new role for glutamate in regulating bone remodeling.

  9. Long-term imipramine treatment increases N-methyl-d-aspartate receptor activity and expression via epigenetic mechanisms.

    Science.gov (United States)

    Nghia, Nguyen An; Hirasawa, Takae; Kasai, Hirotake; Obata, Chie; Moriishi, Kohji; Mochizuki, Kazuki; Koizumi, Schuichi; Kubota, Takeo

    2015-04-05

    Imipramine, a major antidepressant, is known to inhibit reuptake of serotonin and norepinephrine, which contributes to recovery from major depressive disorder. It has recently been reported that acute imipramine treatment inhibits N-methyl-d-aspartate (NMDA) receptor activity. However, the mechanisms underlying long-term effects of imipramine have not been identified. We tested these distinct effects in mouse cortical neurons and found that acute (30s) imipramine treatment decreased Ca(2+) influx through NMDA receptors, whereas long-term treatment (48h) increased Ca(2+) influx via the same receptors. Furthermore, long-term treatment increased NMDA receptor 2B (NR2B) subunit expression via epigenetic changes, including increased acetylation of histones H3K9 and H3K27 in the NR2B promoter and decreased activity of histone deacetylase 3 (HDAC3) and HDAC4. These results suggest that the long-term effects of imipramine on NMDA receptors are quite different from its acute effects. Furthermore, increased NR2B expression via epigenetic alterations might be a part of the mechanism responsible for this long-term effect.

  10. 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.

  11. Ethanol withdrawal is required to produce persisting N-methyl-D-aspartate receptor-dependent hippocampal cytotoxicity during chronic intermittent ethanol exposure

    Science.gov (United States)

    Reynolds, Anna R.; Berry, B. Jennifer N.; Sharrett-Field, Lynda; Prendergast, Mark A.

    2015-01-01

    Chronic intermittent ethanol consumption is associated with neurodegeneration and cognitive deficits in preclinical laboratory animals and in the clinical population. While previous work suggests a role for neuroadaptations in the N-methyl-D-aspartate (NMDA) receptor in the development of ethanol dependence and manifestation of withdrawal, the relative roles of ethanol exposure and ethanol withdrawal in producing these effects have not been fully characterized. To examine underlying cytotoxic mechanisms associated with CIE exposure, organotypic hippocampal slices were exposed to 1–3 cycles of ethanol (50 mM) in cell culture medium for 5 days, followed by 24-hours of ethanol withdrawal in which a portion of slices were exposed to competitive NMDA receptor antagonist (2R)-amino-5-phosphonovaleric acid (APV; 40 µM). Cytotoxicity was assessed using immunohistochemical labeling of neuron specific nuclear protein (NeuN; Fox-3), a marker of mature neurons, and thionine (2%) staining of Nissl bodies. Multiple cycles of CIE produced neurotoxicity, as reflected in persisting losses of neuron NeuN immunoreactivity and thionine staining in each of the primary cell layers of the hippocampal formation. Hippocampi aged in vitro were significantly more sensitive to the toxic effects of multiple CIEs than were non-aged hippocampi. This effect was not demonstrated in slices exposed to continuous ethanol, in the absence of withdrawal, or to a single exposure/withdrawal regimen. Exposure to APV significantly attenuated the cytotoxicity observed in the primary cell layers of the hippocampus. The present findings suggest that ethanol withdrawal is required to produce NMDA receptor-dependent hippocampal cytotoxicity, particularly in the aging hippocampus in vitro. PMID:25746220

  12. Corticosterone enhances N-methyl-D-aspartate receptor signaling to promote isolated ventral tegmental area activity in a reconstituted mesolimbic dopamine pathway

    Science.gov (United States)

    Berry, Jennifer N.; Saunders, Meredith A.; Sharrett-Field, Lynda J.; Reynolds, Anna R.; Bardo, Michael T.; Pauly, James R.; Prendergast, Mark A.

    2015-01-01

    Elevations in circulating corticosteroids during periods of stress may influence activity of the mesolimbic dopamine reward pathway by increasing glutamatergic N-methyl-D-aspartate (NMDA) receptor expression and/or function in a glucocorticoid receptor-dependent manner. The current study employed organotypic co-cultures of the ventral tegmental area (VTA) and nucleus accumbens (NAcc) to examine the effects of corticosterone exposure on NMDA receptor-mediated neuronal viability. Co-cultures were pre-exposed to vehicle or corticosterone (CORT; 1 μM) for 5 days prior to a 24 hour co-exposure to NMDA (200 μM). Co-cultures pre-exposed to a non-toxic concentration of corticosterone and subsequently NMDA showed significant neurotoxicity in the VTA only. This was evidenced by increases in propidium iodide uptake as well as decreases in immunoreactivity of the neuronal nuclear protein (NeuN). Co-exposure to the NMDA receptor antagonist 2-amino-7-phosphonovaleric acid (APV; 50 μM) or the glucocorticoid receptor (GR) antagonist mifepristone (10 μM) attenuated neurotoxicity. In contrast, the combination of corticosterone and NMDA did not produce any significant effects on either measure within the NAcc. Cultures of the VTA and NAcc maintained without synaptic contact showed no response to CORT or NMDA. These results demonstrate the ability to functionally reconstitute key regions of the mesolimbic reward pathway ex vivo and to reveal a GR-dependent enhancement of NMDA receptor-dependent signaling in the VTA. PMID:26631585

  13. Adenosine A1 receptor activation modulates N-methyl-d-aspartate (NMDA) preconditioning phenotype in the brain.

    Science.gov (United States)

    Constantino, Leandra C; Pamplona, Fabrício A; Matheus, Filipe C; Ludka, Fabiana K; Gomez-Soler, Maricel; Ciruela, Francisco; Boeck, Carina R; Prediger, Rui D; Tasca, Carla I

    2015-04-01

    N-methyl-d-aspartate (NMDA) preconditioning is induced by subtoxic doses of NMDA and it promotes a transient state of resistance against subsequent lethal insults. Interestingly, this mechanism of neuroprotection depends on adenosine A1 receptors (A1R), since blockade of A1R precludes this phenomenon. In this study we evaluated the consequences of NMDA preconditioning on the hippocampal A1R biology (i.e. expression, binding properties and functionality). Accordingly, we measured A1R expression in NMDA preconditioned mice (75mg/kg, i.p.; 24h) and showed that neither the total amount of receptor, nor the A1R levels in the synaptic fraction was altered. In addition, the A1R binding affinity to the antagonist [(3)H] DPCPX was slightly increased in total membrane extracts of hippocampus from preconditioned mice. Next, we evaluated the impact of NMDA preconditioning on A1R functioning by measuring the A1R-mediated regulation of glutamate uptake into hippocampal slices and on behavioral responses in the open field and hot plate tests. NMDA preconditioning increased glutamate uptake into hippocampal slices without altering the expression of glutamate transporter GLT-1. Interestingly, NMDA preconditioning also induced antinociception in the hot plate test and both effects were reversed by post-activation of A1R with the agonist CCPA (0.2mg/kg, i.p.). NMDA preconditioning or A1R modulation did not alter locomotor activity in the open field. Overall, the results described herein provide new evidence that post-activation of A1R modulates NMDA preconditioning-mediated responses, pointing to the importance of the cross-talk between glutamatergic and adenosinergic systems to neuroprotection.

  14. 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...

  15. Improving the inhibitory activity of arylidenaminoguanidine compounds at the N-methyl-D-aspartate receptor complex from a recursive computational-experimental structure-activity relationship study.

    Science.gov (United States)

    Ring, Joshua R; Zheng, Fang; Haubner, Aaron J; Littleton, John M; Crooks, Peter A

    2013-04-01

    Using a combination of both the partial least squares (PLS) and back-propagation artificial neural network (ANN) pattern recognition methods, several models have been developed to predict the activity of a series of arylidenaminoguanidine analogs as inhibitory modulators of the N-methyl-D-aspartate receptor complex. This was done by correlating structural and physicochemical descriptors obtained from computation software with the experimentally observed [(3)H]MK-801 displacement ability of a small library of synthesized and in vitro screened arylidenaminoguanidines. Results for the generated PLS model were r(2)=0.814, rmsd=0.208, rCV(2)=0.714, loormsd=0.261. The ANN model was created utilizing the eleven descriptors from the PLS model for comparison. The quality of the ANN model (r(2)=0.828, rmsd=0.200, rCV(2)=0.721, loormsd=0.257) is similar to the PLS model, and indicates that the feature between the inputs and the output is majorly linear. These computational models were able to predict inhibition of the NMDA receptor complex by this series of compounds in silico, affording a predictive structure-based 'pre-screening' paradigm for the arylideneaminoguanidine analogs.

  16. Activation of EphA receptors mediates the recruitment of the adaptor protein Slap, contributing to the downregulation of N-methyl-D-aspartate receptors.

    Science.gov (United States)

    Semerdjieva, Sophia; Abdul-Razak, Hayder H; Salim, Sharifah S; Yáñez-Muñoz, Rafael J; Chen, Philip E; Tarabykin, Victor; Alifragis, Pavlos

    2013-04-01

    Regulation of the activity of N-methyl-d-aspartate receptors (NMDARs) at glutamatergic synapses is essential for certain forms of synaptic plasticity underlying learning and memory and is also associated with neurotoxicity and neurodegenerative diseases. In this report, we investigate the role of Src-like adaptor protein (Slap) in NMDA receptor signaling. We present data showing that in dissociated neuronal cultures, activation of ephrin (Eph) receptors by chimeric preclustered eph-Fc ligands leads to recruitment of Slap and NMDA receptors at the sites of Eph receptor activation. Interestingly, our data suggest that prolonged activation of EphA receptors is as efficient in recruiting Slap and NMDA receptors as prolonged activation of EphB receptors. Using established heterologous systems, we examined whether Slap is an integral part of NMDA receptor signaling. Our results showed that Slap does not alter baseline activity of NMDA receptors and does not affect Src-dependent potentiation of NMDA receptor currents in Xenopus oocytes. We also demonstrate that Slap reduces excitotoxic cell death triggered by activation of NMDARs in HEK293 cells. Finally, we present evidence showing reduced levels of NMDA receptors in the presence of Slap occurring in an activity-dependent manner, suggesting that Slap is part of a mechanism that homeostatically modulates the levels of NMDA receptors.

  17. N-methyl-D-aspartate (NMDA) and the regulation of mitogen-activated protein kinase (MAPK) signaling pathways: a revolving neurochemical axis for therapeutic intervention?

    Science.gov (United States)

    Haddad, John J

    2005-11-01

    Excitatory synaptic transmission in the central nervous system (CNS) is mediated by the release of glutamate from presynaptic terminals onto postsynaptic channels gated by N-methyl-D-aspartate (NMDA) and non-NMDA (AMPA and KA) receptors. Extracellular signals control diverse neuronal functions and are responsible for mediating activity-dependent changes in synaptic strength and neuronal survival. Influx of extracellular calcium ([Ca(2+)](e)) through the NMDA receptor (NMDAR) is required for neuronal activity to change the strength of many synapses. At the molecular level, the NMDAR interacts with signaling modules, which, like the mitogen-activated protein kinase (MAPK) superfamily, transduce excitatory signals across neurons. Recent burgeoning evidence points to the fact that MAPKs play a crucial role in regulating the neurochemistry of NMDARs, their physiologic and biochemical/biophysical properties, and their potential role in pathophysiology. It is the purpose of this review to discuss: (i) the MAPKs and their role in a plethora of cellular functions; (ii) the role of MAPKs in regulating the biochemistry and physiology of NMDA receptors; (iii) the kinetics of MAPK-NMDA interactions and their biologic and neurochemical properties; (iv) how cellular signaling pathways, related cofactors and intracellular conditions affect NMDA-MAPK interactions and (v) the role of NMDA-MAPK pathways in pathophysiology and the evolution of disease conditions. Given the versatility of the NMDA-MAPK interactions, the NMDA-MAPK axis will likely form a neurochemical target for therapeutic interventions.

  18. Selective 5-HT7 Receptor Activation May Enhance Synaptic Plasticity Through N-methyl-D-aspartate (NMDA) Receptor Activity in the Visual Cortex.

    Science.gov (United States)

    Xiang, Kangjian; Zhao, Xuefei; Li, Youjun; Zheng, Liang; Wang, Jue; Li, Yan-Hai

    2016-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that modulates N-methyl-D-aspartate (NMDA) receptor activity by binding to several different 5-HT receptor subtypes. In the present study, we used whole-cell patch-clamp recordings in transverse slice preparations to test the role of 5-HT receptors in modulating the NMDA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex. We found that the NMDA receptor-mediated component of mEPSCs could be potentiated by exogenously applied 5-HT. Similar results were obtained by exogenously applied 5-CT or 8-OH-DPAT (the 5-HT1A and 5-HT7 receptor agonist). A specific antagonist for the 5-HT7 receptor, SB-269970, completely blocked the increase in NMDA receptor-mediated component of mEPSCs by 5-CT or 8- OH-DPAT. Moreover, the selective 5-HT1A receptor antagonist, WAY-100135, displayed no influence on the enhancement in NMDA receptor-mediated component of mEPSCs by 5-CT or 8-OHDPAT. These results indicated that the increase in NMDA receptor-mediated component of mEPSCs by 5-HT in layer II/III pyramidal neurons of the young rat visual cortex requires activation of 5-HT7 receptors, but not 5-HT1A receptors. These observations might be clinically relevant to schizophrenia and Alzheimer's disease (AD), where enhancing NMDA receptor-mediated neurotransmission is considered to be a promising strategy for treatment of these diseases.

  19. Dexamethasone enhances glutamine synthetase activity and reduces N-methyl-D-aspartate neurotoxicity in mixed cultures of neurons and astrocytes

    Directory of Open Access Journals (Sweden)

    Edith Debroas

    2015-05-01

    Full Text Available Astrocytes are claimed to protect neurons against excitotoxicity by clearing glutamate from the extracellular space and rapidly converting it into glutamine. Glutamine, is then released into the extracellular medium, taken up by neurons and transformed back into glutamate which is then stored into synaptic vesicles. Glutamine synthetase (GS, the key enzyme that governs this glutamate/glutamine cycle, is known to be upregulated by glucocorticoids. In the present work we have thus studied in parallel the effects of dexamethasone on glutamine synthetase activity and NMDA-induced neuronal death in cultures derived from the brain cortex of murine embryos. We showed that dexamethasone was able to markedly enhance GS activity in cultures of astrocytes but not in near pure neuronal cultures. The pharmacological characteristics of the dexamethasone action strongly suggest that it corresponds to a typical receptor-mediated effect. We also observed that long lasting incubation (72 h of mixed astrocyte-neuron cultures in the presence of 100 nM dexamethasone significantly reduced the toxicity of NMDA treatment. Furthermore we demonstrated that methionine sulfoximine, a selective inhibitor of GS, abolished the dexamethasone-induced increase in GS activity and also markedly potentiated NMDA toxicity. Altogether these results suggest that dexamethasone may promote neuroprotection through a stimulation of astrocyte glutamine synthetase.

  20. Latent N-methyl-D-aspartate receptors in the recurrent excitatory pathway between hippocampal CA1 pyramidal neurons: Ca(2+)-dependent activation by blocking A1 adenosine receptors.

    Science.gov (United States)

    Klishin, A; Tsintsadze, T; Lozovaya, N; Krishtal, O

    1995-01-01

    When performed at increased external [Ca2+]/[Mg2+] ratio (2.5 mM/0.5 mM), temporary block of A1 adenosine receptors in hippocampus [by 8-cyclopentyltheophylline (CPT)] leads to a dramatic and irreversible change in the excitatory postsynaptic current (EPSC) evoked by Schaffer collateral/commissural (SCC) stimulation and recorded by in situ patch clamp in CA1 pyramidal neurons. The duration of the EPSC becomes stimulus dependent, increasing with increase in stimulus strength. The later occurring component of the EPSC is carried through N-methyl-D-aspartate (NMDA) receptor-operated channels but disappears under either the NMDA antagonist 2-amino-5-phosphonovaleric acid (APV) or the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These findings indicate that the late component of the SCC-evoked EPSC is polysynaptic: predominantly non-NMDA receptor-mediated SCC inputs excite CA1 neurons that recurrently excite each other by predominantly NDMA receptor-mediated synapses. These recurrent connections are normally silent but become active after CPT treatment, leading to enhancement of the late component of the EPSC. The activity of these connections is maintained for at least 2 hr after CPT removal. When all functional NMDA receptors are blocked by dizocilpine maleate (MK-801), subsequent application of CPT leads to a partial reappearance of NMDA receptor-mediated EPSCs evoked by SCC stimulation, indicating that latent NMDA receptors are recruited. Altogether, these findings indicate the existence of a powerful system of NMDA receptor-mediated synaptic contacts in SCC input to hippocampal CA1 pyramidal neurons and probably also in reciprocal connections between these neurons, which in the usual preparation are kept latent by activity of A1 receptors. PMID:8618915

  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. Pathologically activated neuroprotection via uncompetitive blockade of N-methyl-D-aspartate receptors with fast off-rate by novel multifunctional dimer bis(propyl)-cognitin.

    Science.gov (United States)

    Luo, Jialie; Li, Wenming; Zhao, Yuming; Fu, Hongjun; Ma, Dik-Lung; Tang, Jing; Li, Chaoying; Peoples, Robert W; Li, Fushun; Wang, Qinwen; Huang, Pingbo; Xia, Jun; Pang, Yuanping; Han, Yifan

    2010-06-25

    Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and gamma-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [(3)H]MK-801 with a K(i) value of 0.27 mum, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation.

  3. Hydroxyproline-induced Helical Disruption in Conantokin Rl-B Affects Subunit-selective Antagonistic Activities toward Ion Channels of N-Methyl-d-aspartate Receptors.

    Science.gov (United States)

    Kunda, Shailaja; Yuan, Yue; Balsara, Rashna D; Zajicek, Jaroslav; Castellino, Francis J

    2015-07-17

    Conantokins are ~20-amino acid peptides present in predatory marine snail venoms that function as allosteric antagonists of ion channels of the N-methyl-d-aspartate receptor (NMDAR). These peptides possess a high percentage of post-/co-translationally modified amino acids, particularly γ-carboxyglutamate (Gla). Appropriately spaced Gla residues allow binding of functional divalent cations, which induces end-to-end α-helices in many conantokins. A smaller number of these peptides additionally contain 4-hydroxyproline (Hyp). Hyp should prevent adoption of the metal ion-induced full α-helix, with unknown functional consequences. To address this disparity, as well as the role of Hyp in conantokins, we have solved the high resolution three-dimensional solution structure of a Gla/Hyp-containing 18-residue conantokin, conRl-B, by high field NMR spectroscopy. We show that Hyp(10) disrupts only a small region of the α-helix of the Mn(2+)·peptide complex, which displays cation-induced α-helices on each terminus of the peptide. The function of conRl-B was examined by measuring its inhibition of NMDA/Gly-mediated current through NMDAR ion channels in mouse cortical neurons. The conRl-B displays high inhibitory selectivity for subclasses of NMDARs that contain the functionally important GluN2B subunit. Replacement of Hyp(10) with N(8)Q results in a Mg(2+)-complexed end-to-end α-helix, accompanied by attenuation of NMDAR inhibitory activity. However, replacement of Hyp(10) with Pro(10) allowed the resulting peptide to retain its inhibitory property but diminished its GluN2B specificity. Thus, these modified amino acids, in specific peptide backbones, play critical roles in their subunit-selective inhibition of NMDAR ion channels, a finding that can be employed to design NMDAR antagonists that function at ion channels of distinct NMDAR subclasses.

  4. 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

  5. Effects of Immune Activation during Early or Late Gestation on N-Methyl-d-Aspartate Receptor Measures in Adult Rat Offspring

    Directory of Open Access Journals (Sweden)

    Tasnim Rahman

    2017-09-01

    Full Text Available BackgroundGlutamatergic receptor [N-methyl-d-aspartate receptor (NMDAR] alterations within cortex, hippocampus, and striatum are linked to schizophrenia pathology. Maternal immune activation (MIA is an environmental risk factor for the development of schizophrenia in offspring. In rodents, gestational timing of MIA may result in distinct behavioral outcomes in adulthood, but how timing of MIA may impact the nature and extent of NMDAR-related changes in brain is not known. We hypothesize that NMDAR-related molecular changes in rat cortex, striatum, and hippocampus are induced by MIA and are dependent on the timing of gestational inflammation and sex of the offspring.MethodsWistar dams were treated the with viral mimic, polyriboinosinic:polyribocytidylic acid (polyI:C, or vehicle on either gestational day 10 or 19. Fresh-frozen coronal brain sections were collected from offspring between postnatal day 63–91. Autoradiographic binding was used to infer levels of the NMDAR channel, and NR2A and NR2B subunits in cortex [cingulate (Cg, motor, auditory], hippocampus (dentate gyrus, cornu ammonis area 3, cornu ammonis area 1, and striatum [dorsal striatum, nucleus accumbens core, and nucleus accumbens shell (AS]. NR1 and NR2A mRNA levels were measured by in situ hybridization in cortex, hippocampus, and striatum in male offspring only.ResultsIn the total sample, NMDAR channel binding was elevated in the Cg of polyI:C offspring. NR2A binding was elevated, while NR2B binding was unchanged, in all brain regions of polyI:C offspring overall. Male, but not female, polyI:C offspring exhibited increased NMDAR channel and NR2A binding in the striatum overall, and increased NR2A binding in the cortex overall. Male polyI:C offspring exhibited increased NR1 mRNA in the AS, and increased NR2A mRNA in cortex and subregions of the hippocampus.ConclusionMIA may alter glutamatergic signaling in cortical and hippocampal regions via alterations in NMDAR indices; however

  6. Neuroprotective effects of inhibiting N-methyl-D-aspartate receptors, P2X receptors and the mitogen-activated protein kinase cascade: a quantitative analysis in organotypical hippocampal slice cultures subjected to oxygen and glucose deprivation.

    Science.gov (United States)

    Rundén-Pran, E; Tansø, R; Haug, F M; Ottersen, O P; Ring, A

    2005-01-01

    Cell death was assessed by quantitative analysis of propidium iodide uptake in rat hippocampal slice cultures transiently exposed to oxygen and glucose deprivation, an in vitro model of brain ischemia. The hippocampal subfields CA1 and CA3, and fascia dentata were analyzed at different stages from 0 to 48 h after the insult. Cell death appeared at 3 h and increased steeply toward 12 h. Only a slight additional increase in propidium iodide uptake was seen at later intervals. The mitogen-activated protein kinases extracellular signal-regulated kinase 1 and extracellular signal-regulated kinase 2 were activated immediately after oxygen and glucose deprivation both in CA1 and in CA3/fascia dentata. Inhibition of the specific mitogen-activated protein kinase activator mitogen-activated protein kinase kinase by PD98059 or U0126 offered partial protection against oxygen and glucose deprivation-induced cell damage. The non-selective P2X receptor antagonist suramin gave neuroprotection of the same magnitude as the N-methyl-D-aspartate channel blocker MK-801 (approximately 70%). Neuroprotection was also observed with the P2 receptor blocker PPADS. Immunogold data indicated that hippocampal slice cultures (like intact hippocampi) express several isoforms of P2X receptors at the synaptic level, consistent with the idea that the effects of suramin and PPADS are mediated by P2X receptors. Virtually complete neuroprotection was obtained by combined blockade of N-methyl-D-aspartate receptors, P2X receptors, and mitogen-activated protein kinase kinase. Both P2X receptors and N-methyl-D-aspartate receptors mediate influx of calcium. Our results suggest that inhibition of P2X receptors has a neuroprotective potential similar to that of inhibition of N-methyl-D-aspartate receptors. In contrast, our comparative analysis shows that only partial protection can be achieved by inhibiting the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase cascade, one of the

  7. 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)

    Science.gov (United States)

    Vasilescu, Andrei-Nicolae; Schweinfurth, Nina; Borgwardt, Stefan; Gass, Peter; Lang, Undine E; Inta, Dragos; Eckart, Sarah

    2017-01-01

    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 of MDD from the US Food and Drug Administration, representing one of the most promising alternative antidepressants under current investigation.

  8. 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

  9. Microinfusion of the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of wistar rats does not affect latent inhibition and prepulse inhibition, but increases startle reaction and locomotor activity.

    Science.gov (United States)

    Zhang, W N; Bast, T; Feldon, J

    2000-01-01

    Latent inhibition (the retarded conditioning to a stimulus following its repeated non-reinforced pre-exposure) and prepulse inhibition (the reduction in the startle response to an intense acoustic stimulus when this stimulus is immediately preceded by a prepulse) reflect cognitive and sensorimotor gating processes, respectively, and are deficient in schizophrenic patients. The disruption of latent inhibition and prepulse inhibition in the rat is used as an animal model for the attentional deficits associated with schizophrenia. The present study tested the extent to which latent inhibition and prepulse inhibition, startle reaction and locomotor activity in the open field were affected by infusing the non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) into the dorsal hippocampus of Wistar rats. We used the same dose of MK-801 (6.25microg/0.5microl per side) previously found to be effective in the disruption of prepulse inhibition when infused into the dorsal hippocampus of Sprague-Dawley rats [Bakshi V. P. and Geyer M. A. (1998) J. Neurosci. 18, 8394-8401; Bakshi V. P. and Geyer M. A. (1999) Neuroscience 92, 113-121]. Bilateral infusion of MK-801 into the dorsal hippocampus did not disrupt latent inhibition. Furthermore, in contrast to previous studies, we failed to find a significant disruption of prepulse inhibition after MK-801 infusion into the dorsal hippocampus, although MK-801 infusion was effective in increasing the startle amplitude as well as locomotor activity in an open field. From our results, we suggest that N-methyl-D-aspartate receptor-mediated processes within the dorsal hippocampus are not necessary for the normal maintenance of the attentional processes reflected by latent inhibition and prepulse inhibition.

  10. Synthesis, structure activity relationship, radiolabeling and preclinical evaluation of high affinity ligands for the ion channel of the N-methyl-d-aspartate receptor as potential imaging probes for positron emission tomography.

    Science.gov (United States)

    Klein, Pieter J; Christiaans, Johannes A M; Metaxas, Athanasios; Schuit, Robert C; Lammertsma, Adriaan A; van Berckel, Bart N M; Windhorst, Albert D

    2015-03-01

    The N-methyl-d-aspartate receptor (NMDAr) is involved in many neurological and psychiatric disorders including Alzheimer's disease and schizophrenia. Currently, it is not possible to assess NMDAr availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NMDAr ion channel. A series of di- and tri-N-substituted diarylguanidines was synthesized. In addition, in vitro binding affinity for the NMDAr ion channel in rat forebrain membrane fractions was assessed. Compounds 10, 11 and 32 were radiolabeled with either carbon-11 or fluorine-18. Ligands [(11)C]10 and [(18)F]32 were evaluated ex vivo in B6C3 mice. Biodistribution studies showed higher uptake of [(11)C]10 and [(18)F]32 in forebrain regions compared with cerebellum. In addition, for [(11)C]10 54% and for [(18)F]32 70% of activity in the brain at 60min was due to intact tracer. Pre-treatment with MK-801 (0.6mg·kg(-1), ip) slightly decreased uptake in NMDAr-specific regions for [(18)F]32, but not for [(11)C]10. As such [(18)F]32 has the best characteristics as a PET tracer for the ion channel of the NMDAr.

  11. Confocal imaging of N-methyl-D-aspartate receptors in living cortical neurons.

    Science.gov (United States)

    Durand, J; Kojic, L; Wang, Y; Lee, P; Cynader, M S; Gu, Q

    2000-01-01

    fluorescently labeled clusters compared with the control group, neurons in the high potassium group exhibited a higher number of fluorescently labeled receptor clusters. These results suggest that more active neurons may tend to form more N-methyl-D-aspartate synapses during early development.

  12. Neuroprotection of GluR5-containing kainate receptor activation against ischemic brain injury through decreasing tyrosine phosphorylation of N-methyl-D-aspartate receptors mediated by Src kinase.

    Science.gov (United States)

    Xu, Jie; Liu, Yong; Zhang, Guang-Yi

    2008-10-24

    Previous studies indicate that cerebral ischemia breaks the dynamic balance between excitatory and inhibitory inputs. The neural excitotoxicity induced by ionotropic glutamate receptors gain the upper hand during ischemia-reperfusion. In this paper, we investigate whether GluR5 (glutamate receptor 5)-containing kainate receptor activation could lead to a neuroprotective effect against ischemic brain injury and the related mechanism. The results showed that (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), a selective GluR5 agonist, could suppress Src tyrosine phosphorylation and interactions among N-methyl-D-aspartate (NMDA) receptor subunit 2A (NR2A), postsynaptic density protein 95 (PSD-95), and Src and then decrease NMDA receptor activation through attenuating tyrosine phosphorylation of NR2A and NR2B. More importantly, ATPA had a neuroprotective effect against ischemia-reperfusion-induced neuronal cell death in vivo. However, four separate drugs were found to abolish the effects of ATPA. These were selective GluR5 antagonist NS3763; GluR5 antisense oligodeoxynucleotides; CdCl(2), a broad spectrum blocker of voltage-gated calcium channels; and bicuculline, an antagonist of gamma-aminobutyric acid A (GABA(A)) receptor. GABA(A) receptor agonist muscimol could attenuate Src activation and interactions among NR2A, PSD-95 and Src, resulting the suppression of NMDA receptor tyrosine phosphorylation. Moreover, patch clamp recording proved that the activated GABA(A) receptor could inhibit NMDA receptor-mediated whole-cell currents. Taken together, the results suggest that during ischemia-reperfusion, activated GluR5 may facilitate Ca(2+)-dependent GABA release from interneurons. The released GABA can activate postsynaptic GABA(A) receptors, which then attenuates NMDA receptor tyrosine phosphorylation through inhibiting Src activation and disassembling the signaling module NR2A-PSD-95-Src. The final result of this process is that the pyramidal

  13. 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...

  14. Study of the n-methyl-d-aspartate antagonistic properties of anticholinergic drugs

    Energy Technology Data Exchange (ETDEWEB)

    McDonough, J.H.; Shih, T.M.

    1995-12-31

    A study of the N-methyl-D-aspartate antagonistic properties of anticholinergic drugs. PHARMACOL BIOCHEM BEHAV. 51(2/3) 249-253, 1995. Drugs that act at the N-methyl-D-aspartate (NMDA) receptor complex have the ability to terminate nerve agent-induced seizures and modulate the neuropathologic consequences of agent exposure. Drugs with mixed anticholinergic and anti-NMDA properties potentially provide an ideal class of compounds for development as anticonvulsant treatments for nerve agent casualties. The present experiment evaluated the potential NMDA antagonist activity of 11 anticholinergic drugs by determining whether pretreatment with the compound was capable of protecting mice from the lethal effects of NMDA. The following anticholinergic drugs antagonized NMDA lethality and are ranked according to their potency: mecamylamine > procyclidine = benactyzine > biperiden > tribexyphenidyl. The anticholinergics atropine, aprophen, azaprophen, benztropine, 3-quinudidinyl benzilate (QNB), and scopolamine failed to show NMDA antagonist properties. In addition, and unexpectedly, diazepam, ethanol, and pentobarbital were also shown to be capable of antagonizing NMDA lethality over a certain range of doses. The advantages and limitations of using antagonism of NMDA lethality in mice as a bioassay for determining the NMDA antagonist properties of drugs are also discussed.

  15. Kappa opioid receptor antagonist and N-methyl-D- aspartate receptor antagonist affect dynorphin- induced spinal cord electrophysiologic impairment

    Institute of Scientific and Technical Information of China (English)

    Yu Chen; Liangbi Xiang; Jun Liu; Dapeng Zhou; Hailong Yu; Qi Wang; Wenfeng Han; Weijian Ren

    2012-01-01

    The latencies of motor- and somatosensory-evoked potentials were prolonged to different degrees, and wave amplitude was obviously decreased, after injection of dynorphin into the rat subarachnoid cavity.The wave amplitude and latencies of motor- and somatosensory-evoked potentials were significantly recovered at 7 and 14 days after combined injection of dynorphin and either the kappa opioid receptor antagonist nor-binaltorphimine or the N-methyl-D-aspartate receptor antagonist MK-801.The wave amplitude and latency were similar in rats after combined injection of dynorphin and nor-binaltorphimine or MK-801.These results suggest that intrathecal injection of dynorphin causes damage to spinal cord function.Prevention of N-methyl-D-aspartate receptor or kappa receptor activation lessened the injury to spinal cord function induced by dynorphin.

  16. Pharmacology of triheteromeric N-Methyl-D-Aspartate Receptors.

    Science.gov (United States)

    Cheriyan, John; Balsara, Rashna D; Hansen, Kasper B; Castellino, Francis J

    2016-03-23

    The N-Methyl-D-Aspartate Receptors (NMDARs) are heteromeric cation channels involved in learning, memory, and synaptic plasticity, and their dysregulation leads to various neurodegenerative disorders. Recent evidence has shown that apart from the GluN1/GluN2A and GluN1/GluN2B diheteromeric ion channels, the NMDAR also exists as a GluN1/GluN2A/GluN2B triheteromeric channel that occupies the majority of the synaptic space. These GluN1/GluN2A/GluN2B triheteromers exhibit pharmacological and electrophysiological properties that are distinct from the GluN1/GluN2A and GluN1/GluN2B diheteromeric subtypes. However, these receptors have not been characterized with regards to their inhibition by conantokins, as well as their allosteric modulation by polyamines and extracellular protons. Here, we show that the GluN1/GluN2A/GluN2B triheteromeric channels showed less sensitivity to GluN2B-specific conantokin (con)-G and con-RlB, and subunit non-specific con-T, compared to the GluN2A-specific inhibitor TCN-201. Also, spermine modulation of GluN1/GluN2A/GluN2B triheteromers switched its nature from potentiation to inhibition in a pH dependent manner, and was 2.5-fold slower compared to the GluN1/GluN2B diheteromeric channels. Unraveling the distinctive functional attributes of the GluN1/GluN2A/GluN2B triheteromers is physiologically relevant since they form an integral part of the synapse, which will aid in understanding spermine/pH-dependent potentiation of these receptors in pathological settings.

  17. Src, a molecular switch governing gain control of synaptic transmission mediated by N-methyl-d-aspartate receptors

    OpenAIRE

    Yu, Xian-Min; Salter, Michael W

    1999-01-01

    The N-methyl-d-aspartate (NMDA) receptor is a principal subtype of glutamate receptor mediating fast excitatory transmission at synapses in the dorsal horn of the spinal cord and other regions of the central nervous system. NMDA receptors are crucial for the lasting enhancement of synaptic transmission that occurs both physiologically and in pathological conditions such as chronic pain. Over the past several years, evidence has accumulated indicating that the activ...

  18. ON or OFF?: Modulating the N-Methyl-D-Aspartate Receptor in Major Depression

    Science.gov (United States)

    Chan, Shi Yu; Matthews, Edward; Burnet, Philip W. J.

    2017-01-01

    Since the discovery that a single dose of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, had rapid and long-lasting antidepressant effects, there has been increased interest in using NMDAR modulators in the pharmacotherapy of depression. Ketamine’s efficacy seems to imply that depression is a disorder of NMDAR hyperfunctionality. However, studies showing that not all NMDAR antagonists are able to act as antidepressants challenge this notion. Furthermore, NMDAR co-agonists have also been gaining attention as possible treatments. Co-agonists such as D-serine and sarcosine have shown efficacy in both pre-clinical models and human trials. This raises the question of how both NMDAR antagonists and agonists are able to have converging behavioral effects. Here we critically review the evidence and proposed therapeutic mechanisms for both NMDAR antagonists and agonists, and collate several theories on how both activation and inhibition of NMDARs appear to have antidepressant effects. PMID:28133445

  19. Effects of the abused solvent toluene on recombinant N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors expressed in Xenopus oocytes.

    Science.gov (United States)

    Cruz, S L; Mirshahi, T; Thomas, B; Balster, R L; Woodward, J J

    1998-07-01

    Previous studies have shown that toluene, which is commonly abused, depresses neuronal activity and causes behavioral effects in both animals and man similar to those observed for ethanol. In this study, the oocyte expression system was used to test the hypothesis that toluene, like ethanol, inhibits the function of ionotropic glutamate receptors. Oocytes were injected with mRNA for specific N-methyl-D-aspartate (NMDA) or non-NMDA subunits and currents were recorded using conventional two-electrode voltage clamp. To enhance the low water solubility of toluene, drug solutions were prepared by mixing toluene with alkamuls (ethoxylated castor oil) at a 1:1 ratio (v:v) and diluting this mixture to the appropriate concentration with barium-containing normal frog Ringer solution. Alkamuls, up to 0.1%, had no significant effects on membrane leak currents or on NMDA-induced currents. Toluene, up to approximately 9 mM, had only minor effects on membrane leak currents but dose-dependently inhibited NMDA-mediated currents in oocytes. The inhibition of NMDA receptor currents by toluene was rapid, reversible and the potency for toluene's effects was subunit dependent. The NR1/2B subunit combination was the most sensitive with an IC50 value for toluene-induced inhibition of 0.17 mM. The NR1/2A and NR1/2C receptors were 6- and 12-fold less sensitive with IC50 values of 1.4 and 2.1 mM, respectively. In contrast, toluene up to approximately 9 mM did not inhibit kainate-induced currents in oocytes expressing GluR1, GluR1(+)R2 or GluR6 subunits. These results suggest that some of the effects of toluene on neuronal activity and behavior may be mediated by inhibition of NMDA receptors.

  20. Stimulus intensity, cell excitation and the N-methyl-D-aspartate receptor component of sensory responses in the rat spinal cord in vivo.

    Science.gov (United States)

    Chizh, B A; Cumberbatch, M J; Herrero, J F; Stirk, G C; Headley, P M

    1997-09-01

    The importance of receptors for N-methyl-D-aspartate in synaptic plasticity and in triggering long-term pronociceptive changes is explained by their voltage-dependence. This suggests that their contribution to acute nociceptive responses would be determined both by the magnitude of synaptic input and by the level of background excitation. We have now examined the role of N-methyl-D-aspartate receptors in acute nociceptive transmission in the spinal cord. Drugs selectively affecting activity mediated by these receptors were tested on responses of dorsal horn neurons to noxious stimuli of different intensities and at different levels of ongoing spike discharge. The drugs used were the N-methyl-D-aspartate receptor channel blocker ketamine; the competitive antagonists, 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (D-CPP) and D-2-amino-5-phosphonopentanoic acid (D-AP5), and the positive modulator thyrotropin-releasing hormone. The activity of dorsal horn wide dynamic range neurons was recorded extracellularly in alpha-chloralose-anaesthetized spinalized rats. Their responses to noxious stimuli (pinch, heat and electrical) were monitored in parallel with responses to iontophoretic N-methyl-D-aspartate and (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA). Drugs were given i.v. or (D-AP5) iontophoretically. At doses that selectively inhibited responses to exogenous N-methyl-D-aspartate, ketamine (4 or 8, mean 5 mg/kg i.v.) reduced the nociceptive responses of the majority of the cells in deep dorsal horn. Ketamine also reduced wind-up of the responses to repetitive electrical stimulation. Ketamine (4 or 8 mg/kg). D-CPP (2 mg/kg), D-AP5 (iontophoretically) and thyrotrophin-releasing hormone (1 mg/kg) were tested on different magnitude nociceptive responses evoked by alternating intensities of noxious heat or pinch. In percentage terms, the less vigorous responses were affected by all four drugs as much as or more than the more vigorous

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

    Energy Technology Data Exchange (ETDEWEB)

    Skolnick, P.; Marvizon, J.C.G.; Jackson, B.W.; Monn, J.A.; Rice, K.C. (National Institutes of Health, Bethesda, MD (USA)); Lewin, A.H. (Research Triangle Institute, Research Triangle Park, NC (USA))

    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 ({sup 3}H)glycine binding, indicating that conversion to the parent compound may be required to elicit an anticonvulsant action.

  2. The forced swimming-induced behavioural immobility response involves histone H3 phospho-acetylation and c-Fos induction in dentate gyrus granule neurons via activation of the N-methyl-D-aspartate/extracellular signal-regulated kinase/mitogen- and stress-activated kinase signalling pathway.

    Science.gov (United States)

    Chandramohan, Yalini; Droste, Susanne K; Arthur, J Simon C; Reul, Johannes M H M

    2008-05-01

    The hippocampus is involved in learning and memory. Previously, we have shown that the acquisition of the behavioural immobility response after a forced swim experience is associated with chromatin modifications and transcriptional induction in dentate gyrus granule neurons. Given that both N-methyl-D-aspartate (NMDA) receptors and the extracellular signal-regulated kinases (ERK) 1/2 signalling pathway are involved in neuroplasticity processes underlying learning and memory, we investigated in rats and mice whether these signalling pathways regulate chromatin modifications and transcriptional events participating in the acquisition of the immobility response. We found that: (i) forced swimming evoked a transient increase in the number of phospho-acetylated histone H3-positive [P(Ser10)-Ac(Lys14)-H3(+)] neurons specifically in the middle and superficial aspects of the dentate gyrus granule cell layer; (ii) antagonism of NMDA receptors and inhibition of ERK1/2 signalling blocked forced swimming-induced histone H3 phospho-acetylation and the acquisition of the behavioural immobility response; (iii) double knockout (DKO) of the histone H3 kinase mitogen- and stress-activated kinases (MSK) 1/2 in mice completely abolished the forced swimming-induced increases in histone H3 phospho-acetylation and c-Fos induction in dentate granule neurons and the behavioural immobility response; (iv) blocking mineralocorticoid receptors, known not to be involved in behavioural immobility in the forced swim test, did not affect forced swimming-evoked histone H3 phospho-acetylation in dentate neurons; and (v) the pharmacological manipulations and gene deletions did not affect behaviour in the initial forced swim test. We conclude that the forced swimming-induced behavioural immobility response requires histone H3 phospho-acetylation and c-Fos induction in distinct dentate granule neurons through recruitment of the NMDA/ERK/MSK 1/2 pathway.

  3. N-METHYL-d-ASPARTATE RECEPTORS AND LARGE CONDUCTANCE CALCIUM-SENSITIVE POTASSIUM CHANNELS INHIBIT THE RELEASE OF OPIOID PEPTIDES THAT INDUCE μ-OPIOID RECEPTOR INTERNALIZATION IN THE RAT SPINAL CORD

    Science.gov (United States)

    SONG, B.; MARVIZÓN, J. C. G.

    2006-01-01

    Endogenous opioids in the spinal cord play an important role in nociception, but the mechanisms that control their release are poorly understood. To simultaneously detect all opioids able to activate the μ-opioid receptor, we measured μ-opioid receptor internalization in rat spinal cord slices stimulated electrically or chemically to evoke opioid release. Electrical stimulation of the dorsal horn in the presence of peptidase inhibitors produced μ-opioid receptor internalization in half of the μ-opioid receptor neurons. This internalization was rapidly abolished by N-methyl-d-aspartate (IC50=2 μM), and N-methyl-d-aspartate antagonists prevented this effect. μ-Opioid receptor internalization evoked by high K+ or veratridine was also inhibited by N-methyl-d-aspartate receptor activation. N-methyl-d-aspartate did not affect μ-opioid receptor internalization induced by exogenous endomorphins, confirming that the effect of N-methyl-d-aspartate was on opioid release. We hypothesized that this inhibition was mediated by large conductance Ca2+-sensitive K+ channels BK(Ca2+). Indeed, inhibition by N-methyl-d-aspartate was prevented by tetraethylammonium and by the selective BK(Ca2+) blockers paxilline, penitrem A and verruculogen. Paxilline did not increase μ-opioid receptor internalization in the absence of N-methyl-d-aspartate, indicating that it does not produce an increase in opioid release unrelated to the inhibition by N-methyl-d-aspartate. The BK(Ca2+) involved appears to be a subtype with slow association kinetics for iberiotoxin, which was effective only with long incubations. The BK(Ca2+) opener NS-1619 also inhibited the evoked μ-opioid receptor internalization, and iberiotoxin prevented this effect. We concluded that Ca2+ influx through N-methyl-d-aspartate receptors causes the opening of BK(Ca2+) and hyperpolarization in opioid-containing dorsal horn neurons, resulting in the inhibition of opioid release. Since μ-opioid receptors in the dorsal horn

  4. N-methyl-D-aspartate receptors and large conductance calcium-sensitive potassium channels inhibit the release of opioid peptides that induce mu-opioid receptor internalization in the rat spinal cord.

    Science.gov (United States)

    Song, B; Marvizón, J C G

    2005-01-01

    Endogenous opioids in the spinal cord play an important role in nociception, but the mechanisms that control their release are poorly understood. To simultaneously detect all opioids able to activate the mu-opioid receptor, we measured mu-opioid receptor internalization in rat spinal cord slices stimulated electrically or chemically to evoke opioid release. Electrical stimulation of the dorsal horn in the presence of peptidase inhibitors produced mu-opioid receptor internalization in half of the mu-opioid receptor neurons. This internalization was rapidly abolished by N-methyl-D-aspartate (IC50=2 microM), and N-methyl-D-aspartate antagonists prevented this effect. mu-Opioid receptor internalization evoked by high K+ or veratridine was also inhibited by N-methyl-D-aspartate receptor activation. N-methyl-D-aspartate did not affect mu-opioid receptor internalization induced by exogenous endomorphins, confirming that the effect of N-methyl-D-aspartate was on opioid release. We hypothesized that this inhibition was mediated by large conductance Ca2+-sensitive K+ channels BK(Ca2+). Indeed, inhibition by N-methyl-D-aspartate was prevented by tetraethylammonium and by the selective BK(Ca2+) blockers paxilline, penitrem A and verruculogen. Paxilline did not increase mu-opioid receptor internalization in the absence of N-methyl-D-aspartate, indicating that it does not produce an increase in opioid release unrelated to the inhibition by N-methyl-d-aspartate. The BK(Ca2+) involved appears to be a subtype with slow association kinetics for iberiotoxin, which was effective only with long incubations. The BK(Ca2+) opener NS-1619 also inhibited the evoked mu-opioid receptor internalization, and iberiotoxin prevented this effect. We concluded that Ca2+ influx through N-methyl-D-aspartate receptors causes the opening of BK(Ca2+) and hyperpolarization in opioid-containing dorsal horn neurons, resulting in the inhibition of opioid release. Since mu-opioid receptors in the dorsal horn

  5. 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.

  6. Structural Dynamics of the Glycine-binding Domain of the N-Methyl-d-Aspartate Receptor*

    Science.gov (United States)

    Dolino, Drew M.; Cooper, David; Ramaswamy, Swarna; Jaurich, Henriette; Landes, Christy F.; Jayaraman, Vasanthi

    2015-01-01

    N-Methyl-d-aspartate receptors mediate the slow component of excitatory neurotransmission in the central nervous system. These receptors are obligate heteromers containing glycine- and glutamate-binding subunits. The ligands bind to a bilobed agonist-binding domain of the receptor. Previous x-ray structures of the glycine-binding domain of NMDA receptors showed no significant changes between the partial and full agonist-bound structures. Here we have used single molecule fluorescence resonance energy transfer (smFRET) to investigate the cleft closure conformational states that the glycine-binding domain of the receptor adopts in the presence of the antagonist 5,7-dichlorokynurenic acid (DCKA), the partial agonists 1-amino-1-cyclobutanecarboxylic acid (ACBC) and l-alanine, and full agonists glycine and d-serine. For these studies, we have incorporated the unnatural amino acid p-acetyl-l-phenylalanine for specific labeling of the protein with hydrazide derivatives of fluorophores. The single molecule fluorescence resonance energy transfer data show that the agonist-binding domain can adopt a wide range of cleft closure states with significant overlap in the states occupied by ligands of varying efficacy. The difference lies in the fraction of the protein in a more closed-cleft form, with full agonists having a larger fraction in the closed-cleft form, suggesting that the ability of ligands to select for these states could dictate the extent of activation. PMID:25404733

  7. Longitudinal electroencephalographic (EEG) findings in pediatric anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis: the Padua experience.

    Science.gov (United States)

    Nosadini, Margherita; Boniver, Clementina; Zuliani, Luigi; de Palma, Luca; Cainelli, Elisa; Battistella, Pier Antonio; Toldo, Irene; Suppiej, Agnese; Sartori, Stefano

    2015-02-01

    To contribute to characterize electroencephalographic (EEG) activity in pediatric anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis, we reviewed electroclinical data of 5 children with anti-NMDA receptor encephalitis diagnosed in our department. We identified 4 longitudinal electroencephalographic phases: in the early phase, background activity was normal, with intermixed nonreactive slow waves; in the florid phase, background activity deteriorated with appearance of sequences of peculiar rhythmic theta and/or delta activity unrelated to clinical changes, unresponsive to stimuli and antiepileptic medications; in the recovery phase, these sequences decreased and reactive posterior rhythm re-emerged; electroencephalogram normalized 2 to 5 months after onset. In conclusion, in the presence of evocative clinical history, recognizing a characteristic longitudinal electroencephalographic activity could provide ancillary aspects addressing the diagnosis and the overall management of children with anti-N-methyl-d-aspartate receptor encephalitis; in particular, knowing that peculiar and recurrent paroxysmal nonepileptic rhythmic theta-delta patterns can occur in these patients could help distinguish paroxysmal epileptic and nonepileptic electroencephalographic activity.

  8. 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 si...

  9. Learning and memory: regional changes in N-methyl-D-aspartate receptors in the chick brain after imprinting.

    Science.gov (United States)

    McCabe, B J; Horn, G

    1988-01-01

    An extensive series of experiments has implicated a restricted region of the chick forebrain in the learning process of imprinting. The region is the intermediate and medial part of the hyperstriatum ventrale (IMHV). Previous studies have shown that training is associated with an increase in the area of the postsynaptic density of axospinous synapses in the left but not the right IMHV. The postsynaptic density is a site of high receptor density, and at least some axospinous synapses are excitatory. We found that imprinting is associated with a 59% increase in N-methyl-D-aspartate-sensitive binding of the excitatory amino acid L-[3H]glutamic acid in the left IMHV. The increase is probably due to an increased number of binding sites. The profile of sensitivity of the sites to a series of amino-, phosphono-substituted carboxylic acids (2-amino-3-phosphonopropionate to 2-amino-8-phosphonooctanoate) is characteristic of N-methyl-D-aspartate-type receptors. There were no significant effects of training on binding in the right IMHV. The effect of training on left IMHV binding could not be attributed to light exposure, arousal, or motor activity per se but was a function of how much the chicks learned. The changes in the left IMHV could increase the effectiveness of synaptic transmission in a region crucial for information storage and so form a neural basis for recognition memory. PMID:2833757

  10. Colonic N-methyl-d-aspartate receptor contributes to visceral hypersensitivity in irritable bowel syndrome.

    Science.gov (United States)

    Qi, Qingqing; Chen, Feixue; Zhang, Wenxue; Wang, Peng; Li, Yanqing; Zuo, Xiuli

    2017-04-01

    N-methyl-d-aspartate receptor (NMDAR) in brain, spinal cord, and enteric nervous system is involved in visceral hypersensitivity. This study aimed to reveal the functional expression of NMDAR on mucosal cells in colon and to investigate the downstream signal pathway from colonic NMDAR activation to visceral hypersensitivity in irritable bowel syndrome (IBS). The expression of mucosal NMDAR in IBS patients and healthy controls was assessed by immunohistochemistry and Western blot and correlated with abdominal pain/discomfort scores quantified by a validated questionnaire. Electromyography recording in response to colorectal distension was recorded to measure the colonic sensitivity of mice receiving NMDA administration intracolonically. Brain-derived neurotrophic factor (BDNF) expression and extracellular signal-regulated kinase (ERK) pathway activation were examined in human colonic epithelial HT29 cells after NMDA stimulation, with or without MK801 or U0126 pretreatment. A significant upregulation of mucosal NMDAR was observed in IBS patients compared with controls, which was significantly correlated with abdominal pain/discomfort scores. Intracolonic administration of NMDA in normal mice produced increased colonic sensitivity to colorectal distension and elevated expression of BDNF and activation of ERK. Activation of NMDAR in colonic epithelial HT29 cells in vitro induced increased BDNF secretion in cell supernatants and higher BDNF expression in cells, as well as elevated phosphorylated ERK. This study demonstrated that the activation of mucosal NMDAR in colon may contribute to the visceral hypersensitivity in IBS, by increasing production of BDNF in an ERK-dependent pathway. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  11. 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

  12. N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes

    Science.gov (United States)

    Irani, Sarosh R.; Bera, Katarzyna; Waters, Patrick; Zuliani, Luigi; Maxwell, Susan; Zandi, Michael S.; Friese, Manuel A.; Galea, Ian; Kullmann, Dimitri M.; Beeson, David; Lang, Bethan; Bien, Christian G.

    2010-01-01

    Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6–121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a

  13. Cardiac N-methyl D-aspartate receptors as a pharmacological target

    OpenAIRE

    Makhro, Asya; Tian, Qinghai; Kaestner, Lars; Kosenkov, Dmitry; Faggian, Giuseppe; Gassmann, Max; Schwarzwald, Colin; BOGDANOVA, Anna

    2016-01-01

    This study focuses on characterization of the cardiac N-methyl D-aspartate receptors (NMDARs) as a target for endogenous and synthetic agonists and antagonists. Using isolated perfused rat hearts, we have shown that intracoronary administration of the NMDAR agonists and antagonists has a pronounced effect on autonomous heart function. Perfusion of rat hearts with autologous blood supplemented with NMDAR agonists was associated with induction of tachycardia, sinus arrhythmia and ischemia occur...

  14. Effect of propofol on the reactivity of acetylcholinesterase, N-methyl-D-aspartate receptors, and gamma-aminobutyric acid receptors in the hippocampus of aged rats after chronic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Gang Chen; Jiangbei Cao; Weidong Mi

    2011-01-01

    We induced ischemic brain injury in aging rats to examine the effects of varying doses of propofol on hippocampal activities of acetylcholinesterase, N-methyl-D-aspartate receptors, and γ-aminobutyric acid receptors. Propofol exhibited no obvious impact on acetylcholinesterase activity, but directly activated the γ-aminobutyric acid receptor. The neuroprotective function of propofol on the hippocampus of aging rats following cerebral ischemic injury may be related to altered activities of γ-aminobutyric acid receptors and N-methyl-D-aspartate receptors.

  15. 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

  16. Prevalence of serum N-methyl-D-aspartate receptor autoantibodies in refractory psychosis.

    Science.gov (United States)

    Beck, Katherine; Lally, John; Shergill, Sukhwinder S; Bloomfield, Michael A P; MacCabe, James H; Gaughran, Fiona; Howes, Oliver D

    2015-02-01

    N-methyl-d-aspartate receptor (NMDA-R) autoantibodies have been reported in people with acute psychosis. We hypothesised that their presence may be implicated in the aetiology of treatment-refractory psychosis. We sought to ascertain the point prevalence of NMDA-R antibody positivity in patients referred to services for treatment-refractory psychosis. We found that 3 (7.0%) of 43 individuals had low positive NMDA-R antibody titres. This suggests that NMDA-R autoantibodies are unlikely to account for a large proportion of treatment-refractory psychosis.

  17. 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...... glycine (NHP5G) derivatives are selectively recognized by N-methyl- d-aspartic acid (NMDA) receptors and that the ( R)-enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools...

  18. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis in a young Lebanese girl.

    Science.gov (United States)

    Safadieh, Layal; Dabbagh, Omar

    2013-10-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a recently recognized autoimmune neurologic disorder that presents with severe neuropsychiatric symptoms in previously healthy children. A 4-year-old Lebanese girl presented with new-onset behavioral changes, orofacial dyskinesias, fluctuation in consciousness, inability to walk, and mutism. Antibodies directed against NMDA receptors were detected in the patient's serum and cerebrospinal fluid. Prompt treatment with a single course of intravenous immunoglobulin resulted in early complete recovery. This is the first case report of a Middle Eastern child affected with this condition.

  19. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice.

    Science.gov (United States)

    Planagumà, Jesús; Leypoldt, Frank; Mannara, Francesco; Gutiérrez-Cuesta, Javier; Martín-García, Elena; Aguilar, Esther; Titulaer, Maarten J; Petit-Pedrol, Mar; Jain, Ankit; Balice-Gordon, Rita; Lakadamyali, Melike; Graus, Francesc; Maldonado, Rafael; Dalmau, Josep

    2015-01-01

    Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder that associates with prominent memory and behavioural deficits. Patients' antibodies react with the N-terminal domain of the GluN1 (previously known as NR1) subunit of NMDAR causing in cultured neurons a selective and reversible internalization of cell-surface receptors. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients' antibodies cause memory and behavioural deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps that delivered a continuous infusion of patients' or control cerebrospinal fluid (flow rate 0.25 µl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviours (sucrose preference test), depressive-like behaviours (tail suspension, forced swimming tests), anxiety (black and white, elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical). Animals sacrificed at Days 5, 13, 18, 26 and 46 were examined for brain-bound antibodies and the antibody effects on total and synaptic NMDAR clusters and protein concentration using confocal microscopy and immunoblot analysis. These experiments showed that animals infused with patients' cerebrospinal fluid, but not control cerebrospinal fluid, developed progressive memory deficits, and anhedonic and depressive-like behaviours, without affecting other behavioural or locomotor tasks. Memory deficits gradually worsened until Day 18 (4 days after the infusion stopped) and all symptoms resolved over the next week. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies, predominantly in the hippocampus (maximal on Days

  20. Anti-N-Methyl-D-Aspartate Receptor Encephalitis in HIV Infection

    Directory of Open Access Journals (Sweden)

    Eunice Patarata

    2016-12-01

    Full Text Available Anti-N-methyl-D-aspartate receptor (anti-NMDAR encephalitis is a rare condition characterized by emotional and behavioral disturbances, dyskinesias, and extrapyramidal signs. It occurs in young women of reproductive age and is classically described as a paraneoplastic phenomenon. We present a 36-year-old, HIV-positive female who was admitted to the hospital in an acute confusional state, with a stiff posture, periods of motor agitation, and myoclonic jerks of the hands. Her mental state progressively deteriorated. Without evidence of infection, the presence of anti-NMDAR antibodies both in serum and cerebrospinal fluid clinched the diagnosis of autoimmune encephalitis. No evidence of neoplastic disease was found, and the beneficial response to immunosuppressive therapy was exceptional. This is the first report of anti-NMDAR encephalitis in an HIV-infected individual, reminding us that autoimmune encephalitis should be included in the differential diagnosis of a young patient presenting in an acute confusional state.

  1. 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......, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA...... receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence...

  2. 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.

  3. Anti-N-Methyl-D-Aspartate Receptor Encephalitis in HIV Infection

    Science.gov (United States)

    Patarata, Eunice; Bernardino, Vera; Martins, Ana; Pereira, Rui; Loureiro, Conceição; Moraes-Fontes, Maria Francisca

    2016-01-01

    Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a rare condition characterized by emotional and behavioral disturbances, dyskinesias, and extrapyramidal signs. It occurs in young women of reproductive age and is classically described as a paraneoplastic phenomenon. We present a 36-year-old, HIV-positive female who was admitted to the hospital in an acute confusional state, with a stiff posture, periods of motor agitation, and myoclonic jerks of the hands. Her mental state progressively deteriorated. Without evidence of infection, the presence of anti-NMDAR antibodies both in serum and cerebrospinal fluid clinched the diagnosis of autoimmune encephalitis. No evidence of neoplastic disease was found, and the beneficial response to immunosuppressive therapy was exceptional. This is the first report of anti-NMDAR encephalitis in an HIV-infected individual, reminding us that autoimmune encephalitis should be included in the differential diagnosis of a young patient presenting in an acute confusional state. PMID:28101036

  4. Young girl with abnormal behavior: Anti-N-Methyl-D-Aspartate receptor immune encephalitis

    Directory of Open Access Journals (Sweden)

    Vinit Suri

    2013-01-01

    Full Text Available Anti N Methyl D Aspartate receptor immune encephalitis (Anti NMDARE is a recently defined, under-recognized and often misdiagnosed disease, which typically occurs in young females and may be associated with an underlying tumor, usually ovarian teratoma. If diagnosed early, initiation of immunotherapy and tumor removal (if present may result in recovery. We report a case of a 17 years old girl with Anti NMDARE who was initially misdiagnosed as Functional psychosis, Neuroleptic Malignant Syndrome and Sepsis syndrome. To the best of our knowledge, this is only the second case of anti NMDARE being reported from India. This case report underscores the need for a greater awareness of this entity across multiple specialties, e.g., general medicine, psychiatry and neurology, to ensure a heightened diagnostic suspicion, which can lead to timely diagnosis and adequate therapy of this treatable disease.

  5. 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...

  6. 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...

  7. Anti-N-methyl-D-aspartate receptor encephalitis: a new autoimmune encephalitis

    Directory of Open Access Journals (Sweden)

    LI Xiang

    2013-01-01

    Full Text Available Anti-N-methyl-D-aspartate (anti-NMDA receptor encephalitis is a new category of treatable encephalitis associated with anti-NMDA receptor antibody, which attracts more and more attention recently. It is clinically characterized by prodromal fever, schizophrenia-like psychiatric symptoms, seizures, disturbance of consciousness, dyskinesia (particularly orofacial, and autonomic dysfunction, which often occur in young females with ovarian teratomas. Autoantibodies to the anti-NMDA receptor in serum and cerebrospinal fluid are positive. Electroencephalogram (EEG often reveals diffuse δ slowing without paroxysmal discharges, on which " δ rush" is considered as specific characteristic in some patients. Combined therapy including tumor resection and immunotherapy is recommended. The updates in mechanisms, clinical manifestations and diagnostic examinations associated with anti-NMDA receptor encephalitis will be discussed in this review.

  8. Spreading depression induces expression of calcium-independent protein kinase C subspecies in ischaemia-sensitive cortical layers: regulation by N-methyl-D-aspartate receptors and glucocorticoids.

    Science.gov (United States)

    Koponen, S; Keinänen, R; Roivainen, R; Hirvonen, T; Närhi, M; Chan, P H; Koistinaho, J

    1999-01-01

    Spreading depression is a wave of sustained depolarization challenging the energy metabolism of the cells without causing irreversible damage. In the ischaemic brain, sreading depression-like depolarization contributes to the evolution of ischaemia to infarction. The depolarization is propagated by activation of N-methyl-D-aspartate receptors, but changes in signal transduction downstream of the receptors are not known. Because protein phosphorylation is a general mechanism whereby most cellular processes are regulated, and inhibition of N-methyl-D-aspartate receptors or protein kinase C is neuroprotective, the expression of protein kinase C subspecies in spreading depression was examined. Cortical treatment with KCl induced an upregulation of protein kinase Cdelta and zeta messenger RNA at 4 and 8 h, whereas protein kinase Calpha, beta, gamma and epsilon did not show significant changes. The gene induction was the strongest in layers 2 and 3, and was followed by an increased number of protein kinase Cdelta-immunoreactive neurons. Protein kinase Cdelta and zeta inductions were inhibited by pretreatment with an N-methyl-D-aspartate receptor antagonist, dizocilpine maleate, which also blocked spreading depression propagation, and with dexamethasone, which acted without blocking the propagation. Quinacrine, a phospholipase A2 inhibitor, reduced only protein kinase C5 induction. In addition, N(G)(-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, did not influence protein kinase Cdelta or zeta induction, whereas 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptor antagonist, and the cyclo-oxygenase inhibitors indomethacin and diclophenac tended to increase gene expression. The data show that cortical spreading depression induces Ca2(+)-independent protein kinase C subspecies delta and zeta, but not Ca(2+)-dependent subspecies, through activation of N-methyl-D-aspartate receptors and

  9. Src, a Molecular Switch Governing Gain Control of Synaptic Transmission Mediated by N-methyl-D-Aspartate Receptors

    Science.gov (United States)

    Yu, Xian-Min; Salter, Michael W.

    1999-07-01

    The N-methyl-D-aspartate (NMDA) receptor is a principal subtype of glutamate receptor mediating fast excitatory transmission at synapses in the dorsal horn of the spinal cord and other regions of the central nervous system. NMDA receptors are crucial for the lasting enhancement of synaptic transmission that occurs both physiologically and in pathological conditions such as chronic pain. Over the past several years, evidence has accumulated indicating that the activity of NMDA receptors is regulated by the protein tyrosine kinase, Src. Recently it has been discovered that, by means of up-regulating NMDA receptor function, activation of Src mediates the induction of the lasting enhancement of excitatory transmission known as long-term potentiation in the CA1 region of the hippocampus. Also, Src has been found to amplify the up-regulation of NMDA receptor function that is produced by raising the intracellular concentration of sodium. Sodium concentration increases in neuronal dendrites during high levels of firing activity, which is precisely when Src becomes activated. Therefore, we propose that the boost in NMDA receptor function produced by the coincidence of activating Src and raising intracellular sodium may be important in physiological and pathophysiological enhancement of excitatory transmission in the dorsal horn of the spinal cord and elsewhere in the central nervous system.

  10. N-methyl-D-aspartate receptor blockade inhibits estrogenic support of dendritic growth in a sexually dimorphic rat spinal nucleus.

    Science.gov (United States)

    Hebbeler, Sara Louise; Verhovshek, Tom; Sengelaub, Dale Robert

    2002-09-16

    The lumbar spinal cord of rats contains the sexually dimorphic, steroid-sensitive spinal nucleus of the bulbocavernosus (SNB). Dendritic development of SNB motoneurons requires the action of both androgens and estrogens. Estrogenic effects are limited to the initial growth of SNB dendrites through 4 weeks of age. During this postnatal period, dendritic growth in other spinal motoneurons is regulated by N-methyl-D-aspartate (NMDA) receptor activation. In this study, we tested whether NMDA receptor activation was involved in SNB dendritic growth and whether the estrogenic support of SNB dendritic growth was dependent on the activation of NMDA receptors. Motoneuron morphology was assessed in normal males, intact males treated daily with the NMDA receptor antagonist MK-801, castrated males treated with estradiol benzoate (EB), and castrated males treated with both EB and MK-801. SNB motoneurons were retrogradely labeled with cholera toxin-horseradish peroxidase at 4 weeks of age (when dendritic length is normally maximal) and reconstructed in three dimensions. Somal area and dendritic length of SNB motoneurons in MK-801-treated, intact males were below those of normal males. Dendritic growth was partially supported in EB-treated castrates, but this growth was blocked by MK-801 treatment. These results suggest that, as in other motoneurons, dendritic development in the SNB involves NMDA receptors and, furthermore, that the estrogen-sensitive component of SNB dendritic development requires their activation. Copyright 2002 Wiley-Liss, Inc.

  11. Role of hydrogen bonding in ligand interaction with the N-methyl-D-aspartate receptor ion channel

    Energy Technology Data Exchange (ETDEWEB)

    Leeson, P.D.; Carling, R.W.; James, K.; Smith, J.D.; Moore, K.W.; Wong, E.H.; Baker, R. (Merck Sharp Laboratory, Harlow, Essex (England))

    1990-05-01

    Displacement of (3H)MK-801 (dizocilpine, 1) binding to rat brain membranes has been used to evaluate the affinities of novel dibenzocycloalkenimines related to 1 for the ion channel binding site (also known as the phencyclidine or PCP receptor) on the N-methyl-D-aspartate (NMDA) subtype of excitory amino acid receptor. In common with many other agents having actions in the central nervous system, these compounds contain a hydrophobic aromatic moiety and a basic nitrogen atom. The conformational rigidity of these ligands provides a unique opportunity to evaluate the importance of specific geometrical properties that influence active-site recognition, in particular the role of the nitrogen atom in hydrogen-bonding interactions. The relative affinities (IC50s) of hydrocarbon-substituted analogues of 1 and ring homologated cyclooctenimines illustrate the importance of size-limited hydrophobic binding of both aryl rings and of the quaternary C-5 methyl group. Analysis of the binding of a series of the 10 available structurally rigid dibenzoazabicyclo(x.y.z)alkanes, by using molecular modeling techniques, uncovered a highly significant correlation between affinity and a proposed ligand-active site hydrogen bonding vector (r = 0.950, p less than 0.001). These results are used to generate a pharmacophore of the MK-801 recognition site/PCP receptor, which accounts for the binding of all of the known ligands.

  12. Posttranslational nitration of tyrosine residues modulates glutamate transmission and contributes to N-methyl-D-aspartate-mediated thermal hyperalgesia.

    Science.gov (United States)

    Muscoli, Carolina; Dagostino, Concetta; Ilari, Sara; Lauro, Filomena; Gliozzi, Micaela; Bardhi, Erlisa; Palma, Ernesto; Mollace, Vincenzo; Salvemini, Daniela

    2013-01-01

    Activation of the N-methyl-D-aspartate receptor (NMDAR) is fundamental in the development of hyperalgesia. Overactivation of this receptor releases superoxide and nitric oxide that, in turn, forms peroxynitrite (PN). All of these events have been linked to neurotoxicity. The receptors and enzymes involved in the handling of glutamate pathway--specifically NMDARs, glutamate transporter, and glutamine synthase (GS)--have key tyrosine residues which are targets of the nitration process causing subsequent function modification. Our results demonstrate that the thermal hyperalgesia induced by intrathecal administration of NMDA is associated with spinal nitration of GluN1 and GluN2B receptor subunits, GS, that normally convert glutamate into nontoxic glutamine, and glutamate transporter GLT1. Intrathecal injection of PN decomposition catalyst FeTM-4-PyP(5+) prevents nitration and overall inhibits NMDA-mediated thermal hyperalgesia. Our study supports the hypothesis that nitration of key proteins involved in the regulation of glutamate transmission is a crucial pathway used by PN to mediate the development and maintenance of NMDA-mediated thermal hyperalgesia. The broader implication of our findings reinforces the notion that free radicals may contribute to various forms of pain events and the importance of the development of new pharmacological tool that can modulate the glutamate transmission without blocking its actions directly.

  13. Protective effects of PF-4708671 against N-methyl-d-aspartic acid-induced retinal damage in rats.

    Science.gov (United States)

    Hayashi, Ikumi; Aoki, Yuto; Ushikubo, Hiroko; Asano, Daiki; Mori, Asami; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio

    2016-12-01

    We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-d-aspartic acid (NMDA)-induced retinal damage in rats. Rapamycin inhibits mTOR activity, thereby preventing the phosphorylation of ribosomal protein S6, which is a downstream target of S6 kinase. Therefore, we aimed to determine whether PF-4708671, an inhibitor of S6 kinase, protects against NMDA-induced retinal injury. Intravitreal injection of NMDA (200 nmol/eye) caused cell loss in the ganglion cell layer and neuroinflammatory responses, such as an increase in the number of CD45-positive leukocytes and Iba1-positive microglia. Surprisingly, simultaneous injection of PF-4708671 (50 nmol/eye) with NMDA significantly attenuated these responses without affecting phosphorylated S6 levels. These results suggest that PF-4708671 and rapamycin likely protect against NMDA-induced retinal damage via distinct pathways. The neuroprotective effect of PF-4708671 is unlikely to be associated with inhibition of the S6 kinase, even though PF-4708671 is reported to be a S6 kinase inhibitor.

  14. The antiallodynic action target of intrathecal gabapentin: Ca2+ channels, KATP channels or N-methyl-d-aspartic acid receptors?

    Science.gov (United States)

    Cheng, Jen-Kun; Chen, Chien-Chuan; Yang, Jia-Rung; Chiou, Lih-Chu

    2006-01-01

    Gabapentin is a novel analgesic whose mechanism of action is not known. We investigated in a postoperative pain model whether adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channels, N-methyl-d-aspartic acid (NMDA) receptors, and Ca2+ channels are involved in the antiallodynic effect of intrathecal gabapentin. Mechanical allodynia was induced by a paw incision in isoflurane-anesthetized rats. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before and after incision and after intrathecal drug administration. The antiallodynic effect of gabapentin (100 mug) was not affected by intrathecal pretreatment with antagonists of K(ATP) channels, NMDA receptors or gamma-aminobutyric acid (GABA)(A) receptors. K(ATP) channel openers and GABA(A) receptor agonist, per se, had little effect on the postincision allodynic response. The Ca2+ channel blocker of N-type (omega-conotoxin GVIA, 0.1-3 microg), but not of P/Q-type (omega-agatoxin IVA), L-type (verapamil, diltiazem or nimodipine), or T-type (mibefradil), attenuated the incision-induced allodynia, as did gabapentin. Both the antiallodynic effects of gabapentin and omega-conotoxin GVIA were attenuated by Bay K 8644, an L-type Ca2+ channel activator. These results provide correlative evidence to support the contention that N-type Ca2+ channels, but not K(ATP) channels or NMDA or GABA(A) receptors, might be involved in the antiallodynic effect of intrathecal gabapentin.

  15. Recovery from severe frontotemporal dysfunction at 3years after N-methyl-d-aspartic acid (NMDA) receptor antibody encephalitis.

    Science.gov (United States)

    Leypoldt, Frank; Gelderblom, Mathias; Schöttle, Daniel; Hoffmann, Sascha; Wandinger, Klaus-Peter

    2013-04-01

    Encephalitis associated with antibodies against N-methyl-d-aspartic acid (NMDA) receptor is characterized by severe memory deficits, decreased consciousness, epileptic seizures and movement disorders and occurs most commonly in young women. Recovery is mostly good but little is known about the disease course in patients whose treatment has been delayed severely. We present a 16-year-old girl with a 36-month follow-up. A single course of methylprednisolone attenuated some symptoms but severe and incapacitating frontotemporal syndrome remained. Second-line treatment with rituximab was initiated 12months after the onset of symptoms. A surprising recovery occurred 18months after treatment and 30months after onset. Recovery in NMDA receptor antibody-associated encephalitis can be severely delayed and does not have to be linear. Whether delayed therapy contributed to recovery in this patient cannot be answered with certainty. Spontaneous recovery independent of therapy is possible, as it has been observed previously as late as 3years after onset. Although serum antibodies disappeared with recovery in this patient, previous cases have shown serum antibodies to be unreliable markers of disease activity. Second-line treatment, especially with substances as well tolerated as rituximab, should at least be considered in NMDA receptor encephalitis with persistent neuropsychiatric syndromes after first-line therapy.

  16. Anti-N-methyl-D-aspartate receptor encephalitis presenting with acute psychosis in a preteenage girl: a case report

    Directory of Open Access Journals (Sweden)

    Maggina Paraskevi

    2012-07-01

    Full Text Available Abstract Introduction Anti-N-methyl-D-aspartate receptor (anti-NMDAR encephalitis is a rare, newly defined autoimmune clinical entity that presents with atypical clinical manifestations. Most patients with anti-N-methyl-D-aspartate receptor encephalitis develop a progressive illness from psychosis into a state of unresponsiveness, with catatonic features often associated with abnormal movements and autonomic instability. This is the first report of anti-N-methyl-D-aspartate receptor encephalitis in a Greek pediatric hospital. Case presentation An 11-year-old Greek girl presented with clinical manifestations of acute psychosis. The differential diagnosis included viral encephalitis. The presence of a tumor usually an ovarian teratoma, a common clinical finding in many patients, was excluded. Early diagnosis and prompt immunotherapy resulted in full recovery up to one year after the initial diagnosis. Conclusion Acute psychosis is a rare psychiatric presentation in children, diagnosed only after possible organic syndromes that mimic acute psychosis are excluded, including anti-N-methyl-D-aspartate receptor receptor encephalitis. Pediatricians, neurologists and psychiatrists should consider this rare clinical syndrome, in order to make an early diagnosis and instigate appropriate treatment to maximize neurological recovery.

  17. 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...

  18. Inhibition of Calpain Prevents N-Methyl-D-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction

    NARCIS (Netherlands)

    Nimmrich, Volker; Szabo, Robert; Nyakas, Csaba; Granic, Ivica; Reymann, Klaus G.; Schroeder, Ulrich H.; Gross, Gerhard; Schoemaker, Hans; Wicke, Karsten; Moeller, Achim; Luiten, Paul

    2008-01-01

    N-Methyl-D-aspartate( NMDA) receptor-mediated excitotoxicity is thought to underlie a variety of neurological disorders, and inhibition of either the NMDA receptor itself, or molecules of the intracellular cascade, may attenuate neurodegeneration in these diseases. Calpain, a calcium-dependent cyste

  19. 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...

  20. Neuroprotective Effect of Tauroursodeoxycholic Acid on N-Methyl-D-Aspartate-Induced Retinal Ganglion Cell Degeneration.

    Directory of Open Access Journals (Sweden)

    Violeta Gómez-Vicente

    Full Text Available Retinal ganglion cell degeneration underlies the pathophysiology of diseases affecting the retina and optic nerve. Several studies have previously evidenced the anti-apoptotic properties of the bile constituent, tauroursodeoxycholic acid, in diverse models of photoreceptor degeneration. The aim of this study was to investigate the effects of systemic administration of tauroursodeoxycholic acid on N-methyl-D-aspartate (NMDA-induced damage in the rat retina using a functional and morphological approach. Tauroursodeoxycholic acid was administered intraperitoneally before and after intravitreal injection of NMDA. Three days after insult, full-field electroretinograms showed reductions in the amplitudes of the positive and negative-scotopic threshold responses, scotopic a- and b-waves and oscillatory potentials. Quantitative morphological evaluation of whole-mount retinas demonstrated a reduction in the density of retinal ganglion cells. Systemic administration of tauroursodeoxycholic acid attenuated the functional impairment induced by NMDA, which correlated with a higher retinal ganglion cell density. Our findings sustain the efficacy of tauroursodeoxycholic acid administration in vivo, suggesting it would be a good candidate for the pharmacological treatment of degenerative diseases coursing with retinal ganglion cell loss.

  1. 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.

  2. Opioid antinociception, tolerance and dependence: interactions with the N-methyl-D-aspartate system in mice.

    Science.gov (United States)

    Dykstra, Linda A; Fischer, Bradford D; Balter, Rebecca E; Henry, Fredrick E; Schmidt, Karl T; Miller, Laurence L

    2011-09-01

    This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of μ-opioid agonists. A hot-plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced [knockdown (KD)] to approximately 10%, and in mice treated with the NMDA antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959). The μ opioid agonists, morphine, l-methadone and fentanyl, were approximately three-fold less potent in the NR1 KD mice than in wild-type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and the WT mice. Acute administration of the NMDA antagonist, LY235959, produced dose-dependent, leftward shifts in the morphine dose-effect curve in the WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD or the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in μ opioid tolerance.

  3. Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-d-Aspartate Receptor

    Directory of Open Access Journals (Sweden)

    Eric H. Chang

    2015-07-01

    Full Text Available Patients with systemic lupus erythematosus (SLE experience cognitive abnormalities in multiple domains including processing speed, executive function, and memory. Here we show that SLE patients carrying antibodies that bind DNA and the GluN2A and GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR, termed DNRAbs, displayed a selective impairment in spatial recall. Neural recordings in a mouse model of SLE, in which circulating DNRAbs penetrate the hippocampus, revealed that CA1 place cells exhibited a significant expansion in place field size. Structural analysis showed that hippocampal pyramidal cells had substantial reductions in their dendritic processes and spines. Strikingly, these abnormalities became evident at a time when DNRAbs were no longer detectable in the hippocampus. These results suggest that antibody-mediated neurocognitive impairments may be highly specific, and that spatial cognition may be particularly vulnerable to DNRAb-mediated structural and functional injury to hippocampal cells that evolves after the triggering insult is no longer present.

  4. N-methyl-D-aspartate receptor subunit changes after traumatic injury to the developing brain.

    Science.gov (United States)

    Giza, Christopher C; Maria, Naomi S Santa; Hovda, David A

    2006-06-01

    Traumatic brain injury (TBI) is a major cause of disability in the pediatric population and can result in abnormal development. Experimental studies conducted in animals have revealed impaired plasticity following developmental TBI, even in the absence of significant anatomical damage. The N-methyl-D-aspartate receptor (NMDAR) is clearly involved in both normal development and in the pathophysiology of TBI. Following lateral fluid percussion injury in postnatal day (PND) 19 rats, we tested the hypothesis that TBI sustained at an early age would result in impaired NMDAR expression. Using immunoblotting and reverse transcriptase-polymerase chain reaction (RT-PCR), protein and RNA levels of NMDAR subunits were measured in the cerebral cortex and hippocampus on post-injury days (PID) 1, 2, 4, and 7 (though the PID7 analysis was only for protein) and compared with age-matched shams. Significant effects of hemisphere (analysis of variance [ANOVA], pPID1, PID2, PID4, and PID7, respectively. Within the cortex, there was a significant effect of injury (ANOVA, pPID1. It is known that NR2A expression levels increase during normal development, and in response to environmental stimuli. Our data suggest that injury-induced reduction in the expression of NR2A is one likely mechanism for the impaired experience-dependent neuroplasticity seen following traumatic injury to the immature brain.

  5. N-methyl-D-aspartate receptor blockade is neuroprotective in experimental autoimmune optic neuritis.

    Science.gov (United States)

    Sühs, Kurt-Wolfram; Fairless, Richard; Williams, Sarah K; Heine, Katrin; Cavalié, Adolfo; Diem, Ricarda

    2014-06-01

    Optic neuritis is a common clinical manifestation of the chronic inflammatory CNS disease multiple sclerosis that can result in persistent visual impairment caused by degeneration of optic nerve axons and apoptosis of retinal ganglion cells (RGCs). Using a model of experimental autoimmune encephalomyelitis with optic neuritis (Brown Norway rats), we show that administration of the N-methyl-D-aspartate (NMDA) receptor antagonists memantine or MK801 results in RGC protection, axon protection, and reduced demyelination of optic nerves. Calcium imaging revealed that RGC responses to glutamate stimulation predominantly occurred via NMDA receptors and were inhibited by memantine in a dose-dependent manner. In contrast, oligodendrocytes were mainly responsive through the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor. This suggests that NMDA receptor blockade protected RGCs directly and that the protection was independent of effects on oligodendrocytes. Moreover, increased RGC survival was observed before the onset of optic nerve demyelination--when RGC degeneration had already started. These results indicate an important pathophysiologic role for NMDA receptor-mediated glutamate toxicity during the induction phase of this disease model and highlight a potential target for therapeutic neuroprotection in human optic neuritis.

  6. 电磁脉冲对大鼠脑海马N-甲基-D-天冬氨酸受体活性的影响%Effects of electromagnetic pulse on N-methyl-D-aspartate receptor activity in rat hippocampus

    Institute of Scientific and Technical Information of China (English)

    李玉红; 李锦; 苏瑞斌; 吴宁; 李子建; 王水明; 彭瑞云; 王德文

    2005-01-01

    离常数开始下降,照后3 h下降最显著(P<0.05),6 h渐有恢复,48 h恢复至正常水平;受照大鼠海马中N-甲基-D-天冬氨酸受体的最大结合量于照后3 h和6 h显著下降(P<0.05),24 h渐有恢复,照后48 h明显升高,超过正常组水平(P<0.05).结论:电磁脉冲照射导致大鼠海马组织中兴奋性氨基酸含量及谷氨酸/γ-氨基丁酸比值升高;同时N-甲基-D-天冬氨酸受体的亲和力升高及受体密度下降.提示实验动物认知障碍可能与兴奋性氨基酸的过度释放和N-甲基-D-天冬氨酸受体功能改变有关.%BACKGROUND: Electromagnetic pulse (EMP) is high-energy non-ionizing radiation covering a wide spectrum with strong capability of destruction of electronic devices and inducing injuries in biological organisms. In previous studies we found EMP could cause obvious reduction in the learning and memory ability of rats and affect the formation of long-term potentiation of rat hippocampus.OBJECTIVE: To observe the effect of EMP on the content of amino acid neurotransmitters and N-methyl-D-aspartate (NMDA) receptor activity in rat hippocampus.DESIGN: Randomized controlled experiment and analysis of variance.SETTING: Institute of Radiation Medicine, Academy of Military Medical SciencesMATERIALS: The experiment was conducted in the Institute of Radiation Medicine, Academy of Military Medical Sciences from January to March 2004. Totally 32 male Wistar rats were used and randomized into EMP group (n=26) and control group (n=6).METHODS: Rats in the EMP group were decapitated and the hippocampi were removed immediately 3, 6, 24 and 48 hours after EMP radiation (6×104 V/m, with pulse rise time of 20 ns, pulse width of 30 μs, frequency of 2.5 pulses/minute for 2 minutes). Glutamate contents were detected with high-performance liquid chromatograpy (HPLC). Radioactive ligand-receptor binding test was performed with glutamate as the ligand with 3H labeling. The rats in the control group were not given any treatment before

  7. Cholinergic modulation of non-N-methyl-D-aspartic acid glutamatergic transmission in the chick ventral lateral geniculate nucleus.

    Science.gov (United States)

    Guo, J-Z; Sorenson, E M; Chiappinelli, V A

    2010-03-17

    Neurotransmission between glutamatergic terminals of retinal ganglion cells and principal neurons of the ventral lateral geniculate nucleus (LGNv) was examined with patch clamp recordings in chick brain slices during electrical stimulation of the optic tract. Since muscarinic and nicotinic receptors are present in high densities in LGNv, the present study examined possible roles of both receptors in modulating retinogeniculate transmission. During whole-cell recordings from LGNv neurons, acetylcholine (ACh, 100 microM) caused an initial increase in amplitudes of optic tract-evoked non-N-methyl-D-aspartic acid (NMDA) glutamatergic postsynaptic currents (PSCs). This increase was unchanged when 1 microM atropine was present, indicating that this initial enhancement of PSCs was due entirely to activation of nicotinic receptors. However, during washout of ACh the amplitudes of evoked PSCs became significantly decreased by 40.4+/-5.0% for several minutes before recovering to their original amplitudes, an effect blocked by 1 microM atropine. Exogenously applied muscarine (10 microM) markedly depressed optic tract-evoked PSCs, and this decrease in amplitude was blocked by atropine. In a second set of experiments, we examined effects of releasing endogenous ACh prior to optic tract stimulation. This was accomplished by stimulation of the lateral portion of LGNv via a separate conditioning electrode. Following a brief train of low intensity conditioning stimuli, non-NMDA glutamatergic PSCs evoked by optic tract stimulation were potentiated. However, at higher conditioning stimulus intensities the PSCs were markedly decreased compared with control, and this decrease was partially blocked by atropine (1 microM). Neither ACh nor muscarine altered amplitudes of PSCs elicited by exogenously applied glutamate. Muscarine significantly reduced the frequency but not the amplitudes of miniature PSCs, consistent with a presynaptic location for muscarinic receptors mediating these

  8. Antagonist properties of Conus parius peptides on N-methyl-D-aspartate receptors and their effects on CREB signaling.

    Directory of Open Access Journals (Sweden)

    Shailaja Kunda

    Full Text Available Three members of a family of small neurotoxic peptides from the venom of Conus parius, conantokins (Con Pr1, Pr2, and Pr3, function as antagonists of N-methyl-D-aspartate receptors (NMDAR. We report structural characterizations of these synthetic peptides, and also demonstrate their antagonistic properties toward ion flow through NMDAR ion channels in primary neurons. ConPr1 and ConPr2 displayed moderate increases in α-helicity after addition of Mg(2+. Native apo-ConPr3 possessed an α-helical conformation, and the helicity increased only slightly on addition of Mg(2+. Additionally, these peptides diminished NMDA/Gly-mediated currents and intracellular Ca(2+ (iCa(2+ influx in mature rat primary hippocampal neurons. Electrophysiological data showed that these peptides displayed slower antagonistic properties toward the NMDAR than conantokins from other species of cone snails, e.g., ConT and ConG. Furthermore, to demonstrate selectivity of the C. parius-derived conantokins towards specific NMDAR subunits, cortical neurons from GluN2A(-/- and GluN2B(-/- mice were utilized. Robust inhibition of NMDAR-mediated stimulation in GluN2A(-/--derived mouse neurons, as compared to those isolated from GluN2B(-/--mouse brains, was observed, suggesting a greater selectivity of these antagonists towards the GluN2B subunit. These C. parius conantokins mildly inhibited NMDAR-induced phosphorylation of CREB at Ser(133, suggesting that the peptides modulated iCa(2+ entry and, thereby, activation of CREB, a transcription factor that is required for maintaining long-term synaptic activity. Our data mechanistically show that while these peptides effectively antagonize NMDAR-directed current and iCa(2+ influx, receptor-coupled CREB signaling is maintained. The consequence of sustained CREB signaling is improved neuronal plasticity and survival during neuropathologies.

  9. Antagonist properties of Conus parius peptides on N-methyl-D-aspartate receptors and their effects on CREB signaling.

    Science.gov (United States)

    Kunda, Shailaja; Cheriyan, John; Hur, Michael; Balsara, Rashna D; Castellino, Francis J

    2013-01-01

    Three members of a family of small neurotoxic peptides from the venom of Conus parius, conantokins (Con) Pr1, Pr2, and Pr3, function as antagonists of N-methyl-D-aspartate receptors (NMDAR). We report structural characterizations of these synthetic peptides, and also demonstrate their antagonistic properties toward ion flow through NMDAR ion channels in primary neurons. ConPr1 and ConPr2 displayed moderate increases in α-helicity after addition of Mg(2+). Native apo-ConPr3 possessed an α-helical conformation, and the helicity increased only slightly on addition of Mg(2+). Additionally, these peptides diminished NMDA/Gly-mediated currents and intracellular Ca(2+) (iCa(2+)) influx in mature rat primary hippocampal neurons. Electrophysiological data showed that these peptides displayed slower antagonistic properties toward the NMDAR than conantokins from other species of cone snails, e.g., ConT and ConG. Furthermore, to demonstrate selectivity of the C. parius-derived conantokins towards specific NMDAR subunits, cortical neurons from GluN2A(-/-) and GluN2B(-/-) mice were utilized. Robust inhibition of NMDAR-mediated stimulation in GluN2A(-/-)-derived mouse neurons, as compared to those isolated from GluN2B(-/-)-mouse brains, was observed, suggesting a greater selectivity of these antagonists towards the GluN2B subunit. These C. parius conantokins mildly inhibited NMDAR-induced phosphorylation of CREB at Ser(133), suggesting that the peptides modulated iCa(2+) entry and, thereby, activation of CREB, a transcription factor that is required for maintaining long-term synaptic activity. Our data mechanistically show that while these peptides effectively antagonize NMDAR-directed current and iCa(2+) influx, receptor-coupled CREB signaling is maintained. The consequence of sustained CREB signaling is improved neuronal plasticity and survival during neuropathologies.

  10. Potentiation of N-methyl-D-aspartate-induced currents by the nootropic drug nefiracetam in rat cortical neurons.

    Science.gov (United States)

    Moriguchi, Shigeki; Marszalec, William; Zhao, Xilong; Yeh, Jay Z; Narahashi, Toshio

    2003-10-01

    Nefiracetam is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and post-stroke vascular-type dementia. In the brain of Alzheimer's disease patients, down-regulation of both cholinergic and glutamatergic systems has been found and is thought to play an important role in impairment of cognition, learning and memory. We have previously shown that the activity of neuronal nicotinic acetylcholine receptors is potently augmented by nefiracetam. The present study was undertaken to elucidate the mechanism of action of nefiracetam on glutamatergic receptors. Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell patch-clamp technique at a holding potential of -70 mV in Mg2+-free solutions. N-Methyl-D-aspartate (NMDA)-evoked currents were greatly and reversibly potentiated by bath application of nefiracetam resulting in a bell-shaped dose-response curve. The minimum effective nefiracetam concentration was 1 nM, and the maximum potentiation to 170% of the control was produced at 10 nM. Nefiracetam potentiation occurred at high NMDA concentrations that evoked the saturated response, and in a manner independent of NMDA concentrations ranging from 3 to 1,000 microM. Glycine at 3 microM potentiated NMDA currents but this effect was attenuated with an increasing concentration of nefiracetam from 1 to 10,000 nM. 7-Chlorokynurenic acid at 1 microM prevented nefiracetam from potentiating NMDA currents. Nefiracetam at 10 nM shifted the dose-response relationship for the 7-chlorokynurenic acid inhibition of NMDA currents in the direction of higher concentrations. Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid- and kainate-induced currents were not significantly affected by application of 10 nM nefiracetam. It was concluded that nefiracetam potentiated NMDA currents through interactions with the glycine binding site of the NMDA receptor.

  11. N-methyl-D-aspartate receptor channel blockers prevent pentylenetetrazole-induced convulsions and morphological changes in rat brain neurons.

    Science.gov (United States)

    Zaitsev, Aleksey V; Kim, Kira Kh; Vasilev, Dmitry S; Lukomskaya, Nera Ya; Lavrentyeva, Valeria V; Tumanova, Natalia L; Zhuravin, Igor A; Magazanik, Lev G

    2015-03-01

    Alterations in inhibitory and excitatory neurotransmission play a central role in the etiology of epilepsy, with overstimulation of glutamate receptors influencing epileptic activity and corresponding neuronal damage. N-methyl-D-aspartate (NMDA) receptors, which belong to a class of ionotropic glutamate receptors, play a primary role in this process. This study compared the anticonvulsant properties of two NMDA receptor channel blockers, memantine and 1-phenylcyclohexylamine (IEM-1921), in a pentylenetetrazole (PTZ) model of seizures in rats and investigated their potencies in preventing PTZ-induced morphological changes in the brain. The anticonvulsant properties of IEM-1921 (5 mg/kg) were more pronounced than those of memantine at the same dose. IEM-1921 and memantine decreased the duration of convulsions by 82% and 37%, respectively. Both compounds were relatively effective at preventing the tonic component of seizures but not myoclonic seizures. Memantine significantly reduced the lethality caused by PTZ-induced seizures from 42% to 11%, and all animals pretreated with IEM-1921 survived. Morphological examination of the rat brain 24 hr after administration of PTZ revealed alterations in the morphology of 20-25% of neurons in the neocortex and the hippocampus, potentially induced by excessive glutamate. The expression of the excitatory amino acid transporter 1 protein was increased in the hippocampus of the PTZ-treated rats. However, dark neurons did not express caspase-3 and were immunopositive for the neuronal nuclear antigen protein, indicating that these neurons were alive. Both NMDA antagonists prevented neuronal abnormalities in the brain. These results suggest that NMDA receptor channel blockers might be considered possible neuroprotective agents for prolonged seizures or status epilepticus leading to neuronal damage.

  12. Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update

    Directory of Open Access Journals (Sweden)

    C. Chaves

    2009-11-01

    Full Text Available Growing consistent evidence indicates that hypofunction of N-methyl-D-aspartate (NMDA transmission plays a pivotal role in the neuropathophysiology of schizophrenia. Hence, drugs which modulate NMDA neurotransmission are promising approaches to the treatment of schizophrenia. The aim of this article is to review clinical trials with novel compounds acting on the NMDA receptor (NMDA-R. This review also includes a discussion and translation of neuroscience into schizophrenia therapeutics. Although the precise mechanism of action of minocycline in the brain remains unclear, there is evidence that it blocks the neurotoxicity of NMDA antagonists and may exert a differential effect on NMDA signaling pathways. We, therefore, hypothesize that the effects of minocycline on the brain may be partially modulated by the NMDA-R or related mechanisms. Thus, we have included a review of minocycline neuroscience. The search was performed in the PubMed, Web of Science, SciELO, and Lilacs databases. The results of glycine and D-cycloserine trials were conflicting regarding effectiveness on the negative and cognitive symptoms of schizophrenia. D-serine and D-alanine showed a potential effect on negative symptoms and on cognitive deficits. Sarcosine data indicated a considerable improvement as adjunctive therapy. Finally, minocycline add-on treatment appears to be effective on a broad range of psychopathology in patients with schizophrenia. The differential modulation of NMDA-R neurosystems, in particular synaptic versus extrasynaptic NMDA-R activation and specific subtypes of NMDA-R, may be the key mediators of neurogenesis and neuroprotection. Thus, psychotropics modulating NMDA-R neurotransmission may represent future monotherapy or add-on treatment strategies in the treatment of schizophrenia.

  13. N-methyl-D-aspartate increases acetylcholine release from rat striatum and cortex: its effect is augmented by choline

    Science.gov (United States)

    Ulus, I. H.; Buyukuysal, R. L.; Wurtman, R. J.

    1992-01-01

    We examined the effects of N-methyl-D-aspartate (NMDA), a glutamate agonist, and of glutamate itself, on acetylcholine (ACh) release from superfused rat striatal slices. In a Mg(++)-free medium, NMDA (32-1000 microM) as well as glutamate (1 mM) increased basal ACh release by 35 to 100% (all indicated differences, P less than .05), without altering tissue ACh or choline contents. This augmentation was blocked by Mg++ (1.2 mM) or by MK-801 (10 microM). Electrical stimulation (15 Hz, 75 mA) increased ACh release 9-fold (from 400 to 3660 pmol/mg of protein): this was enhanced (to 4850 pmol/mg of protein) by NMDA (100 microM). ACh levels in stimulated slices fell by 50 or 65% depending on the absence or presence of NMDA. The addition of choline (40 microM) increased ACh release both basally (570 pmol/mg of protein) and with electrical stimulation (6900 pmol/mg of protein). In stimulated slices choline acted synergistically with NMDA, raising ACh release to 10,520 pmol/mg of protein. The presence of choline also blocked the fall in tissue ACh. No treatment affected tissue phospholipid or protein levels. NMDA (32-320 microM) also augmented basal ACh release from cortical but not hippocampal slices. Choline efflux from striatal and cortical (but not hippocampal) slices decreased by 34 to 50% in Mg(++)-free medium. These data indicate that NMDA-like drugs may be useful, particularly in combination with choline, to enhance striatal and cortical cholinergic activity. ACh release from rat hippocampus apparently is not affected by NMDA receptors.

  14. 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

  15. A case of non-paraneoplastic anti-N-methyl d-aspartate receptor encephalitis presenting as a neuropsychiatric disorder

    Directory of Open Access Journals (Sweden)

    Bindu Yoga

    2014-11-01

    Full Text Available N-methyl d-aspartate receptor antibody encephalitis can often be a paraneoplastic manifestation of occult malignancy such as ovarian teratoma and rarely teratoma of mediastinum or testis and small cell lung carcinoma. We report a case of non-paraneoplastic anti-N-methyl d-aspartate receptor antibody–positive autoimmune encephalitis in a young patient who presented with neuropsychiatric features and made a very good recovery following treatment with intravenous immunoglobulin and steroids. The case highlights the need for increased vigilance for the condition in young females with or without a previous psychiatric history and emphasises the need for a multidisciplinary approach in the management of this challenging disorder with a good prognosis.

  16. A case of non-paraneoplastic anti-N-methyl d-aspartate receptor encephalitis presenting as a neuropsychiatric disorder.

    Science.gov (United States)

    Yoga, Bindu; Kunc, Marek; Ahmed, Fayyaz

    2014-01-01

    N-methyl d-aspartate receptor antibody encephalitis can often be a paraneoplastic manifestation of occult malignancy such as ovarian teratoma and rarely teratoma of mediastinum or testis and small cell lung carcinoma. We report a case of non-paraneoplastic anti-N-methyl d-aspartate receptor antibody-positive autoimmune encephalitis in a young patient who presented with neuropsychiatric features and made a very good recovery following treatment with intravenous immunoglobulin and steroids. The case highlights the need for increased vigilance for the condition in young females with or without a previous psychiatric history and emphasises the need for a multidisciplinary approach in the management of this challenging disorder with a good prognosis.

  17. Phosphorylation Regulates Removal of Synaptic N-Methyl-d-Aspartate Receptors after Withdrawal from Chronic Ethanol Exposure

    OpenAIRE

    Clapp, Peter; Gibson, Emily S.; Dell'Acqua, Mark L.; Hoffman, Paula L.

    2010-01-01

    Alterations in N-methyl-d-aspartate receptor (NMDAR) protein levels or subcellular localization in brain after chronic ethanol exposure may contribute to withdrawal-associated seizures and neurotoxicity. We have investigated synaptic localization of NMDARs in cultured hippocampal pyramidal neurons after prolonged (7 days) exposure to, and acute withdrawal from, 80 mM ethanol using fluorescence immunocytochemistry techniques. After chronic ethanol exposure, there was a significant increase in ...

  18. N-methyl-d-aspartate-evoked release of [{sup 3}H]acetylcholine in striatal compartments of the rat: regulatory roles of dopamine and GABA

    Energy Technology Data Exchange (ETDEWEB)

    Glowinski, J.; Perez, S.; Desban, M.; Gauchy, C.; Kemel, M.L.; Blanchet, F. [Chaire de Neuropharmacologie, INSERM U114, College de France, 11 place Marcelin Berthelot, 75231 Paris (France)

    1997-08-26

    The N-methyl-d-aspartate-evoked release of [{sup 3}H]acetylcholine previously formed from [{sup 3}H]choline was estimated in striosome- (identified by [{sup 3}H]naloxone binding) or matrix-enriched areas of the rat striatum using an in vitro microsuperfusion procedure. Experiments were performed in either the absence or the presence of dopaminergic and/or GABAergic receptor antagonists. Although the cell bodies of the cholinergic interneurons were mainly found in the matrix, in the absence of magnesium, N-methyl-d-aspartate (50 {mu}M) stimulated the release of [{sup 3}H]acetylcholine in both striatal compartments. These responses were blocked by either magnesium, dizocilpine maleate, 7-chlorokynurenate or tetrodotoxin. N-Methyl-d-aspartate responses were concentration-dependent, but the 1 mM N-methyl-d-aspartate response was higher in striosomes than in the matrix. The co-application of d-serine (10 {mu}M) enhanced the 10 {mu}M N-methyl-d-aspartate response in both compartments, but reduced those induced by 1 mM N-methyl-d-aspartate, this reduction being higher in striosomes. The blockade of dopaminergic transmission with the D{sub 2} and D{sub 1} dopaminergic receptor antagonists, (-)-sulpiride (1 {mu}M) and SCH23390 (1 {mu}M), was without effect on the 50 {mu}M N-methyl-d-aspartate-evoked release of [{sup 3}H]acetylcholine, but markedly enhanced the 1 mM N-methyl-d-aspartate + d-serine-evoked response in striosomes and to a lesser extent in the matrix. Disinhibitory responses of similar amplitude were observed not only in striosomes but also in the matrix when (-)-sulpiride was used alone, while SCH23390 alone enhanced the 1 mM N-methyl-d-aspartate + d-serine response only in striosomes and to a lower extent than (-)-sulpiride. These results indicate that D{sub 2} receptors are mainly involved in the inhibitory effect of dopamine on the 1 mM N-methyl-d-aspartate + d-serine-evoked release of [{sup 3}H]acetylcholine. They also show that the stimulation of D{sub 1

  19. Investigation of antidepressant-like and anxiolytic-like actions and cognitive and motor side effects of four N-methyl-D-aspartate receptor antagonists in mice

    DEFF Research Database (Denmark)

    Refsgaard, Louise Konradsen; Pickering, Darryl S; Andreasen T., Jesper

    2017-01-01

    antagonists. MK-801, ketamine, S-ketamine, RO 25-6981 and the positive control, citalopram, were tested for antidepressant-like and anxiolytic-like effects in mice using the forced-swim test, the elevated zero maze and the novelty-induced hypophagia test. Side effects were assessed using a locomotor activity...... test, the modified Y-maze and the rotarod test. All compounds increased swim distance in the forced-swim test. In the elevated zero maze, the GluN2B subtype-selective RO 25-6981 affected none of the measured parameters, whereas all other compounds showed anxiolytic-like effects. In the novelty......Evidence suggests that N-methyl-D-aspartate receptor (NMDAR) antagonists could be efficacious in treating depression and anxiety, but side effects constitute a challenge. This study evaluated the antidepressant-like and anxiolytic-like actions, and cognitive and motor side effects of four NMDAR...

  20. Investigation of antidepressant-like and anxiolytic-like actions and cognitive and motor side effects of four N-methyl-D-aspartate receptor antagonists in mice

    DEFF Research Database (Denmark)

    Refsgaard, Louise Konradsen; Pickering, Darryl S; Andreasen T., Jesper

    2017-01-01

    Evidence suggests that N-methyl-D-aspartate receptor (NMDAR) antagonists could be efficacious in treating depression and anxiety, but side effects constitute a challenge. This study evaluated the antidepressant-like and anxiolytic-like actions, and cognitive and motor side effects of four NMDAR...... antagonists. MK-801, ketamine, S-ketamine, RO 25-6981 and the positive control, citalopram, were tested for antidepressant-like and anxiolytic-like effects in mice using the forced-swim test, the elevated zero maze and the novelty-induced hypophagia test. Side effects were assessed using a locomotor activity...... test, the modified Y-maze and the rotarod test. All compounds increased swim distance in the forced-swim test. In the elevated zero maze, the GluN2B subtype-selective RO 25-6981 affected none of the measured parameters, whereas all other compounds showed anxiolytic-like effects. In the novelty...

  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. PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-d-aspartate receptor subunit NR2A

    OpenAIRE

    1999-01-01

    Fyn, a member of the Src-family protein-tyrosine kinase (PTK), is implicated in learning and memory that involves N-methyl-d-aspartate (NMDA) receptor function. In this study, we examined how Fyn participates in synaptic plasticity by analyzing the physical and functional interaction between Fyn and NMDA receptors. Results showed that tyrosine phosphorylation of NR2A, one of the NMDA receptor subunits, was reduced in fyn-mutant mice. NR2A was tyrosine-phosphorylated in 293T cells when coexpre...

  3. Psychotic symptoms in anti-N-methyl-d-aspartate (NMDA) receptor encephalitis: A case report and challenges.

    Science.gov (United States)

    Sharma, Pawan; Sagar, Rajesh; Patra, Bichitrananda; Saini, Lokesh; Gulati, Sheffali; Chakrabarty, Biswaroop

    2016-08-01

    Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, only recently first described, is an increasingly well-recognized inflammatory encephalitis that is seen in children and adults. An 11-year old girl admitted to the psychiatry ward with a presentation of acute psychosis was diagnosed with NMDA receptor encephalitis following neurology referral and was treated accordingly. This case highlights psychiatric manifestations in encephalitis and the need for the psychiatrist to have high index of suspicion when atypical symptoms (e.g., dyskinesia, seizure, fever etc.) present in acutely psychotic patients.

  4. 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.)

  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...... of the receptor. In the brain, the distribution of NMDAR subunits depends on the region and developmental stage. Here, we report the circadian expression of the NMDAR1 subunit in the adult rat SCN and depict its splice variants that may constitute the functional receptor channel in the SCN. During ontogenesis...

  6. 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......-CAM contents indicated that NMDA rescued primarily nerve cells. The influence of NMDA in promoting cell survival was blocked by the receptor antagonist, 2-amino-5-phosphonovalerate. The effect depended both on the concentration of NMDA and on the degree of depolarization of cells, the affinity in the presence...... of 15 mM K+ being similar to that of NMDA receptor binding. The results attest a new role for excitatory amino acid transmitters by showing that they can exert a stage-dependent trophic action on developing nerve cells....

  7. Binding of spermine and ifenprodil to a purified, soluble regulatory domain of the N-methyl-d-aspartate receptor

    OpenAIRE

    Han, Xia; Tomitori, Hideyuki; Mizuno, Satomi; Higashi, Kyohei; Füll, Christine; Fukiwake, Tomohide; Terui, Yusuke; Leewanich, Pathama; Nishimura, Kazuhiro; Toida, Toshihiko; Williams, Keith; Kashiwagi, Keiko; Igarashi, Kazuei

    2008-01-01

    The binding of spermine and ifenprodil to the amino terminal regulatory (R) domain of the N-methyl-d-aspartate receptor was studied using purified regulatory domains of the NR1, NR2A and NR2B subunits, termed NR1-R, NR2A-R and NR2B-R. The R domains were overexpressed in Escherichia coli and purified to near homogeneity. The Kd values for binding of [14C]spermine to NR1-R, NR2A-R and NR2B-R were 19, 140 and 33 µM, respectively. [3H]Ifenprodil bound to NR1-R (Kd, 0.18 µM) and NR2B-R (Kd, 0.21 µ...

  8. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis mimicking a primary psychiatric disorder in an adolescent.

    Science.gov (United States)

    Lebon, Sébastien; Mayor-Dubois, Claire; Popea, Irina; Poloni, Claudia; Selvadoray, Nalini; Gumy, Alain; Roulet-Perez, Eliane

    2012-12-01

    Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis likely has a wider clinical spectrum than previously recognized. This article reports a previously healthy 16-year-old girl who was diagnosed with anti-NMDA receptor encephalitis 3 months after onset of severe depression with psychotic features. She had no neurological manifestations, and cerebral magnetic resonance imaging (MRI) was normal. Slow background on electroencephalogram and an oligoclonal band in the cerebrospinal fluid prompted the search for anti-NMDA receptor antibodies. She markedly improved over time but remained with mild neuropsychological sequelae after a trial of late immunotherapy. Only a high index of suspicion enables recognition of the milder forms of the disease masquerading as primary psychiatric disorders.

  9. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: an unusual cause of autistic regression in a toddler.

    Science.gov (United States)

    Scott, Ori; Richer, Lawrence; Forbes, Karen; Sonnenberg, Lyn; Currie, Angela; Eliyashevska, Myroslava; Goez, Helly R

    2014-05-01

    Anti N-methyl-d-aspartate (NMDA) receptor encephalitis in children is associated with psychiatric changes, seizures, and dyskinesias. We present the first report of autistic regression in a toddler caused by this entity. A 33-month-old boy presented with decreased appetite, irritability, and insomnia following an upper respiratory tract infection. Over the next few weeks he lost language and social skills, and abnormal movements of his hand developed. Within a month, this patient came to fit the diagnostic criteria for autistic spectrum disorder. Upon investigation, anti-NMDA receptor antibodies were found in the boy's cerebrospinal fluid. He was treated with intravenous immunoglobulins and steroids, resulting in reacquisition of language and social skills and resolution of movements. Our case emphasizes the significance of suspecting anti-NMDA receptor encephalitis as the cause of autistic regression, even in an age group where the diagnosis of autistic spectrum disorder is typically made, and especially when presentation follows a febrile illness.

  10. Subcellular distribution of N-methyl-D-aspartic acid receptor subunit 1 in neural stem cells within subventricular zone of adult rats

    Institute of Scientific and Technical Information of China (English)

    Zhining Li; Wenlong Lü; Hongyan Dong; Hongbin Fan; Ruiguo Dong; Tiejun Xu

    2011-01-01

    The subcellular localization of N-methyl-D-aspartic acid receptor subunit 1 in neural stem cells of the subventricular zone of adult rats was detected using electron microscopy, following immunohistochemistry and immunogold-silver double staining. Results confirmed the presence of neural stem cells in the subventricular zone, which is a key neurogenic region in the central nervous system of adult mammals. The expression of N-methyl-D-aspartic acid receptor subunit 1 was higher than that of nestin and mainly distributed in the cell membrane, cytoplasm, rough endoplasmic reticulum and Golgi complex of neural stem cells.

  11. 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.

  12. N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro.

    Science.gov (United States)

    Yavas, Ersin; Young, Andrew M J

    2017-02-15

    The N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine, induces behavioral changes in rodents mimicking symptoms of schizophrenia, possibly mediated through dysregulation of glutamatergic control of mesolimbic dopamine release. We tested the hypothesis that NMDA receptor activation modulates accumbens dopamine release, and that phencyclidine pretreatment altered this modulation. NMDA caused a receptor-specific, dose-dependent decrease in electrically stimulated dopamine release in nucleus accumbens brain slices. This decrease was unaffected by picrotoxin, making it unlikely to be mediated through GABAergic neurones, but was decreased by the metabotropic glutamate receptor antagonist, (RS)-α-methyl-4-sulfonophenylglycine, indicating that NMDA activates mechanisms controlled by these receptors to decrease stimulated dopamine release. The effect of NMDA was unchanged by in vivo pretreatment with phencyclidine (twice daily for 5 days), with a washout period of at least 7 days before experimentation, which supports the hypothesis that there is no enduring direct effect of PCP at NMDA receptors after this pretreatment procedure. We propose that NMDA depression of accumbal dopamine release is mediated by metabotropic glutamate receptors located pre- or perisynaptically, and suggest that NMDA evoked increased extrasynaptic spillover of glutamate is sufficient to activate these receptors that, in turn, inhibit dopamine release. Furthermore, we suggest that enduring functional changes brought about by subchronic phencyclidine pretreatment, modeling deficits in schizophrenia, are downstream effects consequent on chronic blockade of NMDA receptors, rather than direct effects on NMDA receptors themselves.

  13. Centrally mediated ejaculatory response via sympathetic outflow in rats: role of N-methyl-D-aspartic acid receptors in paraventricular nucleus.

    Science.gov (United States)

    Xia, J-D; Chen, J; Sun, H-J; Zhou, L-H; Zhu, G-Q; Chen, Y; Dai, Y-T

    2017-01-01

    Ejaculation is mediated by a spinal generator, which integrates inputs related to the sexual activity and coordinates sympathetic, parasympathetic, and motor outflow. Previous clinical studies indicate that primary premature ejaculation is related to the hyperactivity of the sympathetic nervous system. In this study, we explored the roles of N-methyl-D-aspartic acid (NMDA) receptors in paraventricular nucleus of the hypothalamus (PVN) on ejaculatory responses and its potential mechanism in the rats. We found that microinjection of 0.20 nmol NMDA into the PVN reduced the latency of intromission and facilitated ejaculation during copulation. Moreover, delayed ejaculation and intromission were observed after the rats were microinjected with NMDA receptor antagonist D (-)-2-Amino-5-phosphonopentanoic acid (AP-5). However, we discovered that microinjection of NMDA into PVN significantly increased baseline lumbar splanchnic nerve activity (LSNA), and the NMDA dose was positively correlated with the increased LSNA (r = 0.875, p = 0.04). Meanwhile, the plasma norepinephrine level in rats injected with NMDA was much higher than that in rats injected with saline (1453.4 ± 136.4 pg/mL vs. 492.3 ± 36.8 pg/mL, p ejaculation through enhancing the activity of sympathetic system.

  14. Ketamine-Induced Apoptosis in Normal Human Urothelial Cells: A Direct, N-Methyl-d-Aspartate Receptor-Independent Pathway Characterized by Mitochondrial Stress.

    Science.gov (United States)

    Baker, Simon C; Shabir, Saqib; Georgopoulos, Nikolaos T; Southgate, Jennifer

    2016-05-01

    Recreational abuse of ketamine has been associated with the emergence of a new bladder pain syndrome, ketamine-induced cystitis, characterized by chronic inflammation and urothelial ulceration. We investigated the direct effects of ketamine on normal human urothelium maintained in organ culture or as finite cell lines in vitro. Exposure of urothelium to ketamine resulted in apoptosis, with cytochrome c release from mitochondria and significant subsequent caspase 9 and 3/7 activation. The anesthetic mode-of-action for ketamine is mediated primarily through N-methyl d-aspartate receptor (NMDAR) antagonism; however, normal (nonimmortalized) human urothelial cells were unresponsive to NMDAR agonists or antagonists, and no expression of NMDAR transcript was detected. Exposure to noncytotoxic concentrations of ketamine (≤1 mmol/L) induced rapid release of ATP, which activated purinergic P2Y receptors and stimulated the inositol trisphosphate receptor to provoke transient release of calcium from the endoplasmic reticulum into the cytosol. Ketamine concentrations >1 mmol/L were cytotoxic and provoked a larger-amplitude increase in cytosolic Ca(2+) concentration that was unresolved. The sustained elevation in cytosolic Ca(2+) concentration was associated with pathological mitochondrial oxygen consumption and ATP deficiency. Damage to the urinary barrier initiates bladder pain and, in ketamine-induced cystitis, loss of urothelium from large areas of the bladder wall is a reported feature. This study offers first evidence for a mechanism of direct toxicity of ketamine to urothelial cells by activating the intrinsic apoptotic pathway.

  15. Characterization of l-Theanine Excitatory Actions on Hippocampal Neurons: Toward the Generation of Novel N-Methyl-d-aspartate Receptor Modulators Based on Its Backbone.

    Science.gov (United States)

    Sebih, Fatiha; Rousset, Matthieu; Bellahouel, Salima; Rolland, Marc; de Jesus Ferreira, Marie Celeste; Guiramand, Janique; Cohen-Solal, Catherine; Barbanel, Gérard; Cens, Thierry; Abouazza, Mohammed; Tassou, Adrien; Gratuze, Maud; Meusnier, Céline; Charnet, Pierre; Vignes, Michel; Rolland, Valérie

    2017-08-16

    l-Theanine (or l-γ-N-ethyl-glutamine) is the major amino acid found in Camellia sinensis. It has received much attention because of its pleiotropic physiological and pharmacological activities leading to health benefits in humans, especially. We describe here a new, easy, efficient, and environmentally friendly chemical synthesis of l-theanine and l-γ-N-propyl-Gln and their corresponding d-isomers. l-Theanine, and its derivatives obtained so far, exhibited partial coagonistic action at N-methyl-d-aspartate (NMDA) receptors, with no detectable agonist effect at other glutamate receptors, on cultured hippocampal neurons. This activity was retained on NMDA receptors expressed in Xenopus oocytes. In addition, both GluN2A and GluN2B containing NMDA receptors were equally modulated by l-theanine. The stereochemical change from l-theanine to d-theanine along with the substitution of the ethyl for a propyl moiety in the γ-N position of l- and d-theanine significantly enhanced the biological efficacy, as measured on cultured hippocampal neurons. l-Theanine structure thus represents an interesting backbone to develop novel NMDA receptor modulators.

  16. N-methyl-D-aspartate receptor expression in the spinal dorsal horn of a rat model of formalin-induced inflammatory pain following intrathecal injection of butorphanol

    Institute of Scientific and Technical Information of China (English)

    Yichun Wang; Yuan Zhang; Qulian Guo; Xiaohong Liu; Mingde Wang; Hui Luo

    2010-01-01

    Clinical and animal experiments have proved that intrathecal injection of butorphanol has an analgesic effect. However, whether the analgesic effect is associated with activation of the N-methyl-D-aspartate (NMDA) receptor remains unclear. This study presumed that intrathecal injection of butorphanol has an analgesic effect on formalin-induced inflammatory pain in rats, and its analgesic effect is associated with inhibition of NMDA receptors. Concurrently, ketamine was injected into the intrathecal space, which is a non-competitive NMDA receptor antagonist, to determine the analgesic mechanism of butorphanol. The total reflection time in phase 1 and phase 2 of rat hind paws carding action was reduced when the butorphanol dose was increased to 25 μg,or a low dose of butorphanol was combined with ketamine. Intrathecal injection of a high dose of butorphanol alone or a Iow dose of butorphanol combined with ketamine can remarkably reduce NMDA receptor expression in the L5 spinal dorsal horn of formalin-induced pain rats. The results suggest that intrathecal injection of butorphanol has analgesic effects on formalin-induced inflammatory pain, and remarkably reduces NMDA receptor expression in the rat spinal dorsal horn.Ketamine strengthens this analgesic effect. The analgesic mechanism of intrathecal injection of butorphanol is associated with inhibition of NMDA receptor activation.

  17. A serotonin-1A receptor agonist and an N-methyl-D-aspartate receptor antagonist oppose each others effects in a genetic rat epilepsy model.

    Science.gov (United States)

    Filakovszky, J; Gerber, K; Bagdy, G

    1999-02-12

    The WAG/RIJ rats exhibit spontaneously occurring spike-wave discharges (SWD) accompanied by behavioural phenomena, with characteristics similar to the human absence type epilepsy. To study the mechanisms involved in this type of epileptiform activity we investigated the effects of the serotonin-1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801). Intracerebroventricular (i.c.v.) injection of 8-OH-DPAT caused marked, dose dependent increase, MK-801 a decrease in the cumulative duration and number of spike-wave discharges. Pretreatment with MK-801 (10 microg/rat i.c.v.) abolished the increase caused by 8-OH-DPAT (20 microg/rat i.c.v.), but the decrease in SWD to MK-801 was counterbalanced by 8-OH-DPAT. These data provide evidence for an interaction of glutamatergic and serotonergic mechanisms in the triggering and maintenance of epileptic activity in this genetic model of absence epilepsy.

  18. Red blood cells of sickle cell disease patients exhibit abnormally high abundance of N-methyl D-aspartate receptors mediating excessive calcium uptake.

    Science.gov (United States)

    Hänggi, Pascal; Makhro, Asya; Gassmann, Max; Schmugge, Markus; Goede, Jeroen S; Speer, Oliver; Bogdanova, Anna

    2014-10-01

    Recently we showed that N-methyl D-aspartate receptors (NMDARs) are expressed in erythroid precursors (EPCs) and present in the circulating red blood cells (RBCs) of healthy humans, regulating intracellular Ca(2+) in these cells. This study focuses on investigating the possible role of NMDARs in abnormally high Ca(2+) permeability in the RBCs of patients with sickle cell disease (SCD). Protein levels of the NMDAR subunits in the EPCs of SCD patients did not differ from those in EPCs of healthy humans. However, the number and activity of the NMDARs in circulating SCD-RBCs was substantially up-regulated, being particularly high during haemolytic crises. The number of active NMDARs correlated negatively with haematocrit and haemoglobin levels in the blood of SCD patients. Calcium uptake via these non-selective cation channels was induced by RBC treatment with glycine, glutamate and homocysteine and was facilitated by de-oxygenation of SCD-RBCs. Oxidative stress and RBC dehydration followed receptor stimulation and Ca(2+) uptake. Inhibition of the NMDARs with an antagonist memantine caused re-hydration and largely prevented hypoxia-induced sickling. The EPCs of SCD patients showed higher tolerance to memantine than those of healthy subjects. Consequently, NMDARs in the RBCs of SCD patients appear to be an attractive target for pharmacological intervention.

  19. N-methyl-D-aspartate receptor inhibition by an apolipoprotein E-derived peptide relies on low-density lipoprotein receptor-associated protein.

    Science.gov (United States)

    Sheng, Zhenyu; Prorok, Mary; Brown, Brigid E; Castellino, Francis J

    2008-08-01

    The effects of a synthetic apoE peptide, viz., residues 133-149 (apoE[133-149]), a mimetic that comprises the apoE receptor binding domain, on N-methyl-D-aspartate (NMDA)/glycine-induced ion flow through NMDA receptor (NMDAR) channels, have been investigated. The activity of apoE[133-149] was found to depend on the low-density lipoprotein receptor-related protein (LRP). Competition experiments with receptor-associated protein (RAP) and activated alpha(2)-macroglobulin (alpha(2)M*), two proteins that compete for apoE binding to LRP, demonstrate that apoE[133-149] inhibition of NMDAR function is mediated at a locus in LRP that overlaps with the binding sites of RAP and alpha(2)M*. A coreceptor of LRP, cell surface heparin sulfate proteoglycan, did not function in this system. Additional electrophysiology experiments demonstrated that the inhibitory potency of apoE[133-149] was threefold greater for NMDAR-transfected wild-type Chinese hamster ovary (CHO) cells compared with NMDAR-transfected CHO cells deficient in LRP. Studies with truncation and replacement variants of the apoE peptide demonstrated that the NMDAR inhibitory properties of these peptides correlate with their binding affinities for LRP. These novel results indicate that apoE functions as an inhibitor of NMDAR ion channels indirectly via LRP, and are suggestive of a participatory role for LRP in NMDAR-based neuropathies.

  20. The Neuroprotective Effect of Cannabinoid Receptor Agonist (WIN55,212-2 in Paraoxon Induced Neurotoxicity in PC12 Cells and N-methyl-D-aspartate Receptor Interaction

    Directory of Open Access Journals (Sweden)

    Hedayat Sahraei

    2010-01-01

    Full Text Available Objective: Considering that cannabinoids protect neurons against neurodegeneration, inthis study, the neuroprotective effect of WIN55,212-2 in paraoxon induced neurotoxicity inPC12 cells and the role of the N-methyl-D-aspartate (NMDA receptor were evaluated.Materials and Methods: In this study PC12 cells were maintained in Dulbecco's modifiedeagle’s medium (DMEM+F12 culture medium supplemented with 10% fetal bovineserum. The cells were treated with paraoxon (200 μM in the presence or absence ofWIN55,212-2 (0.1 μM, NMDA receptor agonist NMDA (100 μM, cannabinoid receptorantagonist AM251 and NMDA receptor antagonist MK801 (1 μM at 15 minutes intervals.After 48 hours of exposure, cellular viability and protein expression of the CB1 receptorwere evaluated in PC12 cells.Results: Following the exposure of PC12 cells to paraoxon (200 μM, a reduction in cellsurvival and protein level of the CB1 receptor was observed (p<0.01. Treatment of thecells with WIN55,212-2 (0.1 μM and NMDA (100 μM prior to paraoxon exposure significantlyelevated cell survival and protein level of the CB1 receptor (p<0.01. Also, AM251(1μM did not inhibit the cell survival and protein level of the CB1 receptor increase inducedby WIN55,212-2 (p<0.001. However, MK801 (1 μM did inhibit cell survival andprotein expression of the CB1 receptor increase induced by NMDA (p<0.001.Conclusion: The results indicate that WIN55,212-2 and NMDA protect PC12 cellsagainst paraoxon induced toxicity. In addition, the neuroprotective effect of WIN55,212-2and NMDA was cannabinoid receptor-independent and NMDA receptor dependent, respectively.

  1. Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia.

    Science.gov (United States)

    Buchan, A; Pulsinelli, W A

    1990-01-01

    Several laboratories have reported a significant reduction of ischemia-induced injury to hippocampal neurons in rodents treated with competitive and noncompetitive N-methyl-D-aspartate (NMDA) receptor-channel antagonists. This study examined the effects of the noncompetitive antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) in Mongolian gerbils subjected to 5 min of bilateral carotid artery occlusion. In adult female gerbils, single doses of MK-801 injected 1 hr prior to ischemia significantly (p less than 0.01) reduced damage to CA1 hippocampal neurons. However, the drug rendered the postischemic animals comatose and hypothermic for several hours compared with the saline-treated animals. In subsequent experiments, animals pretreated with MK-801 and maintained normothermic during and after forebrain ischemia demonstrated no amelioration of hippocampal damage. Gerbils not treated with MK-801, but kept hypothermic in the postischemic period to approximately the same degree (34.5 degrees C) and duration (8 hr) as was induced by MK-801 therapy showed significant (p less than 0.01) protection of CA1 neurons against ischemia. The neuroprotective activity of MK-801 against transient global ischemia appears to be largely a consequence of postischemic hypothermia rather than a direct action on NMDA receptor-channels.

  2. Selective antinociceptive effects of a combination of the N-methyl-D-aspartate receptor peptide antagonist [Ser1]histogranin and morphine in rat models of pain

    Science.gov (United States)

    Hama, Aldric; Sagen, Jacqueline

    2014-01-01

    Numerous rather than a few analgesic endogenous neuropeptides are likely to work in concert in vivo in ameliorating pain. Identification of effective neuropeptide combinations would also facilitate the development of gene or cell-based analgesics. In this study, opioid peptides endomorphin-1 (EM-1) and endomorphin-2 (EM-2) and the peptide histogranin analogue [Ser1]histogranin (SHG), which possess activity as an N-methyl-d-aspartate (NMDA) receptor antagonist, were intrathecally (i.t.) injected alone and in combination in rat models of acute and persistent pain. None of the peptides when injected alone altered hind paw responses of uninjured rats to acute noxious stimulation. EM-1 and EM-2 showed divergent efficacies in the persistent pain models. For example, EM-1 injected alone was antinociceptive in rats with neuropathic pain, whereas EM-2 demonstrated no efficacy. Demonstration of synergism was also divergent across the models. For example, while SHG combined with EM-1 did not alter the efficacy of EM-1 in rats with neuropathic pain, SHG significantly increased the efficacy of EM-1 in the formalin test. By contrast, the potency and efficacy of the peptides alone and combinations were much less than those of the reference analgesic morphine. Furthermore, morphine combined with the clinically used NMDA receptor antagonist ketamine showed synergism across a broad range of pain states. While the current set of neuropeptides could serve as a basis for analgesic therapeutics, there could be other neuropeptides with greater efficacy and potency and broader therapeutic application. PMID:25505581

  3. N-methyl-D-aspartic acid receptor 1 (NMDAR1) aggravates secondary inflammatory damage induced by hemin-NLRP3 pathway after intracerebral hemorrhage

    Institute of Scientific and Technical Information of China (English)

    Xun Weng; Yan Tan; Xiang Chu; Xiao-Feng Wu; Rui Liu; Yue Tian; Lin Li

    2015-01-01

    Objective:Inflammation plays a critical role in secondary brain damage after intracerebral hemorrhage (ICH).However,the mechanisms of inflammatory injury following ICH are still unclear,particularly the involvement of NLRP3 inflammasome,which are crucial to sterile inflammatory responses.In this study,we aim to test the hypothesis that NLRP3 signaling pathway takes a vital position in ICH-induced secondary inflammatory damage and detect the role of N-methyl-D-aspartic acid receptor 1 (NMDAR1) in this progress.Methods:ICH was induced in mice by microinjection of hemin into the striatum.The protein levels of NMDAR1,NMDAR1 phosphorylation,NLRP3 and IL-1β were measured by Western blot.The binding of NMDAR1 to NLRP3 was detected by immunoprecipitation.Results:The expression of NMDAR1,NMDAR1 phosphorylation,NLRP3 and IL-1 β were rapidly increased after ICH.Hemin treatment enhanced NMDAR1 expression and NMDAR1 phosphorylation,as well in cultured microglial cells treated by hemin.Hemin up-regulated NLRP3 and IL-1β level,which was reversed by MK801 (NMDAR antagonist) in vitro.Hemin also promoted the binding of NMDAR1 to NLRP3.Conclusion:Our findings suggest that NMDAR1 plays a pivotal role in hemin-induced NLRP3-mediated inflammatory damage through synergistic activation.

  4. The calmodulin-dependent protein kinase II inhibitor KN-93 protects rat cerebral cortical neurons from N-methyl-D-aspartic acid-induced injury

    Institute of Scientific and Technical Information of China (English)

    Xuewen Liu; Cui Ma; Ruixian Xing; Weiwei Zhang; Buxian Tian; Xidong Li; Qiushi Li; Yanhui Zhang

    2013-01-01

    In this study, primary cultured cerebral cortical neurons of Sprague-Dawley neonatal rats were treated with 0.25, 0.5, and 1.0 μM calmodulin-dependent protein kinase II inhibitor KN-93 after 50 μM N-methyl-D-aspartic acid-induced injury. Results showed that, compared with N-methyl-Daspartic acid-induced injury neurons, the activity of cells markedly increased, apoptosis was significantly reduced, leakage of lactate dehydrogenase decreased, and intracellular Ca2+ concentrations in neurons reduced after KN-93 treatment. The expression of caspase-3, phosphorylated calmodulin-dependent protein kinase II and total calmodulin-dependent protein kinase II protein decreased after KN-93 treatment. And the effect was apparent at a dose of 1.0 μM KN-93. Experimental findings suggest that KN-93 can induce a dose-dependent neuroprotective effect, and that the underlying mechanism may be related to the down-regulation of caspase-3 and calmodulin- dependent protein kinase II expression.

  5. Mechanisms of Alzheimer’s Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors

    Science.gov (United States)

    Kocahan, Sayad; Doğan, Zumrut

    2017-01-01

    The characteristic features of Alzheimer’s disease (AD) are the appearance of extracellular amyloid-beta (Aβ) plaques and neurofibrillary tangles in the intracellular environment, neuronal death and the loss of synapses, all of which contribute to cognitive decline in a progressive manner. A number of hypotheses have been advanced to explain AD. Abnormal tau phosphorylation may contribute to the formation of abnormal neurofibrillary structures. Many different structures are susceptible to AD, including the reticular formation, the nuclei in the brain stem (e.g., raphe nucleus), thalamus, hypothalamus, locus ceruleus, amygdala, substantia nigra, striatum, and claustrum. Excitotoxicity results from continuous, low-level activation of N-methyl-D-aspartate (NMDA) receptors. Premature synaptotoxicity, changes in neurotransmitter expression, neurophils loss, accumulation of amyloid β-protein deposits (amyloid/senile plaques), and neuronal loss and brain atrophy are all associated with stages of AD progression. Several recent studies have examined the relationship between Aβ and NMDA receptors. Aβ-induced spine loss is associated with a decrease in glutamate receptors and is dependent upon the calcium-dependent phosphatase calcineurin, which has also been linked to long-term depression. PMID:28138104

  6. 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...

  7. N-Methyl-D-Aspartate Receptor Antagonist MK-801 and Radical Scavengers Protect Cholinergic Nucleus Basalis Neurons against β-Amyloid Neurotoxicity

    NARCIS (Netherlands)

    Harkany, T.; Mulder, J.; Sasvári, M.; Ábrahám, I.; Kónya, C.; Zarándi, M.; Penke, B.; Luiten, P.G.M.; Nyakas, C.

    1999-01-01

    Previous experimental data indicate the involvement of Ca2+-related excitotoxic processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in β-amyloid (βA) neurotoxicity. On the other hand, other lines of evidence support the view that free radical generation is a critical step in the β

  8. N-methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect cholinergic nucleus basalis neurons against beta-amyloid neurotoxicity

    NARCIS (Netherlands)

    Harkany, T; Mulder, J; Sasvari, M; Abraham, [No Value; Konya, C; Zarandi, M; Penke, B; Luiten, PGM; Nyakas, C

    1999-01-01

    Previous experimental data indicate the involvement of Ca2+-related excitotoxic processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in beta-amyloid (beta A) neurotoxicity. On the other hand, other lines of evidence support the view that free radical generation is a critical step i

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

    Institute of Scientific and Technical Information of China (English)

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

    2012-01-01

    Status epilepticus was induced via intraperitoneal injection of lithium-pilocarpine. The inhibitory ef-fects of propofol on status epilepticus in rats were judged based on observation of behavior, elec-troencephalography and 24-hour survival rate. Propofol (12.5-100 mg/kg) improved status epilep-ticus 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 in-creased 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 down-regulation of N-methyl-D-aspartate receptor 2B subunit expression after seizures.

  10. Temporal Memory and Its Enhancement by Estradiol Requires Surface Dynamics of Hippocampal CA1 N-Methyl-D-Aspartate Receptors.

    Science.gov (United States)

    Potier, Mylène; Georges, François; Brayda-Bruno, Laurent; Ladépêche, Laurent; Lamothe, Valérie; Al Abed, Alice Shaam; Groc, Laurent; Marighetto, Aline

    2016-05-01

    Identifying the underlying cellular mechanisms of episodic memory is an important challenge, since this memory, based on temporal and contextual associations among events, undergoes preferential degradation in aging and various neuropsychiatric disorders. Memory storage of temporal and contextual associations is known to rely on hippocampal N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity, which depends ex vivo on dynamic organization of surface NMDARs. Whether NMDAR surface trafficking sustains the formation of associative memory, however, remains unknown. We tested this hypothesis, using single nanoparticle imaging, electrophysiology, and behavioral approaches, in hippocampal networks challenged with a potent modulator of NMDAR-dependent synaptic plasticity and memory, 17β-estradiol (E2). We demonstrate that E2 modulates NMDAR surface trafficking, a necessary condition for E2-induced potentiation at hippocampal cornu ammonis 1 synapses. Strikingly, cornu ammonis 1 NMDAR surface trafficking controls basal and E2-enhanced mnemonic retention of temporal, but not contextual, associations. NMDAR surface trafficking and its modulation by the sex hormone E2 is a cellular mechanism critical for a major component of episodic memory, opening a new and noncanonical research avenue in the physiopathology of cognition. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  11. 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.

  12. N-methyl-D-aspartate receptor subtype 3A promotes apoptosis in developing mouse brain exposed to hyperoxia

    Institute of Scientific and Technical Information of China (English)

    Jimei Li; Shanping Yu; Zhongyang Lu; Osama Mohamad; Ling Wei

    2012-01-01

    In the present study, 7 day postnatal C57/BL6 wild-type mice (hyperoxia group) and 7 day postnatal N-methyl-D-aspartate receptor subtype 3A knockout mice (NR3A KO group) were exposed to 75% oxygen and 15% nitrogen in a closed container for 5 days. Wild-type mice raised in normoxia served as controls. TdT-mediated dUTP nick end labeling (TUNEL)/neuron-specific nuclear protein (NeuN) and 5-bromo-2'-deoxyuridine (BrdU)/NeuN immunofluorescence staining showed that the number of apoptotic cells and the number of proliferative cells in the dentate subgranular zone significantly increased in the hyperoxia group compared with the control group. However, in the same hyperoxia environment, the number of apoptotic cells and the number of proliferative cells significantly decreased in the NR3A KO group compared with hyperoxia group. TUNEL+/NeuN+ and BrdU+/NeuN+ cells were observed in the NR3A KO and the hyperoxia groups. These results demonstrated that the NR3A gene can promote cell apoptosis and mediate the potential damage in the developing brain induced by exposure to non-physiologically high concentrations of oxygen.

  13. Cysteinyl leukotriene receptor 1 is involved in /N-methyl-D-aspartate-mediated neuronal injury in mice

    Institute of Scientific and Technical Information of China (English)

    Qian DING; Er-qing WEI; Yan-jun ZHANG; Wei-ping ZHANG; Zhong CHEN

    2006-01-01

    Aim: To determine whether cysteinyl leukotriene receptor 1 (CysLT1 receptor) is involved in N-methyl-D-aspartate (NMDA)-induced excitotoxic injury in the mouse brain. Methods: Brain injury was induced by NMDA microinjection (50-150 nmol in 0.5 μL) into the cerebral cortex. The changes in CysLT1 receptor expression 24 h after NMDA injection and the effects of a CysLT1 receptor antagonist, pranlukast (0.01 and 0.1 mg/kg), an NMDA receptor antagonist, ketamine (30 mg/kg), and an antioxidant, edaravone (9 mg/kg) were observed. Results: In the NMDA-injured brain, the CysLT1 receptor mRNA, and protein expression were upregulated, and the receptor was mainly localized in the neurons and not in the astrocytes. Pranlukast, ketamine and edaravone decreased NMDA-induced injury;pranlukast (0.1 mg/kg) and ketamine inhibited the upregulated expression of the CysLT1 receptor. Conclusion: CysLT1 receptor expression in neurons is upregulated after NMDA injection, and NMDA-induced responses are inhibited by CysLT1 receptor antagonists, indicating that the increased CysLT1 receptor is involved in NMDA excitotoxicity.

  14. Pediatric anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: experience of a tertiary care teaching center from north India.

    Science.gov (United States)

    Chakrabarty, Biswaroop; Tripathi, Manjari; Gulati, Sheffali; Yoganathan, Sangeetha; Pandit, Awadh Kishore; Sinha, Aditi; Rathi, Bhim Singh

    2014-11-01

    Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is characterized by acute- or subacute-onset encephalopathy with extrapyramidal, psychiatric, and epileptic manifestations. Diagnosis is confirmed by positive antibodies to NMDA receptor in cerebrospinal fluid and serum. Eleven pediatric cases presented over a 2-year period at a tertiary care teaching hospital in North India. The average age at presentation was 9 years (range: 2.5 to 18 years, median: 10 years) with a slight female predominance (1.2:1). The common modes of presentation were progressive extrapyramidal syndrome with global neuroregression in 45% (5 of 11), epileptiform encephalopathy in 27% (3 of 11), and an overlap between the 2 in 27% (3 of 11). Fifty-eight percent showed significant response to steroids and intravenous immunoglobulin. This entity should be considered in an acute- or subacute-onset encephalopathy if common infectious etiologies are ruled out and there are specific clinical pointers. Early diagnosis and treatment significantly improves the outcome.

  15. [Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: experience with six pediatric patients. Potential efficacy of methotrexate].

    Science.gov (United States)

    Bravo-Oro, Antonio; Abud-Mendoza, Carlos; Quezada-Corona, Arturo; Dalmau, Josep; Campos-Guevara, Verónica

    2013-11-01

    INTRODUCTION. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a condition that is increasingly more frequently diagnosed in the paediatric age. Unlike adults, in many cases it is not associated to tumours and the most common initial manifestations in children are seizures and movement disorders, while in adults there is a predominance of psychiatric alterations. CASE REPORTS. We present six confirmed paediatric cases with antibodies against the subunit NR1 of the NMDA receptor in serum and cerebrospinal fluid. Five of the cases began with seizures as the initial clinical symptom prior to the development of the classical clinical features of this condition. In all cases, steroids were used as the first line of treatment, although these only brought about control over the manifestations in one of them; the other patients therefore required second-line immunomodulators. All the patients received methotrexate as immunomodulator treatment to prevent relapses, and in all cases there was an improvement in the patients' situation. CONCLUSIONS. In our series of patients with anti-NMDA receptor encephalitis, none were associated with tumours. All of them were given methotrexate for at least one year and no adverse clinical or analytical events were observed; likewise, there were no neurological sequelae or relapses during treatment. Although it is a small series and it would be advisable to increase the number and time to progression, we see methotrexate as an excellent alternative immunomodulator treatment for this pathology.

  16. 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.

  17. Availability of N-Methyl-d-Aspartate Receptor Coagonists Affects Cocaine-Induced Conditioned Place Preference and Locomotor Sensitization: Implications for Comorbid Schizophrenia and Substance Abuse.

    Science.gov (United States)

    Puhl, Matthew D; Berg, Alexandra R; Bechtholt, Anita J; Coyle, Joseph T

    2015-06-01

    Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-d-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists d-serine and glycine. Glycine transporter 1 knockdowns (GlyT1(+/-)) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR(-/-)) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1(+/-) mice displayed hastened extinction of CPP and robust cocaine-induced reinstatement. SR(-/-) mice appeared to immediately "forget" the learned preference, because they did not exhibit cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1(+/-) mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR(-/-) mice with d-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of cocaine abuse.

  18. Dopamine D1-dependent trafficking of striatal N-methyl-D-aspartate glutamate receptors requires Fyn protein tyrosine kinase but not DARPP-32.

    Science.gov (United States)

    Dunah, Anthone W; Sirianni, Ana C; Fienberg, Allen A; Bastia, Elena; Schwarzschild, Michael A; Standaert, David G

    2004-01-01

    Interactions between dopaminergic and glutamatergic systems in the striatum are thought to underlie both the symptoms and adverse effects of treatment of Parkinson's disease. We have previously reported that activation of the dopamine D1 receptor triggers a rapid redistribution of striatal N-methyl-d-aspartate (NMDA) receptors between intracellular and postsynaptic sub-cellular compartments. To unravel the signaling pathways underlying this trafficking, we studied mice with targeted disruptions of either the gene that encodes the dopamine- and cAMP-regulated phosphoprotein (DARPP-32), a potent and selective inhibitor of protein phosphatase-1, or the protein tyrosine kinase Fyn. In striatal tissue from DARPP-32-depleted mice, basal tyrosine and serine phosphorylation of striatal NMDA receptor subunits NR1, NR2A, and NR2B was normal, and activation of dopamine D1 receptors with the agonist SKF-82958 [(+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-benzazepine] produced redistribution of NMDA receptors from vesicular compartments (P3 and LP2) to synaptosomal membranes (LP1). In the Fyn knockout mice, basal tyrosine phosphorylation of NR2A and NR2B was drastically reduced, whereas serine phosphorylation of these NMDA subunits was unchanged. In the Fyn knockout mice, the dopamine D1 receptor agonist failed to induce subcellular redistribution of NMDA receptors. In addition, Fyn-depleted mice lesioned with 6-hydroxydopamine also failed to exhibit l-DOPA-induced behavioral sensitization, but this may be caused, at least in part, by resistance of these mice to the neurotoxic lesion. These findings suggest a novel mechanism for the trafficking of striatal NMDA receptors by signaling pathways that are independent of DARPP-32 but require Fyn protein tyrosine kinase. Strategies that prevent NMDA receptor subcellular redistribution through inhibition of Fyn kinase may prove useful in the treatment of Parkinson's disease.

  19. NR2B phosphorylation at tyrosine 1472 in spinal dorsal horn contributed to N-methyl-D-aspartate-induced pain hypersensitivity in mice.

    Science.gov (United States)

    Li, Shuai; Cao, Jing; Yang, Xian; Suo, Zhan-Wei; Shi, Lei; Liu, Yan-Ni; Yang, Hong-Bin; Hu, Xiao-Dong

    2011-11-01

    Calcium influx via N-methyl-D-aspartate (NMDA)-subtype glutamate receptors (NMDARs) regulates the intracellular trafficking of NMDARs, leading to long-lasting modification of NMDAR-mediated synaptic transmission that is involved in development, learning, and synaptic plasticity. The present study investigated the contribution of such NMDAR-dependent synaptic trafficking in spinal dorsal horn to the induction of pain hypersensitivity. Our data showed that direct activation of NMDARs by intrathecal NMDA application elicited pronounced mechanical allodynia in intact mice, which was concurrent with a specific increase in the abundance of NMDAR subunits NR1 and NR2B at the postsynaptic density (PSD)-enriched fraction. Selective inhibition of NR2B-containing NMDARs (NR2BR) by ifenprodil dose dependently attenuated the mechanical allodynia in NMDA-injected mice, suggesting the importance of NR2BR synaptic accumulation in NMDA-induced pain sensitization. The NR2BR redistribution at synapses after NMDA challenge was associated with a significant increase in NR2B phosphorylation at Tyr1472, a catalytic site by Src family protein tyrosine kinases (SFKs) that has been shown to prevent NR2B endocytosis. Intrathecal injection of a specific SFKs inhibitor, PP2, to block NR2B tyrosine phosphorylation eliminated NMDA-induced NR2BR synaptic expression and also attenuated the mechanical allodynia. These data suggested that activation of spinal NMDARs was able to accumulate NR2BR at synapses via SFK signaling, which might exaggerate NMDAR-dependent nociceptive transmission and contribute to NMDA-induced nociceptive behavioral hyperresponsiveness.

  20. Alpha7 Nicotinic Acetylcholine Receptors Play a Predominant Role in the Cholinergic Potentiation of N-Methyl-D-Aspartate Evoked Firing Responses of Hippocampal CA1 Pyramidal Cells

    Directory of Open Access Journals (Sweden)

    Zsolt K. Bali

    2017-09-01

    Full Text Available The aim of the present study was to identify in vivo electrophysiological correlates of the interaction between cholinergic and glutamatergic neurotransmission underlying memory. Extracellular spike recordings were performed in the hippocampal CA1 region of anesthetized rats in combination with local microiontophoretic administration of N-methyl-D-aspartate (NMDA and acetylcholine (ACh. Both NMDA and ACh increased the firing rate of the neurons. Furthermore, the simultaneous delivery of NMDA and ACh resulted in a more pronounced excitatory effect that was superadditive over the sum of the two mono-treatment effects and that was explained by cholinergic potentiation of glutamatergic neurotransmission. Next, animals were systemically treated with scopolamine or methyllycaconitine (MLA to assess the contribution of muscarinic ACh receptor (mAChR or α7 nicotinic ACh receptor (nAChR receptor-mediated mechanisms to the observed effects. Scopolamine totally inhibited ACh-evoked firing, and attenuated the firing rate increase evoked by simultaneous application of NMDA and ACh. However, the superadditive nature of the combined effect was preserved. The α7 nAChR antagonist MLA robustly decreased the firing response to simultaneous application of NMDA and ACh, suspending their superadditive effect, without modifying the tonic firing rate increasing effect of ACh. These results provide the first in vivo electrophysiological evidence that, in the hippocampal CA1 region, α7 nAChRs contribute to pyramidal cell activity mainly through potentiation of glutamatergic signaling, while the direct cholinergic modulation of tonic firing is notably mediated by mAChRs. Furthermore, the present findings also reveal cellular physiological correlates of the interplay between cholinergic and glutamatergic agents in behavioral pharmacological models of cognitive decline.

  1. Role of antioxidant enzymes in redox regulation of N-methyl-D-aspartate receptor function and memory in middle-aged rats.

    Science.gov (United States)

    Lee, Wei-Hua; Kumar, Ashok; Rani, Asha; Foster, Thomas C

    2014-06-01

    Overexpression of superoxide dismutase 1 (SOD1) in the hippocampus results in age-dependent impaired cognition and altered synaptic plasticity suggesting a possible model for examining the role of oxidative stress in senescent neurophysiology. However, it is unclear if SOD1 overexpression involves an altered redox environment and a decrease in N-methyl-D-aspartate receptor (NMDAR) synaptic function reported for aging animals. Viral vectors were used to express SOD1 and green fluorescent protein (SOD1 + GFP), SOD1 and catalase (SOD1 + CAT), or GFP alone in the hippocampus of middle-aged (17 months) male Fischer 344 rats. We confirm that SOD1 + GFP and SOD1 + CAT reduced lipid peroxidation indicating superoxide metabolites were primarily responsible for lipid peroxidation. SOD1 + GFP impaired learning, decreased glutathione peroxidase activity, decreased glutathione levels, decreased NMDAR-mediated synaptic responses, and impaired long-term potentiation. Co-expression of SOD1 + CAT rescued the effects of SOD1 expression on learning, redox measures, and synaptic function suggesting the effects were mediated by excess hydrogen peroxide. Application of the reducing agent dithiolthreitol to hippocampal slices increased the NMDAR-mediated component of the synaptic response in SOD1 + GFP animals relative to animals that overexpress SOD1 + CAT indicating that the effect of antioxidant enzyme expression on NMDAR function was because of a shift in the redox environment. The results suggest that overexpression of neuronal SOD1 and CAT in middle age may provide a model for examining the role of oxidative stress in senescent physiology and the progression of age-related neurodegenerative diseases.

  2. Modulation of glutamatergic transmission by presynaptic N-methyl-D-aspartate mechanisms in second-order neurons of the rat nucleus tractus solitarius.

    Science.gov (United States)

    Ohi, Yoshiaki; Kimura, Satoko; Haji, Akira

    2015-02-05

    The present study investigated the physiological function of presynaptic N-methyl-d aspartate (NMDA) mechanisms in glutamatergic transmission in the rat nucleus tractus solitarius (NTS). Membrane currents were recorded from the NTS second-order neurons by using whole-cell patch pipettes including MK-801 to block postsynaptic NMDA receptors. All experiments were performed under blockade of inhibitory synaptic transmission. Co-application of NMDA and d-serine decreased the tractus solitarius (TS)-evoked excitatory postsynaptic currents (eEPSCs) in 7/12 (58%) of neurons, and increased the paired pulse ratio. The remaining neurons were insensitive to NMDA and d-serine. Application of an NMDA antagonist D-AP5 had no effect on eEPSCs in all 8 neurons tested. Action potential-independent EPSCs (miniature EPSCs; mEPSCs) were recorded in the presence of tetrodotoxin. Co-application of NMDA and d-serine increased the mEPSC frequency but had no significant effect on the amplitude in 5/28 (18%) of neurons. D-AP5 decreased the mEPSC frequency without effect on the amplitude in 6/18 (33%) of neurons. This study demonstrated that (1) NMDA receptors were presynaptically distributed in a subset of NTS second-order neurons and that (2) the presynaptic NMDA receptors played an inhibitory role in TS-mediated release of glutamate and a facilitatory role in spontaneous release of glutamate. The present results suggest that the activation of presynaptic NMDA receptors modulates glutamatergic transmissions in the rat NTS second-order neurons.

  3. N-methyl-D-aspartate receptor-mediated glutamate transmission in nucleus accumbens plays a more important role than that in dorsal striatum in cognitive flexibility

    Directory of Open Access Journals (Sweden)

    Xuekun eDing

    2014-09-01

    Full Text Available Cognitive flexibility is a critical ability for adapting to an ever-changing environment in humans and animals. Deficits in cognitive flexibility are observed in most schizophrenia patients. Previous studies reported that the medial prefrontal cortex-to-ventral striatum and orbital frontal cortex-to-dorsal striatum circuits play important roles in extra- and intra-dimensional strategy switching, respectively. However, the precise function of striatal subregions in flexible behaviors is still unclear. N-methyl-D-aspartate receptors (NMDARs are major glutamate receptors in the striatum that receive glutamatergic projections from the frontal cortex. The membrane insertion of Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs depends on NMDAR activation and is required in learning and memory processes. In the present study, we measured set-shifting and reversal learning performance in operant chambers in rats and assessed the effects of blocking NMDARs and Ca2+-permeable AMPARs in striatal subregions on behavioral flexibility. The blockade of NMDARs in the nucleus accumbens (NAc core by AP5 impaired set-shifting ability by causing a failure to modify prior learning. The suppression of NMDAR-mediated transmission in the NAc shell induced a deficit in set-shifting by disrupting the learning and maintenance of novel strategies. During reversal learning, infusions of AP5 into the NAc shell and core impaired the ability to learn and maintain new strategies. However, behavioral flexibility was not significantly affected by blocking NMDARs in the dorsal striatum. We also found that the blockade of Ca2+-permeable AMPARs by NASPM in any subregion of the striatum did not affect strategy switching. These findings suggest that NMDAR-mediated glutamate transmission in the NAc contributes more to cognitive execution compared with the dorsal striatum.

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

    Science.gov (United States)

    Hansen, Kasper B; Mullasseril, Praseeda; Dawit, Sara; Kurtkaya, Natalie L; Yuan, Hongjie; Vance, Katie M; Orr, Anna G; Kvist, Trine; Ogden, Kevin K; Le, Phuong; Vellano, Kimberly M; Lewis, Iestyn; Kurtkaya, Serdar; Du, Yuhong; Qui, Min; Murphy, T J; Snyder, James P; Bräuner-Osborne, Hans; Traynelis, Stephen F

    2010-06-01

    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 concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism.

  5. Anticonvulsant effect of dextrometrophan on pentylenetetrazole-induced seizures in mice: Involvement of nitric oxide and N-methyl-d-aspartate receptors.

    Science.gov (United States)

    Mohseni, Gholamreza; Ostadhadi, Sattar; Akbarian, Reyhaneh; Chamanara, Mohsen; Norouzi-Javidan, Abbas; Dehpour, Ahmad-Reza

    2016-12-01

    Dextrometrophan (DM), widely used as an antitussive, has recently generated interest as an anticonvulsant drug. Some effects of dextrometrophan are associated with alterations in several pathways, such as inhibition of nitric oxide synthase (NOS) enzyme and N-methyl d-aspartate (NMDA) receptors. In this study, we aimed to investigate the anticonvulsant effect of acute administration of dextrometrophan on pentylenetetrazole (PTZ)-induced seizures and the probable involvement of the nitric oxide (NO) pathway and NMDA receptors in this effect. For this purpose, seizures were induced by intravenous PTZ infusion. All drugs were administrated by intraperitoneal (i.p.) route before PTZ injection. Our results demonstrate that acute DM treatment (10-100mg/kg) increased the seizure threshold. In addition, the nonselective NOS inhibitor L-NAME (10mg/kg) and the neural NOS inhibitor, 7-nitroindazole (40mg/kg), at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of DM (3mg/kg), while the inducible NOS inhibitor, aminoguanidine (100mg/kg), did not affect the anticonvulsant effect of DM. Moreover, the NOS substrate l-arginine (60mg/kg) blunted the anticonvulsant effect of DM (100mg/kg). Also, NMDA antagonists, ketamine (0.5mg/kg) and MK-801 (0.05mg/kg), augmented the anticonvulsant effect of DM (3mg/kg). In conclusion, we demonstrated that the anticonvulsant effect of DM is mediated by a decline in neural nitric oxide activity and inhibition of NMDA receptors. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. P2X7 receptor antagonists protect against N-methyl-D-aspartic acid-induced neuronal injury in the rat retina.

    Science.gov (United States)

    Sakamoto, Kenji; Endo, Kanako; Suzuki, Taishi; Fujimura, Kyosuke; Kurauchi, Yuki; Mori, Asami; Nakahara, Tsutomu; Ishii, Kunio

    2015-06-05

    Activation of N-methyl-d-aspartic acid (NMDA) receptors followed by a large Ca(2+) influx is thought to be a mechanism of glaucoma-induced neuronal cell death. It is possible that damage-associated molecular patterns leak from injured cells, such as adenosine triphosphate, causing retinal ganglion cell death in glaucoma. In the present study, we histologically investigated whether antagonists of the P2X7 receptor protected against NMDA-induced retinal injury in the rat in vivo. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal injection of NMDA. We used A438079 (3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine) and brilliant blue G as P2X7 receptor antagonists. Upon morphometric evaluation 7 days after an intravitreal injection (200 nmol/eye), NMDA-induced cell loss was apparent in the ganglion cell layer. Intravitreal A438079 (50 pmol/eye) simultaneously injected with NMDA and intraperitoneal brilliant blue G (50 mg/kg) administered just before the NMDA injection as well as 24 and 48h after significantly reduced cell loss. In addition, A438079 decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells 12h after NMDA injection. P2X7 receptors were immunolocalized in the ganglion cell layer and the inner and outer plexiform layers, whereas the immunopositive P2X7 receptor signal was not detected on the Iba1-positive microglial cells that infiltrated the retina 12h after NMDA injection. The present study shows that stimulation of the P2X7 receptor is involved in NMDA-induced histological damage in the rat retina in vivo. P2X7 receptor antagonists may be effective in preventing retinal diseases caused by glutamate excitotoxicity, such as glaucoma and retinal artery occlusion.

  7. (/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.

  8. Effects of memantine, an N-methyl-D-aspartate receptor antagonist, on fatigue and neuronal brain damage in a rat model of combined (physical and mental) fatigue.

    Science.gov (United States)

    Morimoto, Yasuo; Zhang, Qian; Adachi, Koji

    2012-01-01

    Most of the fatigue in everyday life is a combination of physical and mental fatigue. Recently, an animal model of combined fatigue was designed by housing rats in a cage filled with water. We have previously hypothesized that mental fatigue is caused partly by neuronal brain damage through the activation of N-methyl-D-aspartate (NMDA) receptors by quinolinic acid (QUIN), a metabolite of tryptophan (TRP). Therefore, we investigated whether the same mechanism also participates in combined fatigue. Rats were housed for 5 d under water-immersed conditions, and the extent of fatigue was evaluated by a weight-loaded forced swimming test. The swimming time of the water-immersed group was shorter than that of the control group, indicating that rats were fatigued by water-immersion. However, unexpectedly, the blood and brain levels of QUIN in the water-immersed group were lower than those of the control group. QUIN levels in both the blood and brains of a food-restricted nonimmersed group, where body weight was matched with the water-immersed group, were also decreased, suggesting that decreased QUIN in the water-immersed group originated from a reduced intake of TRP-containing food. On the other hand, hippocampal neuronal damage was shown in the water-immersed group, similar to that seen in other fatigue models where QUIN increased. Memantine, an NMDA receptor antagonist, inhibited not only the reduction in swimming times but also the neuronal damage induced by water-immersion. These results suggest that neuronal brain damage by an endogenous NMDA receptor agonist other than QUIN participates in combined fatigue by water immersion.

  9. 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

  10. Maturation of anoxia-induced gasping in the rat: potential role for N-methyl-D-aspartate glutamate receptors.

    Science.gov (United States)

    Gozal, D; Torres, J E

    1997-12-01

    After anoxia-induced apnea, gasping remains the last operative mechanism for survival. In developing rats, the gasping response to anoxia exhibits triphasic characteristics. Because anoxia is associated with enhanced release of glutamate, we hypothesized that N-methyl-D-aspartate (NMDA) glutamate receptors may underlie components of the gasping response. Rat pups aged 2 d (n = 50), 5 d (n = 43), 10 d (n = 42), and 15 d (n = 45) underwent anoxic challenges with 100% N2 in a whole body plethysmograph, 30 min after intraperitoneal administration of MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate; dizocilpine] (3 mg/kg), a noncompetitive NMDA glutamate receptor channel antagonist, or normal saline. In control pups, after primary apnea onset, a triphasic gasping pattern was apparent at all postnatal ages and included two distinct types of gasps (I and II). In 2- and 5-d MK801-treated animals, phase 1 and type I gasps were absent, leading to marked prolongations of the gasp latency and phase 2, the latter displaying type II gasps only. In addition, phase 3 duration was also prolonged with increased type II gasp frequencies. In contrast, in some 10-d-old (40%) and in all 15-d-old MK801-treated pups, although overall gasping duration was prolonged, the triphasic gasping pattern seen in matched controls was also present. We conclude that NMDA glutamate receptors mediate particular phasic components of the gasping response during early postnatal life but not at later stages of development. We speculate that developmental changes occur in both function and expression of NMDA and other neurotransmitters within brainstem regions underlying the neural substrate for gasp generation.

  11. N-methyl-d-aspartate receptor coagonist d-serine suppresses intake of high-preference food.

    Science.gov (United States)

    Sasaki, Tsutomu; Kinoshita, Yoshihiro; Matsui, Sho; Kakuta, Shigeru; Yokota-Hashimoto, Hiromi; Kinoshita, Kuni; Iwasaki, Yusaku; Kinoshita, Toshio; Yada, Toshihiko; Amano, Naoji; Kitamura, Tadahiro

    2015-09-01

    d-Serine is abundant in the forebrain and physiologically important for modulating excitatory glutamatergic neurotransmission as a coagonist of synaptic N-methyl-d-aspartate (NMDA) receptor. NMDA signaling has been implicated in the control of food intake. However, the role of d-serine on appetite regulation is unknown. To clarify the effects of d-serine on appetite, we investigated the effect of oral d-serine ingestion on food intake in three different feeding paradigms (one-food access, two-food choice, and refeeding after 24-h fasting) using three different strains of male mice (C57Bl/6J, BKS, and ICR). The effect of d-serine was also tested in leptin signaling-deficient db/db mice and sensory-deafferented (capsaicin-treated) mice. The expression of orexigenic neuropeptides [neuropeptide Y (Npy) and agouti-related protein (Agrp)] in the hypothalamus was compared in fast/refed experiments. Conditioned taste aversion for high-fat diet (HFD) was tested in the d-serine-treated mice. Under the one-food-access paradigm, some of the d-serine-treated mice showed starvation, but not when fed normal chow. HFD feeding with d-serine ingestion did not cause aversion. Under the two-food-choice paradigm, d-serine suppressed the intake of high-preference food but not normal chow. d-Serine also effectively suppressed HFD intake but not normal chow in db/db mice and sensory-deafferented mice. In addition, d-serine suppressed normal chow intake after 24-h fasting despite higher orexigenic gene expression in the hypothalamus. d-Serine failed to suppress HFD intake in the presence of L-701,324, the selective and full antagonist at the glycine-binding site of the NMDA receptor. Therefore, d-serine suppresses the intake of high-preference food through coagonism toward NMDA receptors. Copyright © 2015 the American Physiological Society.

  12. Colonic mucosal N-methyl-D-aspartate receptor mediated visceral hypersensitivity in a mouse model of irritable bowel syndrome.

    Science.gov (United States)

    Qi, Qing Qing; Chen, Fei Xue; Zhao, Dong Yan; Li, Li Xiang; Wang, Peng; Li, Yan Qing; Zuo, Xiu Li

    2016-07-01

    The aim of this study was to investigate whether colonic mucosal N-methyl-D-aspartate receptor (NMDAR) participates in visceral hypersensitivity in irritable bowel syndrome (IBS). C57BL/6 mice were administered intrarectally with trinitrobenzenesulfonic acid (TNBS) for the establishment of an IBS-like visceral hypersensitivity model. Those received an equivalent volume of 50% ethanol were regarded as the controls. Abdominal withdrawal reflex (AWR) scores in response to colorectal distention (CRD) were used to assess visceral sensitivity. NMDAR levels in the colonic mucosa were detected by both immunohistochemistry and Western blot. The concentrations of glutamate and ammonia in the feces of the mice were measured. Changes in visceral sensitivity after the intracolonic administration of ammonia or NMDAR antagonist were recorded. The established IBS-like mouse model of visceral hypersensitivity showed no evident inflammation in the colon. NMDAR levels in the colonic mucosa of the IBS-like mice were significantly higher compared with the controls, and were positively associated with AWR scores. The glutamate level in the feces of the TNBS-treated mice was similar to that of the controls, although the ammonia level was significantly higher. Intracolonic administration of ammonia induced visceral hypersensitivity in mice, which was repressed by pretreatment with NMDAR antagonist MK801. Overexpressed NMDAR in the colonic mucosa may participate in the pathogenesis of visceral hypersensitivity in IBS. Our study identifies the effect of ammonia in the colonic lumen on NMDAR in the colonic mucosa as a potential novel targeted mechanism for IBS treatment. © 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

  13. Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine.

    Science.gov (United States)

    Savignac, Helene M; Corona, Giulia; Mills, Henrietta; Chen, Li; Spencer, Jeremy P E; Tzortzis, George; Burnet, Philip W J

    2013-12-01

    The influence of the gut microbiota on brain chemistry has been convincingly demonstrated in rodents. In the absence of gut bacteria, the central expression of brain derived neurotropic factor, (BDNF), and N-methyl-d-aspartate receptor (NMDAR) subunits are reduced, whereas, oral probiotics increase brain BDNF, and impart significant anxiolytic effects. We tested whether prebiotic compounds, which increase intrinsic enteric microbiota, also affected brain BDNF and NMDARs. In addition, we examined whether plasma from prebiotic treated rats released BDNF from human SH-SY5Y neuroblastoma cells, to provide an initial indication of mechanism of action. Rats were gavaged with fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS) or water for five weeks, prior to measurements of brain BDNF, NMDAR subunits and amino acids associated with glutamate neurotransmission (glutamate, glutamine, and serine and alanine enantiomers). Prebiotics increased hippocampal BDNF and NR1 subunit expression relative to controls. The intake of GOS also increased hippocampal NR2A subunits, and frontal cortex NR1 and d-serine. Prebiotics did not alter glutamate, glutamine, l-serine, l-alanine or d-alanine concentrations in the brain, though GOSfeeding raised plasma d-alanine. Elevated levels of plasma peptide YY (PYY) after GOS intake was observed. Plasma from GOS rats increased the release of BDNF from SH-SY5Y cells, but not in the presence of PYY antisera. The addition of synthetic PYY to SH-SY5Y cell cultures, also elevated BDNF secretion. We conclude that prebiotic-mediated proliferation of gut microbiota in rats, like probiotics, increases brain BDNF expression, possibly through the involvement of gut hormones. The effect of GOS on components of central NMDAR signalling was greater than FOS, and may reflect the proliferative potency of GOS on microbiota. Our data therefore, provide a sound basis to further investigate the utility of prebiotics in the maintenance of brain health and

  14. Anti-N-Methyl-D-Aspartate Receptor Encephalitis Causing a Prolonged Depressive Disorder Evolving to Inflammatory Brain Disease

    Directory of Open Access Journals (Sweden)

    Sara Mariotto

    2014-02-01

    Full Text Available Background: Anti-N-methyl-D-aspartate receptor (anti-NMDAR encephalitis is a rapidly evolving condition that combines psychiatric and neurologic manifestations. Much remains unclear about its clinical onset and subsequent course. Although successful treatment depends on diagnosing the disorder early and therefore minimizing long-term complications, this is a difficult task owing to the atypical onset of this condition and the prolonged clinical course that has been observed in some patients. This report, illustrating a patient with slowly progressing psychiatric manifestations, unusual imaging and electrophysiological features, extends the information on varied clinical phenotypes. Case Report: A 32-year-old woman suffered from an isolated depressive disorder for 4 months before undergoing psychiatric evaluation. During the following 5 months, she manifested hypersexuality, dysarthria, imbalance, dyskinesias and decreased word output. Brain magnetic resonance imaging (MRI showed multifocal hyperintense T2/FLAIR lesions, a few contrast-enhanced, involving the corona radiata, the periventricular white matter, the deep gray nuclei, the optic nerves and the brainstem. MRI spectroscopy disclosed confluent bilateral demyelination and focal optic nerve involvement suggesting widespread encephalitis. Visual evoked potential studies indicated a demyelinating disorder. Serological screening and total body positron-emission tomography yielded negative findings for malignancies. Cerebrospinal fluid examination disclosed IgG oligoclonal bands and anti-NMDAR antibodies. Corticosteroids and intravenous immunoglobulin provided only slight improvement, whereas switching to cyclophosphamide markedly improved her neurological status. Conclusion: In patients with a prolonged clinical course, including psychiatric and neurological symptoms, the differential diagnosis should be anti-NMDAR encephalitis. This report expands the known disease phenotypes in this emerging

  15. Adolescent social defeat alters N-methyl-D-aspartic acid receptor expression and impairs fear learning in adulthood.

    Science.gov (United States)

    Novick, Andrew M; Mears, Mackenzie; Forster, Gina L; Lei, Yanlin; Tejani-Butt, Shanaz M; Watt, Michael J

    2016-05-01

    Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies.

  16. Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia.

    Science.gov (United States)

    Kort, Naomi S; Ford, Judith M; Roach, Brian J; Gunduz-Bruce, Handan; Krystal, John H; Jaeger, Judith; Reinhart, Robert M G; Mathalon, Daniel H

    2017-03-15

    Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia. In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared. N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen's d = 1.14) and schizophrenia (Cohen's d = .85). Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

    Gallagher, M. [Curriculum in Neurobiology, University of North Carolina Chapel Hill, NC (United States); Gill, T.M. [Department of Psychology, University of North Carolina at Chapel Hill Chapel Hill, NC (United States); Shivers, A. [Department of Biology, University of North Carolina Chapel Hill, NC (United States); Nicolle, M.M. [Curriculum in Neurobiology, University of North Carolina Chapel Hill, NC (United States)

    1997-02-03

    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 [{sup 3}H]glutamate and [{sup 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 [{sup 3}H]kainate binding. It also induced an increase in the density of [{sup 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 [{sup 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 [{sup 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 [{sup 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

  18. NOC/oFQ contributes to hypoxic-ischemic impairment of N-methyl-D-aspartate-induced cerebral vasodilation.

    Science.gov (United States)

    Armstead, W M

    2000-06-16

    Previous studies in piglets show that either hypoxia, ischemia-reperfusion (I+R) or combined hypoxia-ischemia-reperfusion (H+I+R) attenuated N-methyl-D-aspartate (NMDA)-induced pial artery dilation. This study was designed to determine the contribution of the newly described opioid nociceptin orphanin FQ (NOC/oFQ) to hypoxic-ischemic impairment of NMDA induced cerebral vasodilation in piglets equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased P(O(2)) to 35+/-3 mmHg with unchanged P(CO(2)). I+R elevated CSF NOC/oFQ from 67+/-4 to 266+/-29 pg/ml ( approximately 10(-10) M) while H+I+R elevated CSF NOC/oFQ to 483+/-67 pg/ml within 1 h of reperfusion. Such elevated NOC/oFQ levels returned to control within 4 h in I+R animals and within 12 h in H+I+R animals. Topical NOC/oFQ (10(-10) M) had no effect on pial artery diameter by itself but attenuated NMDA (10(-8), 10(-6) M) induced pial dilation (control, 9+/-1 and 16+/-1; coadministered NOC/oFQ, 5+/-1 and 10+/-1%). NMDA induced pial artery dilation was attenuated by I+R or H+I+R; but such dilation was partially restored by pretreatment with the putative NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH(2) (10(-6) M) (control, 9+/-1 and 16+/-1; I+R, 3+/-1 and 5+/-1; I+R+NOC/oFQ antagonist, 6+/-1 and 11+/-1%) Similar results were obtained for glutamate. These data suggest that NOC/oFQ release contributes to impaired NMDA and glutamate-induced cerebrovasodilation following I+R or H+I+R.

  19. Variations of movement disorders in anti-N-methyl-D-aspartate receptor encephalitis: A nationwide study in Taiwan.

    Science.gov (United States)

    Duan, Bi-Chun; Weng, Wen-Chin; Lin, Kuang-Lin; Wong, Lee Chin; Li, Sung-Tse; Hsu, Mei-Hsin; Lin, Jainn-Jim; Fan, Pi-Chaun; Lin, Ming-I; Chiu, Nan-Chang; Lin, Yu-Ching; Wang, Huei-Shyong; Hung, Kun-Long; Lee, Wang-Tso

    2016-09-01

    Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common autoimmune encephalitis that presents with a wide variety of movement disorders. The purpose of our study is to review the manifestations and duration of movement disorders in different ages with NMDAR encephalitis.A retrospective cohort of 28 patients (20 females and 8 males) with positive cerebrospinal fluid (CSF) anti-NMDAR antibody in a 5-year period from major hospitals in Taiwan was enrolled. They were categorized into 3 age groups: 7 patients were ≤10 years, 14 patients were 10 to 18 years, and 7 patients were >18 years.Total 28 patients (20 females and 8 males) with age ranging from 8 months to 38 years were enrolled. Nearly all patients (n = 27/28, 96%) presented with at least 2 types of disorders, including orofacial-lingual dyskinesia (OFLD; n = 20), catatonia (n = 19), tremor (n = 11), bradykinesia (n = 11), dystonia (n = 11), choreoathethosis (n = 9), and ballism (n = 3). Only 1 patient below 10 years presented with isolated periodic choreoathethosis without other movement disorders. OFLD was common in all age groups. Choreoathetosis was most common in patients aged ≤10 years, while catatonia was most common in patients aged >10 years (P = 0.001 and 0.020, respectively). Bradykinesia was also more common in patients aged >10 years (P = 0.020). The clinical presentations of movement disorders were not significantly different in the age of 10 to 18 years and those >18 years. Neither patient ≤10 years old nor male patients had associated tumors. All patients' movement disorders were improved after treatment, while female patients with tumors had worse short-term outcome (P = 0.014). Compared with other disorders, choreoathetosis persisted significantly longer in patients ≤10 years (P = 0.038), while OFLD and catatonia last longer in patients >10 years (P = 0.047 and 0.002, respectively).Our study shows that

  20. Translating the N-methyl-D-aspartate receptor antagonist model of schizophrenia to treatments for cognitive impairment in schizophrenia.

    Science.gov (United States)

    Meltzer, Herbert Y; Rajagopal, Lakshmi; Huang, Mei; Oyamada, Yoshihiro; Kwon, Sunoh; Horiguchi, Masakuni

    2013-11-01

    The N-methyl-D-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT(1A), and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT(1A) partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5-10 fold greater than those

  1. Autoantibodies against the N-Methyl-d-Aspartate Receptor Subunit NR1: Untangling Apparent Inconsistencies for Clinical Practice

    Science.gov (United States)

    Ehrenreich, Hannelore

    2017-01-01

    This viewpoint review provides an integrative picture of seemingly contradictory work published on N-methyl-d-aspartate receptor 1 (NMDAR1) autoantibodies (AB). Based on the present state of knowledge, it gives recommendations for the clinical decision process regarding immunosuppressive treatment. Brain antigen-directed AB in general and NMDAR1-AB in particular belong to a preexisting autoimmune repertoire of mammals including humans. Specific autoimmune reactive B cells may get repeatedly (perhaps transiently) boosted by various potential stimulants (e.g., microbiome, infections, or neoplasms) plus less efficiently suppressed over lifespan (gradual loss of tolerance), likely explaining the increasing seroprevalence upon aging (>20% NMDAR1-AB in 80-year-old humans). Pathophysiological significance emerges (I) when AB-specific plasma cells settle in the brain and produce large amounts of brain antigen-directed AB intrathecally and/or (II) in conditions of compromised blood–brain barrier (BBB), for instance, upon injury, infection, inflammation, or genetic predisposition (APOE4 haplotype), which then allows substantial access of circulating AB to the brain. Regarding NMDAR1-AB, functional effects on neurons in vitro and elicitation of brain symptoms in vivo have been demonstrated for immunoglobulin (Ig) classes, IgM, IgA, and IgG. Under conditions of brain inflammation, intrathecal production and class switch to IgG may provoke high NMDAR1-AB (and other brain antigen-directed AB) levels in cerebrospinal fluid (CSF) and serum, causing the severe syndrome named “anti-NMDAR encephalitis,” which then requires immunosuppressive therapy on top of the causal encephalitis treatment (if available). However, negative CSF NMDAR1-AB results cannot exclude chronic effects of serum NMDAR1-AB on the central nervous system, since the brain acts as “immunoprecipitator,” particularly in situations of compromised BBB. In any case of suspected symptomatic consequences of

  2. Synthetic conantokin peptides potently inhibit N-methyl-D-aspartate receptor-mediated currents of retinal ganglion cells.

    Science.gov (United States)

    Huang, Luoxiu; Balsara, Rashna D; Castellino, Francis J

    2014-12-01

    Retinal ganglion cells (RGCs), which are the sole output neurons of the retina, express N-methyl-D-aspartate receptors (NMDARs), rendering these cells susceptible to glutamate excitotoxicity, with implications for loss of normal RGC excitatory responses in disorders such as glaucoma and diabetic retinopathy. Therefore, antagonists that inhibit NMDAR-mediated currents specifically by targeting the GluN2B component of the ion channel have the potential to serve as a basis for developing potential therapeutics. The roles of peptidic conantokins, which are potent brain neuronal NMDAR inhibitors, were studied. By using patch-clamp whole-cell analyses in dissociated RGCs and retinal whole-mount RGCs, we evaluated the effects of synthetic conantokin-G (conG) and conantokin-T (conT), which are small γ-carboxyglutamate-containing peptides, on NMDA-mediated excitatory responses in mouse RGCs. Both conG and conT inhibited the NMDA-mediated currents of dark-adapted dissociated and whole-mount RGCs in a dose-dependent, reversible, noncompetitive manner. Inhibition of NMDA-mediated steady-state currents by NMDAR nonsubunit-selective conT was approximately threefold greater than GluN2B-selective conG or ifenprodil, demonstrating its potential ability to inhibit both GluN2A- and GluN2B-containing ion channels in RGCs. Because the extent of inhibition of NMDA-evoked currents by conG and the pharmacologic GluN2B-selective inhibitor ifenprodil were similar (40-45%) to that of the GluN2A-selective antagonist NVP-AAM0077, we conclude that the levels of GluN2A and GluN2B subunits are similar in RGCs. These results provide a novel basis for developing effective neuroprotective agents to aid in the prevention of undesired glutamatergic excitotoxicity in neurodegenerative diseases of the retina and demonstrate functional assembly of NMDARs in RGCs.

  3. Evidence that gonadal steroids modulate nitric oxide efflux in the medial preoptic area: effects of N-methyl-D-aspartate and correlation with luteinizing hormone secretion.

    Science.gov (United States)

    Pu, S; Xu, B; Kalra, S P; Kalra, P S

    1996-05-01

    Several lines of evidence suggest that nitric oxide (NO) is involved in the neuroendocrine control of reproductive function. This study was undertaken to determine 1) NO activity in the medial preoptic area (MPOA) where LHRH- and NO synthase-containing neurons are coextensive; 2) whether N-methyl-D-aspartate (NMDA) receptor activation, which stimulates LHRH release, augments NO activity in the MPOA; and 3) whether NO activation in the MPOA underlies the steroid dependency of NMDA-induced pituitary LH release. As extracellular levels of cGMP in discrete brain sites are a reliable index of basal and stimulated activity of NO, extracellular cGMP levels in the MPOA of freely moving, awake rats were measured by microdialysis in the current study. In the first experiment, the MPOA of intact and castrated male rats were microdialyzed with artificial cerebrospinal fluid at a rate of 5 microliters/min. The basal level of cGMP efflux was determined from the initial seven samples collected at 20-min intervals. The NO response to a single i.v. injection of NMDA (10 mg/kg) or saline was assessed in the next five samples. In the second experiment, the basal and NMDA-evoked NO effluxes in the MPOA of ovariectomized (ovx) and estrogen-treated ovx rats were examined. Results showed that in both sexes, the absence of gonadal steroids resulted in significantly lower basal cGMP levels. Additionally, the cGMP response to NMDA was steroid dependent. Whereas in castrated rats it failed to affect cGMP efflux, NMDA in intact male rats promptly raised cGMP levels at 20 min, and these elevated levels were maintained through the duration of the experiment. This NMDA-induced cGMP response, observed selectively in intact rats, was also associated with stimulation of plasma LH levels. In female rats, NMDA similarly enhanced MPOA cGMP efflux and pituitary LH secretion in estradiol benzoate-treated, but not in oil-treated, ovx rats. The NMDA receptor antagonist D,L-amino-5-phosphoropentanoic acid

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

    Energy Technology Data Exchange (ETDEWEB)

    Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M. (Eli Lilly and Company, Indianapolis, IN (USA))

    1990-12-01

    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.

  5. 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

  6. Selective inhibition by ethanol of mitochondrial calcium influx mediated by uncoupling protein-2 in relation to N-methyl-D-aspartate cytotoxicity in cultured neurons.

    Directory of Open Access Journals (Sweden)

    Ryo Fukumori

    Full Text Available BACKGROUND: We have shown the involvement of mitochondrial uncoupling protein-2 (UCP2 in the cytotoxicity by N-methyl-D-aspartate receptor (NMDAR through a mechanism relevant to the increased mitochondrial Ca(2+ levels in HEK293 cells with acquired NMDAR channels. Here, we evaluated pharmacological profiles of ethanol on the NMDA-induced increase in mitochondrial Ca(2+ levels in cultured murine neocortical neurons. METHODOLOGY/PRINCIPAL FINDINGS: In neurons exposed to glutamate or NMDA, a significant increase was seen in mitochondrial Ca(2+ levels determined by Rhod-2 at concentrations of 0.1 to 100 µM. Further addition of 250 mM ethanol significantly inhibited the increase by glutamate and NMDA in Rhod-2 fluorescence, while similarly potent inhibition of the NMDA-induced increase was seen after exposure to ethanol at 50 to 250 mM in cultured neurons. Lentiviral overexpression of UCP2 significantly accelerated the increase by NMDA in Rhod-2 fluorescence in neurons, without affecting Fluo-3 fluorescence for intracellular Ca(2+ levels. In neurons overexpressing UCP2, exposure to ethanol resulted in significantly more effective inhibition of the NMDA-induced increase in mitochondrial free Ca(2+ levels than in those without UCP2 overexpression, despite a similarly efficient increase in intracellular Ca(2+ levels irrespective of UCP2 overexpression. Overexpression of UCP2 significantly increased the number of dead cells in a manner prevented by ethanol in neurons exposed to glutamate. In HEK293 cells with NMDAR containing GluN2B subunit, more efficient inhibition was similarly induced by ethanol at 50 and 250 mM on the NMDA-induced increase in mitochondrial Ca(2+ levels than in those with GluN2A subunit. Decreased protein levels of GluN2B, but not GluN2A, subunit were seen in immunoprecipitates with UCP2 from neurons with brief exposure to ethanol at concentrations over 50 mM. CONCLUSIONS/SIGNIFICANCE: Ethanol could inhibit the interaction between

  7. Nonopioid motor effects of dynorphin A and related peptides: structure dependence and role of the N-methyl-D-aspartate receptor.

    Science.gov (United States)

    Shukla, V K; Prasad, J A; Lemaire, S

    1997-11-01

    Dynorphin (Dyn) A and related opioid and nonopioid peptides were tested for their ability to produce motor effects in mice. Central (intracerebroventricular) administration of Dyn A in mice produced marked motor effects characterized by wild running, jumping, circling and/or barrel rolling with an ED50 value of 14.32 (95% confidence limits, 10.09-20.32) nmol/mouse. The order of potency of the various Dyn A-related peptides and fragments in producing motor effects was Dyn A approximately Dyn A-(1-13) > [Ala1]Dyn A-(1-13) approximately Dyn A-(2-13) > alpha-Neo-End > Dyn A-(1-8) approximately Dyn B approximately Dyn A-(2-8) > Dyn A-(3-8). Dyn A-(1- 5) (or Leu-Enk) and Dyn A-(6-10) displayed no motor effect at doses up to 100 nmol/mouse. The potencies of Dyn A and Dyn A-(2-13) were not affected by preadministration of naloxone (5 mg/kg s.c.), but the motor effects of Dyn A-(1-13) (20 nmol/mouse i.c.v.) were significantly reduced by coadministration of low doses (0.2-0.6 nmol/mouse) of the N-methyl-D-aspartate (NMDA) receptor antagonists dextrorphan, MK-801 and CPP. Dyn A was also a potent inhibitor of the binding of the phencyclidine receptor ligand, [3H]MK-801, to rat brain membranes, with a Ki value of 0.41 microM. However, the order of potency of the various Dyn A-related peptides and fragments in inhibiting [3H]MK-801 binding did not correlate with their ability to produce motor effects. On the other hand, Dyn A and related peptides produced a significant potentiation of the binding of the competitive NMDA antagonist [3H]CGP-39653 to rat brain membranes, an effect that correlated well (r = 0.91) with their potency in producing motor effects. These results indicate that the nonopioid motor effects of Dyn A and related peptides are structure dependent, with Dyn A-(2-8) being the minimal core peptide for motor activity. In addition, these effects most likely involve the participation of the excitatory amino acid binding domain on the NMDA receptor complex.

  8. Anti-N-methyl-D-aspartic acid receptor encephalitis: clinical analysis of 7 cases%抗NMDA受体脑炎七例临床分析

    Institute of Scientific and Technical Information of China (English)

    宋璐; 刘爱华

    2013-01-01

    目的 总结抗NMDA受体脑炎的临床及辅助检查的特点、提高对该病的认识.方法 分析2010年1月至2012年12月在宣武医院神经内科就诊的7例抗NMDA受体脑炎患者的临床特征、辅助检查,总结不同治疗方案的预后.结果 7例患者表现为显著的精神症状、癫痫、运动障碍,部分患者伴随自主神经功能异常,MRI显示边缘系统异常信号;CSF及血清NMDA受体抗体阳性,5例患者预后良好.结论 及时的诊断及治疗有助于抗NMDA受体脑炎患者的恢复.%Objective To summarize the clinical manifestations,immunotherapeutic response and prognosis of anti-N-methyl-D-aspartic acid (NMDA) receptor encephalitis.Methods We analyzed the clinical features,tumor markers,serum/cerebrospinal fluid (CSF) antibodies of seven cases with antiNMDA receptor encephalitis.And the prognosis of different treatments was observed.Results Seven patients presented with significant psychiatric symptoms,memory loss,epilepsy,movement disorders and decrease consciousness.And some patients required assisted ventilation because of dysautonomia.All electroencephalographs showed slow wave activity without epileptic form discharges.Magnetic resonance imaging was normal or showed T2W and Flair-phase high signal in limbic system,cortex,thalamus.And CSF and serum anti-NMDA receptor antibodieswere positive (n =6).Conclusion Anti-NMDA receptor encephalitis is a kind of fatal but treatable condition.And timely diagnosis and treatment may yield a favorable prognosis.

  9. Expression of mRNA-encoding subunits of N-methyl-D-aspartate receptor in the hypothalamus in sustained monaural block of auditory air-conduction model rats

    Institute of Scientific and Technical Information of China (English)

    Ping Wan; Xiaojian Lai; Cheng Huang; Xinde Sun

    2011-01-01

    A sustained monaural block of auditory air-conduction model was established in rats through subcutaneous suture in the right ear canal. The gene expression levels of hypothalamic N-methyl-D-aspartate receptor NR1, NR2A, NR2B and NR2C mRNA in the auditory central nervous system of Sprague-Dawley rats at postnatal 9, 23, 37 days were determined after an environmental change. Reverse transcription-PCR assay showed that the critical period for the development of NR1, NR2A, and NR2B subunits in the left hypothalamus and NR1- and NR2B-dependent auditory neurons in the right hypothalamus terminated 23 days after the suture in the right ear. The critical period for the development of NR2A subunit-dependent auditory neurons in the right hypothalamus was terminated by postnatal day 37. The results confirmed that N-methyl-D-aspartate receptor subunits in the hypothalamus may be regulated by the auditory environment.

  10. Competitive binding of postsynaptic density 95 and Ca2+-calmodulin dependent protein kinase Ⅱ to N-methyl-D-aspartate receptor subunit 2B in rat brain

    Institute of Scientific and Technical Information of China (English)

    Fan-jie MENG; Jun GUO; Bo SONG; Xue-bo YAN; Guang-yi ZHANG

    2004-01-01

    AIM: To investigate the interactions among postsynaptic density 95 (PSD-95), Ca2+-calmodulin dependent protein kinase Ⅱα (CaMKⅡα), and N-methyl-D-aspartate receptor subunit 2B (NR2B) during ischemia and reperfusion in hippocampus of rats. METHODS: Brain ischemia was induced by four-vessel occlusion procedure in rats. Immunoprecipitation and immunoblotting were performed to study the interactions and phosphorylation of proteins. The association-dissociation of PSD-95 and CaMKⅡα to and from N-methyl-D-aspartate (NMDA) receptor induced by ischemia and reperfusion and the effects of 1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenyl-piperazine (KN-62, a selective inhibitor of CaMKⅡ) on these protein interactions were investigated. Coimmunoprecipitation and immunoblotting were performed for the studies of interactions among proteins. RESULTS: The alternations of the binding level of PSD-95 and CaMKⅡα to NR2B during ischemia and reperfusion demonstrated the negative correlation to each other. Pre-administration of KN62 through both cerebral ventricles inhibited the 10 min ischemia-induced increase of the binding of PSD-95 to NR2B and, on the contrary, promoted the binding of CaMKⅡα to NR2B. CONCLUSION: PSD-95 competes with CaMKⅡ to bind to NR2B during ischemia and reperfusion in rat hippocampus.

  11. 抗NMDA受体脑炎纠误挽治回顾分析%Retrospective Analysis of Anti-N-methyl-D-aspartate Receptor Encephalitis

    Institute of Scientific and Technical Information of China (English)

    刘佳福; 于洋; 王树云; 陈向军; 潘曙明

    2015-01-01

    目的:总结抗N-甲基-D-天冬氨酸( N-methyl-D-asparate, NMDA)受体脑炎早期诊断要点,减少误诊。方法回顾性分析1例抗NMDA受体脑炎临床资料。结果患者为青年女性,因反复发热20余日,伴精神异常进行性加重9d就诊,外院诊断为呼吸道感染、精神分裂症,予相应治疗效果不佳,入我院。入院后怀疑脑炎,行血清炎性指标、脑脊液常规及生化检查无异常,脉搏氧饱和度降低,考虑有中枢性通气不足,病程中出现唾液分泌明显增多,口面部不自主运动,动态脑电图提示弥漫性慢波,盆腔影像学提示畸胎瘤,高度怀疑抗NMDA受体脑炎,行血液及脑脊液抗NMDA受体抗体检测阳性,明确诊断。在免疫治疗的基础上行手术切除畸胎瘤后,患者康复出院。结论对年轻患者临床出现不明原因的精神症状伴意识和运动障碍,特别是伴卵巢畸胎瘤者,应高度怀疑抗NMDA受体脑炎,积极行脑脊液和(或)血液抗NMDA受体抗体检测,以明确诊断。%Objective To summarize the early diagnosis points of anti-N-methyl-D-aspartate (NMDA) receptor en-cephalitis, in order to reduce the misdiagnosis rate. Methods Clinical data of a misdiagnosed female patient with NMDA re-ceptor encephalitis was retrospectively analyzed. Results The patient had a history of fever for more than 20 days, and pro-gressive mental disorder for 9 days, and was diagnosed as having respiratory tract infection and schizophrenia. She was admit-ted to our hospital without improvement after treatment by other hospitals. The patient had a lower SpO2 , PCT 0. 04 ng/ml, CRP 19 mg/L, normal routine cerebrospinal fluid tests. Central hypoventilation was indicated. New symptoms appeared, in-cluding hypersalivation, occasional lip licking, tongue protrusion. Video-Electroencephalography ( EEG) demonstrated abnor-mal diffuse low-voltage slow-activities. She had an ovarian teratoma. NMDA receptor encephalitis was highly suspected. Posi

  12. Systematic screening for mutations in the human N-methyl-D-aspartate receptor 1 gene in schizophrenic patients from the German population.

    Science.gov (United States)

    Paus, Sebastian; Rietschel, Marcella; Schulze, Thomas G; Ohlraun, Stephanie; Diaconu, Carmen C; Van Den Bogaert, Ann; Maier, Wolfgang; Propping, Peter; Cichon, Sven; Nöthen, Markus M

    2004-12-01

    Evidence for a dysfunction of the N-methyl-D-aspartate (NMDA) type of ionotropic glutamate receptors in schizophrenic patients, comes from neurochemical and clinical pharmacologic data. Therefore, the NMDAR1 gene can be regarded as an interesting candidate gene for schizophrenia. Several groups have tried to identify variants of this gene in schizophrenic patients in different, however not in German, populations. We sought to identify sequence changes of potential functional relevance in genomic DNA from 46 German unrelated schizophrenic patients by means of single-strand conformation analysis. No mutations of likely functional relevance were observed. We identified two synonymous coding Single Nucleotide Polymorphisms (cSNPs) in exons 6 and 7, and two SNPs in exon-flanking intronic sequences. Genotype distribution of these four SNPs was not significantly different between schizophrenic patients and controls. Our results suggest that the NMDAR1 subunit is not frequently involved in the development of schizophrenia in the German population.

  13. Changes in N-methyl-D-aspartate receptor 2A subunit expression caused by binocular form deprivation and chondroitin sulfate proteoglycan degradation

    Institute of Scientific and Technical Information of China (English)

    Mingming Liu; Wei Qin; Hanping Xie

    2011-01-01

    Light deprivation is known to induce a significant decrease in the percentage of N-methyl-D- aspartate receptor 2A subunit (NR2A)-expressing neurons during development. The purpose of this study was to investigate the effects of binocular form deprivation (BFD) and chondroitin sulfate proteoglycan (CSPG) degradation on NR2A expression via an immunohistochemical study, around the end of a critical developmental period. The results show that the positive staining of NR2A in the normal rat visual cortex increases gradually from postnatal 3-5 weeks (P 0.05). The positive staining of NR2A in the CSPG-treated group was insignificant compared with the BFD group at the same time point from 4 weeks to 7 weeks (P > 0.05). Thus, the effect of BFD on NR2A expression in the rat visual cortex was similar to that of CSPG degradation around the end of the critical developmental period.

  14. Synthesis, radiolabeling and evaluation of novel amine guanidine derivatives as potential positron emission tomography tracers for the ion channel of the N-methyl-d-aspartate receptor.

    Science.gov (United States)

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

    2016-08-08

    The N-Methyl-d-Aspartate receptor (NMDAR) is involved in many neurological and psychiatric disorders including Alzheimer's disease and schizophrenia. The aim of this study was to develop a positron emission tomography (PET) ligand to assess the bio-availability of the NMDAR ion channel in vivo. A series of tri-N-substituted diarylguanidines was synthesized and their in vitro binding affinities for the NMDAR ion channel assessed in rat forebrain membrane fractions. Compounds 21, 23 and 26 were radiolabeled with either carbon-11 or fluorine-18 and ex vivo biodistribution and metabolite studies were performed in Wistar rats. Biodistribution studies showed high uptake especially in prefrontal cortex and lowest uptake in cerebellum. Pre-treatment with MK-801, however, did not decrease uptake of the radiolabeled ligands. In addition, all three ligands showed fast metabolism.

  15. Effect of Xingnaojing Injection (醒脑静注射液) on Hippocampal N-methyl-D-aspartic Acid Receptors of Focal Cerebral Ischemia in Rats

    Institute of Scientific and Technical Information of China (English)

    沈思钰; 蔡定芳; 陈伟华; 刘静; 陈虎; 应健

    2003-01-01

    Objective: To observe and elucidate the neuroprotective effect of Xingnaojing (XNJ) injection on hippocampal N-methyl-D-aspartic acid (NMDA) receptors of focal cerebral ischemia in rats. Methods: Cerebral ischemia was established by occluding the middle cerebral artery with an intraluminal suture technique in rats. Neurological deficit score, infarct volume and quantity of NMDA receptors were estimated in all groups and compared. Results: After being treated with XNJ, the score decreased in the initial 6 hours and infarct volume decreased in 24 hours. And within 24 hours,the quantity of NMDA receptors obviously decreased compared with the model group(P<0.01). It indicated that XNJ could ameliorate neurological behavior of middle cerebral artery occlusion rats and down-regulate the expression of hippocampal NMDA receptors. Conclusion: The neuroprotective effect of XNJ on focal cerebral ischemia is possibly related to down-regulating the expression of NMDA receptors in rats.

  16. Non-tumor-Associated Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis in Chinese Girls With Positive Anti-thyroid Antibodies.

    Science.gov (United States)

    Guan, Wenjuan; Fu, Zhenqiang; Zhang, Hui; Jing, Lijun; Lu, Jingjing; Zhang, Jing; Lu, Hong; Teng, Junfang; Jia, Yanjie

    2015-10-01

    Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a new category of autoimmune encephalitis associated with anti-NMDA receptor antibodies. The disease was first described in 2007, and it predominantly affects young women with or without ovarian teratomas. Most patients typically present with seizures, a decreased consciousness level, dyskinesia, autonomic dysfunction, and psychiatric symptoms. The presence of anti-thyroid antibodies in non-tumor-associated anti-NMDA receptor encephalitis was first described in 2010. Additionally, anti-thyroid antibodies were found in teratoma-associated anti-NMDA receptor encephalitis. We report the cases of 3 Chinese girls with non-tumor-associated anti-NMDA receptor encephalitis with positive anti-thyroid antibodies. We followed up the details of their titers and suggest that anti-thyroid antibodies were an indicator of autoimmune predisposition in the development of non-tumor-associated anti-NMDA receptor encephalitis.

  17. Approach to the Management of Pediatric-Onset Anti-N-Methyl-d-Aspartate (Anti-NMDA) Receptor Encephalitis: A Case Series.

    Science.gov (United States)

    Brenton, J Nicholas; Kim, Joshua; Schwartz, Richard H

    2016-08-01

    Anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis is a treatable cause of autoimmune encephalitis. It remains unclear if the natural history of this disease is altered by choice of acute therapy or the employment of chronic immunotherapy. Chart review was undertaken for pediatric patients diagnosed with anti-NMDA receptor encephalitis. Data obtained included patient demographics, disease manifestations, treatment course, and clinical outcomes. Ten patients with anti-NMDA receptor encephalitis were identified. All patients were treated with immunotherapy in the acute period, and all patients experienced good recovery. Neurologic relapse did not occur in any patient. All patients received varied forms of chronic immunosuppression to prevent relapses. Complications of chronic immunotherapy occurred in 50% of patients. The benefits of chronic immunotherapy and the duration of use should be carefully weighed against the risks. Complications from immunotherapy are not uncommon and can be serious. Clinical trials assessing the benefit of long-term immunotherapy in this population are needed.

  18. A young woman presenting with psychotic and mood symptoms from anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis: an emerging diagnosis.

    Science.gov (United States)

    Yuan, Neal; Glezer, Anna

    2013-01-01

    Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis, first characterized in 2005, is a neurological disease with prominent psychiatric features that frequently involves the consultation of psychiatrists. Since its discovery, the rate of diagnosis of new cases has increased rapidly and several epidemiological studies now confirm that NMDA-R encephalitis may be as common as many other prominent infectious etiologies of encephalitis. We describe a case of a young woman presenting initially with psychotic and mood symptoms who was found to have anti-NMDA-R encephalitis. We further provide details of her treatment and prolonged recovery process after hospital discharge with a review of the literature and discussion of the epidemiology, symptomology, diagnosis, and management of both the neurologic and psychiatric manifestations of this condition. Last, we contextualize the importance of anti-NMDA-R encephalitis for psychiatrists, highlighting the role for psychiatrists in establishing the initial diagnosis as well as in providing ongoing psychiatric care.

  19. 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

    Energy Technology Data Exchange (ETDEWEB)

    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. (Merck Sharp and Dohme Research Labs., Essex (England))

    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 ({sup 3}H)glycine binding to rat cerebral cortex synaptic membranes with an IC{sub 50} of 12.5 {mu}M, whereas (-)-HA-966 had an IC{sub 50} value of 339 {mu}M. 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 {gamma}-butyrolactone, disruption of striatal dopaminergic mechanisms may be responsible for this action.

  20. Early Growth Response 1 (Egr-1) Regulates N-Methyl-d-aspartate Receptor (NMDAR)-dependent Transcription of PSD-95 and α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor (AMPAR) Trafficking in Hippocampal Primary Neurons*

    Science.gov (United States)

    Qin, Xike; Jiang, Yongjun; Tse, Yiu Chung; Wang, Yunling; Wong, Tak Pan; Paudel, Hemant K.

    2015-01-01

    The N-methyl-d-aspartate receptor (NMDAR) controls synaptic plasticity and memory function and is one of the major inducers of transcription factor Egr-1 in the hippocampus. However, how Egr-1 mediates the NMDAR signal in neurons has remained unclear. Here, we show that the hippocampus of mice lacking Egr-1 displays electrophysiology properties and ultrastructure that are similar to mice overexpressing PSD-95, a major scaffolding protein of postsynaptic density involved in synapse formation, synaptic plasticity, and synaptic targeting of AMPA receptors (AMPARs), which mediate the vast majority of excitatory transmission in the CNS. We demonstrate that Egr-1 is a transcription repressor of the PSD-95 gene and is recruited to the PSD-95 promoter in response to NMDAR activation. Knockdown of Egr-1 in rat hippocampal primary neurons blocks NMDAR-induced PSD-95 down-regulation and AMPAR endocytosis. Likewise, overexpression of Egr-1 in rat hippocampal primary neurons causes reduction in PSD-95 protein level and promotes AMPAR endocytosis. Our data indicate that Egr-1 is involved in NMDAR-mediated PSD-95 down-regulation and AMPAR endocytosis, a process important in the expression of long term depression. PMID:26475861

  1. 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 n

  2. Anti-N-methyl-d-aspartate receptor encephalitis in a patient with a 7-year history of being diagnosed as schizophrenia: complexities in diagnosis and treatment

    Directory of Open Access Journals (Sweden)

    Huang C

    2015-06-01

    Full Text Available Chaohua Huang,1,2,4,* Yukun Kang,1,* Bo Zhang,1 Bin Li,1 Changjian Qiu,1 Shanming Liu,1 Hongyan Ren,1,2 Yanchun Yang,1 Xiehe Liu,1 Tao Li,1–3 Wanjun Guo1,21Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2State Key Laboratory of Biotherapy, Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Mental Health Education Center, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Mental Health Center, Affiliated Hospital of Luzhou Medical College, Luzhou, People’s Republic of China*These authors contributed equally to this workAbstract: Anti-N-methyl-d-aspartate receptor (NMDAR encephalitis is a form of autoimmune encephalitis associated with antibodies against the NR1 subunits of NMDARs. Although new-onset acute prominent psychotic syndromes in patients with NMDAR encephalitis have been well documented, there is a lack of case studies on differential diagnosis and treatment of anti-NMDAR encephalitis after a long-term diagnostic history of functional psychotic disorders. The present study reports an unusual case of anti-NMDAR encephalitis. The patient had been diagnosed with schizophrenia 7 years earlier, and was currently hospitalized for acute-onset psychiatric symptoms. The diagnosis became unclear when the initial psychosis was confounded with considerations of other neurotoxicities (such as neuroleptic malignant syndrome. Finally, identification of specific immunoglobulin G NR1 autoantibodies in the cerebrospinal fluid and greater effectiveness of immunotherapy over antipsychotics alone (which has been well documented in anti-NMDAR encephalitis indicated the diagnosis of anti-NMDAR encephalitis in this case. Based on the available evidence, however, the relationship between the newly diagnosed anti-NMDAR encephalitis and the seemingly clear, long-term history of schizophrenia in the preceding 7

  3. Cdk5 inhibitor roscovitine alleviates neuropathic pain in the dorsal root ganglia by downregulating N-methyl-D-aspartate receptor subunit 2A.

    Science.gov (United States)

    Yang, Lei; Gu, Xiaoping; Zhang, Wei; Zhang, Juan; Ma, Zhengliang

    2014-09-01

    Cyclin-dependent kinase 5 (Cdk5) is a member of the small proline-directed serine/threonine kinase family. Cdk5 is not involved in cell cycle regulation, but is implicated in neurodegenerative disorders. However, the role of Cdk5 in neuropathic pain remains unclear. This study aimed to evaluate the possibility that Cdk5 is involved in neuropathic pain in the dorsal root ganglia (DRG). We injected intrathecally Cdk5 inhibitor roscovitine in rat model of chronic compression of dorsal root ganglion and examined pain behaviors and the expression of N-methyl-d-aspartate receptor subunit 2A (NR2A) but not NR2B or NR1 in DRG. We found that roscovitine alleviated neuropathic pain, causing decline in paw withdrawal mechanical threshold and paw withdrawal thermal latency. Furthermore, roscovitine inhibited NR2A expression in DRG. These data suggest that Cdk5-NR2A pathway regulates neuropathic pain in DRG, and intrathecal injection of roscovitine could alleviate neuropathic pain. Our findings provide new insight into the analgesic effects of Roscovitine and identify Cdk5-NR2A pathway as a potential target for effective treatment of neuropathic pain.

  4. Water-soluble lipopolymer delivery of N-methyl-D-aspartic acid receptor 2B siRNA relieves chronic neuropathic pain in rats

    Institute of Scientific and Technical Information of China (English)

    Jianhua Lu; Yuanxiang Tao; Xue Yang; Weifeng Tu; Hao Chen; Jiaxiang Xiong; Chungui Hu

    2011-01-01

    Spinal dorsal horn N-Methyl-D-aspartic acid receptor 2B (NR2B) overexpression plays an important role in the production and maintenance of neuropathic pain. Because small interfering RNA (siRNA) can inhibit NR2B expression, siRNA may provide a novel approach to treat neuropathic pain and possibly nerve injury. However, an efficient and safe vector for NR2B siRNA has not been discovered. This study shows that a water soluble lipopolymer (WSLP) comprised of low molecular weight polyethyleneimine (PEI) and cholesterol can deliver siRNA targeting NR2B for the treatment of neuropathic pain. Results show that intrathecal injection of WSLP/siRNA complexes for 3 days inhibit NR2B gene expression with reductions in mRNA and protein levels by 59% and 54%, respectively, compared with control rats (P < 0.01). Injection of WSLP complexed with scrambled siRNA, or PEI with siRNA did not show this inhibitory effect. Moreover, injection of WSLP/siRNA complexes significantly relieved neuropathic pain at 3, 7, 12, and 21 days, while injection of WSLP with scrambled siRNA or PEI with siRNA did not. These results demonstrate that WSLP can efficiently deliver siRNA targeting NR2B in vivo and relieve neuropathic pain.

  5. 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.

  6. Changes in synaptic and extrasynaptic N-methyl-D-aspartate receptor-mediated currents at early-stage epileptogenesis in adult mice

    Institute of Scientific and Technical Information of China (English)

    Juegang Ju; Sheng-tian Li

    2011-01-01

    Previous reports have shown that N-methyl-D-aspartate (NMDA) receptors are extensively involved in epilepsy genesis and recurrence.Recent studies have shown that synaptic and extrasynaptic NMDA receptors play different, or even opposing, roles in various signaling pathways, including synaptic plasticity and neuronal death.The present study analyzed changes in synaptic and extrasynaptic NMDA receptor-mediated currents during epilepsy onset.Mouse models of lithium chloride pilocarpine-induced epilepsy were established, and hippocampal slices were prepared at 24 hours after the onset of status epilepticus.Synaptic and extrasynaptic NMDA receptor-mediated excitatory post-synaptic currents (NMDA-EPSCs) were recorded in CA1 pyramidal neurons by whole-cell patch clamp technique.Results demonstrated no significant difference in rise and delay time of synaptic NMDA-EPSCs compared with normal neurons.Peak amplitude, area-to-peak ratio,and rising time of extrasynaptic NMDA-EPSCs remained unchanged, but decay of extrasynaptic NMDA-EPSCs was faster than that of normal neurons.These results suggest that extrasynaptic NMDA receptors play a role in epileptogenesis.

  7. 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

    2017-09-11

    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 scoreCentral 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.

  8. 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

  9. N-Methyl-D-aspartate receptor antibody could be a cause of catatonic symptoms in psychiatric patients: case reports and methods for detection

    Science.gov (United States)

    Tsutsui, Ko; Kanbayashi, Takashi; Takaki, Manabu; Omori, Yuki; Imai, Yumiko; Nishino, Seiji; Tanaka, Keiko; Shimizu, Tetsuo

    2017-01-01

    The symptoms of catatonia have been reported to be similar to the initial symptoms of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Subsequently, this autoimmune limbic encephalitis has been noticed by many psychiatrists. For a differential diagnosis of catatonic state, it is important to detect anti-NMDAR encephalitis. This encephalitis is expected to be in remission by early detection and treatment. We should be more cautious about catatonic symptoms of schizophrenia. When a patient is suspected of having encephalitis, we should screen for anti-NMDAR antibodies in cerebrospinal fluid samples using a cell-based assay. We describe the methods of NMDAR antibody detection and the etiology of this encephalitis with case reports. Two representative cases with catatonia and non-catatonia (brief psychotic disorder) were reported. Schizophrenia is a general, heterogeneous, and complicated disorder, and its pathophysiology is unknown. There is an established evidence of NMDAR hypofunction, which is the functional disconnection of the central component; this is one of the most recognized models for schizophrenia. Furthermore, it is said that autoimmune mechanisms have been involved, at least in subgroups of schizophrenia patients. Further study of anti-NMDAR antibody and its related encephalitis would give essential clues for the research of schizophrenia, catatonia, and atypical psychosis. PMID:28223808

  10. Tyrosine phosphorylation of the N-Methyl-D-Aspartate receptor 2B subunit in spinal cord contributes to remifentanil-induced postoperative hyperalgesia: the preventive effect of ketamine

    Directory of Open Access Journals (Sweden)

    Cui Songqin

    2009-12-01

    Full Text Available Abstract Background Experimental and clinical studies showed that intraoperative infusionof remifentanil has been associated with postoperative hyperalgesia. Previous reports suggested that spinal N-methyl-D-aspartate (NMDA receptors may contribute to the development and maintenance of opioid-induced hyperalgesia. In the present study, we used a rat model of postoperative pain to investigate the role of tyrosine phosphorylation of NMDA receptor 2B (NR2B subunit in spinal cord in the postoperative hyperalgesia induced by remifentanil and the intervention of pretreatment with ketamine. Results Intraoperative infusion of remifentanil (0.04 mg/kg, subcutaneous significantly enhanced mechanical allodynia and thermal hyperalgesia induced by the plantar incision during the postoperative period (each lasting between 2 h and 48 h, which was attenuated by pretreatment with ketamine (10 mg/kg, subcutaneous. Correlated with the pain behavior changes, immunocytochemical and western blotting experiments in our study revealed that there was a marked increase in NR2B phosphorylation at Tyr1472 in the superficial dorsal horn after intraoperative infusion of remifentanil, which was attenuated by pretreatment with ketamine. Conclusions This study provides direct evidence that tyrosine phosphorylation of the NR2B at Tyr1472 in spinal dosal horn contributes to postoperative hyperalgesia induced by remifentanil and supports the potential therapeutic value of ketamine for improving postoperative hyperalgesia induced by remifentanil.

  11. Protective effects of N-methyl-D-aspartate receptor antagonism on VX-induced neuronal cell death in cultured rat cortical neurons.

    Science.gov (United States)

    Wang, Yushan; Weiss, M Tracy; Yin, Junfei; Tenn, Catherine C; Nelson, Peggy D; Mikler, John R

    2008-01-01

    Exposure of the central nervous system to organophosphorus (OP) nerve agents induces seizures and neuronal cell death. Here we report that the OP nerve agent, VX, induces apoptotic-like cell death in cultured rat cortical neurons. The VX effects on neurons were concentration-dependent, with an IC(50) of approximately 30 microM. Blockade of N-methyl-D-aspartate receptors (NMDAR) with 50 microM. D-2-amino-5-phosphonovalerate (APV) diminished 30 microM VX-induced total cell death, as assessed by alamarBlue assay and Hoechst staining. In contrast, neither antagonists of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) nor metabotropic glutamate receptors (mGluRs) had any effect on VX-induced neurotoxicity. VX-induced neuronal cell death could not be solely attributed to acetylcholinesterase (AChE) inhibition, since neither the reversible pharmacological cholinesterase inhibitor, physostigmine, nor the muscarinic receptor antagonist, atropine, affected VX-induced cell death. Importantly, APV was found to be therapeutically effective against VX-induced cell death up to 2 h post VX exposure. These results suggest that NMDARs, but not AMPARs or mGluRs, play important roles in VX-induced cell death in cultured rat cortical neurons. Based on their therapeutic effects, NMDAR antagonists may be beneficial in the treatment of VX-induced neurotoxicities.

  12. 抗NMDAR抗体脑炎研究进展%Research on the advances of anti-N-methyl-D-aspartate receptor (NMDAR)encephalitis

    Institute of Scientific and Technical Information of China (English)

    周晶; 秦新月

    2011-01-01

    抗N-甲基-M-天冬氨酸受体(N-methyl-D-aspartate receptor,NMDA)脑炎是近年来新发现的一类副肿瘤性边缘叶脑炎(limbic encephalitis,IE),病因及机制不详.该病发病率低,常发生于伴有卵巢畸胎瘤的年轻女性,临床表现多样,以初期的上感症状发展到精神异常、意识障碍、异常运动和自主神经功能紊乱、癫痫发作、中枢性通气功能障碍为常见表现,脑脊液常为炎性改变.MRI在大脑皮质或小脑可表现短暂异常或颞叶内侧高信号影改变.脑电图多为非特异性改变.血及脑脊液抗NMDA受体抗体阳性可确诊.包括肿瘤切除和免疫治疗、重症监护和物理康复在内的联合治疗为最佳治疗方案.本文就抗NMDA受体脑炎的研究进展做一综述.

  13. Anti-N-methyl-D-aspartate receptor encephalitis:A new limbic encephalitis%抗NMDAR脑炎:一种新型边缘叶脑炎

    Institute of Scientific and Technical Information of China (English)

    周晨光; 王建平

    2014-01-01

    抗N-甲基-M-天冬氨酸受体(N-methyl-D-aspartate receptor)脑炎是一种自2007年确认的由抗NMDA受体抗体介导的可治性新型边缘叶脑炎,好发于年轻女性,临床上主要表现为发展迅速的神经和精神障碍综合征,包括突出的精神行为异常、癫痫发作、异常运动、自主神经功能紊乱等,其中口面颌肌张力障碍和中枢性通气不足是该病的相对特征性表现.MRI检查无特异性改变,脑电图常提示弥漫性的异常,常规脑脊液检查无特异性,血和脑脊液中的NMDAR亚单位NR1抗体阳性可以明确诊断.对糖皮质激素、免疫球蛋白、血浆置换等免疫治疗及肿瘤切除反应良好.为更好地认识该疾病,本文对其临床特点及发病机制等做一综述.

  14. 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.

  15. 脑缺血时NMDA受体通过Src激酶和Ca2+/钙调蛋白依赖性蛋白激酶Ⅱ调控ERKs激活%N-methyl-D-aspartate receptors mediate diphosphorylation of extracellular signal-regulated kinases through Src family tyrosine kinases and Ca2+/calmodulin-dependent protein kinase Ⅱ in rat hippocampus after cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    吴辉文; 李洪福; 郭军

    2007-01-01

    目的 ERKs是钙依赖性激活蛋白,本研究旨在探讨钙依赖性蛋白激酶是否参与了脑缺血后ERK级联的调控.方法 采用四动脉结扎诱导大鼠前脑缺血,用免疫印迹的方法观察几个钙依赖性蛋白激酶含量及活性的变化.结果 致死性脑缺血以NMDA受体依赖的方式激活ERKs,并差异性上调Src和Ca2+/钙调蛋白依赖性蛋白激酶Ⅱ(CaMKⅡ)的活性.Src激酶和CaMKⅡ的抑制剂PP2和KN62能显著的阻止缺血诱导的ERKs激活.然而,缺血诱导的Src过度激活也伴随着ERKs的活性抑制.结论 致死性脑缺血刺激NMDA受体通过Src激酶和CaMKⅡ介导ERKs活性上调,但是脑缺血诱导的Src过度激活可能也参与了ERKs信号通路的负性调控.%Objective: Extracellular signal-regulated kinases (ERKs) can be activated by calcium signals. In this study, we investigated whether calcium-dependent kinases were involved in ERKs cascade activation after global cerebral ischemia.Methods Cerebral ischemia was induced by four-vessel occlusion, and the calcium-dependent proteins were detected by immunoblot. Results Lethal-simulated ischemia significantly resulted in ERKs activation in N-methyl-D-aspartate (NMDA)receptor-dependent manner, accompanying with differential upregulation of Src kinase and Ca2+/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) activities. With the inhibition of Src family tyrosine kinases or CaMKⅡ by administration of PP2or KN62, the phosphorylation of ERKs was impaired dramatically during post-ischemia recovery. However, ischemic challenge also repressed ERKs activity when Src kinase was excessively activated. Conclusions Src family tyrosine kinases and CaMKⅡ might be involved in the activation of ERKs mediated by NMDA receptor in response to acute ischemic stimuli in vivo, but the intense activation of Src kinase resulted from ischemia may play a reverse role in the ERKs cascade.

  16. Heteromerization of ligand binding domains of N-methyl-D-aspartate receptor requires both coagonists, L-glutamate and glycine.

    Science.gov (United States)

    Cheriyan, John; Mezes, Christina; Zhou, Ning; Balsara, Rashna D; Castellino, Francis J

    2015-01-27

    NMDA receptors (NMDAR) are voltage- and glutamate-gated heteromeric ion channels found at excitatory neuronal synapses, the functions of which are to mediate the mechanisms of brain plasticity and, thereby, its higher order functions. In addition to Glu, the activation of these heteromeric receptors requires Gly or d-Ser as a coagonist. However, it is not fully known as to why coagonism is required for the opening of NMDAR ion channels. We show herein that the ligand binding domains (LBD) of the GluN1 and GluN2A subunits of the NMDAR heterodimerize only when both coagonists, Glu and Gly/d-Ser, bind to their respective sites on GluN2 and GluN1. In the agonist-free state, these domains form homomeric interactions, which are disrupted by binding of their respective agonists. Also, in a heteromer formed by the LBDs, GluN2A is more sensitized to bind Glu, while the affinity of Gly for GluN1 remains unchanged. We thus provide direct evidence to show that coagonism is necessary for heteromeric pairing of LBDs, which is an essential step in forming functional ion channels in NMDARs.

  17. Intrathecal administration of roscovitine prevents remifentanil-induced postoperative hyperalgesia and decreases the phosphorylation of N-methyl-D-aspartate receptor and metabotropic glutamate receptor 5 in spinal cord.

    Science.gov (United States)

    Liu, Xiaojie; Liu, Yue; Zhang, Juan; Zhang, Wei; Sun, Yu-E; Gu, Xiaoping; Ma, Zhengliang

    2014-07-01

    N-methyl-D-aspartate receptor (NMDAR) and metabotropic glutamate receptor 5 (mGluR5) play an important role in nociceptive processing and central sensitization. Our previous study showed that tyrosine phosphorylation of NMDAR subunit 2B (NR2B) at Tyr1472 in spinal dorsal horn contributes to the postoperative hyperalgesia induced by remifentanil. Cyclin-dependent kinase 5 (Cdk5) has been implicated in synaptic plasticity, learning, memory and pain signaling via regulating the phosphorylation of NMDAR and mGluR5. In the present study, a rat model of postoperative pain was used to investigate the role of Cdk5 in spinal dorsal horn in remifentanil-induced hyperalgesia and the intervention of pretreatment with Cdk5 inhibitor roscovitine. Intraoperative infusion of remifentanil (0.04 mg/kg, subcutaneous) significantly enhanced mechanical allodynia and thermal hyperalgesia induced by plantar incision during the postoperative period (each lasting between 2 h and 48 h), which were attenuated by pretreatment with roscovitine. Correlated with the pain behavior changes, Western blotting revealed that there was a significant increase in the expression of Cdk5 and its activator p35/p25, and further the kinase activity of Cdk5 in spinal dorsal horn after intraoperative infusion of remifentanil. The phosphorylation of NR2A at Ser1232, the phosphorylation of NR2B at Tyr1472 and the phosphorylation of mGluR5 at Ser1167 were also significantly up-regulated. Furthermore, these increases were attenuated by pretreatment with roscovitine. These results suggested that Cdk5 may contribute to remifentanil-induced postoperative hyperalgesia via regulating the phosphorylation of NMDAR and mGluR5 in spinal dorsal horn. These findings provide experimental evidence for the further application of Cdk5 inhibitor in preventing remifentanil-induced hyperalgesia. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Chronic unpredictable stress before pregnancy reduce the expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor in hippocampus of offspring rats associated with impairment of memory.

    Science.gov (United States)

    Huang, Yuejun; Shi, Xuechuan; Xu, Hongwu; Yang, Hanhua; Chen, Tian; Chen, Sihong; Chen, Xiaodong

    2010-07-01

    To investigate the effect of stress before pregnancy on memory function and serum corticosterone (COR) levels, as well as the expression of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate (NMDA) 2A (NR2A) and 2B (NR2B) receptors in the hippocampus of the offspring rats when they were 2 months postnatally. Adult female Sprague-Dawley (SD) rats were divided randomly into two groups: control group (n = 8) and chronic unpredictable stress (CUS) group (n = 12). All rats were tested in the open field test and sucrose intake test before and after CUS. The memory function of their offspring were tested in the Morris water maze. Serum COR levels were determined by using a standard radioimmunoassay kit. The expression of BDNF, NR2A and NR2B in the hippocampus of the offspring rats were studied by immunoreactivity quantitative analysis and real-time RT-PCR. (1) Following CUS, reduced open field test activity and decreased sucrose consumption were observed relative to controls. (2) The Morris water maze task demonstrated increased escape latency in the offspring rats of CUS group relative to controls (P BDNF and NR2B in the offspring of CUS group was decreased in the CA3 and DG regions of the hippocampus compared to the control group offspring, but NR2A levels were not altered between the offspring of the two groups. (5) Real-time RT-PCR demonstrated that BDNF and NR2B mRNAs were significantly decreased in the offspring of the CUS group compared with the control group (P BDNF and NR2B in the hippocampus of offspring. These alterations are associated with impairment of memory in the adult offspring. These data suggest that, stress before pregnancy might have a profound influence on brain development of offspring, that may persist into and be manifested in adulthood.

  19. Dizocilpine (MK-801) induces distinct changes of N-methyl-D-aspartic acid receptor subunits in parvalbumin-containing interneurons in young adult rat prefrontal cortex.

    Science.gov (United States)

    Xi, Dong; Zhang, Wentong; Wang, Huai-Xing; Stradtman, George G; Gao, Wen-Jun

    2009-11-01

    N-methyl-D-aspartic acid receptor (NMDAR) hypofunction has long been implicated in schizophrenia and NMDARs on gamma-aminobutyric acid (GABA)ergic interneurons are proposed to play an essential role in the pathogenesis. However, controversial results have been reported regarding the regulation of NMDAR expression, and direct evidence of how NMDAR antagonists act on specific subpopulations of prefrontal interneurons is missing. We investigated the effects of the NMDAR antagonist dizocilpine (MK-801) on the expression of NMDAR subtypes in the identified interneurons in young adult rat prefrontal cortex (PFC) by using laser microdissection and real-time polymerase chain reaction, combined with Western blotting and immunofluorescent staining. We found that MK-801 induced distinct changes of NMDAR subunits in the parvalbumin-immunoreactive (PV-ir) interneurons vs. pyramidal neurons in the PFC circuitry. The messenger RNA (mRNA) expression of all NMDAR subtypes, including NR1 and NR2A to 2D, exhibited inverted-U dose-dependent changes in response to MK-801 treatment in the PFC. In contrast, subunit mRNAs of NMDARs in PV-ir interneurons were significantly down-regulated at low doses, unaltered at medium doses, and significantly decreased again at high doses, suggesting a biphasic dose response to MK-801. The differential effects of MK-801 in mRNA expression of NMDAR subunits were consistent with the protein expression of NR2A and NR2B subunits revealed with Western blotting and double immunofluorescent staining. These results suggest that PV-containing interneurons in the PFC exhibit a distinct responsiveness to NMDAR antagonism and that NMDA antagonist can differentially and dose-dependently regulate the functions of pyramidal neurons and GABAergic interneurons in the prefrontal cortical circuitry.

  20. The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats.

    Science.gov (United States)

    Buchan, A; Li, H; Pulsinelli, W A

    1991-04-01

    The neuroprotective effects of dizocilipine maleate (MK-801), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor/channel, were tested in the 4-vessel occlusion rat model of forebrain ischemia. Adult Wistar rats, treated intraperitoneally with MK-801 or saline using several different treatment paradigms were subjected to 5 (n = 208) or 15 (n = 62) min of severe, transient forebrain ischemia. In saline-treated animals, 15 min of ischemia (n = 13) produced extensive and consistent loss of pyramidal neurons in the CA1 zone of hippocampus. The degree and distribution of cell loss were not reduced by single dose preischemic administration of MK-801 at 1 (n = 7), 2.5 (n = 4), or 5 mg/kg (n = 8). In other animals subjected to 15 min of forebrain ischemia, multiple doses of MK-801 (5, 2.5, and 2.5 mg/kg) given immediately and at approximately 8 and 20 hr after cerebral reperfusion (n = 5) did not alter CA1 injury compared to saline-treated controls (n = 5). Five minutes of forebrain ischemia in saline-treated animals, (n = 82) resulted in significantly fewer (p less than 0.001) dead CA1 pyramidal cells and a greater variance compared to animals subjected to 15 min of ischemia. Power analysis of the preliminary saline-treated animals subjected to 5 min of ischemia (n = 22) indicated that 60 animals per group were necessary to detect a 15% difference between MK-801 and vehicle-treated groups. Multidose treatment with MK-801 (1 mg/kg) given 1 hr prior to 5 min of ischemia (n = 60) and again at approximately 8 and 16 hr after recirculation failed to attenuate hippocampal injury.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. 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

    2017-01-01

    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, r2 = 0.928–0.988,  = 0.894–0.954, RMSE = 0.002–0.412, s = 0.001–0.214), and the predicted pKi values by SVM-Score were found to be in good agreement with the observed values for the training samples (n = 24, r2 = 0.967,  = 0.899, RMSE = 0.295, s = 0.170) and test samples (n = 13, q2 = 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.

  2. 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.

  3. N-Methyl-D-aspartate receptors in the ventral tegmental area are involved in retrieval of inhibitory avoidance memory by nicotine.

    Science.gov (United States)

    Ahmadi, Shamseddin; Zarrindast, Mohammad Reza; Nouri, Maryam; Haeri-Rohani, Ali; Rezayof, Ameneh

    2007-10-01

    The interaction of opiate, cholinergic, glutamatergic and (possibly) dopaminergic inputs in the ventral tegmental area (VTA) influencing a learned behavior is certainly a topic of great interest. In the present study, the effect of intra-VTA administration of N-methyl-d-aspartate (NMDA) receptor agents on nicotine's effect in morphine state-dependent learning was investigated. An inhibitory avoidance (IA) task was used for memory assessment in male Wistar rats. Subcutaneous (s.c.) administration of morphine (5 and 7.5mg/kg) immediately after training decreased IA response on the test day, which was reinstated by pre-test administration of the same doses of the opioid; this is known as state-dependency. Moreover, pre-test administration of nicotine (0.2, 0.4 and 0.6 mg/kg, s.c.) also reversed the decrease in IA response because of post-training morphine (5mg/kg). Here, we also show that when infused into the VTA before testing, NMDA (0.01 and 0.1 microg/rat) reverse the post-training morphine effect on memory. In addition, the sub-effective doses of NMDA (0.0001 and 0.001 microg/rat) in combination with a low dose of nicotine (0.1mg/kg) which had no effects by themselves, synergistically improved retrieval of IA memory on the test day. In contrast, pre-test administration of a competitive NMDA receptor antagonist D-AP5 (0.5, 1 and 2 microg/rat) which had no effect alone prevented the nicotine reversal of morphine effect on memory. Our data indicate that NMDA receptors in the VTA are involved in the reversing effect of nicotine on morphine induced state-dependency.

  4. Prenatal Stress Induced Gender-specific Alterations of N-Methyl-D-Aspartate Receptor Subunit Expression and Response to Aβ in Offspring Hippocampal Cells.

    Science.gov (United States)

    Fang, Yuan; Li, Hui; Chang, Lirong; Song, Yizhi; Ma, Longhui; Lu, Liying; Du, Zunshu; Li, Yan; Liu, Jinping; Wu, Yan

    2017-08-27

    Prenatal stress (PS) is one of adverse life events during pregnancy, which may increase vulnerability to cognitive impairment in adult offspring. Aβ synaptotoxicity is one important pathological factor for cognitive impairment, and PS-induced cognitive disorder is closely associated with N-Methyl-D-Aspartate receptor (NMDAR), which acts as a key mediator of Aβ synaptotoxicity. In the present study, we tried to explore whether PS affects offspring's Aβ levels and NMDAR subunit expression in a gender-specific manner in hippocampal CA and DG subregions, and whether PS affects synaptic proteins and NMDAR subunit expression in cultured offspring hippocampal cells exposed to Aβ. Pregnant SD rats with restraint stress from gestation day 8 to 20 were used as PS model. Morris water maze, ELISA, immunofluorescence and western blot were tested on postnatal day 90 in male and female PS offspring. Our results showed that female offspring is more vulnerable to PS-induced cognitive impairment. Surprisingly, PS enhanced Aβ1-40 levels in the hippocampal DG subregion of male offspring. Furthermore, WB results implied that the decreased GluN2A in CA of female may contribute to the PS-induced cognitive impairment, while in DG, the increased GluN2A and decreased GluN2B contributed to protective effects against Aβ. Interestingly, we found PS could alleviate Aβ synaptotoxicity in male offspring's hippocampal cells. Overall, our results provided a fundamental understanding of PS-induced gender-specific alterations of NMDAR subunit expression and the susceptibility to Aβ, and paved the road for the development of timely preventive interventions on cognitive disorders of PS offspring. Copyright © 2017. Published by Elsevier B.V.

  5. MicroRNA-217 suppresses homocysteine-induced proliferation and migration of vascular smooth muscle cells via N-methyl-D-aspartic acid receptor inhibition.

    Science.gov (United States)

    Duan, Hongyan; Li, Yongqiang; Yan, Lijie; Yang, Haitao; Wu, Jintao; Qian, Peng; Li, Bing; Wang, Shanling

    2016-10-01

    Hyperhomocysteine has become a critical risk for atherosclerosis and can stimulate proliferation and migration of vascular smooth muscle cells (VSMCs). N-methyl-D-aspartic acid receptor (NMDAR) is a receptor of homocysteine and mediates the effects of homocysteine on VSMCs. Bioinformatics analysis has shown NMDAR is a potential target of microRNA-217 (miR-217), which exerts multiple functions in cancer tumorigenesis and carotid plaque progression. In this study, we sought to investigate the role of miR-217 in VSMCs phenotype transition under homocysteine exposure and elucidate its effect on atherosclerotic plaque formation. After treating with several doses of homocysteine (0-8 × 10(-4)  mol/L) for 24 hours, the expression of miR-217 in HA-VSMCs and rat aortic VSMCs was not altered. Intriguingly, the expression of NMDAR mRNA and protein was reduced by homocysteine in a dose-dependent manner. Transfection of miR-217 mimic significantly inhibited the proliferation and migration of VSMCs with homocysteine treatment, while transfection of miR-217 inhibitor promoted VSMCs migration. Moreover, miR-217 mimic down-regulated while miR-217 inhibitor up-regulated NMDAR protein expression but not NMDAR mRNA expression. Through luciferase reporter assay, we showed that miR-217 could directly bind to the 3'-UTR of NMDAR. MiR-217 mimic transfection also released the inhibition of cAMP-response element-binding protein (CREB)-PGC-1α signalling induced by homocysteine. Additionally, restoration of PGC-1α expression via AdPGC-1α infection markedly suppressed VSMCs proliferation through the degradation of NADPH oxidase (NOX1) and reduction of reactive oxygen species (ROS). Collectively, our study identified the role of miR-217 in regulating VSMCs proliferation and migration, which might serve as a target for atherosclerosis therapy.

  6. Pharmacokinetics, metabolism and excretion of [(14)C]-lanicemine (AZD6765), a novel low-trapping N-methyl-d-aspartic acid receptor channel blocker, in healthy subjects.

    Science.gov (United States)

    Guo, Jian; Zhou, Diansong; Grimm, Scott W; Bui, Khanh H

    2015-03-01

    1.(1S)-1-phenyl-2-(pyridin-2-yl)ethanamine (lanicemine; AZD6765) is a low-trapping N-methyl-d-aspartate (NMDA) channel blocker that has been studied as an adjunctive treatment in major depressive disorder. The metabolism and disposition of lanicemine was determined in six healthy male subjects after a single intravenous infusion dose of 150 mg [(14)C]-lanicemine. 2.Blood, urine and feces were collected from all subjects. The ratios of Cmax and AUC(0-∞) of lanicemine to plasma total radioactivity were 84 and 66%, respectively, indicating that lanicemine was the major circulating component with T1/2 at 16 h. The plasma clearance of lanicemine was 8.3 L/h, revealing that lanicemine is a low-clearance compound. The mean recovery of radioactivity from urine was 93.8% of radioactive dose. 3.In urine samples, 10 metabolites of lanicemine were identified. Among which, an O-glucuronide conjugate (M1) was the most abundant metabolite (∼11% of the dose in excreta). In plasma, the circulatory metabolites were identified as a para-hydroxylated metabolite (M1), an O-glucuronide (M2), an N-carbamoyl glucuronide (M3) and an N-acetylated metabolite (M6). The average amount of each of metabolite was less than 4% of total radioactivity detected in plasma or urine. 4.In conclusion, lanicemine is a low-clearance compound. The unchanged drug and metabolites are predominantly eliminated via urinary excretion.

  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. Identification of N-methyl-D-aspartic acid (NMDA) receptor subtype-specific binding sites that mediate direct interactions with scaffold protein PSD-95.

    Science.gov (United States)

    Cousins, Sarah L; Stephenson, F Anne

    2012-04-13

    N-methyl-D-aspartate (NMDA) neurotransmitter receptors and the postsynaptic density-95 (PSD-95) membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins are integral components of post-synaptic macromolecular signaling complexes that serve to propagate glutamate responses intracellularly. Classically, NMDA receptor NR2 subunits associate with PSD-95 MAGUKs via a conserved ES(E/D)V amino acid sequence located at their C termini. We previously challenged this dogma to demonstrate a second non-ES(E/D)V PSD-95-binding site in both NMDA receptor NR2A and NR2B subunits. Here, using a combination of co-immunoprecipitations from transfected mammalian cells, yeast two-hybrid interaction assays, and glutathione S-transferase (GST) pulldown assays, we show that NR2A subunits interact directly with PSD-95 via the C-terminal ESDV motif and additionally via an Src homology 3 domain-binding motif that associates with the Src homology 3 domain of PSD-95. Peptide inhibition of co-immunoprecipitations of NR2A and PSD-95 demonstrates that both the ESDV and non-ESDV sites are required for association in native brain tissue. Furthermore, we refine the non-ESDV site within NR2B to residues 1149-1157. These findings provide a molecular basis for the differential association of NMDA receptor subtypes with PSD-95 MAGUK scaffold proteins. These selective interactions may contribute to the organization, lateral mobility, and ultimately the function of NMDA receptor subtypes at synapses. Furthermore, they provide a more general molecular mechanism by which the scaffold, PSD-95, may discriminate between potential interacting partner proteins.

  9. Identification of N-Methyl-d-aspartic Acid (NMDA) Receptor Subtype-specific Binding Sites That Mediate Direct Interactions with Scaffold Protein PSD-95*

    Science.gov (United States)

    Cousins, Sarah L.; Stephenson, F. Anne

    2012-01-01

    N-methyl-d-aspartate (NMDA) neurotransmitter receptors and the postsynaptic density-95 (PSD-95) membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins are integral components of post-synaptic macromolecular signaling complexes that serve to propagate glutamate responses intracellularly. Classically, NMDA receptor NR2 subunits associate with PSD-95 MAGUKs via a conserved ES(E/D)V amino acid sequence located at their C termini. We previously challenged this dogma to demonstrate a second non-ES(E/D)V PSD-95-binding site in both NMDA receptor NR2A and NR2B subunits. Here, using a combination of co-immunoprecipitations from transfected mammalian cells, yeast two-hybrid interaction assays, and glutathione S-transferase (GST) pulldown assays, we show that NR2A subunits interact directly with PSD-95 via the C-terminal ESDV motif and additionally via an Src homology 3 domain-binding motif that associates with the Src homology 3 domain of PSD-95. Peptide inhibition of co-immunoprecipitations of NR2A and PSD-95 demonstrates that both the ESDV and non-ESDV sites are required for association in native brain tissue. Furthermore, we refine the non-ESDV site within NR2B to residues 1149–1157. These findings provide a molecular basis for the differential association of NMDA receptor subtypes with PSD-95 MAGUK scaffold proteins. These selective interactions may contribute to the organization, lateral mobility, and ultimately the function of NMDA receptor subtypes at synapses. Furthermore, they provide a more general molecular mechanism by which the scaffold, PSD-95, may discriminate between potential interacting partner proteins. PMID:22375001

  10. Mice heterozygous for neurotrophin-3 display enhanced vulnerability to excitotoxicity in the striatum through increased expression of N-methyl-D-aspartate receptors.

    Science.gov (United States)

    Torres-Peraza, J; Pezzi, S; Canals, J M; Gavaldà, N; García-Martínez, J M; Pérez-Navarro, E; Alberch, J

    2007-01-19

    The striatum is one of the brain areas most vulnerable to excitotoxicity, a lesion that can be prevented by neurotrophins. In the present study, intrastriatal injection of the N-methyl-d-aspartate receptor (NMDAR) agonist quinolinate (QUIN) was performed in mice heterozygous for neurotrophin-3 (NT3 +/-) or brain-derived neurotrophic factor (BDNF +/-) to analyze the role of endogenous neurotrophins on the regulation of striatal neurons susceptibility to excitotoxic injury. QUIN injection induced a decrease in dopamine- and cyclic AMP-regulated phosphoprotein of 32 kDa (DARPP-32) protein levels that was higher in NT-3 +/- than in BDNF+/- or wild type animals. This enhanced susceptibility was specific for enkephalin- and tachykinin-positive projection neurons, and also for parvalbumin-positive interneurons. However the excitotoxic damage in large interneurons was not modified in NT-3 +/- mice compared with wild type animals. This effect can be related to the regulation of NMDARs by endogenous NT-3. Thus, our results show that there is an age-dependent regulation of NMDAR subunits NR1 and NR2A, but not NR2B, in NT-3 +/- mice. The deficit of endogenous NT-3 induced a decrease in NR1 and NR2A subunits at postnatal day (P) 0 and P3 mice respectively, whereas an upregulation was observed in 12 week old NT-3 +/- mice. This differential effect was also observed after administration of exogenous NT-3. In primary striatal cultures, NT-3 treatment induced an enhancement in NR2A, but not NR2B, protein levels. However, intrastriatal grafting of NT-3 secreting-cells in adult wild type mice produced a down-regulation of NR2A subunit. In conclusion, NT-3 regulates the expression of NMDAR subunits modifying striatal neuronal properties that confers the differential vulnerability to excitotoxicity in projection neurons and interneurons in the striatum.

  11. N-methyl-D-aspartate receptor NR2B subunit involved in depression-like behaviours in lithium chloride-pilocarpine chronic rat epilepsy model.

    Science.gov (United States)

    Peng, Wei-Feng; Ding, Jing; Li, Xin; Fan, Fan; Zhang, Qian-Qian; Wang, Xin

    2016-01-01

    Depression is a common comorbidity in patients with epilepsy with unclear mechanisms. This study is to explore the role of glutamate N-methyl-D-aspartate (NMDA) receptor NR1, NR2A and NR2B subunits in epilepsy-associated depression. Lithium chloride (Licl)-pilocarpine chronic rat epilepsy model was established and rats were divided into epilepsy with depression (EWD) and epilepsy without depression (EWND) subgroups based on forced swim test. Expression of NMDA receptor NR1, NR2A and NR2B subunits was measured by western blot and immunofluorescence methods. The immobility time (IMT) was significantly greater in Licl-pilocarpine model group than in Control group, which was also greater in EWD group than in EWND group. No differences of spontaneous recurrent seizure (SRS) counts over two weeks and latency were found between EWD and EWND groups. The number of NeuN positive cells was significantly less in Licl-pilocarpine model group than in Control group, but had no difference between EWD and EWND groups. The ratios of phosphorylated NR1 (p-NR1)/NR1 and p-NR2B/NR2B were significantly greater in the hippocampus in EWD group than in EWND group. Moreover, the expression of p-NR1 and p-NR2B in the CA1 subfield of hippocampus were both greater in Licl-pilocarpine model group than Control group. Selective blockage of NR2B subunit with ifenprodil could alleviate depression-like behaviours of Licl-pilocarpine rat epilepsy model. In conclusion, glutamate NMDA receptor NR2B subunit was involved in promoting depression-like behaviours in the Licl-pilocarpine chronic rat epilepsy model and might be a target for treating epilepsy-associated depression.

  12. 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 (pimmobility score compared with saline control. Furthermore, pre-treatment with acute ketamine significantly enhanced by the fluoxetine-induced decrease in immobility score. In contrast, pre-treatment with NMDA (150mg/kg) significantly (pimmobility 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

  13. N-Methyl-D-aspartate receptor antibody could be a cause of catatonic symptoms in psychiatric patients: case reports and methods for detection

    Directory of Open Access Journals (Sweden)

    Tsutsui K

    2017-02-01

    Full Text Available Ko Tsutsui,1 Takashi Kanbayashi,1,2 Manabu Takaki,3 Yuki Omori,1 Yumiko Imai,4 Seiji Nishino,5 Keiko Tanaka,6 Tetsuo Shimizu1,2 1Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, 2International Institute for Integrative Sleep Medicine (WPI-IIIS, University of Tsukuba, Tsukuba, 3Department of Neuropsychiatry, Okayama University, Okayama, 4Biological Informatics and Experimental Therapeutics, Akita University Graduate School of Medicine, Akita, Japan; 5Sleep and Circadian Neurobiology Laboratory, Stanford University School of Medicine, Palo Alto, California, USA; 6Brain Research Institute, Niigata University, Niigata, Japan Abstract: The symptoms of catatonia have been reported to be similar to the initial symptoms of anti-N-methyl-D-aspartate receptor (NMDAR encephalitis. Subsequently, this autoimmune limbic encephalitis has been noticed by many psychiatrists. For a differential diagnosis of catatonic state, it is important to detect anti-NMDAR encephalitis. This encephalitis is expected to be in remission by early detection and treatment. We should be more cautious about catatonic symptoms of schizophrenia. When a patient is being doubted with encephalitis, we should screen for anti-NMDAR antibodies in cerebrospinal fluid samples using a cell-based assay. We describe the methods of NMDAR antibody detection and the etiology of this encephalitis with case reports. Two representative cases with catatonia and non-catatonia (brief psychotic disorder were reported. Schizophrenia is a general, heterogeneous, and complicated disorder, and its pathophysiology is unknown. There is an established evidence of NMDAR hypofunction, which is the functional disconnection of the central component; this is one of the most recognized models for schizophrenia. Furthermore, it is said that autoimmune mechanisms have been involved, at least in subgroups of schizophrenia patients. Further study of anti-NMDAR antibody and its related

  14. Effects of Augmenting N-Methyl-D-Aspartate Receptor Signaling on Working Memory and Experience-Dependent Plasticity in Schizophrenia: An Exploratory Study Using Acute d-cycloserine.

    Science.gov (United States)

    Forsyth, Jennifer K; Bachman, Peter; Mathalon, Daniel H; Roach, Brian J; Ye, Elissa; Asarnow, Robert F

    2017-09-01

    Cognitive deficits in schizophrenia have been hypothesized to reflect N-methyl-D-aspartate receptor (NMDAR) dysfunction. However, the mechanisms through which the NMDAR contributes to individual cognitive functions differ. To explore how NMDAR signaling relates to specific cognitive deficits in schizophrenia, we tested the effects of enhancing NMDAR signaling on working memory and experience-dependent plasticity using d-cycloserine (DCS). Plasticity was assessed using an EEG paradigm that utilizes high-frequency visual stimulation (HFvS) to induce neural potentiation, and 2 learning tasks, the information integration (IIT) and weather prediction (WPT) tasks. Working memory was assessed using an N-back task. Forty-five schizophrenia patients were randomized to receive a single 100 mg DCS dose (SZ-DCS; n = 24) or placebo (SZ-PLC; n = 21) in a double-blind, between-groups design. Testing occurred on a single day after placebo or DCS administration; baseline values were not obtained. DCS did not affect plasticity, as indicated by similar neural potentiation, and similar IIT and WPT learning between groups. However, among patients who successfully engaged in the working memory task (ie, performed above chance), SZ-DCS (n = 17) showed superior 2-back performance compared to SZ-PLC (n = 16). Interestingly, SZ-DCS also showed larger pre-HFvS neural responses during the LTP task. Notably, this pattern of DCS effects is the opposite of those found in our prior study of healthy adults. Results are consistent with target engagement of the NMDAR by DCS, but suggest that NMDAR signaling was not translated into synaptic plasticity changes in schizophrenia. Results highlight the importance of considering how distinct NMDAR-associated processes contribute to individual cognitive deficits in schizophrenia. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  15. 儿童抗N-甲基-D-天冬氨酸受体脑炎%Anti-N-methyl-D-aspartate receptor encephalitis in children

    Institute of Scientific and Technical Information of China (English)

    陈晨

    2013-01-01

    抗N-甲基-D-天冬氨酸受体(N-methyl-D-asparate receptor,NMDAR)脑炎是免疫介导的中枢神经系统综合征,主要临床表现有精神症状、运动障碍、抽搐发作等,常被误诊为病毒性脑炎,与肿瘤尤其卵巢畸胎瘤关系密切;儿童患病率高,抗NMDAR抗体是其较特异的检查;治疗主要为免疫抑制,一线治疗为激素、免疫球蛋白、血浆置换,二线治疗主要包括生物制剂、细胞毒药物;早期诊断及治疗对神经系统的恢复至关重要,总体预后良好.%Anti-N-methyl-D-aspartate receptor encephalitis is an autoimmune syndrome of central nervous system.The main clinical manifestations include psychiatric symptoms,movement disorders and seizures.It is often misdiagnosed as viral encephalitis.Tumors,especially the ovarian teratoma,play an important role in the disease.The prevalence in children is beyond imagination.Anti-NMDAR antibodies are specific diagnostic tests.Immune suppression is the main treatment.The first-line treatments include corticosteroids,intravenous immunoglobulin,and plasmapheresis.The second-line treatments include biological agents and cytotoxic drugs.Early diagnosis and treatment are essential for neurologic recovery.Overall prognosis is good.

  16. The uncompetitive N-methyl-D-aspartate antagonist memantine reduces binge-like eating, food-seeking behavior, and compulsive eating: role of the nucleus accumbens shell.

    Science.gov (United States)

    Smith, Karen L; Rao, Rahul R; Velázquez-Sánchez, Clara; Valenza, Marta; Giuliano, Chiara; Everitt, Barry J; Sabino, Valentina; Cottone, Pietro

    2015-03-13

    Binge-eating disorder is characterized by excessive, uncontrollable consumption of palatable food within brief periods of time. The role of the glutamatergic N-methyl-D-aspartate (NMDA) receptor system in hedonic feeding is poorly understood. The aim of this study was to characterize the effects of the uncompetitive NMDA receptor antagonist memantine on palatable food-induced behavioral adaptations using a rat model, which mimics the characteristic symptomatology observed in binge-eating disorder. For this purpose, we allowed male Wistar rats to respond to obtain a highly palatable, sugary diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day, under a fixed-ratio 1 (FR1) schedule of reinforcement. Upon stabilization of food responding, we tested the effects of memantine on the Chow and Palatable food groups' intake. Then, we tested the effects of memantine on food-seeking behavior, under a second-order schedule of reinforcement. Furthermore, we investigated the effects of memantine on the intake of food when it was offered in an aversive, bright compartment of a light/dark conflict test. Finally, we evaluated the effects of memantine on FR1 responding for food, when microinfused into the nucleus accumbens (NAcc) shell or core. Memantine dose-dependently decreased binge-like eating and fully blocked food-seeking behavior and compulsive eating, selectively in the Palatable food group. The drug treatment did not affect performance of the control Chow food group. Finally, intra-NAcc shell, but not core, microinfusion of memantine decreased binge-like eating. Together, these findings substantiate a role of memantine as a potential pharmacological treatment for binge-eating disorder.

  17. N-甲基-D-天门冬氨酸和非N-甲基-D-天门冬氨酸类受体在新生大鼠延髓脑片呼吸节律性放电中的作用%Roles of N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors in the respiratory rhythmical discharge of the hypoglossal nerve in the brainstem slice from neonatal rats

    Institute of Scientific and Technical Information of China (English)

    潘秉兴; 吴中海; 王宁黔

    2001-01-01

    目的探讨N-甲基-D-天门冬氨酸(N-methyl-D-aspartate, NMDA)和非NMDA类受体在基本呼吸节律发生和调节中的作用。方法在新生SD大鼠离体延髓脑片上记录舌下神经的呼吸节律性放电活动,在改良的Krebs液中加入兴奋性氨基酸类递质及相应的拮抗剂, 观察其RRDA的影响。结果使用非NMDA受体激动剂海人酸(Kainic acid, KA)后,可见呼吸周期及呼气时间有所延长, NMDA受体激动剂对呼吸活动则没有明显影响(P>0.1);相应的拮抗剂6-氰基-7-硝基喹恶啉土卫四(6,7-dinitroquinoxaline-2, 3-dione, DNQX)和2-氨基磷酸戊酸(D-2-amino-5- phosphonopentanoic, AP5)均可使放电频率和积分幅值明显降低吸气时间显著缩短(P<0.01),DNQX同时可致呼吸周期和呼气时间明显缩短(P<0.05)。结论在哺乳动物基本呼吸节律的产生和调节中,NMDA类受体主要对呼吸活动的强度产生调节作用;而非NMDA类受体不仅可以影响呼吸的强度,同时对呼吸的频率也发挥调节作用。%Objective To study the role of N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the generation and modulation of basic respiratory rhythm. Methods Respiratory rhythmical discharge activity (RRDA) of the hypoglossal nerve was recorded by suction electrode on the brainstem slices isolated from the neonatal rats, and the effects of the excitatory amino acids and its antagonists on the RRDA were investigated by adding these drugs into the modified Kreb's solution perfusing the brainstem slices. Results After application of the non-NMDA receptors agonist KA, it was found that the respiratory cycle and the expiratory time were slightly lengthened, but the NMDA receptor agonist NMDA had no effect on the RRDA. Both of the mutual antagonist DNQX and AP5 remarkably decreased the discharge frequency and the integral amplitude, accompanied by the shortening of the inspiratory time; DNQA simultaneously shortened the respiratory cycle and the expiratory time

  18. Expression and distribution of N-methyl-D-aspartate receptor 2A/B in anterior thalamic nuclei and hippocampus of rats

    Institute of Scientific and Technical Information of China (English)

    Kai Fan; Xiaokai Ma; Bin Wang

    2006-01-01

    BACKGROUND: Several immunohistochemical and in situ hybridization studies have demonstrated the localization of various N-methyl-D-aspartate receptors (NMDAR) subunits in certain brain regions of mammals. These studies indicate that NMDAR are widespread in mammal brains, especially in cerebral cortex and hippocam pus.OBJECTIVE: To validate whether or not the NMDAR 2A/B localizes in rat anterior thalamic nuclei (ATN) and hippocampus, and observe its expression and distribution characteristics. DESIGN: Controlled study.SETTING: Department of Anatomy, College of Basic Medicine, Dalian Medical University. MATERIALS: Ten adult Sprague-Dawley rats of either gender, weighing 180-250 g, of clean grade, were provided by the Experimental Animal Center, Dalian Medical University. Rabbit polyclonal antibody to NMDAR 2A/B was the product of Chemicon Company.METHODS: This experiment was carried out in the Department of Anatomy, College of Basic Medicine, Dalian Medical University from September 2005 to May 2006. The anesthetized SD rats were transcardially perfused with 100 mL phosphate buffer solution, then perfused with paraformaldehyde through ascending aorta. After 30 minutes, their brains were harvested and post-fixed in PFA at 4 ℃ overnight. Hippocampal and anterior thalamic nuclear tissues were sliced in the coronal plane at 40 μm. The sections were stained by immunohistochemical ABC method, visualized by DAB, dehydrated routinely, performed transparence and coverslipped. Expression and distribution of NMDAR 2A/B in ATN and hippocampus of rats were observed under an optical microscope.MAIN OUTCOME MEASURES: Distribution and expression of NMDAR 2A/B in ATN and hippocampus of rats, RESULTS: NMDAR 2A/B positive neurons localized in ATN, pyramidal layer of hippocampus and granular layer of dentate gyrus in a compact and orderly pattern, and immunostained intensely. NMDAR 2A/B receptor positive neurons scattered with lower intensity of immunolabeling in other regions of

  19. Sensitivity of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials and synaptic plasticity to TCN 201 and TCN 213 in rat hippocampal slices.

    Science.gov (United States)

    Izumi, Yukitoshi; Zorumski, Charles F

    2015-02-01

    Whereas ifenprodil has been used as a selective GluN1/GluN2B (NR1/NR2B, B-type) receptor antagonist to distinguish between GluN2B (NR2B) and GluN2A (NR2A)-containing N-methyl-d-aspartate receptors (NMDARs), TCN 201 (3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide) and TCN 213 [N-(cyclohexylmethyl)-2-[{5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio]acetamide] have been found to be selective GluN1/GluN2A (NR1/NR2A, A-type) antagonists. Based on the premise that A- and B-types are major synaptic NMDARs, we examined whether inhibition of NMDAR excitatory postsynaptic potentials (EPSPs) by the TCN compounds and ifenprodil are complementary. Contrary to this prediction, inhibition of NMDAR EPSPs by the TCN compounds and ifenprodil were largely overlapping in the CA1 region of hippocampal slices from 30-day-old rats. After partial inhibition by ifenprodil, TCN compounds produced little further suppression of NMDAR EPSPs. Similarly, after partial inhibition by TCN compounds ifenprodil failed to further suppress NMDAR EPSPs. However, low micromolar d-2-amino-5-phosphonovalerate, a competitive NMDAR antagonist, which alone only partially inhibits NMDAR EPSPs, markedly suppresses residual NMDAR responses in the presence of ifenprodil or the TCNs, suggesting that low 2-amino-5-phosphonovalerate antagonizes both ifenprodil- and TCN-insensitive synaptic NMDARs. These observations can be most readily interpreted if ifenprodil and TCNs act on a similar population of synaptic NMDARs. Recent lines of evidence suggest that the majority of hippocampal synaptic NMDARs are triheteromers. If so, modulation of GluN2A, and not just GluN2B NMDARs, could dampen long-term depression (LTD). Indeed, both TCNs, like ifenprodil, blocked LTD, suggesting the involvement of ifenprodil- and TCN-sensitive NMDARs in LTD induction. However, the TCNs plus ifenprodil failed to inhibit long-term potentiation (LTP), suggesting that neither ifenprodil- nor TCN

  20. Novel class of amino acid antagonists at non-N-methyl-D-aspartic acid excitatory amino acid receptors. Synthesis, in vitro and in vivo pharmacology, and neuroprotection

    Energy Technology Data Exchange (ETDEWEB)

    Krogsgaard-Larsen, P.; Ferkany, J.W.; Nielsen, E.O.; Madsen, U.; Ebert, B.; Johansen, J.S.; Diemer, N.H.; Bruhn, T.; Beattie, D.T.; Curtis, D.R. (Royal Danish School of Pharmacy, Copenhagen (Denmark))

    1991-01-01

    The isoxazole amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) (1), which is a highly selective agonist at the AMPA subtype of excitatory amino acid (EAA) receptors, has been used as a lead for the development of two novel EAA receptor antagonists. One of the compounds, 2-amino-3-(3-(carboxymethoxy)-5-methylisoxazol-4-yl)propionic acid (AMOA, 7), was synthesized via O-alkylation by ethyl chloroacetate of the amino acid protected AMPA derivative 4. The other compound, 2-amino-3-(2-(3-hydroxy-5-methylisoxazol-4-yl)-methyl-5-methyl-3-+ ++oxoisoxazolin -4-yl)propionic acid (AMNH, 14) was synthesized with use of 4-(chloromethyl)-3-methoxy-5-methylisoxazole (8) as the starting material. The intermediate 4-(chloromethyl)-2-(3-methoxy-5-methylisoxazol-4-yl)methyl-5-me thylisoxazolin- 3-one (11) was converted into the acetamidomalonate (12), which was stepwise deprotected to give 14. Compounds 7 and 14 were stable in aqueous solution at pH values close to physiological pH. Neither 7 nor 14 showed detectable affinities for the receptor, ion channel, or modulatory sites of the N-methyl-D-aspartic acid (NMDA) receptor complex. Quantitative receptor autoradiographic and conventional binding techniques were used to study the affinities of 7 and 14 for non-NMDA receptor sites. Both compounds were inhibitors of the binding of (3H)AMPA (IC50 = 90 and 29 microM, respectively). Compounds 14 and 7 were both very weak inhibitors of the high-affinity binding of radioactive kainic acid ((3H)KAIN). Compound 14, but not 7, was, however, shown to be an inhibitor of low-affinity (3H)KAIN binding as determined in the presence of 100 mM calcium chloride. In the rat cortical slice preparation, 7 was shown to antagonize excitation induced by 1 with some selectivity, whereas 14 proved to be a rather selective antagonist of KAIN-induced excitation.

  1. Prazosin blocks the glutamatergic effects of N-methyl-D-aspartic acid on lordosis behavior and luteinizing hormone secretion in the estrogen-primed female rat

    Directory of Open Access Journals (Sweden)

    Landa A.I.

    2006-01-01

    Full Text Available We have observed that intracerebroventricular (icv injection of selective N-methyl-D-aspartic acid (NMDA-type glutamatergic receptor antagonists inhibits lordosis in ovariectomized (OVX, estrogen-primed rats receiving progesterone or luteinizing hormone-releasing hormone (LHRH. When NMDA was injected into OVX estrogen-primed rats, it induced a significant increase in lordosis. The interaction between LHRH and glutamate was previously explored by us and another groups. The noradrenergic systems have a functional role in the regulation of LHRH release. The purpose of the present study was to explore the interaction between glutamatergic and noradrenergic transmission. The action of prazosin, an alpha1- and alpha2b-noradrenergic antagonist, was studied here by injecting it icv (1.75 and 3.5 µg/6 µL prior to NMDA administration (1 µg/2 µL in OVX estrogen-primed Sprague-Dawley rats (240-270 g. Rats manually restrained were injected over a period of 2 min, and tested 1.5 h later. The enhancing effect induced by NMDA on the lordosis/mount ratio at high doses (67.06 ± 3.28, N = 28 when compared to saline controls (6 and 2 µL, 16.59 ± 3.20, N = 27 was abolished by prazosin administration (17.04 ± 5.52, N = 17, and 9.33 ± 3.21, N = 20, P < 0.001 for both doses. Plasma LH levels decreased significantly only with the higher dose of prazosin (1.99 ± 0.24 ng/mL, N = 18, compared to saline-NMDA effect, 5.96 ± 2.01 ng/mL, N = 13, P < 0.05. Behavioral effects seem to be more sensitive to the alpha-blockade than hormonal effects. These findings strongly suggest that the facilitatory effects of NMDA on both lordosis and LH secretion in this model are mediated by alpha-noradrenergic transmission.

  2. [Review of the psychiatric aspects of anti-NMDA (N-methyl-D-aspartic acid) receptor encephalitis, case report, and our plans for a future study].

    Science.gov (United States)

    Herman, Levente; Zsigmond, Ildiko Reka; Peter, Laszlo; Rethelyi, Janos M

    2016-12-01

    Anti-NMDAR (N-methyl-D-aspartic acid receptor) encephalitis, first described in 2007, is a rare, autoimmune limbic encephalitis. In half of the cases anti-NMDAR antibodies are paraneoplastic manifestations of an underlying tumor (mostly ovarian teratoma). In the early stage of the disease psychiatric symptoms are prominent, therefore 60-70% of the patients are first treated in a psychiatric department. In most of the cases, typical neurological symptoms appear later. Besides the clinical picture and typical symptoms, verifying presence of IgG antibodies in the serum or CSF is necessary to set up the diagnosis. Other diagnostic tools, including laboratory tests, MRI, lumbar puncture or EEG are neither specific, nor sensitive enough. Therapy is based on supportive care, plasma exchange and immune suppression, intensive care administration can be necessary. If there is an underlying tumor, tumor removal is the first-line treatment. The disease can cause fatal complications in the acute phase but with adequate therapy long-term prognosis is good, although rehabilitation can last for months. In the past few years besides the typical clinical picture and illness course an increasing number of case reports described no typical neurological symptoms, only psychiatric symptoms, including psychosis, disorganized behavior, and catatonic symptoms. Immune suppressive treatment was still effective in most of these cases. Such cases present a difficult diagnostic challenge. These patients may receive unnecessary antipsychotic treatment because of the suspected schizophrenia, although they often suffer from serious extrapyramidal side effects. A few years ago there was a hypothesis that a small part of the patients who are treated with therapy-resistant schizophrenia may suffer from anti-NMDAR encephalitis, so they require a different kind of medication. Evidence from the latest publications did not confirm this hypothesis, although the connection between anti-NMDAR antibodies and

  3. Expression of N-methyl-D-aspartic acid 2A-B and 2B receptors in anterior thalamic nucleus and subiculum complex of rats

    Institute of Scientific and Technical Information of China (English)

    Yuanshan Fu; Xiaokai Ma; Xiaoling Yue; Bin Wang

    2008-01-01

    BACKGROUND: Glutamate acid ionotropic receptor N-methyl-D-aspartic acid (NMDA) takes part in long-term potentiation, thereby influencing the process of learning and memory.OBJECTIVE: To verify expression of NMDA 2A/B and 2B receptors in the anterior thalamic nucleus and subieulum complex of rats.DESIGN, TIME AND SETTING: A single-sample observation was performed at Department of Anatomy in Dalian Mcdical University (Dalian, Liaoning, China) from April to September in 2007.MATERIALS: Ten adult Wistar rats were used for this study, as well as rabbit anti-NMDA 2A/B and 2Bantibodies.METHODS: The rats were anesthetized and perfused, followed by brain resection and coronal sectioning of the brain tissue. A 1:3 series was selected for immunohistochemistry, using antibodies specific to NMDA 2A/B and 2B receptors. Photos were taken using the Nikon image analysis system.MAIN OUTCOME MEASURES: Expression and distribution of immunohistochemistry staining of NMDA 2A/B and 2B receptor subunits.RESULTS: There were a large number of NMDA 2A/B and 2B receptor-positive neurons distributed throughout the anterior dorsal thalamic nucleus. In the anterior ventral thalamic nucleus, distribution of positive neurons was rare, staining intensity was lighter, and cell bodies were smaller compared with the anterior dorsal thalamic nucleus. In the subiculum complex, staining intensity of NMDA 2A/B and 2B-positive neurons was weakest in the molecular layer and stronger in the pyramidal layer, in particular the region with large cell bodies adjacent to the molecular layer. In the multiform layer, more positive neurons of various sizes were detected.CONCLUSION: NMDA 2A/B and 2B receptor subunits were richly distributed in the anterior thalamic nucleus, with a small difference existing between the anterior dorsal nucleus and anterior ventral nucleus.These neurons were also differentially distributed within the three layers of the subiculum complex.

  4. Association Study of N-Methyl-D-Aspartate Receptor Subunit 2B (GRIN2B Polymorphisms and Schizophrenia Symptoms in the Han Chinese Population.

    Directory of Open Access Journals (Sweden)

    Yongfeng Yang

    Full Text Available Schizophrenia (SZ is a common and complex psychiatric disorder that has a significant genetic component. The glutamatergic system is the major excitatory neurotransmitter system in the central nervous system, and is mediated by N-methyl-D-aspartate (NMDA receptors. Disturbances in this system have been hypothesized to play a major role in SZ pathogenesis. Several studies have revealed that the NMDA receptor subunit 2B (GRIN2B potentially associates with SZ and its psychiatric symptoms. In this study, we performed a case-control study to identify polymorphisms of the GRIN2B gene that may confer susceptibility to SZ in the Han Chinese population. Thirty-four single nucleotide polymorphisms (SNPs were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was observed in allele and genotype between SZ and controls at rs2098469 (χ2 = 8.425 and 4.994; p = 0.025 and 0.014, respectively. Significant associations were found in the allele at rs12319804 (χ2 = 4.436; p = 0.035, as well as in the genotype at rs12820037 and rs7298664 between SZ and controls (χ2 = 11.162 and 38.204; p = 0.003 and 4.27×10(-8, respectively. After applying the Bonferroni correction, rs7298664 still had significant genotype associations with SZ (p = 1.71×10(-7. In addition, rs2098469 genotype and allele frequencies, and 12820037 allele frequencies were nominally associated with SZ. Three haplotypes, CGA (rs10845849-rs12319804-rs10845851, CC (rs12582848-rs7952915, and AAGAC (rs2041986-rs11055665-rs7314376-rs7297101-rs2098469, had significant differences between SZ and controls (χ2 = 4.324, 4.582, and 4.492; p = 0.037, 0.032, and 0.034, respectively. In addition, three SNPs, rs2098469, rs12820037, and rs7298664, were significantly associated with cognition factors PANSS subscores in SZ (F = 16.799, 7.112, and 13.357; p = 0.000, 0.017, and 0.000, respectively. In conclusion, our study provides novel evidence for an association between GRIN2B

  5. 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

  6. Association Study of N-Methyl-D-Aspartate Receptor Subunit 2B (GRIN2B) Polymorphisms and Schizophrenia Symptoms in the Han Chinese Population

    Science.gov (United States)

    Zhang, Hongxing; Yang, Ge; Wang, Xiujuan; Ding, Minli; Jiang, Tianzi; Lv, Luxian

    2015-01-01

    Schizophrenia (SZ) is a common and complex psychiatric disorder that has a significant genetic component. The glutamatergic system is the major excitatory neurotransmitter system in the central nervous system, and is mediated by N-methyl-D-aspartate (NMDA) receptors. Disturbances in this system have been hypothesized to play a major role in SZ pathogenesis. Several studies have revealed that the NMDA receptor subunit 2B (GRIN2B) potentially associates with SZ and its psychiatric symptoms. In this study, we performed a case–control study to identify polymorphisms of the GRIN2B gene that may confer susceptibility to SZ in the Han Chinese population. Thirty-four single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was observed in allele and genotype between SZ and controls at rs2098469 (χ2 = 8.425 and 4.994; p = 0.025 and 0.014, respectively). Significant associations were found in the allele at rs12319804 (χ2 = 4.436; p = 0.035), as well as in the genotype at rs12820037 and rs7298664 between SZ and controls (χ2 = 11.162 and 38.204; p = 0.003 and 4.27×10-8, respectively). After applying the Bonferroni correction, rs7298664 still had significant genotype associations with SZ (p = 1.71×10-7). In addition, rs2098469 genotype and allele frequencies, and 12820037 allele frequencies were nominally associated with SZ. Three haplotypes, CGA (rs10845849—rs12319804—rs10845851), CC (rs12582848—rs7952915), and AAGAC (rs2041986—rs11055665—rs7314376—rs7297101—rs2098469), had significant differences between SZ and controls (χ2 = 4.324, 4.582, and 4.492; p = 0.037, 0.032, and 0.034, respectively). In addition, three SNPs, rs2098469, rs12820037, and rs7298664, were significantly associated with cognition factors PANSS subscores in SZ (F = 16.799, 7.112, and 13.357; p = 0.000, 0.017, and 0.000, respectively). In conclusion, our study provides novel evidence for an association between

  7. Inhibition of glycogen synthase kinase-3β prevents remifentanil-induced hyperalgesia via regulating the expression and function of spinal N-methyl-D-aspartate receptors in vivo and vitro.

    Directory of Open Access Journals (Sweden)

    Yize Li

    Full Text Available A large number of experimental and clinical studies have confirmed that brief remifentanil exposure can enhance pain sensitivity presenting as opioid-induced hyperalgesia (OIH. N-methyl-D-aspartate (NMDA receptor antagonists have been reported to inhibit morphine analgesic tolerance in many studies. Recently, we found that glycogen synthase kinase-3β (GSK-3β modulated NMDA receptor trafficking in a rat model of remifentanil-induced postoperative hyperalgesia. In the current study, it was demonstrated that GSK-3β inhibition prevented remifentanil-induced hyperalgesia via regulating the expression and function of spinal NMDA receptors in vivo and in vitro. We firstly investigated the effects of TDZD-8, a selective GSK-3β inhibitor, on thermal and mechanical hyperalgesia using a rat model of remifentanil-induced hyperalgesia. GSK-3β activity as well as NMDA receptor subunits (NR1, NR2A and NR2B expression and trafficking in spinal cord L4-L5 segments were measured by Western blot analysis. Furthermore, the effects of GSK-3β inhibition on NMDA-induced current amplitude and frequency were studied in spinal cord slices by whole-cell patch-clamp recording. We found that remifentanil infusion at 1 μg·kg(-1·min(-1 and 2 μg·kg(-1·min(-1 caused mechanical and thermal hyperalgesia, up-regulated NMDA receptor subunits NR1 and NR2B expression in both membrane fraction and total lysate of the spinal cord dorsal horn and increased GSK-3β activity in spinal cord dorsal horn. GSK-3β inhibitor TDZD-8 significantly attenuated remifentanil-induced mechanical and thermal hyperalgesia from 2 h to 48 h after infusion, and this was associated with reversal of up-regulated NR1 and NR2B subunits in both membrane fraction and total lysate. Furthermore, remifentanil incubation increased amplitude and frequency of NMDA receptor-induced current in dorsal horn neurons, which was prevented with the application of TDZD-8. These results suggest that inhibition of

  8. Intrathecal injection of the peptide myr-NR2B9c attenuates bone cancer pain via perturbing N-methyl-D-aspartate receptor-PSD-95 protein interactions in mice.

    Science.gov (United States)

    Liu, Yue; Cui, Xinlong; Sun, Yu-E; Yang, Xuli; Ni, Kun; Zhou, Yu; Ma, Zhengliang; Gu, Xiaoping

    2014-06-01

    N-methyl-D-aspartate receptor (NMDARs)-dependent central sensitization plays an important role in cancer pain. Binding of NMDAR subunit 2B (NR2B) by postsynaptic density protein-95 (PSD-95) can couple NMDAR activity to intracellular enzymes, such as neuronal nitric oxide synthase (nNOS), facilitate downstream signaling pathways, and modulate NMDAR stability, contributing to synaptic plasticity. In this study, we investigated whether perturbing the specific interaction between spinal NR2B-containing NMDAR and PSD-95, using a peptide-mimetic strategy, could attenuate bone cancer-related pain behaviors. Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce progressive bone cancer-related pain behaviors. Western blotting was applied to examine the expression of spinal phospho-Tyr1472 NR2B, nNOS, and PSD-95. We further investigated the effects of intrathecal injection of the mimetic peptide Myr-NR2B9c, which competitively disrupts the interaction between PSD-95 and NR2B, on nociceptive behaviors and on the upregulation of phospho-Tyr1472 NR2B, nNOS, and PSD-95 associated with bone cancer pain in the spinal cord. Inoculation of osteosarcoma cells induced progressive bone cancer pain and resulted in a significant upregulation of phospho-Tyr1472 NR2B, nNOS, and PSD-95. Intrathecal administration of Myr-NR2B9c attenuated bone cancer-evoked mechanical allodynia, thermal hyperalgesia, and reduced spinal phospho-Tyr1472 NR2B, nNOS, and PSD-95 expression. Intrathecal administration of Myr-NR2B9c reduced bone cancer pain. Internalization of spinal NR2B and dissociation NR2B-containing NMDARs activation from downstream nNOS signaling may contribute to the analgesic effects of Myr-NR2B9c. This approach may circumvent the negative consequences associated with blocking NMDARs, and may be a novel strategy for the treatment of bone cancer pain.

  9. N-甲基-D-天门冬氨酸受体、脑缺血性损伤和运动训练%N-methyl-D-aspartate Receptor, Cerebral Ischemia and Exercise (review)

    Institute of Scientific and Technical Information of China (English)

    张安静; 白玉龙

    2012-01-01

    N-甲基-D-天门冬氨酸(NMDA)受体是一种离子型谷氨酸受体,与突触可塑性、皮质和海马神经元长时程增强和抑制效应等中枢神经系统的生理、病理过程相关.本文就近年来NMDA受体在脑缺血中所起作用的研究进展进行综述.%N-methyl-D-aspartate (NMDA) receptors are a group of ionotropic glutamate receptors, which are in close contact with the synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) in the cerebral cortex or the hippocampus. This article reviewed the recent development in this field.

  10. 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.

  11. 儿童抗N-甲基-D-天冬氨酸受体脑炎的脑电图特征%Electroencephalographic features of anti-N-methyl-D-aspartate receptor encephalitis in children

    Institute of Scientific and Technical Information of China (English)

    高鑫; 杨志仙; 薛姣; 季涛云; 张尧; 刘晓燕; 吴晔; 张月华; 包新华

    2016-01-01

    Objective To investigate electroencephalographic (EEG) characteristics of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis in children.Method Clinical data of 28 children diagnosed as anti-NMDAR encephalitis were retrospectively analyzed for EEG characteristics in different periods and severity of disease and outcome.Result Among the 28 patients with anti-NMDAR encephalitis,15 were males and 13 were females.Their age at disease onset ranged from 1 year 3 months to 12 years 4 months.Patients were divided into mild group (5 cases) and severe group (23 cases).In the different stage of the disease,occipital background activity of the EEG was preserved in more than half of patients.Accompanied by the evolution of disease course,the occipital background activity and slow waves gradually recovered to normal.In the peak phase of disease,occipital background activity in the awake state was preserved in 4/5 patients of the mild group and 9/17 patients of the severe group.Alpha and theta band rhythms in non-rapid eye movement (NREM) sleep existed in 77% (17/22) patients.EEG monitoring showed delta brushes in 2 cases,and the delta brushes were mixed with background fast waves in one case;71% (20/28) patients had epileptiform discharges in EEG during the course,and among them,6 patients had secondary epilepsy.Conclusion The background activity in the awake state and abnormal diffuse slow waves of EEG were evolved and gradually recovered during the course of the disease.Regardless milder or severe illness condition,occipital background activity was still preserved during different stages in most patients.Alpha and theta rhythms in NREM sleep might represent a relatively ovcrt EEG characteristic.The presence of delta brush in EEG was rare,and sometimes they were difficult to be distinguished from fast wave activities caused by drugs.The presence of epileptiform discharges in EEG suggested the possibility of secondary epilepsy.%目的 探讨儿童抗N-甲基-D-天

  12. Clinical utility of circulating anti-N-methyl-d-aspartate receptor subunits NR2A/B antibody for the diagnosis of neuropsychiatric syndromes in systemic lupus erythematosus and Sjögren's syndrome: An updated meta-analysis.

    Science.gov (United States)

    Tay, Sen Hee; Fairhurst, Anna-Marie; Mak, Anselm

    2017-02-01

    Neuropsychiatric (NP) events are found in patients with rheumatic diseases, commonly in systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). The standard nomenclature and case definitions for 19 NPSLE syndromes by the American College of Rheumatology (ACR) Committee on Research cover a wide range of NP events seen in both SLE and SS. Despite advances in the understanding of SLE and SS, NP syndromes continue to pose diagnostic challenges. Correct attribution of NP events is critical in determining the correct treatment and prognosis. Anti-N-methyl-d-aspartate receptor subunits NR2A/B (anti-NR2A/B) antibodies have been demonstrated in the sera of SLE and SS patients and have been associated with collective or specific NP syndromes, though not consistently. Interpretation of anti-NR2A/B antibody data in the medical literature is rendered difficult by small sample size of patient groups. By combining different studies to generate a pooled effect size, a meta-analysis can increase the power to detect differences in the presence or absence of NP syndromes. Hence, we set out to perform a meta-analysis to assess the association between anti-NR2A/B antibodies and NP syndromes in SLE and SS. A literature search was conducted using PubMed and other databases from inception to June 2016. We abstracted data relating to anti-NR2A/B antibodies from the identified studies. The random effects model was used to calculate overall combined odds ratio (OD) with its corresponding 95% confidence interval (CI) to evaluate the relationship between anti-NR2A/B antibodies and NP syndromes in SLE and SS patients with and without NP events. We also included our own cohort of 57 SLE patients fulfilling the ACR 1997 revised classification criteria and 58 healthy controls (HCs). In total, 17 studies with data on anti-NR2A/B antibodies in 2212 SLE patients, 66 SS patients, 99 disease controls (DCs) (e.g. antiphospholipid syndrome, myasthenia gravis and autoimmune polyendocrine syndrome

  13. Clinical and electroencephalographic analysis of anti-N-methyl-D-aspartate receptor encephalitis in children%儿童抗N-甲基-D-天冬氨酸受体脑炎临床与脑电图分析

    Institute of Scientific and Technical Information of China (English)

    李华; 王晓慧; 方方; 丁昌红; 吕俊兰; 陈春红; 韩彤立; 伍妘; 张炜华

    2016-01-01

    目的 总结儿童抗N-甲基-D-天冬氨酸(NMDA)受体脑炎的临床与脑电图特征.方法 回顾性分析2011年8月至2015年3月在首都医科大学附属北京儿童医院神经内科确诊并住院治疗的105例抗NMDA受体脑炎患儿的临床与脑电图资料.105例患儿中男38例、女67例,发病年龄为6月龄至15岁8个月,平均(8±4)岁;确诊时间4~850 d,中位数24.5 d.根据改良的Rankin量表对患儿进行病情评估,同时进行持续脑电图监测,对监测结果进行分析总结.结果 105例患儿中病情轻、中、重度者分别为12、65和28例.91例(86.7%)患儿脑电图异常,其中背景活动减慢28例(26.7%),广泛性或弥漫性慢波25例(23.8%),限局性慢波33例(31.4%),癫痫样波形41例(39.O%).10例患儿(9.5%)在睡眠非快速眼运动(NREM)期呈现单侧或弥漫性α-θ频段节律,7例(6.7%)存在极度δ刷状波(EDB).病情轻、中和重3组间脑电图异常分别为5例、58例(89.2%)和28例(100.0%),7例EDB现象患儿均为重度组,10例异常α-θ节律患儿均为中度组.结论 儿童抗NMDA受体脑炎脑电图表现符合一般脑炎的脑电图改变,且脑电图异常程度与病情严重程度成正比.脑电图出现EDB现象和异常α-θ节律对本病诊断及病情的严重性均有提示作用.%Objective To study the clinical and electroencephalographic (EEG) characteristics of anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARencephalitis) in children.Method Retrospective analysis was performed on the clinical and EEG data of 105 patients with anti-NMDAR encephalitis treated in Beijing Children's Hospital (August 2011-March 2015).Of the 105 patients,38 were male and 67 were female.The age of onset was from 6 months and 26 days to 15 years and 8 months (average (8±4)years).The time for confirmed diagnosis was from 4 days to 850 days (median 24.5 days).According to the modified Rankin scales,the patient's clinical conditions were assessed and

  14. Expression of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) GluR2/3 receptors in the developing rat pineal gland.

    Science.gov (United States)

    Kaur, C; Sivakumar, V; Ling, E A

    2005-10-01

    The expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type glutamate (GluR2/3) receptors and N-methyl-D-aspartate receptor subtype 1 (NMDAR1) was carried out by immunohistochemistry, double immunofluorescence and real-time RT-PCR analysis in the pineal glands of 1-day to 6-wk-old rats in the present study. GluR2/3 immunopositive cells were distributed throughout the pineal gland and showed branching processes in all age groups. The NMDAR1 immunoreactivity, however, was observed in fewer branched cells. A constitutive mRNA expression of NMDAR1, GluR2 and GluR3 was detected in the pineal glands of various ages and showed no significant difference between the age groups studied. Immunohistochemical and double immunofluorescence results showed that the GluR2/3 were mainly expressed and co-localized with OX-42-positive microglia/macrophages and the glial fibrillary acidic protein (GFAP)-positive astrocytes. Co-localization of NMDAR1 with OX-42- and GFAP-positive cells was much less. The expression of these receptors on the glial cells suggests that they may be involved in the development and growth of the pineal gland in the early postnatal period (1 day to 3 wk) and subsequently in the regulation of melatonin synthesis.

  15. 同型半胱氨酸与N-甲基-D-天冬氨酸受体的研究进展%Advances in Research into Relationship Between Homocysteine and N-methyl-D-aspartic Acid Receptor

    Institute of Scientific and Technical Information of China (English)

    李莉; 陆国平

    2007-01-01

    同型半胱氨酸(homocysteine,Hcy)是心血管疾病的独立危险因子,作用机制涉及损伤血管功能、活化炎症细胞和血小板、促进凝血及心肌肥大等方面.N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)受体是兴奋性氨基酸受体的一种亚型,传统现点认为其主要分布在中枢神经系统,在神经元回路的形成及学习、记忆过程中起关键作用,并与神经退行性疾病密切相关.近年来,NMDA受体在心血管疾病中的作用得到人们的关注.现就NMDA受体在Hcy致心血管细胞功能损伤中的作用方面的研究进展作一综述.

  16. In utero exposure of mice to diesel exhaust particles affects spatial learning and memory with reduced N-methyl-D-aspartate receptor expression in the hippocampus of male offspring.

    Science.gov (United States)

    Yokota, Satoshi; Sato, Akira; Umezawa, Masakazu; Oshio, Shigeru; Takeda, Ken

    2015-09-01

    Diesel exhaust consists of diesel exhaust particles (DEPs) and gaseous compounds. Previous studies reported that in utero exposure to diesel exhaust affects the central nervous system. However, there was no clear evidence that these effects were caused by diesel exhaust particles themselves, gaseous compounds, or both. Here, we explored the effects of in utero exposure to DEPs on learning and memory in male ICR mice. DEP solutions were administered subcutaneously to pregnant ICR mice at a dose of 0 or 200 μg/kg body weight on gestation days 6, 9, 12, 15, and 18. We examined learning and memory in 9-to-10-week-old male offspring using the Morris water maze test and passive avoidance test. Immediately after the behavioral tests, hippocampi were isolated. Hippocampal N-methyl-D-aspartate receptor (NR) expression was also measured by quantitative RT-PCR analysis. Mice exposed to DEPs in utero showed deficits in the Morris water maze test, but their performance was not significantly different from that of control mice in the passive avoidance test. In addition, DEP-exposed mice exhibited decreased hippocampal NR2A expression. The present results indicate that maternal DEP exposure disrupts learning and memory in male offspring, which is associated with reduced hippocampal NR2A expression.

  17. Mechanisms responsible for the effect of median nerve electrical stimulation on traumatic brain injury-induced coma: orexin-A-mediated N-methyl-D-aspartate receptor subunit NR1 upregulation

    Directory of Open Access Journals (Sweden)

    Zhen Feng

    2016-01-01

    Full Text Available Electrical stimulation of the median nerve is a noninvasive technique that facilitates awakening from coma. In rats with traumatic brain injury-induced coma, median nerve stimulation markedly enhances prefrontal cortex expression of orexin-A and its receptor, orexin receptor 1. To further understand the mechanism underlying wakefulness mediated by electrical stimulation of the median nerve, we evaluated its effects on the expression of the N-methyl-D-aspartate receptor subunit NR1 in the prefrontal cortex in rat models of traumatic brain injury-induced coma, using immunohistochemistry and western blot assays. In rats with traumatic brain injury, NR1 expression increased with time after injury. Rats that underwent electrical stimulation of the median nerve (30 Hz, 0.5 ms, 1.0 mA for 15 minutes showed elevated NR1 expression and greater recovery of consciousness than those without stimulation. These effects were reduced by intracerebroventricular injection of the orexin receptor 1 antagonist SB334867. Our results indicate that electrical stimulation of the median nerve promotes recovery from traumatic brain injury-induced coma by increasing prefrontal cortex NR1 expression via an orexin-A-mediated pathway.

  18. Nursing care of seven patients with severe anti-N-methyl-D-aspartate receptor(NMDAR) encephalitis%7例重症抗N-甲基-D天冬氨酸受体脑炎患者的护理

    Institute of Scientific and Technical Information of China (English)

    邓秋霞; 杜鸿雁; 林华; 高岚

    2015-01-01

    总结分析7例重症抗N-甲基-D天冬氨酸(N-methyl-D-aspartate,NMDA)受体脑炎患者的护理经验.其护理要点包括:综合患者的临床表现和发病机制,早期发现和处理中枢性通气不足、不自主运动和自主神经功能障碍等,做好用药护理、血浆置换的配合及护理.本组7例患者中5例病情好转出院、1例预后不佳、1例死亡,5例出院患者中除遗留不同程度的智力功能障碍外无其他后遗症.

  19. Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors.

    Science.gov (United States)

    Chao, C C; Hu, S; Ehrlich, L; Peterson, P K

    1995-12-01

    The cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, produced by glial cells within the brain, appear to contribute to the neuropathogenesis of several inflammatory neurodegenerative diseases; however, little is known about the mechanism underlying cytokine-induced neurotoxicity. Using human fetal brain cell cultures composed of neurons and glial cells, we investigated the injurious effects of IL-1beta and TNF-alpha, cytokines which are known to induce nitric oxide (NO) production by astrocytes. Although neither cytokine alone was toxic, IL-1beta and TNF-alpha in combination caused marked neuronal injury. Brain cell cultures treated with IL-1beta plus TNF-alpha generated substantial amounts of NO. Blockade of NO production with a NO synthase inhibitor was accompanied by a marked reduction (about 45%) of neuronal injury, suggesting that NO production by astrocytes plays a role in cytokine-induced neurotoxicity. Addition of N-methly-D-aspartate (NMDA) receptor antagonists to brain cell cultures also blocked IL-1beta plus TNF-alpha-induced neurotoxicity (by 55%), implicating the involvement of NMDA receptors in cytokine-induced neurotoxicity. Treatment of brain cell cultures with IL-1beta plus TNF-alpha was found to inhibit [3H]-glutamate uptake and astrocyte glutamine synthetase activity, two major pathways involved in NMDA receptor-related neurotoxicity. These in vitro findings suggest that agents which suppress NO production or inhibit NMDA receptors may protect against neuronal damage in cytokine-induced neurodegenerative diseases.

  20. Advance in studies of the tracer of N-methyl-D-aspartate receptor%N-甲基-D-天冬氨酸受体显像剂研究进展

    Institute of Scientific and Technical Information of China (English)

    颜成龙; 周杏琴; 曹国宪

    2009-01-01

    N-methyl-D-aspartate receptors have recently been a novel target of drug development related to neurodegenerative diseases such as Parkinson diseases, Alzheimer disease, schizophrenia, epilepsy and Huntingtons disease. NMDA receptor imaging agents can provide a sensitive molecular prob and a powerful diagnostic tool for the early diagnosis and therapy of neurodegenerative diseases. Because of inadequate lipophilicity and affinity, many NMDA receptor imaging agents couldn't be used in clinical. 123I-N-(1-napthyl) -N'-(3-iodophenyl)-N-methylguanidine (123I-CNS1261)has the potential to be a NMDA receptor imaging agent. Basing on the researches which has accomplished in the abroad at present, this review concluded the progresses of the tracer of NMDA receptor.%N-甲基-D-天冬氨酸(NMDA)受体已成为发展帕金森病、阿尔茨海默病、精神分裂症、癫痫、亨廷顿舞蹈症等神经变性疾病药物的新靶点.NMDA受体显像剂的研制将为神经变性疾病的早期诊断和治疗提供灵敏的分子探针和特异的诊断方法.多数NMDA受体显像剂因脂溶性和亲和力欠佳而不宜用于临床,有希望成为NMDA受体显像剂的是123I-CNS1261.该文综述了近年来关于NMDA受体显像剂的研究进展.

  1. NMDAR在瑞芬太尼引起痛觉过敏机制和防治的研究进展%The Role of N-methyl-D-aspartate Receptor in the Mechanism and Prevention of Remifentanil Induced Hyperalgesia

    Institute of Scientific and Technical Information of China (English)

    李燕; 王国年; 林鹰; 杨光; 徐德生

    2015-01-01

    阿片类药物引起痛觉过敏(opioid-induced hyperalgesia,OIH)是指暴露于阿片类药物的患者出现一种痛阈降低和对正常疼痛刺激的超敏反应为特点的感觉异常现象.瑞芬太尼是一种μ受体激动剂,且由于起效迅速,时量半衰期短而恒定,重复用药亦无蓄积,这些良好的药代动力学特点导致它发生的痛觉过敏现象也明显频于、强于其他阿片类药物. N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR)激活在产生超敏现象中是非常重要的.但是关于NMDAR在瑞芬太尼诱发痛觉过敏的机制尚未完全清楚,仍然缺乏系统的预防和治疗方案.本文简要介绍了NMDAR,总结了NMDAR在瑞芬太尼引起痛觉过敏的机制中的作用,归纳了临床上一些NMDAR拮抗药物来预防瑞芬太尼引起的痛觉过敏现象,以期对后续的围术期的疼痛管理提供理论依据.

  2. Rodent Mismatch Negativity (MMN)/Theta Neuro-Oscillatory Response as a Translational Neurophysiological Biomarker for N-Methyl-D-Aspartate Receptor-Based New Treatment Development in Schizophrenia.

    Science.gov (United States)

    Lee, Migyung; Balla, Andrea; Sershen, Henry; Sehatpour, Pejman; Lakatos, Peter; Javitt, Daniel C

    2017-08-17

    Deficits in the generation of auditory mismatch negativity (MMN) generation are among the most widely replicated neurophysiological abnormalities in schizophrenia and linked to underlying dysfunction of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission. Here, we evaluate physiological properties of rodent MMN, along with sensitivity to NMDAR agonist and antagonist treatment, relative to known patterns of dysfunction in schizophrenia. Epidural neurophysiological responses to frequency- and duration-deviants, along with responses to standard stimuli, were obtained at baseline and following 2 and 4 weeks treatment from rats treated with saline, phencyclidine (PCP, 15 mg/kg/d by osmotic minipump), or PCP+glycine (16% by weight diet) interventions. Responses were analyzed using both event-related potential (ERP) and neuro-oscillatory (evoked power) approaches. At baseline, rodent duration MMN was associated with increased theta (θ)-frequency response similar to that observed in humans. PCP significantly reduced rodent duration MMN (p<0.001) and θ-band (p<0.01) response. PCP effects were prevented by concurrent glycine treatment (p<0.01 vs PCP alone). Effects related to stimulus-specific adaptation (SSA) were observed primarily in the alpha (α) and beta (β) frequency ranges. PCP-treatment also significantly reduced α-frequency response to standard stimuli while increasing θ-band response, reproducing the pattern of deficit observed in schizophrenia. Overall, we demonstrate that rodent duration MMN shows neuro-oscillatory signature similar to human MMN, along with sensitivity to the NMDAR antagonist and agonist administration. These findings reinforce recent human studies linking MMN deficits to θ-band neuro-oscillatory dysfunction and support utility of rodent duration MMN as a translational biomarker for investigation of mechanisms underlying impaired local circuit function in schizophrenia.Neuropsychopharmacology accepted article preview online

  3. A single-channel method for evaluation of very magnitudes of Ca2+ ion fluxes through epsilon4/zeta1 N-methyl-D-aspartate receptor channels in bilayer lipid membranes.

    Science.gov (United States)

    Wakabayashi, M; Hirano, A; Sugawara, M; Uchino, S; Nakajima-Iijima, S

    2001-01-01

    A single-channel method for evaluating agonist selectivity in terms of the very number of Ca2+ ions passed through the epsilon4/zeta1 N-methyl-D-aspartate (NMDA) receptor ion channel in bilayer lipid membranes (BLMs) is described. The number of Ca2+ passed through the single-channel was obtained from single-channel recordings in a medium where the primary permeant ion is Ca2+. The recombinant epsilon4/zeta1 NMDA channel was partially purified from Chinese hamster ovary cells expressing the channel and incorporated in BLMs formed by the tip-dip method. It was found that the epsilon4/zeta1 channel in BLMs is permeable to Ca2+ and Na+, but the number of Ca2+ passed through the channel is much fewer than that of Na+. The integrated Ca2+ currents induced by three typical agonists NMDA, L-glutamate and L-CCG-IV were obtained at concentration of 50 microM, where the integrated currents for all the agonists reached their saturated values. The integrated Ca2+ currents obtained are (3.1+/-0.21) x 10(-13) C/s for NMDA, (4.6+/-0.31) x 10(-13) C/s for L-glutamate and (5.7+/-0.25) x 10(-13) C/s for L-CCG-IV, respectively, suggesting that the three kinds of agonists have different efficacies to induce permeation of Ca2+. The range of the agonist selectivity thus obtained is much narrower than that of binding affinities for the NMDA receptors from rat brain. The present method is able to detect Ca2+ permeation with a detection limit of approximately 10(5) Ca2+ ions/s.

  4. Dose-dependent and combined effects of N-methyl- D-aspartate receptor antagonist MK-801 and nitric oxide synthase inhibitor nitro-L-arginine on the survival of retinal ganglion cells in adult hamsters

    Institute of Scientific and Technical Information of China (English)

    Yaoyu Li; An'an Yang; Tingting Zhu; Zhao Liu; Siwei You; Kwok-Fai So

    2012-01-01

    This study investigated the effects of daily intraperitoneal injections of N-methyl-D-aspartate receptor antagonist MK-801 and nitric oxide synthase inhibitor nitro-L-arginine (L-NA) on the survival of retinal ganglion cells (RGCs) at 1 and 2 weeks after unilateral optic nerve transection in adult hamsters. The left optic nerves of all animals were transected intraorbitally 1 mm from the optic disc and RGCs were retrogradely labeled with Fluorogold before they received different daily dosages of single MK-801 or L-NA as well as daily combinational treatments of these two chemicals. All experimental and control animals survived for 1 or 2 weeks after optic nerve transection. Our results revealed that the mean numbers of surviving RGCs increased and then decreased when the dosage of MK-801 (1.0, 3.0 and 4.5 mg/kg) and L-NA (1.5, 3.0, 4.5 and 6.0 mg/kg) increased at both 1 and 2 weeks survival time points. Daily combinational use of 1.0 mg/kg MK-801 and 1.5 mg/kg L-NA lead to a highest RGC number that was even higher than the sum of the RGC numbers in 1.0 mg/kg MK-801 and 1.5 mg/kg L-NA subgroups at 2 weeks. These findings indicated that both MK-801 and L-NA can protect axotomized RGCs in a dose-dependent manner and combinational treatment of these chemicals possesses a potentiative and protective effect.

  5. Role of the NR2A/2B subunits of the N-methyl-D-aspartate receptor in glutamate-induced glutamic acid decarboxylase alteration in cortical GABAergic neurons in vitro.

    Science.gov (United States)

    Monnerie, H; Hsu, F-C; Coulter, D A; Le Roux, P D

    2010-12-29

    The vulnerability of brain neuronal cell subpopulations to neurologic insults varies greatly. Among cells that survive a pathological insult, for example ischemia or brain trauma, some may undergo morphological and/or biochemical changes that may compromise brain function. The present study is a follow-up of our previous studies that investigated the effect of glutamate-induced excitotoxicity on the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67)'s expression in surviving DIV 11 cortical GABAergic neurons in vitro [Monnerie and Le Roux, (2007) Exp Neurol 205:367-382, (2008) Exp Neurol 213:145-153]. An N-methyl-D-aspartate receptor (NMDAR)-mediated decrease in GAD expression was found following glutamate exposure. Here we examined which NMDAR subtype(s) mediated the glutamate-induced change in GAD protein levels. Western blotting techniques on cortical neuron cultures showed that glutamate's effect on GAD proteins was not altered by NR2B-containing diheteromeric (NR1/NR2B) receptor blockade. By contrast, blockade of triheteromeric (NR1/NR2A/NR2B) receptors fully protected against a decrease in GAD protein levels following glutamate exposure. When receptor location on the postsynaptic membrane was examined, extrasynaptic NMDAR stimulation was observed to be sufficient to decrease GAD protein levels similar to that observed after glutamate bath application. Blocking diheteromeric receptors prevented glutamate's effect on GAD proteins after extrasynaptic NMDAR stimulation. Finally, NR2B subunit examination with site-specific antibodies demonstrated a glutamate-induced, calpain-mediated alteration in NR2B expression. These results suggest that glutamate-induced excitotoxic NMDAR stimulation in cultured GABAergic cortical neurons depends upon subunit composition and receptor location (synaptic vs. extrasynaptic) on the neuronal membrane. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered

  6. 抗N-甲基-D-天冬氨酸受体脑炎:一种新型自身免疫性脑炎%Anti-N-methyl-D-aspartate receptor encephalitis: a new autoimmune encephalitis

    Institute of Scientific and Technical Information of China (English)

    陈向军; 李翔

    2013-01-01

    Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is a new category of treatable encephalitis associated with anti-NMDA receptor antibody, which attracts more and more attention recently. It is clinically characterized by prodromal fever, schizophrenia - like psychiatric symptoms, seizures, disturbance of consciousness, dyskinesia (particularly orofacial), and autonomic dysfunction, which often occur in young females with ovarian teratomas. Autoantibodies to the anti-NMDA receptor in serum and cerebrospinal fluid are positive. Electroencephalogram (EEG) often reveals diffuse δ slowing without paroxysmal discharges, on which " δ rush" is considered as specific characteristic in some patients. Combined therapy including tumor resection and immunotherapy is recommended. The updates in mechanisms, clinical manifestations and diagnostic examinations associated with anti - NMDA receptor encephalitis will be discussed in this review.%抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎是目前较受关注的自身免疫性脑炎,可伴或不伴卵巢畸胎瘤.临床表现包括显著前驱高热、精神症状、癫发作、意识障碍、口手运动障碍及自主神经功能障碍等;脑脊液和血清抗NMDAR 抗体检测呈阳性反应,脑电图呈特异性"δ刷"表现.早期施行肿瘤切除和免疫抑制剂治疗有效.本文拟就抗NMDAR 脑炎发病机制、临床表现、辅助检查等研究进展进行概述.

  7. Anti-N-methyl-D-aspartate receptor encephalitis: an adolescent with ovarian teratoma%抗N-甲基-D-天冬氨酸受体脑炎一例

    Institute of Scientific and Technical Information of China (English)

    许春伶; 郝增平; 冀晓俊; 赵伟秦; 李继梅; 王佳伟; 王淑辉; 王得新; 刘美云; 乔衫衫; 靳家玉

    2010-01-01

    Objective To investigate the clinical presentation,diagnosis,and surgical management of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis.Methods One case of anti-NMDA receptor encephalitis in a previously healthy 17-year-old female related to the development of NMDA receptor autoantibodies triggered by an ovarian teratoma was reported.The related literature was reviewed and the clinical feature was summarized.Results Removal of the ovarian teratoma combined with intravenous immuneglobulin and corticosteroid proved curative with eventual resolution of the paraneoplastic disease process and associated psychiatric symptoms.Conclusion Increasingly,reports of anti-NMDA receptor encephalitis associated with ovarian teratomas,as well as a novel assay to measure these antibodies suggest an etiology for this disease process that may be amenable to prompt surgical excision.%目的 探讨抗N-甲基-M-天冬氨酸(NMDA)受体脑炎的临床特点、诊断及治疗.方法报道1例伴卵巢畸胎瘤的抗NMDA受体脑炎患者的临床表现及诊治过程,并总结其临床特征.结果患者为青年女性,表现为精神行为异常及抽搐,意识障碍及通气不足.早期发现畸胎瘤,脑脊液中抗NMDA受体抗体阳性.行畸胎瘤手术切除,联合静脉用免疫球蛋白和激素冲击治疗,患者临床痊愈.结论 抗NMDA受体脑炎是一种自身免疫性的、能用血清学方法诊断的疾病.早期明确诊断和给予及时治疗,预后良好.

  8. 抗 NMDA 受体脑炎患者11例临床资料分析%Clinical Features of 11 Patients with Anti-N-methyl-D-aspartate Receptor Encephalitis

    Institute of Scientific and Technical Information of China (English)

    李庭毅; 卢祖能

    2015-01-01

    目的:探讨抗 NMDA 受体脑炎的临床表现、磁共振(MRI)图像及脑脊液特点。方法:回顾性分析我院11例抗 NMDA 受体脑炎患者的临床资料。结果:11例患者主要表现为精神症状、癫痫发作、运动障碍等;头部 MRI 检查无特异性;2例女性患者腹部 CT 发现畸胎瘤;11例患者脑脊液抗 NMDA 抗体(+)。结论:以精神行为异常、癫痫发作、运动障碍为主要表现的青年脑炎患者,要警惕抗 NMDA 受体脑炎的可能,需及时行脑脊液抗 NMDA 抗体检测。%Objective: To explore the characteristics of clinical presentations, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) of Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. Methods: The clinical data of 11 patients with anti-NMDA receptor encephalitis, were retrospectively analyzed. Results: Eleven patients presented with psychiatric symptoms, epilepsy and movement disorders. MRI did not show specific changes. Two female patients suffered from teratoma. All patients were diagnosed by the presence of antibodies to the anti-NMDA receptor in CSF. Conclusion: The young cases with encephalitis, who presented with psychiatric symptoms, epilepsy and movement disorders, may hint at anti-NMDA receptor encephalitis. Timely autoantibody detection is necessary.

  9. Effects of lobeline and dimethylphenylpiperazinium iodide (DMPP) on N-methyl-D-aspartate (NMDA)-evoked acetylcholine release in vitro: evidence for a lack of involvement of classical neuronal nicotinic acetylcholine receptors.

    Science.gov (United States)

    Rao, T S; Correa, L D; Lloyd, G K

    1997-01-01

    Biochemical, behavioral and electrophysiological evidence suggests interactions between pathways containing neuronal nicotinic acetylcholine receptors (NAChRs) and excitatory amino acid receptors. Recently, protective effects of nicotine against N-methyl-D-aspartate (NMDA)-induced toxicity in primary cortical cultures were reported. To address possible interactions between NAChR and NMDA receptor containing pathways, several NAChR agonists were evaluated for their effects on NMDA-evoked [3H]acetylcholine ([3H]ACh) release from slices of rat striatum. Nicotine, cytisine and epibatidine had no effect on NMDA-evoked release or basal release of [3H]ACh over a wide range of concentrations. Lobeline and dimethylphenylpiperazinium iodide (DMPP), however, decreased basal [3H]ACh release and attenuated NMDA-evoked [3H]ACh release with EC50 values of 35 and 155 microM, respectively. The NAChR antagonists, dihydro-beta-erythroidine (DH beta E) and d-tubocurarine had no effect on NMDA-evoked [3H]ACh release, whereas mecamylamine attenuated the NMDA-evoked [3H]ACh evoked release with an EC50 value of 144 microM. Methyllycaconitine (MLA), a highly selective and potent antagonist of the alpha-bungarotoxin-sensitive alpha 7 NAChR subtype, also had no effect on NMDA-evoked [3H]ACh release at concentrations upto 10 microM. The inhibitory effects of DMPP and lobeline on NMDA-evoked [3H[ACh release were relatively insensitive to mecamylamine, d-tubocurarine, MLA and DH beta E. In addition, DMPP or lobeline-induced attenuation of basal [3H]ACh release was insensitive to blockade by sulpiride, a dopamine (D2) receptor antagonist. In contrast to their effects on NMDA-evoked striatal [3H]ACh release, both DMPP and lobeline increased basal release of striatal [3H]DA and hippocampal [3H]norepinephrine ([3H]NE) and did not attenuate NMDA-evoked release of these two transmitters. Instead, DMPP and lobeline appeared to have an additive effect on both NMDA-evoked hippocampal [3H]NE release and

  10. 抗N-甲基-D-天冬氨酸受体脑炎1例报告%The Clinical Characteristics of Anti-N-methyl-D-aspartate-receptor Encephalitis:One Case Report

    Institute of Scientific and Technical Information of China (English)

    刘文钰; 田林郁; 郭佳南; 陈佳妮; 周东

    2015-01-01

    Aim To help the physician understand anti-N-methyl-D-aspartate-receptor encephalitis (anti-NMDA encephalitis). Methods With the description of one young female patient with anti-NMDA encephalitis, the treatment especially tumor search of anti-NMDA encephalitis combined with the literatures were discussed. Results A 18 year-old young girl had positive reaction to NMDAR antibody but tumor detection was negative twice. Then she received the first and second line immunotherapy, ventilator breathing and antiepileptic drugs with somehow improvement. About 5 months later, a teratoma was found near her cyst. Then she accepted laparoscopic resection. Pathologic analysis conifrmed teratoma. Advanced nerval function recovered quickly after the operation. Conclusion Anti-NMDA encephalitis may impact on the quality of life of the patients, especially for young women. Efforts for tumor search should always be encouraged.%目的:提高临床医生对抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎的认识。方法收集1例18岁女性抗NMDAR脑炎患者的临床资料,对抗NMDAR脑炎的治疗及肿瘤搜索结合文献进行探讨。结果患者因头痛发热9 d,言语行为异常5 d入院,入院后频繁癫发作。肿瘤标记物、免疫、TORCH检查和影像学肿瘤搜索2次检查结果均为阴性,但抗NMDAR抗体阳性,诊断抗NMDAR脑炎、癫持续状态。经呼吸机辅助呼吸、抗癫药和免疫治疗后症状好转。病程约5个月后发现卵巢肿瘤,接受腹腔镜肿瘤切除,病理检查提示畸胎瘤。术后患者高级神经功能迅速恢复。结论抗NMDAR脑炎严重影响患者生活质量,尤其对于年轻女性应积极进行肿瘤搜索,切除肿瘤后患者恢复更快。

  11. Clinical analysis of five cases positive for anti-N-methyl-D-aspartic acid (NMDA) receptor antibodies%抗NMDA受体抗体检测在抗NMDA受体脑炎诊断中的意义

    Institute of Scientific and Technical Information of China (English)

    刘媛媛; 曹秉振; 唐吉刚; 胡怀强; 李传芬

    2015-01-01

    目的:总结间接免疫荧光法检测抗NMDA受体抗体阳性患者的临床特点及诊疗思路。方法回顾性分析2012年4月到2014年11月在济南军区总医院神经内科住院期间检测抗NMDA受体抗体阳性的5例患者的诊断、临床特点、治疗及预后。结果5例患者中4例临床确诊为抗NMDA受体脑炎,1例诊断为单纯疱疹病毒性脑炎(herpes simplex virus encephalitis, HSE)。5例患者发病相似,3例有明确的流感样前驱感染史,3例以精神症状首次发病,4例病情发展到一定阶段出现癫痫、呼吸衰竭入住NICU。4例抗NMDA受体脑炎患者病情后期均出现突出的运动障碍等症状。患者颅脑MRI、脑电图存在不同程度及范围异常,4例合并病毒学及免疫学指标异常。抗NMDA受体脑炎患者经激素、免疫球蛋白等治疗病情好转;HSE患者经抗病毒等治疗后病情改善。随访1年后2例抗NMDA受体脑炎患者出现肿瘤,1例死亡。结论间接免疫荧光检测抗NMDA受体抗体阳性的患者多数为抗NMDA受体脑炎,少数可为HSE等,诊断要综合患者病情及各项检查分析,防止误诊、漏诊,以正确指导治疗。%Objective To summarize and analysis the clinical features, diagnosis and treatment of the cases which were positive for anti-N-methyl-D-aspartic acid (NMDA) receptor antibodies by indirect immunofluorescence assay (IFA). Methods We analyzed the disease process, clinical characteristics, auxiliary examination , diagnosis, treat-ment, and prognosis of five cases positive for anti NMDA receptor antibodies in their serum and cerebrospinal fluid (CSF). Results Four of the five cases positive for anti-N-methyl-D-aspartic acid (NMDA) receptor antibodies were di-agnosed with anti-NMDA receptor encephalitis and one was diagnosed with Herpes Simplex Virus Encephalitis(HSE). The five cases had a similar disease presentation including prodromal flu-like symptoms in three cases and

  12. Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

    Science.gov (United States)

    Witkin, J M; Mitchell, S N; Wafford, K A; Carter, G; Gilmour, G; Li, J; Eastwood, B J; Overshiner, C; Li, X; Rorick-Kehn, L; Rasmussen, K; Anderson, W H; Nikolayev, A; Tolstikov, V V; Kuo, M-S; Catlow, J T; Li, R; Smith, S C; Mitch, C H; Ornstein, P L; Swanson, S; Monn, J A

    2017-04-01

    The ability of the N-methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O2 in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent

  13. 抗N-甲基-D-天门冬氨酸受体脑炎11例临床分析%Anti-N-methyl-D-aspartate receptor encephalitis: clinical analysis of 11 cases

    Institute of Scientific and Technical Information of China (English)

    吴颖颖; 时英英; 张弥兰; 刘建锋; 周瑶; 黄月; 刘慧勤; 马明明; 张杰文

    2015-01-01

    目的 分析抗N-甲基-D-天门冬氨酸(NMDA)受体脑炎的临床表现、实验室及影像学资料,以提高对该病的认识.方法 对2013年1月至2015年2月在郑州大学人民医院神经内科就诊的11例抗NMDA受体脑炎患者的临床表现、实验室及影像学资料进行回顾性分析.结果 主要临床表现为癫痫9例,精神症状7例,运动障碍5例,自主神经功能障碍3例.11例脑脊液抗NMDA受体抗体均阳性,其中5例同时出现血清抗NMDA受体抗体阳性.1例合并肺癌.11例患者均接受免疫治疗,出院时4例基本恢复正常,7例存在不同程度的功能障碍.电话随访1 ~18个月,1例失访,10例随访患者中3例完全恢复,7例遗留不同程度的后遗症.结论 无精神病史的患者出现不明原因的精神症状伴痫性发作、记忆障碍、意识障碍、运动障碍、自主神经功能障碍等表现,应尽早做血清及脑脊液抗NMDA受体抗体检测,以便于早诊断、早治疗,改善预后.%Objective To analyze the clinical manifestation,laboratory findings,radiological data of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis.Methods The clinical manifestation,laboratory findings,radiological data of eleven patients with anti-NMDA receptor encephalitis were analyzed.Results Main symptoms included epilepsy presented in 9 cases,psychiatric symptom in 7 cases,dyskinesia in 5 cases,autonomic dysfunction in 3 cases.The anti-NMDA receptor antibody was found in all the patients' cerebrospinal fluid (CSF).No teratoma was detected in any of the patients,and 1 case had lung cancer.All the patients received immune therapy.And at discharge,4 cases recuperated generally,7 cases had different degrees of dysfunction.After telephone follow-up of 1-18 months,1 case was lost,3 cases had complete recovery,and 7 cases had different degrees of sequela.Conclusion When Patients without mental illness history presents with unexplained mental symptoms accompanied by seizures

  14. 抗NMDA受体脑炎患者卵巢囊肿剔除术的麻醉处理%Anesthetic management for ovarian cystectomy in patients with anti-N-methyl-D-aspartate receptor encephalitis undergoing general anesthesia

    Institute of Scientific and Technical Information of China (English)

    陈雯; 桑诺尔; 罗爱伦; 黄宇光

    2014-01-01

    Objective Anti-N-methyl-D-Aspartate (NMDA) receptor encephalitis is a rare disease,recently described as autoimmune disorder of paraneoplastic limbic encephalitis,which is related to the NMDA receptor antibodies and frequently develops in young women with ovarian teratoma.The disease is usually accompanied by symptoms of psychosis and abnormal behaviors,autonomic nervous system dysfunction,central hypoventilation,and hyperthermia.During induction and maintenance of general anesthesia,we should be aware of adverse reactions such as cardiovascular events,hyperthermia and respiratory insufficiency.In order to maintain vital signs stable,pharmacological agents including vasopressors,β-blockers,antihypertensives,and anticholinergics should be prepared before the surgery.Invasive monitoring for blood pressure can be set if necessary.This study described the method for anesthetic management of 3 patients with anti-NMDA receptor encephalitis undergoing resection of ovarian teratoma under general anesthesia.Preoperative treatment included antipsychotic,anti-infective and immune therapy.General anesthesia was induced with propofol,rocuronium,fentanyl and midazolam to facilitate tracheal intubation and was maintained with inhalation of sevoflurane (mixed with oxygen and air) and intermittent iv boluses of fentanyl and rocuronium during the surgery.All the drugs mentioned above had no interaction or had slight indirect action on anti-NMDA receptors to avoid NMDA-related adverse reactions.In conclusion,the adequate preparation for the surgery should be done in this kind of patients,we should avoid using anesthetics having NMDA receptor antagonism (such as ketamine,N2O,methadone,dextromethorphan,phencyclidine) or other anesthetics acting indirectly (such as pentobarbital) on the NMDA receptors during anesthetic management in the patients with anti-NMDA receptor encephalitis.%目的 抗NMDA受体脑炎是一种与抗NMDA受体抗体相关的、自身免疫性副肿瘤边缘叶

  15. 儿童抗N-甲基-D-天冬氨酸受体脑炎七例%Anti-N-methyl-D-aspartate receptor encephalitis in seven children

    Institute of Scientific and Technical Information of China (English)

    王晓慧; 任海涛; 许春伶; 方方; 丁昌红; 吕俊兰; 韩彤立; 刘丽英; 李久伟; 伍妘; 崔丽英

    2012-01-01

    Objective To study the clinical and laboratory features and diagnosis of the patient with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children.Method The data of clinical feature,laboratory findings,and radiological manifestation were reviewed and analyzed.Result Of the 7 patients,4 were female and 3 were male.The age of onset was from 6.6 to 15.5 years (average 9.5 years).The onset of 4 cases started with convulsion.Six cases had seizures which was difficult to control by antiepileptic drugs.All patients had psychiatric symptoms and speech disorder.Six cases had different levels of decreased consciousness and dyskinesias.6 cases had autonomic nerve instability,and 7 cases developed sleep disorders.The results of MRI examination were normal in all patients.The EEG of most patients showed focal or diffuse slow waves.Six cases had oligoclonal bands.All cases were confirmed to have the disease by detection of anti-NMDA receptor antibodies.No tumor was detected in any of the patients.All patients received immunotherapy.Conclusion Anti-NMDAR encephalitis is a severe but treatable disorder that frequently affects children and adolescents.Pediatric patients had clinical manifestations similar to those of adult patients.But children have a lower incidence of tumors and hypoventilation also occurs less frequently in children.Most of children had a good prognosis.%目的 探讨儿童抗N-甲基-D-天冬氨酸(NMDA)受体脑炎临床特点和诊断,提高对该病的认识.方法 对确诊为抗NMDA受体脑炎患儿的临床表现、实验室及影像学资料进行回顾性分析.结果 本组7例,女4例,男3例,年龄6岁8个月至15岁6个月,平均年龄9岁6个月.4例以惊厥起病,6例病程中存在抗癫(癎)药物难以控制的惊厥发作;7例均有精神症状及语言障碍;6例具有不同程度意识障碍、锥体外系不自主运动,其中口舌面异常运动6例、舞蹈和(或)手足徐动5例、姿势异常5例;6例

  16. 抗 NMDA 受体脑炎45例特点和临床转归分析%The clinical characteristics and outcomes of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis:a study of 45 cases

    Institute of Scientific and Technical Information of China (English)

    冯雪丹; 胡永强; 冯文良; 程家玲; 张隆辉; 邓欢; 王琳

    2016-01-01

    Objective To investigate the clinical characteristics of anti-N-methyl-D-aspartate receptor (NMDAR)encephalitis in the group. Methods The clinical data of 45 cases with anti-NMDAR encephalitis at neurology department of Beijing Youanmen Hospital and Beijing Xuanwu hospital from October 2012 to April 2015 were collected. The clinical features and followed-up outcomes were analyzed retrospectively. Results In the study of 45 patients, the outbreak age was between 14-61 years old, the mean age was 32.2±13.24 years. Twenty-seven patients were male, three of who(11%)had an underlying tumors. Eighteen were female, five of who(28%)had ovarian teratomas. Prodiomal symptoms were noted in 23(51%)of patients. The main clinical manifestations include psychiatric symptoms(91%), seizures(76%), involuntary movement(42%), hypoventilation(24%), decreased level of consciousness(47%)and autonomic instability(40%).The CSF routine test and biochemistry panel were abnormal in 89% patients and test for anti-NMDA receptor antibodies in CSF were positive in all patients. The EEG records main show generalized or frontal to temporal slow waves wild mild degree(21%)to middle degree(59%) abnormal. Brain CT or magnetic resonance imaging(MRI)were abnormal in 53% of patients and majority of them showing that T2 or FLAIR hyperintensities within frontal lobes and temporal lobes. All patients were treated with a combination of corticosteroids and IVIg .Six patients were received immunosuppressive agent(Clclophosphamide or Mycophenolate Mofetil). Except one was lost to follow-up, 86% experienced complete or near-complete recovery (modified rankin scale[MRS]0-2). Conclusion The incidence of anti-NMDAR encephalitis is not uncommon in men, and this disease is less associated with tumor. Anti-NMDAR encephalitis is characterized by psychiatric-behavior abnormality, seizures and anti-NMDAR antibody positive in CSF. 79% patients received a substantial recovery by early first-line immunosuppressive

  17. Clinical analysis of relapsing anti-N-methyl-D-aspartate receptor encephalitis%复发性抗N-甲基-D-天冬氨酸受体脑炎临床分析

    Institute of Scientific and Technical Information of China (English)

    关鸿志; 孔维泽; 彭斌; 黄颜; 卢强; 袁晶; 柳青; 沈航; 任海涛

    2015-01-01

    目的 探讨复发性抗N-甲基-D-天冬氨酸(NMDA)受体脑炎的临床特点、诊断与诊疗.方法 回顾2011年6月至2014年11月在北京协和医院神经科收治的复发性抗NMDA受体脑炎16例,分析症状学、脑脊液学、神经影像学、免疫学和肿瘤学等特点及治疗方案.结果 男5例,女11例,平均21.2岁.首次发病的起病症状包括:精神症状10例,不自主运动2例,癫痫发作3例,近记忆力减退1例;主要症状数:2 ~8个(平均5.8个);入ICU救治43.8%;改良Rankin评分(mRS)平均4.56;1例于首次发病时发现卵巢畸胎瘤并行切.16例共发生复发32次,多次复发者8例,平均复发间隔5.0个月.复发时症状数1~7个,其中以单一症状复发者11例次,多症状复发者21例次;复发期平均症状数2.59个/例次,低于初次发病(P<0.05).复发期mRS评分1~5分,平均2.69,低于初次发病(P<0.05).2例复发时出现不同于首次发病时的新症状.复发期脑脊液抗NMDA受体抗体阳性率为100%,血清抗NMDA受体抗体阳性率为53.1%.复发期脑电图异常12例.头MRI首次发病检查中8例异常,复发时原有病灶均消失,7例见新病灶.5例于复发期行头PET,均有异常.2例于复发期发现卵巢畸胎瘤并手术切除.16例给予一线免疫治疗,12例加用二线免疫治疗.全部病例经免疫治疗后病情缓解,mRS评分0~2分,平均0.78分.结论 抗NMDA受体脑炎具有一次复发和多次复发的可能性,即使切除畸胎瘤仍有可能复发.多数患者在复发时症状较轻.症状学、脑脊液抗体检测和神经影像学等为判断和评估复发的重要方法.为预防复发,选择长程免疫治疗方案是必要的,并需要遵循个体化的原则.%Objective With the discovery of more patients with anti-N-methyl-D-aspartate (antiNMDAR) encephalitis,frequent clinical relapses pose a new challenge to neurologists.Methods Retrospective reviews were conducted for 16 hospitalized patients with relapsing

  18. 重症抗 N-甲基-D-天冬氨酸受体脑炎的临床特点及预后分析%Clinical characteristic and prognostic analysis of severe anti-N-methyl-D-aspartate receptor encephalitis

    Institute of Scientific and Technical Information of China (English)

    黄小钦; 樊春秋; 叶静

    2016-01-01

    目的:探讨重症抗N-甲基-D-天冬氨酸受体( NMDAR)脑炎的临床特点及预后。方法回顾性分析9例重症抗NMDAR脑炎患者的临床资料。结果9例患者(女7例,男2例)均入住ICU治疗;平均发病年龄27.7岁;平均病程22.4 d, ICU平均住院时间50.9 d。主要临床表现有发热(7例)、精神行为异常(9例)、癫痫发作(9例)、意识障碍(8例)、运动功能异常(7例)、自主神经功能障碍(9例)及低通气(6例)。3例合并畸胎瘤。所有患者CSF抗NMDAR抗体均阳性,6例血清抗NMDAR抗体阳性,7例CSF-IgA升高。3例患者头颅MRI示颞叶或海马异常信号。5例患者EEG示异常慢波。9例患者接受糖皮质激素、丙种球蛋白或血浆置换等免疫调节治疗。5例患者完全恢复,4例患者症状改善伴残留症状。结论重症抗NMDAR脑炎常表现为进展迅速的精神行为改变、癫痫等症状,还有意识障碍、运动障碍、自主神经功能障碍,合并肿瘤并不多见。多数重症抗NMDAR脑炎患者积极免疫治疗预后较好。%Objective To observe the clinical characteristic and prognostic analysis of severe anti-N-methyl-D-aspartate receptor ( anti-NMDAR) encephalitis.Methods The clinical data of 9 patients with severe anti-NMDAR encephalitis were retrospective analyzed.Results Nine patients ( two male and seven females ) were taken care at ICU.They were 27.7 years old at average.The median course was 22.4 d and median length of stay in ICU was 50. 9 d.The mainly clinical characteristics were fever(7 cases), psychiatric behavioral symptoms(9 cases), seizures(9 cases) , decreased consciousness ( 8 cases ) , abnormal movement ( 7 cases ) , automatic instability ( 9 cases ) and hypoventilation(6 cases) .Three cases had ovarian teratoma.Anti-NMDAR antibodies in CSF of all patients were testing positive, while in serum were 6 cases.CSF-IgA in 7 cases were increased.The brain MRI indicated

  19. 血管性痴呆小鼠海马NMDA受体mRNA表达特征及喜得镇的影响%The effect of hydergine on N-methyl-D-aspartate receptor in neuron of hippocampus in mice with vascular dementia in situ hybridization

    Institute of Scientific and Technical Information of China (English)

    梁翠萍; 樊敬峰; 吕佩源; 王伟斌; 尹昱

    2005-01-01

    目的观察喜得镇对血管性痴呆(vascular dementia,VD)小鼠海马神经元N-甲基D-天门冬氨酸(N-methyl-D-aspartate,NMDA)受体原位杂交变化的影响,并探讨NMDA受体原位杂交变化特征及喜得镇对其变化的影响.方法双侧颈总动脉结扎,反复缺血-再灌注法制备模型,药物组用喜得镇溶液灌胃,跳台试验和水迷宫试验观察其行为学改变,采用原位杂交技术观察小鼠海马神经元NMDA受体的表达变化.结果药物组小鼠学习、记忆成绩优于模型组(P<0.01),其海马N-甲基-D-天门冬氨酸受体表达也明显增高(P<0.01).结论喜得镇能改善血管性痴呆小鼠模型的学习、记忆功能,这可能与N-甲基D-天门冬氨酸受体mRNA水平正常化有关.

  20. Endogenous interleukin-1β in neuropathic rats enhances glutamate release from the primary afferents in the spinal dorsal horn through coupling with presynaptic N-methyl-D-aspartic acid receptors.

    Science.gov (United States)

    Yan, Xisheng; Weng, Han-Rong

    2013-10-18

    Excessive activation of glutamate receptors and overproduction of proinflammatory cytokines, including interleukin-1β (IL-1β) in the spinal dorsal horn, are key mechanisms underlying the development and maintenance of neuropathic pain. In this study, we investigated the mechanisms by which endogenous IL-1β alters glutamatergic synaptic transmission in the spinal dorsal horn in rats with neuropathic pain induced by ligation of the L5 spinal nerve. We demonstrated that endogenous IL-1β in neuropathic rats enhances glutamate release from the primary afferent terminals and non-NMDA glutamate receptor activities in postsynaptic neurons in the spinal dorsal horn. Myeloid differentiation primary response protein 88 (MyD88) is a mediator used by IL-1β to enhance non-NMDA glutamate receptor activities in postsynaptic neurons in the spinal dorsal horn. Presynaptic NMDA receptors are effector receptors used by the endogenous IL-1β to enhance glutamate release from the primary afferents in neuropathic rats. This is further supported by the fact that NMDA currents recorded from small neurons in the dorsal root ganglion of normal rats are potentiated by exogenous IL-1β. Furthermore, we provided evidence that functional coupling between IL-1β receptors and presynaptic NMDA receptors at the primary afferent terminals is mediated by the neutral sphingomyelinase/ceramide signaling pathway. Hence, functional coupling between IL-1β receptors and presynaptic NMDA receptors at the primary afferent terminals is a crucial mechanism leading to enhanced glutamate release and activation of non-NMDA receptors in the spinal dorsal horn neurons in neuropathic pain conditions. Interruption of such functional coupling could be an effective approach for the treatment of neuropathic pain.

  1. Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic N-methyl-D-aspartate receptor function and neuronal excitotoxicity.

    Science.gov (United States)

    Zhou, Xianju; Ding, Qi; Chen, Zhuoyou; Yun, Huifang; Wang, Hongbing

    2013-08-16

    GluN2A and GluN2B are the major subunits of functional NMDA receptors (NMDAR). Previous studies have suggested that GluN2A and GluN2B may differentially mediate NMDAR function at synaptic and extrasynaptic locations and play opposing roles in excitotoxicity, such as neurodegeneration triggered by ischemic stroke and brain injury. By using pharmacological and molecular approaches to suppress or enhance the function of GluN2A and GluN2B in cultured cortical neurons, we examined NMDAR-mediated, bidirectional regulation of prosurvival signaling (i.e. the cAMP response element-binding protein (CREB)-Bdnf cascade) and cell death. Inhibition of GluN2A or GluN2B attenuated the up-regulation of prosurvival signaling triggered by the activation of either synaptic or extrasynaptic NMDAR. Inhibition of GluN2A or GluN2B also attenuated the down-regulation of prosurvival signaling triggered by the coactivation of synaptic and extrasynaptic receptors. The effects of GluN2B on CREB-Bdnf signaling were larger than those of GluN2A. Consistently, compared with suppression of GluN2A, suppression of GluN2B resulted in more reduction of NMDA- and oxygen glucose deprivation-induced excitotoxicity as well as NMDAR-mediated elevation of intracellular calcium. Moreover, excitotoxicity and down-regulation of CREB were exaggerated in neurons overexpressing GluN2A or GluN2B. Together, we found that GluN2A and GluN2B are involved in the function of both synaptic and extrasynaptic NMDAR, demonstrating that they play similar rather than opposing roles in NMDAR-mediated bidirectional regulation of prosurvival signaling and neuronal death.

  2. Inhibition of N-Methyl-D-aspartate-induced Retinal Neuronal Death by Polyarginine Peptides Is Linked to the Attenuation of Stress-induced Hyperpolarization of the Inner Mitochondrial Membrane Potential.

    Science.gov (United States)

    Marshall, John; Wong, Kwoon Y; Rupasinghe, Chamila N; Tiwari, Rakesh; Zhao, Xiwu; Berberoglu, Eren D; Sinkler, Christopher; Liu, Jenney; Lee, Icksoo; Parang, Keykavous; Spaller, Mark R; Hüttemann, Maik; Goebel, Dennis J

    2015-09-01

    It is widely accepted that overactivation of NMDA receptors, resulting in calcium overload and consequent mitochondrial dysfunction in retinal ganglion neurons, plays a significant role in promoting neurodegenerative disorders such as glaucoma. Calcium has been shown to initiate a transient hyperpolarization of the mitochondrial membrane potential triggering a burst of reactive oxygen species leading to apoptosis. Strategies that enhance cell survival signaling pathways aimed at preventing this adverse hyperpolarization of the mitochondrial membrane potential may provide a novel therapeutic intervention in retinal disease. In the retina, brain-derived neurotrophic factor has been shown to be neuroprotective, and our group previously reported a PSD-95/PDZ-binding cyclic peptide (CN2097) that augments brain-derived neurotrophic factor-induced pro-survival signaling. Here, we examined the neuroprotective properties of CN2097 using an established retinal in vivo NMDA toxicity model. CN2097 completely attenuated NMDA-induced caspase 3-dependent and -independent cell death and PARP-1 activation pathways, blocked necrosis, and fully prevented the loss of long term ganglion cell viability. Although neuroprotection was partially dependent upon CN2097 binding to the PDZ domain of PSD-95, our results show that the polyarginine-rich transport moiety C-R(7), linked to the PDZ-PSD-95-binding cyclic peptide, was sufficient to mediate short and long term protection via a mitochondrial targeting mechanism. C-R(7) localized to mitochondria and was found to reduce mitochondrial respiration, mitochondrial membrane hyperpolarization, and the generation of reactive oxygen species, promoting survival of retinal neurons.

  3. Long-term exposure to dieldrin reduces gamma-aminobutyric acid type A and N-methyl-D-aspartate receptor function in primary cultures of mouse cerebellar granule cells.

    Science.gov (United States)

    Babot, Zoila; Vilaró, M Teresa; Suñol, Cristina

    2007-12-01

    The organochlorine pesticide dieldrin is a persistent organic pollutant that accumulates in the fatty tissue of living organisms. In mammals, it antagonizes the GABA(A) receptor, producing convulsions after acute exposure. Although accumulation in human brain has been reported, little is known about the effects of long-term exposure to dieldrin in the nervous system. Homeostatic control of the balance between excitation and inhibition has been reported when neuronal activity is chronically altered. We hypothesized that noncytotoxic concentrations of dieldrin could decrease glutamatergic neurotransmission as a consequence of a prolonged reduction in GABA(A) receptor function. Long-term exposure of primary cerebellar granule cell cultures to 3 microM dieldrin reduced the GABA(A) receptor function to 55% of control, as measured by the GABA-induced (36)Cl(-) uptake. This exposure produced a significant reduction (approximately 35%) of the NMDA-induced increase in [Ca(2+)](i) and of the [(3)H]MK-801 binding, which was not accompanied by a reduction in the NMDA receptor subunit NR1, as determined by Western blot. Consistent with the decreased NMDA receptor function, dieldrin-treated cultures were insensitive to an excitotoxic stimulus induced by exposure to high potassium. In summary, we report that the chronic reduction of GABA(A) receptor function induced by dieldrin decreases the number of functional NMDA receptors, which may be attributable to a mechanism of synaptic scaling. These effects could underlie neural mechanisms involved in cognitive impairment produced by low-level exposure to dieldrin. (c) 2007 Wiley-Liss, Inc.

  4. 儿童抗N-甲基-D-天冬氨酸受体脑炎的临床护理%Clinical nursing care of children with anti N-methyl-D-aspartate receptor encephalitis

    Institute of Scientific and Technical Information of China (English)

    潘月瑢

    2016-01-01

    目的:总结抗N-甲基-D-天冬氨酸受体脑炎的临床护理方法。方法:选取神经内科明确诊断的10例抗NMDA受体脑炎患儿,实施病情观察、安全护理、皮肤护理、康复护理及心理护理等护理措施,对所采用的护理方法及效果进行总结。结果:经积极治疗及有效护理,10例患儿中6例基本恢复,3例遗留轻微肢体功能障碍,1例存在语言障碍,无1例护理并发症及死亡病例。结论:对抗N-甲基-D-天冬氨酸受体脑炎的患儿采取积极有效的护理方法,能够减少并发症的发生,促进疾病的恢复。%Objective:To summarize the clinical nursing methods of anti NMDA receptor encephalitis.Method:Select the Department of internal medicine in our hospital.10 cases of anti NMDA receptor encephalitis,the implementation of patient observation,safety nursing, skin nursing,rehabilitation nursing and psychological nursing, the nursing method and effect of the summary.Result:After active treatment and effective nursing,10 cases in 6 cases recovered, 3 cases of minor residual limb dysfunction,1 case there is a language barrier,no 1 example nursing complications and deaths.Conclusion:Against anti NMDA receptor encephalitis of children to take positive and effective nursing method, can reduce the complication the occurrence,promote disease recovery.

  5. Role of N-methyl-D-aspartate receptor one in visceral hypersensitivity forming of transient intestinal infection induced rat%N-甲基-D-天冬氨酸受体1在一过性肠道感染大鼠内脏高敏感形成中的意义

    Institute of Scientific and Technical Information of China (English)

    杨小军; 沈蕾; 钱伟; 官阳; 侯晓华

    2012-01-01

    目的 研究N-甲基-D-天冬氨酸受体1(NMDA-R1)在SD大鼠—过性肠道感染旋毛虫后形成的内脏高敏感中的作用.方法 40只SD大鼠均分为健康对照组、内脏高敏感组、0.9%氯化钠溶液组、MK-801组,其中内脏高敏感组、0.9%氯化钠溶液组和MK 801组分别予旋毛虫感染造模.8周后,0.9%氯化钠溶液组和MK-801组分别予0.9%氯化钠溶液和NMDA-R1拮抗剂MK-801.观察各组在20、40、60和80 mm Hg(1 mm Hg=0.133 kPa)结直肠扩张压力下腹壁肌电活动反应.测定腹壁肌电活动后,取大鼠结肠标本,采用Western印迹检测NMDA-R1蛋白水平的表达.统计学处理采用Bivariate相关分析和LSD检验.结果 健康对照组、内脏高敏感组、0.9%氯化钠溶液组和MK-801组腹壁肌电图曲线下面积(AUC)与扩张压力之间均有相关性(r=0.823、0.618、0.913、0.889,均P<0.01).在20、40、60和80 mm Hg扩张压力下,MK-801组与内脏高敏感组AUC间差异均有统计学意义(LSD检验,P值均<0.05),MK-801组AUC均小于健康对照组,但只在80 mm Hg扩张压力下差异有统计学意义(LSD检验,P=0.029).MK-801组NMDA-R1蛋白积分吸光度相对值为1.238±0.210,较内脏高敏感组(2.231±0.450)和0.9%氯化钠溶液组(2.104±0.220)均显著降低(LSD检验,P=0.025和0.046),内脏高敏感组NMDA-R1蛋白积分吸光度相对值和0.9%氯化钠溶液组较健康对照组显著升高(1SD检验,P=0.007和0.014).结论 内脏高敏感的形成与突触后NMDA-R1的高表达密切相关,抑制肠道神经系统中NMDA-R1的表达可调节内脏高敏感性.%Objective To investigate the role of N-methyl-D-aspartate receptor one(NMDA-R1 )in visceral hypersensitivity forming of Sprague-Dawley rat model induced by transient Trichinella spiralis intestinal infection.Methods Forty male Sprague-Dawley rats were divided into healthy control group,visceral hypersensitivity group,0.9% NaCl group and MK-801 group.The rats in visceral

  6. NMDA受体亚单位NR1在离体人神经干细胞中的表达%The expression of N-methyl-D-aspartate receptors subunit 1 in the human hippocampus neural stem cells in vitro

    Institute of Scientific and Technical Information of China (English)

    胡忠浩; 王姗姗; 徐铁军

    2011-01-01

    目的 研究离体培养的人海马神经干细胞(NSCs)中NMDA受体亚单位NR1的表达.方法 分离培养胎龄8~12周人胚脑海马神经干细胞,对NSCs进行Nestin和分化鉴定.用免疫细胞化学、Western blot免疫印迹和RT-PCR等方法检测原代、传代1次、传代2次的人胚胎海马NSCs中NR1蛋白和mRNA的表达.结果 在孕8~12周人胚脑海马分离培养的NSCs中,NMDA受体亚单位NR1免疫细胞化学反应呈阳性,该受体亚单位的蛋白和mRNA均被检测到.结论 体外培养的早期人胚胎海马NSCs能稳定表达NMDA受体亚单位NR1.%Objective To investigate the expression of N - methyl - D - aspartate (NMDA) receptor subunit 1 in the cuhured human hippocampus neural stem cells (NSCs). Methods NSCs from hippocampus of abortion human embryonic tissue (8 -12 weeks post conception) were cultured and passaged in suspension. The neurospheres were identified by Nestin immunocytochemistry and the differentiation potential of NSCs were also detected. The protein and mRNA expression of NMDA receptor subunit 1 in the human hippocampus NSCs of primitive, passage 1 and 2 were measured by immunocytochemistry, Western blot and reverse transcription polymerase chain reaction (RT -PCR). Results NRI immunostaining positive cells could be found in the human hippocampus NSCs. The protein and mRNA of NR1 were identified in the same cells. Conclusion NSCs from the human embryonic hippocampus can express NMDA receptor subunitl in vitro.

  7. Anti-N-methyl-D-aspartate Receptor Encephalitis Mimicking Herpes Simplex Encephalitis Onset%发病酷似单纯疱疹病毒脑炎的抗N-甲基-D-天冬氨酸受体脑炎

    Institute of Scientific and Technical Information of China (English)

    王瑞金; 齐冬; 王淑辉; 张拥波

    2015-01-01

    目的 提高对发病酷似单纯疱疹病毒脑炎(Herpes simplex encephalitis,HSE)的抗N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体脑炎的认识.方法 报道2例发病酷似单纯疱疹病毒脑炎的抗NMDA受体脑炎,并复习相关文献.结果 2例患者均急性起病,表现为发热、抽搐、认知功能减退、精神行为异常等.脑MRI均未见异常.病例1、病例2脑脊液白细胞最高分别为20×106/L、21×106/L.脑脊液蛋白、葡萄糖以及氯化物水平均正常.2例患者早期均被诊断为HSE,并接受阿昔洛韦抗病毒治疗,但病情仍进展.抗NMDA受体抗体检测显示例1脑脊液及血液均阳性,例2脑脊液阳性,从而明确了抗NMDA受体脑炎的诊断.结论 对脑MRI无异常,脑脊液白细胞无明显升高的边缘系统脑炎,应想到抗NMDA受体脑炎可能.

  8. 氯胺酮对N-甲基-D-天冬氨酸诱导大鼠脊髓背角星形胶质细胞损伤的作用%Influence of ketamine on astrocyte damage in spinal dorsal horn of rats induced by N-methyl-D-aspartic acid

    Institute of Scientific and Technical Information of China (English)

    李清; 刘菊英; 周青山; 朱涛; 秦成名

    2006-01-01

    组,差异显著[分别为(25.26±6.13)%,(5.66±2.24)%,P<0.01],100μmol/LN-甲基-D-天冬氨酸+1 mmol/L氯胺酮组低于100 μmol/L N-甲基-D-天冬氨酸组,差异显著[分别为(24.41±4.82)%,(25.26±6.13)%,P<0.01].③丙二醛含量和超氧化物歧化酶活性变化:100 μmol/L N-甲基-D-天冬氨酸使星形胶质细胞内丙二醛含量显著升高,而超氧化物歧化酶活性明显降低;1 mmol/L氯胺酮明显降低丙二醛含量,显著增强超氧化物歧化酶活性,该效应在临床镇痛剂量以内有明显量效关系,与N-甲基-D-天冬氨酸组相比差异显著(P<0.01).1 mmol/L氯胺酮组与对照组相比、100μmol/L N-甲基-D-天冬氨酸+0.1 mmol/L氯胺酮组与N-甲基-D-天冬氨酸组相比差异均无显著性.结论:N-甲基-D-天冬氨酸受体过度激活可诱导大鼠脊髓背角星形胶质细胞大量凋亡,适量氯胺酮显著抑制细胞凋亡,其机制可能增强星形胶质细胞Bcl-2蛋白表达,同时抑制自由基的产生和增强超氧化物歧化酶活性.%BACKGROUND: Ketamine is a kind of frequently used general venous anesthesia drug in clinic, and the medication in vein or epidural cavum has analgesic effect. It is N-methyl-D-aspartic acid (NMDA) receptor noncompetitive antagonist, which can inhibit toxic effect of excitatory amino acids.OBJECTIVE: To observe effect of ketamine on apoptosis of dorsal horn astrocytes of spinal cord of rats induced by NMDA receptor over activation and explore its possible mechanism of action.DESIGN: Randomized controlled observation.SETTING: Department of Anesthesiology, Taihe Hospital Affiliated to Yunyang Medical College.MATERIALS: The experiment was conducted at Cell Biology Laboratory,Institute of Basic Medical Sciences, Yunyang Medical College between September 2003 and January 2005. Neonatal Wistar rats of two or three days were provided by Animal Experimental Center of Wuhan University. METHODS: Primary astrocytes in dorsal horn of T11-L6 spinal cord of Wistar rats were purified and

  9. 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

    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...

  10. Relationship between N-methyl-D-aspartate receptor and stroke as well as its nuclide imaging agents%N-甲基-D-天冬氨酸受体与脑卒中的关系及其核素显像剂

    Institute of Scientific and Technical Information of China (English)

    孔艳艳; 周杏琴; 曹国宪

    2010-01-01

    脑卒中具有极高的致死率和致残率,在当今老龄化社会中其危害性日益突出.N-甲基-D-天冬氨酸受体(NMDAR)是一类配体门控离子型谷氨酸受体,参与兴奋性突触传递、突触可塑性和神经精神疾病的发生和发展.NMDAR在不同的脑区分布有差异,如海马和皮层密度最高,这些区域对脑缺血很敏感.谷氨酸介导的兴奋性神经毒对脑卒中的发生、发展起着极其关键的作用,引起了人们对中枢神经系统兴奋性神经递质和NMDAR的高度重视.同时,脑卒中后对Ca2+通透的NMDAR、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体、海人藻酸受体高度兴奋,引起细胞内钙超载,进而触发级联细胞死亡.NMDAR有特殊的结构和药理学特性,对NMDAR显像剂的研究为脑卒中的早期诊断和研发特异性拮抗剂提供了新的靶点.通过活体断层显像可以观察到缺血缺氧后神经细胞的变化,从而对NMDAR拮抗剂的神经保护作用作出评价.%Stroke is one of the leading causes of death and disability, especially for the old population in modern world. As one of ligand-gating ionotropic glutamate receptors, N-methyl-D-aspartate rece pto r (NMDAR) involves in excitatory synaptic transmission, synaptic plasticity and the cause and development of numerous neurological as well as psychiatric disorders. Since the distribution of NMDAR varies in different regions, certain brain regions such as hippocampus and cortex with the highest density of NMDAR, are especially sensitive to ischemia. Much emphasizes have been put on the changes of excitatory neurotransmission and NMDAR in central nervous system after ischemia, because the glutamate-mediated excitatory neurotoxicity play a key role in the development of stroke. It has been shown that neuronal death after ischemia results from excessive Ca2+influx, which is due to the hyperactivity of NMDAR, Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor

  11. Modulatory effect of neurokinin- 1 and non- N- methyl- D- aspartate receptors on cardiosomatic reflex in rat spinal cord%脊髓NK1受体与非NMDA受体对大鼠心脏-躯体运动反射的调节作用

    Institute of Scientific and Technical Information of China (English)

    韩曼; 刘晓华; 杜剑青

    2014-01-01

    Objective To investigate the role of neurokinin-1 (NK1) receptor and non-N-methyl-D-aspartate (non-NMDA) receptor in modulating the cardiosomatic reflex in the spinal cord of rat. Methods The effects of intrathecal injection of NK1 receptor agonist Sar-SP and antagonist CP-96345 and non-NMDA receptor agonist NMDA and antagonist 6, 7-dinitro-1,4-dihydro-quinoxaline-2,3-dione (DNQX) on the cardiosomatic reflex were observed in rats. The changes of the cardiosomatic reflex were monitored by observing the electromyogram (EMG) responses of the dorsal spinotrapezius muscle to intrapericardial bradykinin (BK) injection. Results Intrathecal injection of Sar-SP significantly facilitated EMG responses to intrapericardial BK injection (P<0.05), which was completely blocked by intrathecal injection of NK1 antagonist CP-96345. Similarly, intrathecal injection of NMDA obviously facilitated the EMG responses (P<0.05), which was partially reversed by intrathecal injection of non-NMDA receptor antagonist DNQX. Intrathecal injection of Sar-SP along with NMDA significantly increased EMG as compared with single administration of Sar-SP or NMDA (P<0.05). Conclusion The spinal cord levels of NK1 receptor and non-NMDA receptor are involved in the modulation of the cardiosomatic reflex in rats.%目的:观察脊髓水平神经激肽-1(NK1)受体和非N-甲基-D-天门冬氨酸(NMDA)受体对大鼠心脏-躯体运动反射的调节作用。方法鞘内注射NK1受体激动剂Sar-SP及拮抗剂CP-96345与非NMDA受体激动剂NMDA及拮抗剂6,7-二硝基喹喔啉-2,3-二酮(DNQX),观察心包内注射缓激肽(BK)诱发大鼠心脏-躯体运动反射的变化,该反射以背斜方肌肌电(EMG)为观测指标。结果鞘内注射NK1受体激动剂Sar-SP后,对心包内BK诱发的背斜方肌EMG有明显的易化作用(P<0.05),这种易化作用被鞘内预先注射NK1拮抗剂CP-96345完全阻断;鞘内注射非NMDA受体激动剂NMDA后,对心包

  12. THE EFFECTS OF ZINC DEFICIENCY ON THE CONCENTRATION OF BRAIN FREE AMINO ACIDS AND SYNAPTIC MEMBRANES N-METHYL-D-ASPARTATE RECEPTORS IN RATS%缺锌对大鼠脑组织游离氨基酸和突触膜 N-甲基-D-天冬氨酸受体含量的影响

    Institute of Scientific and Technical Information of China (English)

    刘燕强; 顾景范

    2003-01-01

    本研究进行了两系列实验以探讨缺锌对大鼠脑组织游离氨基酸和突触膜N-甲基-D-天冬氨酸受体含量的影响.在第一系列实验中,把生长大鼠随机分为三组即缺锌组(ZD)、对喂组(PF)和缺锌补锌组(ZS),分别饲喂低锌饲料(3.3mg/kg)、常锌饲料但给料量与缺锌组一致以及先饲喂缺锌饲料21d后再饲喂常锌饲料,持续饲喂35d.饲养实验结束后,采取脑组织样本以分析其中的游离氨基酸的含量.在第二系列实验中,第1和第2组的处理与实验1一致,而第3组则不限食地饲喂常锌饲料,持续饲喂28d.然后取海马组织以分析其中的NMDA受体的含量.结果表明,缺锌显著降低端脑中游离谷氨酸、牛磺酸、苏氨酸、丝氨酸、丙氨酸、半胱氨酸和精氨酸含量,同时使海马中NMDA受体的最大结合率降低.此结果可能与缺锌降低大鼠学习记忆功能有关.%Two experiments were used to evaluate the effects of zinc deficiency on the concentration of free amino acids and N-methyl-D-aspartate (NMDA) receptor. In Exp. 1, Growing rats respectively consumed a low zinc (3.3mg/kg) diet (ZD), the adequate zinc but restricted according to feed consumption of ZD group (PF) or an adequate zinc diet after a low zinc diet for 21d(ZS). The duration is 35d. The telencephalon tissues were used for free amino acid concentration analysis. In Exp. 2, The treatment of group 1 and 2 were similar to Exp.1, but the rats of group 3 consumed adequate zinc diet ad libitum. The duration is 28d. The hippocampus tissues were used for NMDA receptor concentration analysis. Zinc deficiency significantly reduced the concentration of glutamate, taurine, threonine, serine, alanine, cysteine and arginine in telencephalon tissues,and Bmax of NMDA receptors in hippocampus tissues. The results provides a good explanation for low learning and memory ability in zinc deficient rats.

  13. Effect of Wendan Decoction on Receptor of Glutamic Acid and N-methyl-D-aspartate in Rats with Schizophrenia%温胆汤对精神分裂症模型鼠海马谷氨酸和N-甲基-D-天冬门氨酸受体亚单位表达的影响

    Institute of Scientific and Technical Information of China (English)

    杨翠萍; 蔡长春; 杨晓金; 万红娇; 肖纯

    2011-01-01

    Objective:To explore the effect of Wendan Decoction (WDD) on the receptor of glutamic acid (Glu) and N-methyl-D-aspartate (NMDA) in rats with schizophrenia. Method: Thirty SD rats were divided randomly into 3 groups with 10 in each group: normal group (A), model group (B) and WDD group (C). WDD group was administered intragatrically with 20 g· kg -1WDD;the other groups were administered the same volume of normal saline (20 mL·kg-1). The 3 groups were treated for 21 days. Except the normal group, the other groups were given MK801 with sinistro-intraperitoneal injection to set the schizophrenia model after 1 hour of intragastrical administration in the last 3 days. The dosage was 0. 1 mL per 20 g. By the changes in immunohistochemistry and neuropathological morphology, we observed the influence of WDD on expression of receptor Glu in hippocampus,receptor subunit NR1 and NR2B of NMDA and protective effects on pathological injuries in hippocampus of the model rats. Result: The morphological observation showed that there were significant differences in expression of Glu, subunit NR1 and NR2B of NMDA receptor in all groups and there also were significant differences in cell structure and cell denaturalization of CA1 area in hippocampus. Conclusion: WDD can improve disorder of cell rearrangement, relieve the process of nuclei dissolution, postpone the denaturalization of hippocampus cell. It indicates WDD has certain protective effects on pathological injury in hippocampus of the model rats.%目的:观察温胆汤对精神分裂症模型鼠海马谷氨酸(Glu)和N-甲基-D-天冬门氨酸(NMDA)受体亚单位表达的影响.方法:将30只SD大鼠,随机分3组,每组10只,分别为正常组(A)、模型组(B)及温胆汤组(C),A,B组ig生理盐水20mL·kg-1,C组ig温胆汤20 g·kg-1,每天1次,21 d后地卓西平马来酸盐(MK801)ip诱发精神分裂症,造模3 d后,4 ℃ 4%多聚甲醛磷酸盐缓冲液大脑灌注固定、制备脑组织切片,免疫组化染色,观

  14. Clinical analysis of patients with anti-N-methyl-D-aspartate receptor encephalitis: a report of 3 cases%抗N-甲基D-天冬氨酸受体脑炎临床分析(附三例报道)

    Institute of Scientific and Technical Information of China (English)

    黄曜纬; 颜振兴; 贺荣霓; 谢惠芳

    2015-01-01

    Objective To explore the clinical features,laboratory test results,diagnosis,treatment and prognosis of patients with anti-N-methyl-D-aspartic acid receptor (NMDAR) encephalitis.Methods A retrospectives analysis of clinical characteristics,laboratory test,treatment and prognosis of 3 patients with NMDRA encephalitis,admitted to our hospital from February 2012 to November 2014,was performed in our study.Results The most predominant symptoms of 3 patients with anti-NMDAR encephalitis included fever,psychiatric behavioral disturbances,seizures,orofacial dyskinesias and movement disorders and autonomic dysfunction.One patient had immature ovarian teratoma and one had mature mediastinal teratoma.Anti-NMDAR antibody was positive in serum and cerebrospinal fluid of two patients with teratoma,and anti-NMDAR antibody was positive in cerebrospinal fluid and negative in serum of one patient without tumour;all three patients showed abnormal electroencephalography,and 2 had increased signal on MR imaging T2 sequences or fluid-attenuated inversion.Patients were responsive to early immunotherapy and tumour resection.Conclusion The patient with NMDAR encephalitis presented with characteristic clinical manifestations;detection of anti-NMDAR antibody in serum and cerebrospinal fluid may be important for early diagnosis;early immunotherapy and tumour resection are effective for patients with NMDAR encephalitis.%目的 分析抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎的临床特点、实验室检查结果及诊断治疗方法与预后. 方法 收集自南方医科大学珠江医院神经内科自2012年2月至2014年11月收治的3例NMDAR脑炎患者的临床资料,回顾性分析其临床症状特点、实验室检查、治疗及预后. 结果 3例患者临床以发热、精神行为异常、抽搐、口面部不自主运动、自主神经功能紊乱为主要特征,其中1例伴有卵巢未成熟型畸胎瘤,l例伴有纵膈成熟型畸胎瘤,2例血及脑脊

  15. The characteristics of clinical manifestations, brain MRI and cerebrospinal fluid findings in patients with anti-N-methyl-D-aspartate receptor encephalitis%抗N-甲基-D-天冬氨酸受体脑炎患者的临床、磁共振成像和脑脊液特征分析

    Institute of Scientific and Technical Information of China (English)

    贺菲菲; 叶静; 董恺; 赵筱玲

    2014-01-01

    目的 分析我国成年人抗N-甲基-D-天冬氨酸(NMDA)受体脑炎患者的临床、头MRI和脑脊液特点.方法 收集29例抗NMDA受体脑炎患者的临床、MRI和脑脊液资料.结果 29例抗NMDA受体脑炎中,主要临床表现为精神异常占86%(25例),癫痫83%(24例),意识障碍55%(16例),不自主运动55%(16例),中枢性通气障碍34%(10例),大量唾液分泌17%(5例),尚有自主神经紊乱、偏瘫、失语等.14%(4例)伴有畸胎瘤.头MRI异常者占62%(18例),病灶分布于颞叶、海马、丘脑、脑干、扣带回、额顶叶、胼胝体、内囊/基底节/脑室旁.83%腰椎穿刺结果异常,其中脑脊液寡克隆区带阳性率为95% (19/20).3年内复发率为31% (9/29).结论 抗NMDA受体脑炎患者主要临床表现为精神异常、癫痫,特征性临床表现有不自主运动、中枢性通气障碍、大量唾液分泌;MRI病灶分布不仅局限于边缘叶;是复发率较高但可治疗的疾病.%Objective To analyze the clinical manifestations and the features of brain MRI and cerebrospinal fluid (CSF) findings in adult Chinese patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.Methods We reviewed the clinical manifestations,brain MRI and CSF examinations of 29 patients who were diagnosed as anti-NMDAR encephalitis.Results The major clinical features of anti-NMDAR encephalitis patients included psychiatric symptoms (86%,25/29),seizures (83%,24/29),decreased consciousness (55%,16/29),involuntary movements (55%,16/29),central hypoventilation (34%,10/29),and hypersalivation (17%,5/29).Some patients also experienced autonomic instability,hemiplegia and aphasia.Underlying ovarian teratoma was identified in 14% of affected patients(4/29).Brain MRI was found abnormal in up to 62% patients (18/29),located in the temporal lobes,hippocampus,thalamus,brain stem,cingulate gyrus,frontal and parietal cortex,corpus callosum,internal capsule,basal ganglia and

  16. Effect of mild hypothermia on the expression N-methyl-D-aspartate receptor 1 in hippocampus of rats after traumatic brain injury%亚低温干预对创伤性颅脑损伤后N-甲基-D-天冬氨酸受体1表达的影响

    Institute of Scientific and Technical Information of China (English)

    殷玉华; 李明; 贾锋; 江基尧; 徐蔚

    2013-01-01

    Objective To investigate the effect of mild hypothermia on the expression of N-methyl-D-aspartate receptor 1 (NMDAR1) after fluid percussion traumatic brain injury (TBI) in rats.Methods A total of 54 adult male Sprague-Dawley rats were randomly divided into three groups:TBI with hypothermia treatment ([33.0±0.5] ℃,n =24),TBI with normothermia ([37.0 ± 0.3] ℃,n =24),and sham injured group (n =6).TBI model was induced by fluid percussion TBI device.Mild hypothermia was achieved by partial immersion in a water bath (0 ℃) under general anesthesia for 4 h.All the rats were killed at 4,6,12 and 24 h after TBI,respectively.The rats in the sham injured group were killed 24 h after treatment.The mRNA and protein levels of NMDAR1 in hippocampus were measured by realtime-polgmerase chain reaction (RT-PCR) and Western-blot techniques,respectively.Results Compared with sham injured group,NMDAR1 mRNA levels in injured hippocampus of normothermia and hypothermia groups were significantly increased at 4,6 and 12 h after TBI (all P<0.05),but there were no significant differences in NMDAR1 mRNA between these three groups at 24 h after TBI (all P>0.05).Compared with normothermia group,NMDAR1 mRNA levels were significantly decreased at 4,6 and 12 h after TBI in hypothermia group (all P<0.05),while there were no significant differences at 24 h after TBI (P>0.05).The expression of NMDAR1 protein in injured hippocampus of normothermia and hypothermia groups were significantly increased at 4,6,12 and 24 h after TBI as compared with that of sham injured group (all P<0.05),while NMDAR1 protein levels in hypothermia group were significantly lower than that in normothermia group (all P<0.05).Conclusion Mild hypothermia can efficiently suppress NMDAR1 expression in the rats with TBI induced by fluid percussion and have good neuroprotection effect.%目的 探讨创伤性颅脑损伤(TBI)后亚低温治疗对N-甲基-D-天冬氨酸受体1(NMDAR1)表达的影响.方法 将54

  17. Effects of N-methyl-D-aspartate Receptor Antagonist MK-801 on Expression of Glial Fibrillary Acidic Protein in the Subventricular Zone of Neonatal Rat%NMDA受体拮抗剂MK-801对新生大鼠室管膜下区胶质纤维酸性蛋白表达的影响

    Institute of Scientific and Technical Information of China (English)

    李晓泉; 陈芳芳; 王伟; 来青伟; 耿德勤; 樊红彬

    2013-01-01

    Aim To investigate the effects of the N-methyl-D-aspartate(NMDA)-receptor antagonist MK801 on the expression of glial fibrillary acidic protein(GFAP) in the subventricular zone(SVZ) of neonatal rat.Methods 40 neonatal SD rats were assigned into two groups,a MK-801 group and a control group.Each group was respectively divided into four time points,including P7 d (postnatal 7 days),P14 d,P21 d and P28 d.Rats in the experiment group were intraperitoneally injected selective non-competitive NMDA receptor antagonist MK-801 (10 mg·kg1),while rats in the control group were intraperitoneally injected saline.Immunohistochemical staining was used to assay the number of GFAP-positive cells in the SVZ.Results ① In the control group,the number of GFAP-positive cells increased at P14 d,and the number of GFAP-positive cells reached maximum at P21 d,positive cells decreased significantly at 28 d.② Compared with the control group,the number of GFAP-positive cells reduced significantly at P 14 d (65.40 ± 6.11) and P21 d (239.60 ± 12.92),and the number of GFAP-positive cells increased significantly [P14 d(79.20 ± 5.26),P21 d(265.20 ± 7.40)](P<0.01),while the number of positive cells without obvious changes at P7 d and P28 d in the MK-801 group.Conclusion NMDA-receptor antagonist MK-801 could reduce the expression of GFAP in the SVZ,and inhibit the neural stem cells proliferation and differentiation.%目的 研究N-甲基-D-天冬氨酸(NMDA)受体拮抗剂MK-801对新生7d大鼠室管膜下区(SVZ)胶质纤维酸性蛋白(GFAP)表达的影响.方法 将40只新生SD大鼠分成对照组和MK-801组,各组按出生后口(P)时间点再随机分成4个亚组:P7d、P14d、P21 d、P28d组.新生大鼠均于生后第3天给药,MK-801组腹腔注射MK-801 10 mg·kg-1;对照组腹腔注射同量生理盐水.通过免疫组化学方法观察大鼠SVZ区GFAP阳性细胞数.结果 ①对照组GFAP阳性细胞数于P14 d开始增加,至P21 d达最大值;但P28 d时阳

  18. The expression changes of N-methyl-D-aspartic acid receptor in hippocampus of offspring from female rats exposed to aluminum in the pregnancy and lactation%孕哺期铝暴露对仔鼠海马 N-甲基-D-天门冬氨酸受体表达的影响

    Institute of Scientific and Technical Information of China (English)

    靳翠红; 巫生文; 逯晓波; 唐秋实; 刘秋芳; 蔡原

    2011-01-01

    Objective To investigate the effects of aluminum on learning and memory and the expression of N-methyl-D-aspartic acid receptor (NMDAR) of hippocampus in offspring from female rats exposed to Al in the pregnancy or lactation, and to explore the mechanism of toxic effects of Al on central nervous system (CNS) during development. Methods The pregnant Wistar rats were randomly divided into 3 groups based on their body weight, I.e. Control group was exposed to distilled water, low exposure group (0.2 %AlCl3) and high exposure group (0.4 %AlCl3) were exposed orally to AlCl3 in pregnancy and lactation for 6 weeks, 10 rats each group. Aluminum content in blood and brains was determined by atomic absorption spectrophotometry (AAS). Platform experiment was used to detect the abilities of learning and memory. The expression levels of NMDARs were detected by western blot assay. Results The Al content in blood and brains of rats in exposure groups increased significantly with Al dose, as compared with the control group ( P<0.05 ). In platform experiment, the incubation periods of rats in low and high exposure groups were (202.71±81.99 ) and ( 19.67±8.44 )s respectively, which were significantly lower than that [( 300.00±0.00 )s] in control group (P<0.01), but the mistake times of rats in low and high exposure groups were 1.43±0.85 and 2.47±0.99 respectively, which were significantly higher than that (0.00±0.00) in control group (P<0.01). The Al exposure could change the proportion of NMDAR subtypes, the expression levels of NR1 and NR2B in hippocampus of newborn rats in low and high exposure groups were 25.22±0.68, 81.23±15.37 and 24.75±0.71, 56.63 ±7.82, respectively, which were significantly lower than those (31.69±3.44, 107.61±9.05 ) in control group (P<0.05). Conclusion Aluminum exposure in pregnancy and lactation could reduce theabilities of learning and memory in newborn rats, and change the proportion of NMDAR subtypes. The reduced NR1and NR2B

  19. Immunotherapy strategy for 35 cases of severe anti-N-methyl-D-aspartate receptor encephalitis%重症抗N-甲基-D-天冬氨酸受体脑炎35例免疫治疗分析

    Institute of Scientific and Technical Information of China (English)

    袁晶; 彭斌; 关鸿志; 黄颜; 卢强; 任海涛; 杨洵哲; 姜南; 朱以诚

    2016-01-01

    目的 分析重症抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎病例的临床特点及治疗方案,以及与国外进行比较,为制定我国该病临床标准化治疗方案提供证据支持.方法 回顾性分析在北京协和医院住院诊治的重症抗NMDAR脑炎患者35例.应用统一设计的研究表格记录所有研究对象的人口学资料,临床病史,既往病史,实验室检查,影像学检查,详细记录治疗方案,以及追踪随访情况.结果 全部患者出现精神行为异常、癫痫发作、意识水平下降;不自主运动、言语障碍/缄默、记忆力下降、中枢性低通气、自主神经功能障碍发生率在45% ~ 65%.16例(45.71%)患者需要机械通气支持.发病时mRS评分为4~5分(平均4.86分).脑脊液压力、白细胞数及蛋白升高的比例分别为42.86%、60.00%、14.29%.31.43%患者头部核磁检查发现病灶,病灶分布于额叶、颞叶、岛叶、海马、扣带回、胼胝体、脑干、小脑部位.一线免疫治疗:全部患者接受1~7个疗程不等的静脉丙种球蛋白治疗,平均3个疗程;91.43%患者接受糖皮质激素治疗,其中54.29%接受高剂量甲泼尼龙冲击治疗;5.71%接受血浆置换.二线免疫治疗5例(14.29%),包括利妥昔单抗4例与静脉CTX 1例.15例(42.86%)患者接受了长程免疫治疗.全部患者经免疫治疗均好转并转出重症病房,患者中位ICU治疗周期为46 d,中位住院日为72 d).出院时2例mRS评分5分,其他1~4分,住院期间无死亡病例.中位随访时间17.57个月,85.71%患者改良Rankin评分下降至0~2分,1例(2.86%)于出院两年后死亡,11例(31.43%)复发.结论 重症抗NMDAR脑炎患者的激素联合静脉丙种球蛋白治疗效果良好,但初始效果不明显者,可重复静脉丙种球蛋白和(或)甲泼尼龙冲击治疗也仍有效.%Objective To provide evidence for establishing standardized treatment strategy of severe anti-N-methyl-D-aspartate

  20. The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner.

    Science.gov (United States)

    Page, S C; Hamersky, G R; Gallo, R A; Rannals, M D; Calcaterra, N E; Campbell, M N; Mayfield, B; Briley, A; Phan, B N; Jaffe, A E; Maher, B J

    2017-03-14

    Disruption of the laminar and columnar organization of the brain is implicated in several psychiatric disorders. Here, we show in utero gain-of-function of the psychiatric risk gene transcription factor 4 (TCF4) severely disrupts the columnar organization of medial prefrontal cortex (mPFC) in a transcription- and activity-dependent manner. This morphological phenotype was rescued by co-expression of TCF4 plus calmodulin in a calcium-dependent manner and by dampening neuronal excitability through co-expression of an inwardly rectifying potassium channel (Kir2.1). For we believe the first time, we show that N-methyl-d-aspartate (NMDA) receptor-dependent Ca(2+) transients are instructive to minicolumn organization because Crispr/Cas9-mediated mutation of NMDA receptors rescued TCF4-dependent morphological phenotypes. Furthermore, we demonstrate that the transcriptional regulation by the psychiatric risk gene TCF4 enhances NMDA receptor-dependent early network oscillations. Our novel findings indicate that TCF4-dependent transcription directs the proper formation of prefrontal cortical minicolumns by regulating the expression of genes involved in early spontaneous neuronal activity, and thus our results provides insights into potential pathophysiological mechanisms of TCF4-associated psychiatric disorders.Molecular Psychiatry advance online publication, 14 March 2017; doi:10.1038/mp.2017.37.

  1. Oxygen/Glucose Deprivation and Reperfusion Cause Modifications of Postsynaptic Morphology and Activity in the CA3 Area of Organotypic Hippocampal Slice Cultures

    OpenAIRE

    Jung, Yeon Joo; Suh, Eun Cheng; Lee, Kyung Eun

    2012-01-01

    Brain ischemia leads to overstimulation of N-methyl-D-aspartate (NMDA) receptors, referred as excitotoxicity, which mediates neuronal cell death. However, less attention has been paid to changes in synaptic activity and morphology that could have an important impact on cell function and survival following ischemic insult. In this study, we investigated the effects of reperfusion after oxygen/glucose deprivation (OGD) not only upon neuronal cell death, but also on ultrastructural and biochemic...

  2. 应激浓度皮质酮对大鼠海马神经元兴奋性氨基酸受体的快速作用%Rapid effect of stressful concentration corticosterone on glutamate receptor and its subtype N-methyl-D-aspartate receptor activity in cultured hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    刘玲; 张仁良; 郁文博; 张申宁; 王春安; 孙继虎

    2006-01-01

    目的:研究大鼠应激浓度皮质酮对兴奋性谷氨酸受体--N-甲基-D-天冬氨酸(NMDA)受体的快速调控作用及其机制.方法:运用常规膜片钳技术,研究细胞外给予应激浓度皮质酮(CORT)对原代培养的大鼠海马神经元谷氨酸(Glu)和NMDA诱发电流(IGlu和INMDA)的快速作用,以及细胞内透析CORT对INMDA影响.结果:CORT(10μmol/L)可快速、可逆地抑制大鼠海马神经元IGlu和INMDA;细胞外牛血清清蛋白耦联的皮质酮(CORT-BSA,10μmol/L)有与CORT相似的作用;细胞内CORT(10 μmol/L)对INMDA的峰值无明显影响.结论:提示应激浓度CORT对大鼠中枢神经系统兴奋性突触传递过程有快速抑制作用,对谷氨酸受体(GluR)的作用主要是通过NMDA受体实现的;该作用是通过细胞外快速膜机制产生的.

  3. Relationship between G protein-coupled receptor kinase 6 and N-methyl-D-aspartate receptor in the mechanism study underlying motor complications in Parkinson's disease%帕金森病运动并发症发生机制中G蛋白偶联受体激酶6与N-甲基-D-天冬氨酸受体关系的研究

    Institute of Scientific and Technical Information of China (English)

    吴娜; 杨新新; 宋璐; 刘振国

    2011-01-01

    目的 研究G蛋白偶联受体激酶6(GRK6)在帕金森病(PD)运动并发症发生机制中与N-甲基-D-天冬氨酸(NMDA)受体的关系.方法 建立PD运动并发症大鼠模型,25只大鼠分为3组.异动症(LID)组10只,腹腔注射左旋多巴甲酯23 d;MK-801处理组10只,第23天左旋多巴甲酯注射前腹腔注射MK-801;PD组5只,腹腔注射0.2%维生素C液.另设假手术组5只为对照组.观察MK-801处理左旋多巴诱导的运动并发症模型大鼠的行为变化,并用免疫组织化学方法和Western印迹方法检测大鼠纹状体区GRK6蛋白的表达情况.结果 PD组大鼠长期使用左旋多巴后出现明显的异常不自主运动,与人类LID具有相似特征.免疫组化结果显示.PD组损伤侧纹状体区GRK6阳性细胞指数减少至(4.81±1.31)×103(P<0.05),LID组损伤侧GRK6阳性细胞指数进一步减少至(3.23±0.41)×103(P<0.01).MK-801组LID大鼠异常不自主运动评分减少,药效期延长,同时损伤侧纹状体区GRK6阳性细胞指数增多至(4.64±1.39)×103(P<0.05).Western印迹法检测结果同免疫组化基本相符,PD组损毁侧/未损毁侧纹状体区GRK6含量比值为(83.7±2.1)%,LID组GRK6值降低为(76.8±2.2)%,而MK-801组GRK6值升高至(91.1±2.7)%(P<0.01).结论 NMDA受体拮抗剂能逆转大鼠运动并发症的发生,其机制可能与GRK6增多,抑制了谷氨酸受体的过度活化有关.%Objective To investigate the relationship between G protein-coupled receptor kinase 6 (GRK6) and N-methyl-D-aspartate (NMDA) receptor in the mechanism study underlying motor complications in Parkinson's disease (PD).Methods The rat models (n= 25) of Parkinsonism related motor complications were established and were randomly divided into levodopa-induced dyskinesia (LID) group (n= 10,intraperitoneal injection of levodopa for 23 d),MK-801 treatment group (n= 10,intraperitoneal injection of MK-801 at day23 after intraperitoneal injection with levodopa for 22 days) and PD group (n

  4. Effects of the N-methyl-D-Aspartate receptor antagonist dextromethorphan on vibrotactile adaptation

    Directory of Open Access Journals (Sweden)

    Folger Stephen E

    2008-09-01

    Full Text Available Abstract Background Previous reports have demonstrated that short durations of vibrotactile stimuli (less than or equal to 2 sec effectively and consistently modify both the perceptual response in humans as well as the neurophysiological response in somatosensory cortex. The change in cortical response with adaptation has been well established by a number of studies, and other reports have extended those findings in determining that both GABA- and NMDAR-mediated neurotransmission play a significant role in the dynamic response of somatosensory cortical neurons. In this study, we evaluated the impact that dextromethorphan (DXM, an NMDAR antagonist, had on two distinct vibrotactile adaptation tasks. Results All subjects, both those that ingested 60 mg DXM and those that ingested placebo, were evaluated for their amplitude discriminative capacity between two simultaneously delivered vibrotactile stimuli both with and without 3 conditions of pre-exposure to adapting stimulation. The results demonstrated that the perceptual metrics of subjects who ingested 60 mg DXM were significantly altered from that of controls when the amplitude discrimination task followed one of the conditions of adapting stimulation. Without the condition of pre-exposure to an adapting stimulus (or stimuli, there was little difference between the observations obtained from the subjects that ingested DXM and controls. Peak impact on subject response occurred at 60 min post-ingestion, whereas the scores of controls who ingested placebo were not impacted. Conclusion The results – that DXM blocks vibrotactile adaptation – is consistent with the suggestion that NMDAR-mediated neurotransmission plays a significant role in the perceptual adaptive response. This finding is also consistent with neurophysiological findings that report observations of the effects of NMDAR block on the SI cortical response to repetitive vibrotactile stimulation.

  5. Effects of the N-methyl-D-Aspartate receptor antagonist dextromethorphan on vibrotactile adaptation

    Science.gov (United States)

    Folger, Stephen E; Tannan, Vinay; Zhang, Zheng; Holden, Jameson K; Tommerdahl, Mark

    2008-01-01

    Background Previous reports have demonstrated that short durations of vibrotactile stimuli (less than or equal to 2 sec) effectively and consistently modify both the perceptual response in humans as well as the neurophysiological response in somatosensory cortex. The change in cortical response with adaptation has been well established by a number of studies, and other reports have extended those findings in determining that both GABA- and NMDAR-mediated neurotransmission play a significant role in the dynamic response of somatosensory cortical neurons. In this study, we evaluated the impact that dextromethorphan (DXM), an NMDAR antagonist, had on two distinct vibrotactile adaptation tasks. Results All subjects, both those that ingested 60 mg DXM and those that ingested placebo, were evaluated for their amplitude discriminative capacity between two simultaneously delivered vibrotactile stimuli both with and without 3 conditions of pre-exposure to adapting stimulation. The results demonstrated that the perceptual metrics of subjects who ingested 60 mg DXM were significantly altered from that of controls when the amplitude discrimination task followed one of the conditions of adapting stimulation. Without the condition of pre-exposure to an adapting stimulus (or stimuli), there was little difference between the observations obtained from the subjects that ingested DXM and controls. Peak impact on subject response occurred at 60 min post-ingestion, whereas the scores of controls who ingested placebo were not impacted. Conclusion The results – that DXM blocks vibrotactile adaptation – is consistent with the suggestion that NMDAR-mediated neurotransmission plays a significant role in the perceptual adaptive response. This finding is also consistent with neurophysiological findings that report observations of the effects of NMDAR block on the SI cortical response to repetitive vibrotactile stimulation. PMID:18796147

  6. N-methyl-D-aspartate promotes the survival of cerebellar granule cells in culture

    DEFF Research Database (Denmark)

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

    1988-01-01

    Our previous studies on the survival-promoting influence of elevated concentrations of extracellular K+ ([K+]e) on cultured cerebellar granule cells led to the proposal that depolarization in vitro mimics the effect of the earliest afferent inputs received by the granule cells in vivo. This, in t...

  7. N-Methyl-D-Aspartate Receptor Antibodies in Herpes Simplex Encephalitis

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-02-01

    Full Text Available Researchers at Charite University Medicine Berlin, and other centers in Germany, Spain and the US performed a retrospective analysis of 44 patients with polymerase chain reaction-proven herpes simplex encephalitis (HSE for the presence of onconeuronal and synaptic receptor antibodies.

  8. [Clinical diagnosis and treatment of anti-NMDA (N-methyl-D-aspartate) receptor encephalitis].

    Science.gov (United States)

    Kamei, Satoshi

    2013-05-01

    Recent clinical management of anti-NMDA receptor encephalitis is reviewed. This illness is required the management of the neurological emergency. Typical symptoms of anti-NMDA receptor encephalitis develop in several stages that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and respiratory instability. The diagnosis is depended on the detection of the NMDA receptor antibody in CSF or serum under the above characteristic symptoms of encephalitis. The disorder predominantly affects children and young adults, occurs with or without tumor association. The presence of a tumor (usually an ovarian teratoma) is dependent on age and sex, being more frequent in women older than 18 years. Anti-NMDA receptor encephalitis should be treated with tumor resection and immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) responded faster to treatment and less frequently needed second-line immunotherapy (cyclophosphamide or rituximab, or both).

  9. Effects of electroacupuncture on expression of c-fos protein and N-methyl-D-aspartate receptor 1 in the rostral ventromedia medulla of rats with chronic visceral hyperalgesia%电针对慢性内脏痛觉敏感大鼠延髓头端腹内侧核c-fos蛋白和NR1受体表达的影响

    Institute of Scientific and Technical Information of China (English)

    祁德波; 李为民

    2012-01-01

    ,LPGi,GiA and NRM (P<0.05).No such effects on PTP values,AWR scores and the number of immunoreactive neurons of c-fos and IR1 were observed after sham-EA treatment.CONCLUSION:These data provide the evidence that EA can relieve chronic visceral hyperalgesia in rats with IBS,and such an effect may be correlated with inhibitory modulation of hyperactivity of neurons by means of down-regulating the high expression of NR1 in RVM of IBS model rats.%目的:针刺治疗对肠易激综合征(irritable bowel syndrome,IBS)患者的慢性腹痛具有良好疗效,然而,其神经生物学机制仍不清楚.本研究在电针(electroacupuncture,EA)缓解IBS模型大鼠慢性内脏痛觉敏感的基础上,观察和分析IBS大鼠延髓头端腹内侧核(rostral ventromedia medulla,RVM)中内脏反应神经元的兴奋性在针刺治疗前后的改变,以及RVM中N-甲基-D-门冬氨酸1型受体(N-methyl-D-aspartate receptor 1,NRl)在针刺缓解IBS模型大鼠慢性内脏痛敏中的参与机制.方法:采用新生9d的Sprague-Dawley雄性幼鼠,通过结直肠机械扩张刺激制作IBS慢性内脏痛觉敏感模型,持续两周.饲养6~8周后,观察大鼠由结直肠扩张(colorectal distention,CRD)诱发的痛阈压力值(pain threshold pressure,PTP)和腹部撤回反射(abdominal withdrawal reflex,AWR)评分变化.电针组穴位取双侧“足三里”和“上巨虚”,连续隔日治疗4次,假电针组不通电,其余与电针组相同.治疗结束后,取材并用免疫组织化学方法观察各组大鼠RVM中c-fos蛋白和NR1受体的表达变化.结果:与正常大鼠相比,成年IBS模型大鼠PTP值明显降低,且AWR评分明显升高(P<0.01);与电针治疗前相比,IBS大鼠电针治疗后PTP值明显升高(P<0.01),AWR评分明显降低(P<0.05);与正常大鼠相比,IBS模型大鼠RVM各个亚核包括中缝大核(nucleus raphe magnus,NRM)、网状巨细胞核α部(nucleus reticularis gigantocellularis pars alpha,GiA)、外侧旁巨细胞核(nucleus lateralis

  10. Switching off LTP: mGlu and NMDA receptor-dependent novelty exploration-induced depotentiation in the rat hippocampus.

    Science.gov (United States)

    Qi, Yingjie; Hu, Neng-Wei; Rowan, Michael J

    2013-04-01

    Both electrically induced synaptic long-term potentiation (LTP) and long-term depression have been extensively studied as models of the cellular basis of learning and memory mechanisms. Recently, considerable interest has been generated by the possibility that the activity-dependent persistent reversal of previously established synaptic LTP (depotentiation) may play a role in the time- and state-dependent erasure of memory. Here, we examined the requirement for glutamate receptor activation in experience-induced reversal of previously established LTP in the CA1 area of the hippocampus of freely behaving rats. Continuous exploration of non-aversive novelty for ~30 min, which was associated with hippocampal activation as measured by increased theta power in the electroencephalogram, triggered a rapid and persistent reversal of high frequency stimulation-induced LTP both at apical and basal synapses. Blockade of metabotropic glutamate (mGlu) receptors with mGlu5 subtype-selective antagonists, or N-methyl-D-aspartate (NMDA) receptors with GluN2B subunit-selective antagonists, prevented novelty-induced depotentiation. These findings strongly indicate that activation of both mGlu5 receptors and GluN2B-containing NMDA receptors is required for experience-triggered induction of depotentiation at CA3-CA1 synapses. The mechanistic concordance of the present and previous studies of experience-induced and electrically induced synaptic depotentiation helps to integrate our understanding of the neurophysiological underpinnings of learning and memory.

  11. Extended Synaptotagmin Interaction with the Fibroblast Growth Factor Receptor Depends on Receptor Conformation, Not Catalytic Activity.

    Science.gov (United States)

    Tremblay, Michel G; Herdman, Chelsea; Guillou, François; Mishra, Prakash K; Baril, Joëlle; Bellenfant, Sabrina; Moss, Tom

    2015-06-26

    We previously demonstrated that ESyt2 interacts specifically with the activated FGF receptor and is required for a rapid phase of receptor internalization and for functional signaling via the ERK pathway in early Xenopus embryos. ESyt2 is one of the three-member family of Extended Synaptotagmins that were recently shown to be implicated in the formation of endoplasmic reticulum (ER)-plasma membrane (PM) junctions and in the Ca(2+) dependent regulation of these junctions. Here we show that ESyt2 is directed to the ER by its putative transmembrane domain, that the ESyts hetero- and homodimerize, and that ESyt2 homodimerization in vivo requires a TM adjacent sequence but not the SMP domain. ESyt2 and ESyt3, but not ESyt1, selectively interact in vivo with activated FGFR1. In the case of ESyt2, this interaction requires a short TM adjacent sequence and is independent of receptor autophosphorylation, but dependent on receptor conformation. The data show that ESyt2 recognizes a site in the upper kinase lobe of FGFR1 that is revealed by displacement of the kinase domain activation loop during receptor activation.

  12. Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain

    DEFF Research Database (Denmark)

    Thomsen, Morten S; Hay-Schmidt, Anders; Hansen, Henrik H

    2010-01-01

    alpha(7) nicotinic acetylcholine receptor (nAChR) agonists are candidates for the treatment of cognitive deficits in schizophrenia. Selective alpha(7) nAChR agonists, such as SSR180711, activate neurons in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (ACCshell) in rats, regions...

  13. Toll-Like Receptor-Dependent Immune Complex Activation of B Cells and Dendritic Cells.

    Science.gov (United States)

    Moody, Krishna L; Uccellini, Melissa B; Avalos, Ana M; Marshak-Rothstein, Ann; Viglianti, Gregory A

    2016-01-01

    High titers of autoantibodies reactive with DNA/RNA molecular complexes are characteristic of autoimmune disorders such as systemic lupus erythematosus (SLE). In vitro and in vivo studies have implicated the endosomal Toll-like receptor 9 (TLR9) and Toll-like receptor 7 (TLR7) in the activation of the corresponding autoantibody producing B cells. Importantly, TLR9/TLR7-deficiency results in the inability of autoreactive B cells to proliferate in response to DNA/RNA-associated autoantigens in vitro, and in marked changes in the autoantibody repertoire of autoimmune-prone mice. Uptake of DNA/RNA-associated autoantigen immune complexes (ICs) also leads to activation of dendritic cells (DCs) through TLR9 and TLR7. The initial studies from our lab involved ICs formed by a mixture of autoantibodies and cell debris released from dying cells in culture. To better understand the nature of the mammalian ligands that can effectively activate TLR7 and TLR9, we have developed a methodology for preparing ICs containing defined DNA fragments that recapitulate the immunostimulatory activity of the previous "black box" ICs. As the endosomal TLR7 and TLR9 function optimally from intracellular acidic compartments, we developed a facile methodology to monitor the trafficking of defined DNA ICs by flow cytometry and confocal microscopy. These reagents reveal an important role for nucleic acid sequence, even when the ligand is mammalian DNA and will help illuminate the role of IC trafficking in the response.

  14. The Chromatin Remodeler CHD8 Is Required for Activation of Progesterone Receptor-Dependent Enhancers

    Science.gov (United States)

    Giannopoulou, Eugenia G.; Soronellas, Daniel; Vázquez-Chávez, Elena; Vicent, Guillermo P.; Elemento, Olivier; Beato, Miguel; Reyes, José C.

    2015-01-01

    While the importance of gene enhancers in transcriptional regulation is well established, the mechanisms and the protein factors that determine enhancers activity have only recently begun to be unravelled. Recent studies have shown that progesterone receptor (PR) binds regions that display typical features of gene enhancers. Here, we show by ChIP-seq experiments that the chromatin remodeler CHD8 mostly binds promoters under proliferation conditions. However, upon progestin stimulation, CHD8 re-localizes to PR enhancers also enriched in p300 and H3K4me1. Consistently, CHD8 depletion severely impairs progestin-dependent gene regulation. CHD8 binding is PR-dependent but independent of the pioneering factor FOXA1. The SWI/SNF chromatin-remodelling complex is required for PR-dependent gene activation. Interestingly, we show that CHD8 interacts with the SWI/SNF complex and that depletion of BRG1 and BRM, the ATPases of SWI/SNF complex, impairs CHD8 recruitment. We also show that CHD8 is not required for H3K27 acetylation, but contributes to increase accessibility of the enhancer to DNaseI. Furthermore, CHD8 was required for RNAPII recruiting to the enhancers and for transcription of enhancer-derived RNAs (eRNAs). Taken together our data demonstrate that CHD8 is involved in late stages of PR enhancers activation. PMID:25894978

  15. Melittin modulates keratinocyte function through P2 receptor-dependent ADAM activation.

    Science.gov (United States)

    Sommer, Anselm; Fries, Anja; Cornelsen, Isabell; Speck, Nancy; Koch-Nolte, Friedrich; Gimpl, Gerald; Andrä, Jörg; Bhakdi, Sucharit; Reiss, Karina

    2012-07-06

    Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-α, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent.

  16. The chromatin Remodeler CHD8 is required for activation of progesterone receptor-dependent enhancers.

    Science.gov (United States)

    Ceballos-Chávez, María; Subtil-Rodríguez, Alicia; Giannopoulou, Eugenia G; Soronellas, Daniel; Vázquez-Chávez, Elena; Vicent, Guillermo P; Elemento, Olivier; Beato, Miguel; Reyes, José C

    2015-04-01

    While the importance of gene enhancers in transcriptional regulation is well established, the mechanisms and the protein factors that determine enhancers activity have only recently begun to be unravelled. Recent studies have shown that progesterone receptor (PR) binds regions that display typical features of gene enhancers. Here, we show by ChIP-seq experiments that the chromatin remodeler CHD8 mostly binds promoters under proliferation conditions. However, upon progestin stimulation, CHD8 re-localizes to PR enhancers also enriched in p300 and H3K4me1. Consistently, CHD8 depletion severely impairs progestin-dependent gene regulation. CHD8 binding is PR-dependent but independent of the pioneering factor FOXA1. The SWI/SNF chromatin-remodelling complex is required for PR-dependent gene activation. Interestingly, we show that CHD8 interacts with the SWI/SNF complex and that depletion of BRG1 and BRM, the ATPases of SWI/SNF complex, impairs CHD8 recruitment. We also show that CHD8 is not required for H3K27 acetylation, but contributes to increase accessibility of the enhancer to DNaseI. Furthermore, CHD8 was required for RNAPII recruiting to the enhancers and for transcription of enhancer-derived RNAs (eRNAs). Taken together our data demonstrate that CHD8 is involved in late stages of PR enhancers activation.

  17. Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents

    DEFF Research Database (Denmark)

    Bubser, Michael; Bridges, Thomas M; Dencker, Ditte;

    2014-01-01

    an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central...... PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801...

  18. Melittin Modulates Keratinocyte Function through P2 Receptor-dependent ADAM Activation*

    Science.gov (United States)

    Sommer, Anselm; Fries, Anja; Cornelsen, Isabell; Speck, Nancy; Koch-Nolte, Friedrich; Gimpl, Gerald; Andrä, Jörg; Bhakdi, Sucharit; Reiss, Karina

    2012-01-01

    Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-α, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent. PMID:22613720

  19. Potentiation of NMDA receptor-dependent cell responses by extracellular high mobility group box 1 protein.

    Directory of Open Access Journals (Sweden)

    Marco Pedrazzi

    Full Text Available BACKGROUND: Extracellular high mobility group box 1 (HMGB1 protein can operate in a synergistic fashion with different signal molecules promoting an increase of cell Ca(2+ influx. However, the mechanisms responsible for this effect of HMGB1 are still unknown. PRINCIPAL FINDINGS: Here we demonstrate that, at concentrations of agonist per se ineffective, HMGB1 potentiates the activation of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR in isolated hippocampal nerve terminals and in a neuroblastoma cell line. This effect was abolished by the NMDA channel blocker MK-801. The HMGB1-facilitated NMDAR opening was followed by activation of the Ca(2+-dependent enzymes calpain and nitric oxide synthase in neuroblastoma cells, resulting in an increased production of NO, a consequent enhanced cell motility, and onset of morphological differentiation. We have also identified NMDAR as the mediator of HMGB1-stimulated murine erythroleukemia cell differentiation, induced by hexamethylenebisacetamide. The potentiation of NMDAR activation involved a peptide of HMGB1 located in the B box at the amino acids 130-139. This HMGB1 fragment did not overlap with binding sites for other cell surface receptors of HMGB1, such as the advanced glycation end products or the Toll-like receptor 4. Moreover, in a competition assay, the HMGB1((130-139 peptide displaced the NMDAR/HMGB1 interaction, suggesting that it comprised the molecular and functional site of HMGB1 regulating the NMDA receptor complex. CONCLUSION: We propose that the multifunctional cytokine-like molecule HMGB1 released by activated, stressed, and damaged or necrotic cells can facilitate NMDAR-mediated cell responses, both in the central nervous system and in peripheral tissues, independently of other known cell surface receptors for HMGB1.

  20. Effect of N-Methyl-D-Aspartate Receptor Antagonist Dextromethorphan on Opioid Analgesia in Pediatric Intensive Care Unit

    Directory of Open Access Journals (Sweden)

    Mohammed Naeem

    2016-01-01

    Full Text Available Objective. Pain control is an essential goal in the management of critical children. Narcotics are the mainstay for pain control. Patients frequently need escalating doses of narcotics. In such cases an adjunctive therapy may be beneficial. Dextromethorphan (DM is NMDA receptor antagonist and may prevent tolerance to narcotics; however, its definitive role is still unclear. We sought whether dextromethorphan addition could decrease the requirements of fentanyl to control pain in critical children. Design. Double-blind, randomized control trial (RCT. Setting. Pediatric multidisciplinary ICU in tertiary care center. Patients. Thirty-six pediatric patients 2–14 years of age in a multidisciplinary PICU requiring analgesia were randomized into dextromethorphan and placebo. The subjects in both groups showed similarity in most of the characteristics. Interventions. Subjects while receiving fentanyl for pain control received dextromethorphan or placebo through nasogastric/orogastric tubes for 96 hours. Pain was assessed using FLACC and faces scales. Measurements and Main Results. This study found no statistical significant difference in fentanyl requirements between subjects receiving dextromethorphan and those receiving placebo (p=0.127. Conclusions. Dextromethorphan has no effect on opioid requirement for control of acute pain in children admitted with acute critical care illness in PICU. The registration number for this trial is NCT01553435.

  1. 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...... for the inhibition of the PSD-95/NMDA receptor interaction. Initially, truncation and alanine scan studies were carried out, which resulted in a pentapeptide with wild-type affinity, as examined in a fluorescence polarization assay. Further examination was performed by systematic substitutions with natural...

  2. 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...

  3. Pretreatment with Lovastatin Prevents N-Methyl-D-Aspartate-Induced Neurodegeneration in the Magnocellular Nucleus Basalis and Behavioral Dysfunction

    NARCIS (Netherlands)

    Dolga, Amalia; Granic, Ivica; Nijholt, Ingrid M.; Nyakas, Csaba; van der Zee, Eddy A.; Luiten, Paul G. M.; Eisel, Ulrich L. M.; Bierhaus, Angelika

    2009-01-01

    Besides a beneficial cardiovascular effect, it was recently suggested that statins can also exert neuroprotective actions. In a previous study, we provided in vitro evidence that lovastatin treatment abates excitotoxic cell death in primary cortical neurons. Here, we investigated the neuroprotective

  4. Electroencephalographic and fluorodeoxyglucose-positron emission tomography correlates in anti-N-methyl-d-aspartate receptor autoimmune encephalitis

    Directory of Open Access Journals (Sweden)

    John C. Probasco

    2014-01-01

    Conclusions and relevance: This case of anti-NMDAR autoimmune encephalitis illustrates the challenges of distinguishing prolonged LE from LSE. We discuss the parallels between these two conditions and propose a management paradigm to optimize evaluation and treatment.

  5. In vitro neuronal network activity in NMDA receptor encephalitis

    Directory of Open Access Journals (Sweden)

    Jantzen Sabine U

    2013-02-01

    Full Text Available Abstract Background Anti-NMDA-encephalitis is caused by antibodies against the N-methyl-D-aspartate receptor (NMDAR and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. It predominantly occurs in young women and is associated in 59% with an ovarian teratoma. Results We describe effects of cerebrospinal fluid (CSF from an anti-N-methyl-D-aspartate receptor (NMDAR encephalitis patient on in vitro neuronal network activity (ivNNA. In vitro NNA of dissociated primary rat cortical populations was recorded by the microelectrode array (MEA system. The 23-year old patient was severely affected but showed an excellent recovery following multimodal immunomodulatory therapy and removal of an ovarian teratoma. Patient CSF (pCSF taken during the initial weeks after disease onset suppressed global spike- and burst rates of ivNNA in contrast to pCSF sampled after clinical recovery and decrease of NMDAR antibody titers. The synchrony of pCSF-affected ivNNA remained unaltered during the course of the disease. Conclusion Patient CSF directly suppresses global activity of neuronal networks recorded by the MEA system. In contrast, pCSF did not regulate the synchrony of ivNNA suggesting that NMDAR antibodies selectively regulate distinct parameters of ivNNA while sparing their functional connectivity. Thus, assessing ivNNA could represent a new technique to evaluate functional consequences of autoimmune encephalitis-related CSF changes.

  6. NMDA receptor activity in neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Shaheen E Lakhan

    2013-06-01

    Full Text Available N-Methyl-D-aspartate (NMDA receptors play a variety of physiologic roles and their proper signaling is essential for cellular homeostasis. Any disruption in this pathway, leading to either enhanced or decreased activity, may result in the manifestation of neuropsychiatric pathologies such as schizophrenia, mood disorders, substance induced psychosis, Huntington's disease, Alzheimer's disease, and neuropsychiatric systemic lupus erythematosus. Here, we explore the notion that the overlap in activity of at least one biochemical pathway, the NMDA receptor pathway, may be the link to understanding the overlap in psychotic symptoms between diseases. This review intends to present a broad overview of those neuropsychiatric disorders for which alternations in NMDA receptor activity is prominent thus suggesting that continued direction of pharmaceutical intervention to this pathway may present a viable option for managing symptoms.

  7. PGE2 released by primary sensory neurons modulates Toll-like receptor 4 activities through an EP4 receptor-dependent process.

    Science.gov (United States)

    Tse, Kai-Hei; Chow, Kevin B S; Wise, Helen

    2016-04-15

    Exogenous prostaglandin E2 (PGE2) displays mixed regulatory properties with regard to inflammatory gene expression in dorsal root ganglion (DRG) cells. We show here that endogenously-produced nanomolar concentrations of PGE2, such as that generated in response to Toll-like receptor 4 (TLR4) stimulation, inhibits both cyclooxygenase-2 (COX-2) and tumour necrosis factor alpha (TNFα) mRNA expression in DRG cells in an EP4 receptor-dependent manner. DRG neurons appear to be the major source of PGE2 in the DRG and likely serve as both an autocrine and paracrine system for limiting over-activation of both DRG neurons and glial cells in response to TLR4 stimulation. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Hydroxylated polybrominated diphenyl ethers exhibit different activities on thyroid hormone receptors depending on their degree of bromination

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Xiao-Min, E-mail: rxm200318@gmail.com; Guo, Liang-Hong, E-mail: LHGuo@rcees.ac.cn; Gao, Yu, E-mail: francesscototti@gmail.com; Zhang, Bin-Tian, E-mail: nktianster@gmail.com; Wan, Bin, E-mail: binwan@rcees.ac.cn

    2013-05-01

    Polybrominated diphenyl ethers (PBDEs) have been shown to disrupt thyroid hormone (TH) functions in experimental animals, and one of the proposed disruption mechanisms is direct binding of hydroxylated PBDE (OH-PBDE) to TH receptors (TRs). However, previous data on TH receptor binding and TH activity of OH-PBDEs were very limited and sometimes inconsistent. In the present paper, we examined the binding potency of ten OH-PBDEs with different degrees of bromination to TR using a fluorescence competitive binding assay. The results showed that the ten OH-PBDEs bound to TR with potency that correlated to their bromination level. We further examined their effect on TR using a coactivator binding assay and GH3 cell proliferation assay. Different TR activities of OH-PBDEs were observed depending on their degree of bromination. Four low-brominated OH-PBDEs (2′-OH-BDE-28, 3′-OH-BDE-28, 5-OH-BDE-47, 6-OH-BDE-47) were found to be TR agonists, which recruited the coactivator peptide and enhanced GH3 cell proliferation. However, three high-brominated OH-PBDEs (3-OH-BDE-100, 3′-OH-BDE-154, 4-OH-BDE-188) were tested to be antagonists. Molecular docking was employed to simulate the interactions of OH-PBDEs with TR and identify the structural determinants for TR binding and activity. According to the docking results, low-brominated OH-PBDEs, which are weak binders but TR agonists, bind with TR at the inner side of its binding pocket, whereas high-brominated compounds, which are potent binders but TR antagonists, reside at the outer region. These results indicate that OH-PBDEs have different activities on TR (agonistic or antagonistic), possibly due to their different binding geometries with the receptor. - Highlights: ► Thyroid hormone (TH) activity of OH-PBDEs with different Br number was evaluated. ► Four different experimental approaches were employed to investigate the mechanism. ► Low-brominated OH-PBDEs were agonists, but high-brominated ones were antagonists.

  9. Endothelin-1 induces proliferation of human lung fibroblasts and IL-11 secretion through an ET(A) receptor-dependent activation of MAP kinases.

    Science.gov (United States)

    Gallelli, Luca; Pelaia, Girolamo; D'Agostino, Bruno; Cuda, Giovanni; Vatrella, Alessandro; Fratto, Donatella; Gioffrè, Vincenza; Galderisi, Umberto; De Nardo, Marilisa; Mastruzzo, Claudio; Salinaro, Elisa Trovato; Maniscalco, Mauro; Sofia, Matteo; Crimi, Nunzio; Rossi, Francesco; Caputi, Mario; Costanzo, Francesco S; Maselli, Rosario; Marsico, Serafino A; Vancheri, Carlo

    2005-11-01

    Endothelin-1 (ET-1) is implicated in the fibrotic responses characterizing interstitial lung diseases, as well as in the airway remodeling process occurring in asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal human lung fibroblasts (NHLFs), the ET-1 receptor subtypes, and the intracellular signal transduction pathways involved in the proliferative effects of this peptide. Therefore, cells were exposed to ET-1 in the presence or absence of an overnight pre-treatment with either ET(A) or ET(B) selective receptor antagonists. After cell lysis, immunoblotting was performed using monoclonal antibodies against the phosphorylated, active forms of mitogen-activated protein kinases (MAPK). ET-1 induced a significant increase in MAPK phosphorylation pattern, and also stimulated fibroblast proliferation and IL-6/IL-11 release into cell culture supernatants. All these effects were inhibited by the selective ET(A) antagonist BQ-123, but not by the specific ET(B) antagonist BQ-788. The stimulatory influence of ET-1 on IL-11, but not on IL-6 secretion, was prevented by MAPK inhibitors. Therefore, such results suggest that in human lung fibroblasts ET-1 exerts a profibrogenic action via an ET(A) receptor-dependent, MAPK-mediated induction of IL-11 release and cell proliferation.

  10. EGF Receptor-Dependent Mechanism May be Involved in the Tamm–Horsfall Glycoprotein-Enhanced PMN Phagocytosis via Activating Rho Family and MAPK Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Ko-Jen Li

    2014-01-01

    Full Text Available Our previous studies showed that urinary Tamm–Horsfall glycoprotein (THP potently enhanced polymorphonuclear neutrophil (PMN phagocytosis. However, the domain structure(s, signaling pathway and the intracellular events responsible for THP-enhanced PMN phagocytosis remain to be elucidated. THP was purified from normal human urine. The human promyelocytic leukemia cell line HL-60 was induced to differentiate into PMNs by all-trans retinoid acid. Pretreatment with different MAPK and PI3K inhibitors was used to delineate signaling pathways in THP-enhanced PMN phagocytosis. Phosphorylation of molecules responsible for PMN phagocytosis induced by bacterial lipopolysaccharide (LPS, THP, or human recombinant epidermal growth factor (EGF was evaluated by western blot. A p38 MAPK inhibitor, SB203580, effectively inhibited both spontaneous and LPS- and THP-induced PMN phagocytosis. Both THP and LPS enhanced the expression of the Rho family proteins Cdc42 and Rac that may lead to F-actin re-arrangement. Further studies suggested that THP and EGF enhance PMN and differentiated HL-60 cell phagocytosis in a similar pattern. Furthermore, the EGF receptor inhibitor GW2974 significantly suppressed THP- and EGF-enhanced PMN phagocytosis and p38 and ERK1/2 phosphorylation in differentiated HL-60 cells. We conclude that EGF receptor-dependent signaling may be involved in THP-enhanced PMN phagocytosis by activating Rho family and MAP kinase.

  11. Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase.

    Science.gov (United States)

    Zhang, Jingfei; Malik, Aqsa; Choi, Hyun B; Ko, Rebecca W Y; Dissing-Olesen, Lasse; MacVicar, Brian A

    2014-04-02

    Complement receptor 3 (CR3) activation in microglia is involved in neuroinflammation-related brain disorders and pruning of neuronal synapses. Hypoxia, often observed together with neuroinflammation in brain trauma, stroke, and neurodegenerative diseases, is thought to exacerbate inflammatory responses and synergistically enhance brain damage. Here we show that when hypoxia and an inflammatory stimulus (lipopolysaccharide [LPS]) are combined, they act synergistically to trigger long-term synaptic depression (LTD) that requires microglial CR3, activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and GluA2-mediated A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Microglial CR3-triggered LTD is independent of N-methyl-D-aspartate receptors (NMDARs), metabotropic glutamate receptors (mGluRs), or patterned synaptic activity. This type of LTD may contribute to memory impairments and synaptic disruptions in neuroinflammation-related brain disorders.

  12. Resilience dysregulation in major depressive disorder: focus on glutamatergic imbalance and microglial activation.

    Science.gov (United States)

    Réus, Gislaine Z; de Moura, Airam B; Silva, Ritele H; Resende, Wilson R; Quevedo, João

    2017-06-30

    Many studies have been shown an important role of glutamatergic system as well microglial activation in the pathophysiology of major depressive disorder (MDD). Experimental and clinical data suggest that attenuation of N-methyl-D-aspartate (NMDA) receptor function exerts antidepressant effects. Glutamatergic system is involved with memory establishment and function, and it regulates plasticity in the brain. Microglial cells play pivotal role to the brain functions; however, under chronic inflammation status microglial could be turn activated and increase the pro-inflammatory cytokines. In humans most resistant to the development of psychiatric disorders, including MDD, are observed a greater degree of resilience resulting from stress. Less resilience is associated with neuroendocrine and neuroinflammatory markers, as well as with glutamatergic system dysregulation. Thus, this review we highlighted findings from literature identifying the function of glutamatergic system, microglial activation and inflammation in resilience. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Modulation of antioxidant enzymatic activities by certain antiepileptic drugs (valproic acid, oxcarbazepine, and topiramate): evidence in humans and experimental models.

    Science.gov (United States)

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress.

  14. Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate): Evidence in Humans and Experimental Models

    Science.gov (United States)

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides III; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress. PMID:24454986

  15. Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate: Evidence in Humans and Experimental Models

    Directory of Open Access Journals (Sweden)

    Noemí Cárdenas-Rodríguez

    2013-01-01

    Full Text Available It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity. This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS activation and the generation of reactive oxygen species (ROS. Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA, oxcarbazepine (OXC, and topiramate (TPM modulate oxidative stress.

  16. [Blocking action of Nephila clavata spider toxin on ionic currents activated by glutamate and its agonists in isolated hippocampal neurons].

    Science.gov (United States)

    Kiskin, N I; Kliuchko, E M; Kryshtal', O A; Tsyndrenko, A Ia; Akaike, N

    1989-01-01

    The blocking action of the Nephila clavata spider neurotoxin was studied using the concentration clamp method in isolated neurons of the rat hippocampus. Crude venom JSTX blocked L-glutamate-, quisqualate- and kainate-activated ionic currents mediated by activation of the non-N-methyl-D-aspartate (non-NMDA) membrane receptors. Ionic currents elicited by all agonists were depressed by crude JSTX venom to 34-35% of its initial amplitude with no recovery during prolonged washing. An active fraction of JSTX venom blocked ionic currents almost completely, but its action was partially reversible. The concentration dependences of blocking kinetics allowed determining the rate constants of JSTX interaction with glutamate receptors. It is supposed that JSTX blocks the non-NMDA ionic channels in some of their open states and may be one of useful tools in further biochemical and electrophysiological characterization of the glutamate-mediated synaptic transmission.

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

    DEFF Research Database (Denmark)

    Dalby, Nils Ole; Thomsen, C

    1996-01-01

    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...... against sound-induced convulsions in DBA/2 mice and DMCM-induced seizures in mice but were inactive against seizures induced by administration of pentylenetetrazol or by electrical stimulation. These data suggest that mGluR ligands modulate seizure activity in mice and this effect may be mediated via...

  18. A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans.

    Science.gov (United States)

    Cacciaglia, Raffaele; Nees, Frauke; Pohlack, Sebastian T; Ruttorf, Michaela; Winkelmann, Tobias; Witt, Stephanie H; Nieratschker, Vanessa; Rietschel, Marcella; Flor, Herta

    2013-09-01

    People at high risk for alcoholism show deficits in aversive learning, as indicated by impaired electrodermal responses during fear conditioning, a basic form of associative learning that depends on the amygdala. A positive family history of alcohol dependence has also been related to decreased amygdala responses during emotional processing. In the present study we report reduced amygdala activity during the acquisition of conditioned fear in healthy carriers of a risk variant for alcoholism (rs2072450) in the NR2A subunit-containing N-methyl-d-aspartate (NMDA)-receptor. These results indicate that rs2072450 might confer risk for alcohol dependence through deficient fear acquisition indexed by a diminished amygdala response during aversive learning, and provide a neural basis for a weak behavioral inhibition previously documented in individuals at high risk for alcohol dependence. Carriers of the risk variant additionally exhibit dampened insula activation, a finding that further strengthens our data, given the importance of this brain region in fear conditioning.

  19. 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.

  20. Discovery of orally bioavailable cyclohexanol-based NR2B-selective NMDA receptor antagonists with analgesic activity utilizing a scaffold hopping approach.

    Science.gov (United States)

    Anan, Kosuke; Masui, Moriyasu; Hara, Shinichiro; Ohara, Miho; Kume, Masaharu; Yamamoto, Shoichi; Shinohara, Shunji; Tsuji, Hiroki; Shimada, Shinji; Yagi, Shigenori; Hasebe, Nobuyoshi; Kai, Hiroyuki

    2017-09-01

    NR2B subunit containing N-methyl-d-aspartate (NMDA) receptor is an attractive target for chronic pain due to its involvement in disease states and its limited distribution in the central nervous system. Cyclohexanol-based leads 6a and 6c were identified as potent NR2B-selective NMDA antagonists utilizing a scaffold hopping approach. Further optimization of this series through replacement of the amide in the leads with an isoxazole and efforts to optimize the pharmacokinetic profiles led to the discovery of orally available brain penetrants 7k and 7l, which demonstrated analgesic activity in the mouse formalin test at early and late phases. Copyright © 2017. Published by Elsevier Ltd.

  1. N-methyl-D-aspartate receptor antagonist MK-801 impairs learning but not memory fixation or expression of classical fear conditioning in goldfish (Carassius auratus).

    Science.gov (United States)

    Xu, X; Davis, R E

    1992-04-01

    The amnestic effects of the noncompetitive antagonist MK-801 on visually mediated, classic fear conditioning in goldfish (Carassius auratus) was examined in 5 experiments. MK-801 was administered 30 min before the training session on Day 1 to look for anterograde amnestic effects, immediately after training to look for retrograde amnestic effects, and before the training or test session, or both, to look for state-dependence effects. The results showed that MK-801 produced anterograde amnesia at doses that did not produce retrograde amnesia or state dependency and did not impair the expression of conditioned or unconditioned branchial suppression responses (BSRs) to the conditioned stimulus. The results indicate that MK-801 disrupts the mechanism of learning of the conditioned stimulus-unconditioned stimulus relation. Evidence is also presented that the learning processes that are disrupted by MK-801 occur during the initial stage of BSR conditioning.

  2. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder.

    Science.gov (United States)

    DiazGranados, Nancy; Ibrahim, Lobna A; Brutsche, Nancy E; Ameli, Rezvan; Henter, Ioline D; Luckenbaugh, David A; Machado-Vieira, Rodrigo; Zarate, Carlos A

    2010-12-01

    Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-D-asparate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD). Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and were rated at baseline and at 40, 80, 120, and 230 minutes postinfusion with the Scale for Suicide Ideation (SSI), the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. The study was conducted between October 2006 and January 2009. Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first 4 hours postinfusion (P Depression, anxiety, and hopelessness were significantly improved at all time points (P < .001). Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health. clinicaltrials.gov Identifier: NCT00088699. © Copyright 2010 Physicians Postgraduate Press, Inc.

  3. N-methyl-D-aspartate (NMDA)-stimulated noradrenaline (NA) release in rat brain cortex is modulated by presynaptic H3-receptors.

    Science.gov (United States)

    Fink, K; Schlicker, E; Göthert, M

    1994-02-01

    In superfused rat brain cortex slices and synaptosomes preincubated with [3H]noradrenaline the effect of agonists or antagonists at presynaptic H3 receptors on NMDA-evoked [3H]noradrenaline release was investigated. In experiments on slices, histamine and the preferential H3 receptor agonist R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow (IC20 values 0.27 mumol/l or 0.032 mumol/l, respectively); S-(+)-alpha-methylhistamine (up to 10 mumol/l) as well as the selective H1 receptor agonist (2-(2-thiazolyl)ethylamine and the selective H2 receptor agonist dimaprit (each up to 10 mumol/l) were ineffective. The H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine whereas the preferential H1 receptor antagonist dimetindene and the preferential H2 receptor antagonist ranitidine were ineffective. In experiments on synaptosomes, histamine and R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow, whereas 2-(2-thiazolyl)ethylamine or dimaprit had no effect. The inhibitory effect of histamine was abolished by thioperamide. When tritium overflow was stimulated by NMDA in the presence of omega-conotoxin GVIA (which by itself decreased the response to NMDA by about 55%), R-(-)-alpha-methylhistamine did not inhibit NMDA-evoked overflow. It is concluded that NMDA-evoked noradrenaline release in the cerebral cortex can be modulated by inhibitory H3 receptors. NMDA receptors and H3 receptors are both located presynaptically and may interact at the same noradrenergic varicosity. An unimpaired function of the N-type voltage-sensitive calcium channel probably is a prerequisite for the inhibition of NMDA-evoked noradrenaline release by H3 receptor stimulation.

  4. Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction

    DEFF Research Database (Denmark)

    Bach, Anders*; Eildal, Jonas Nii Nortey*; Stuhr-Hansen, Nicolai

    2011-01-01

    The protein--protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treating ischemic brain diseases, neuropathic pain, and Alzheimer's disease. We have previously demonstrated that N-alkylated tetrapeptides are potent inhibitors...... to identification of N-cyclohexylethyl-ETA(S)V (54) as the most potent, plasma-stable and cell-permeable inhibitor, which is a promising tool in unraveling the therapeutic potential of the PSD-95/NMDA receptor interaction....

  5. 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

    (pressure and von Frey hair). A total of 15 patients (12 amputees and three patients with other nerve injuries) completed the study. There was no difference between memantine and placebo on any of the outcome measures. We conclude that memantine at a dosage of 20 mg/d does not reduce spontaneous or evoked...

  6. 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

    glycine site antagonist, 1-thioxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (TK40). Here, we show by Schild analysis that TK40 is a potent competitive antagonist with Kb values of 21-63 nm at the GluN1 glycine-binding site of the four recombinant GluN1/N2A-D receptors. In addition, TK40...

  7. The fibrosis of ketamine, a noncompetitive N-methyl-d-aspartic acid receptor antagonist dose-dependent change in a ketamine-induced cystitis rat model.

    Science.gov (United States)

    Song, Miho; Yu, Hwan Yeul; Chun, Ji-Youn; Shin, Dong-Myung; Song, Soo Hyun; Choo, Myung-Soo; Song, Yun Seob

    2016-01-01

    Ketamine abusers have greatly increased in number worldwide during recent years. The consumption of ketamine has increased, as have the number of published accounts of devastating urological sequelae. However, the mechanism of ketamine-associated urinary tract dysfunction remains unclear. This study was to evaluate the ketamine dose-dependency of ketamine-induced cystitis (KC) in a rat model. A total of 42 Sprague-Dawley rats (female, 10-week-old) were used. Each of the 7 KC rat models were induced by 1, 5, 10, 25 and 50 mg/kg ketamine intravenous injection for two weeks. For the sham group (n = 7), a phosphate-buffered saline (PBS) vehicle was used rather than ketamine hydrochloride. The cystometric parameters, histological examinations, staining for Masson's trichome, cytokeratin, toluidine blue and quantitative PCR were measured at two weeks following the intervention. The voiding interval gradually decreased depending upon the ketamine dose of 1, 5, 10, 25, or 50 mg/kg, respectively, and was decreased compared with Sham. Bladder capacity was decreased as ketamine dose increased. In particular, the increase of fibrosis and submucosal apoptosis were found according to the increase of the ketamine dose. The bladder apoptosis in the KC rat model makes the fibrotic bladder change, and led us to hypothesize that fibrosis could contribute to the lower urinary-tract symptoms. We suggest that according to the pathophysiology evidence, fibrosis induced by apoptosis plays a key role in KC.

  8. 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

    , 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...... of SR to intracellular membranes. Our data highlight an atypical role of FBXO22 in enhancing d-serine synthesis that is unrelated to its classical effects as a component of the ubiquitin-proteasome degradation pathway....

  9. 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)

    Holmgaard, Kim; Aalkjaer, Christian; Lambert, John D C

    2007-01-01

    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......PURPOSE: Retinal hyperperfusion resulting from disturbances in the regulation of arteriolar tone is involved in the pathophysiology of a variety of retinal diseases. The mechanisms underlying this regulation of tone involve cellular components in both the vascular wall and the perivascular tissue....... 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...

  10. Anti-N-methyl-D-aspartate (anti-NMDA) receptor antibody encephalitis in a male adolescent with a large mediastinal teratoma.

    Science.gov (United States)

    Sommeling, Charlotte; Santens, Patrick

    2014-05-01

    We present a case of a 16-year-old boy with Klinefelter syndrome who presented with a syndrome of impaired alertness, orofacial dyskinesias, choreiform movements, epileptic seizures, and autonomic instability, pointing to a diagnosis of anti-N-methyl-Daspartate (anti-NMDA) receptor antibody encephalitis.

  11. 抗N-甲基-D-天冬氨酸受体脑炎%Anti-N-Methyl-D-Aspartate Receptor Encephalitis

    Institute of Scientific and Technical Information of China (English)

    杨爱君; 崔红; 魏田力

    2011-01-01

    IN - Methyl - D - Aspartate (NMDA) receptors Eire ion channels that contain binding sites of glutamate and glycine. They play a pivotal role in the regulation of synaptic transmission and synaptic plasticity in the central nervous system. There are 3 NMDA receptor subtypes demonstrated, which have own distribution and function. Anti - NMDA receptor encephalitis is a treatable disorder predominantly affecting young women which was recently identified. It is characterized by a combination of psychotic encephalopathy, seizures, and abnormal movements of the trunk and face, particularly in the form of jaw dystonia. The anti - NMDA receptor encephalitis of children increases recently. Accordingly, enhanced awareness of the typical presentation can increase the index of suspicion and facilitate initiation of appropriate treatment.%N-甲基-D-天冬氨酸(NMDA)受体是包含谷氨酸和甘氨酸结合位点的离子通道,在中枢神经系统的突触传递和突触可塑性调节中起重要作用.已证实的3种NMDA亚基,在体内有着不同的分布和功能.抗NMDA受体脑炎是近年才被确认的好发于年轻女性的可治疗的疾病,其临床特点为精神病性脑病、癫(癎)样发作以及躯干和面部的异常运动,特别是下颌关节肌张力异常.近年儿童抗NMDA受体脑炎有逐渐增多趋势.因此,增加对典型临床表现的认识,可提高对本病的早期识别并给予适当的治疗.

  12. Puerarin activates endothelial nitric oxide synthase through estrogen receptor-dependent PI3-kinase and calcium-dependent AMP-activated protein kinase

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Yong Pil; Kim, Hyung Gyun [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Hien, Tran Thi [College of Pharmacy, Chosun University, Gwangju (Korea, Republic of); Jeong, Myung Ho [Heart Research Center, Chonnam National University Hospital, Gwangju (Korea, Republic of); Jeong, Tae Cheon, E-mail: taecheon@ynu.ac.kr [College of Pharmacy, Yeungnam University, Gyungsan (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2011-11-15

    The cardioprotective properties of puerarin, a natural product, have been attributed to the endothelial nitric oxide synthase (eNOS)-mediated production of nitric oxide (NO) in EA.hy926 endothelial cells. However, the mechanism by which puerarin activates eNOS remains unclear. In this study, we sought to identify the intracellular pathways underlying eNOS activation by puerarin. Puerarin induced the activating phosphorylation of eNOS on Ser1177 and the production of NO in EA.hy926 cells. Puerarin-induced eNOS phosphorylation required estrogen receptor (ER)-mediated phosphatidylinositol 3-kinase (PI3K)/Akt signaling and was reversed by AMP-activated protein kinase (AMPK) and calcium/calmodulin-dependent kinase II (CaMKII) inhibition. Importantly, puerarin inhibited the adhesion of tumor necrosis factor (TNF)-{alpha}-stimulated monocytes to endothelial cells and suppressed the TNF-{alpha} induced expression of intercellular cell adhesion molecule-1. Puerarin also inhibited the TNF-{alpha}-induced nuclear factor-{kappa}B activation, which was attenuated by pretreatment with N{sup G}-nitro-L-arginine methyl ester, a NOS inhibitor. These results indicate that puerarin stimulates eNOS phosphorylation and NO production via activation of an estrogen receptor-mediated PI3K/Akt- and CaMKII/AMPK-dependent pathway. Puerarin may be useful for the treatment or prevention of endothelial dysfunction associated with diabetes and cardiovascular disease. -- Highlights: Black-Right-Pointing-Pointer Puerarin induced the phosphorylation of eNOS and the production of NO. Black-Right-Pointing-Pointer Puerarin activated eNOS through ER-dependent PI3-kinase and Ca{sup 2+}-dependent AMPK. Black-Right-Pointing-Pointer Puerarin-induced NO was involved in the inhibition of NF-kB activation. Black-Right-Pointing-Pointer Puerarin may help for prevention of vascular dysfunction and diabetes.

  13. Preliminary evidence that ketamine inhibits spreading depolarizations in acute human brain injury

    DEFF Research Database (Denmark)

    Sakowitz, Oliver W; Kiening, Karl L; Krajewski, Kara L

    2009-01-01

    by the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine. This restored electrocorticographic activity. CONCLUSIONS: These anecdotal electrocorticographic findings suggest that ketamine has an inhibitory effect on spreading depolarizations in humans. This is of potential interest for future...

  14. T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10.

    Science.gov (United States)

    Hamilton, Kristia S; Phong, Binh; Corey, Catherine; Cheng, Jing; Gorentla, Balachandra; Zhong, Xiaoping; Shiva, Sruti; Kane, Lawrence P

    2014-06-10

    Signaling to the mechanistic target of rapamycin (mTOR) regulates diverse cellular processes, including protein translation, cellular proliferation, metabolism, and autophagy. Most models place Akt upstream of the mTOR complex, mTORC1; however, in T cells, Akt may not be necessary for mTORC1 activation. We found that the adaptor protein Carma1 [caspase recruitment domain (CARD)-containing membrane-associated protein 1] and at least one of its associated proteins, the paracaspase MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), were required for optimal activation of mTOR in T cells in response to stimulation of the T cell receptor (TCR) and the co-receptor CD28. However, Bcl10, which binds to Carma1 and MALT1 to form a complex that mediates signals from the TCR to the transcription factor NF-κB (nuclear factor κB), was not required. The catalytic activity of MALT1 was required for the proliferation of stimulated CD4+ T cells, but not for early TCR-dependent activation events. Consistent with an effect on mTOR, MALT1 activity was required for the increased metabolic flux in activated CD4+ T cells. Together, our data suggest that Carma1 and MALT1 play previously unappreciated roles in the activation of mTOR signaling in T cells after engagement of the TCR.

  15. A conserved aspartic acid is important for agonist (VUAA1 and odorant/tuning receptor-dependent activation of the insect odorant co-receptor (Orco.

    Directory of Open Access Journals (Sweden)

    Brijesh N Kumar

    Full Text Available Insect odorant receptors function as heteromeric odorant-gated cation channels comprising a conventional odorant-sensitive tuning receptor, and a conserved co-receptor (Orco. An Orco agonist, VUAA1, is able to activate both heteromeric and homomeric Orco-containing channels. Very little is known about specific residues in Orco that contribute to cation permeability and gating. We investigated the importance of two conserved Asp residues, one in each of transmembrane domains 5 and 7, for channel function by mutagenesis. Drosophila melanogaster Orco and its substitution mutants were expressed in HEK cells and VUAA1-stimulated channel activity was determined by Ca(2+ influx and whole-cell patch clamp electrophysiology. Substitution of D466 in transmembrane 7 with amino acids other than glutamic acid resulted in a substantial reduction in channel activity. The D466E Orco substitution mutant was ~2 times more sensitive to VUAA1. The permeability of the D466E Orco mutant to cations was unchanged relative to wild-type Orco. When D466E Orco is co-expressed with a conventional tuning odorant receptor, the heteromeric complex also shows increased sensitivity to an odorant. Thus, the effect of the D466E mutation is not specific to VUAA1 agonism or dependent on homomeric Orco assembly. We suggest the gain-of-activation characteristic of the D466E mutant identifies an amino acid that is likely to be important for activation of both heteromeric and homomeric insect odorant receptor channels.

  16. A Conserved Aspartic Acid Is Important for Agonist (VUAA1) and Odorant/Tuning Receptor-Dependent Activation of the Insect Odorant Co-Receptor (Orco)

    Science.gov (United States)

    Kumar, Brijesh N.; Taylor, Robert W.; Pask, Gregory M.; Zwiebel, Laurence J.; Newcomb, Richard D.; Christie, David L.

    2013-01-01

    Insect odorant receptors function as heteromeric odorant-gated cation channels comprising a conventional odorant-sensitive tuning receptor, and a conserved co-receptor (Orco). An Orco agonist, VUAA1, is able to activate both heteromeric and homomeric Orco-containing channels. Very little is known about specific residues in Orco that contribute to cation permeability and gating. We investigated the importance of two conserved Asp residues, one in each of transmembrane domains 5 and 7, for channel function by mutagenesis. Drosophila melanogaster Orco and its substitution mutants were expressed in HEK cells and VUAA1-stimulated channel activity was determined by Ca2+ influx and whole-cell patch clamp electrophysiology. Substitution of D466 in transmembrane 7 with amino acids other than glutamic acid resulted in a substantial reduction in channel activity. The D466E Orco substitution mutant was ∼2 times more sensitive to VUAA1. The permeability of the D466E Orco mutant to cations was unchanged relative to wild-type Orco. When D466E Orco is co-expressed with a conventional tuning odorant receptor, the heteromeric complex also shows increased sensitivity to an odorant. Thus, the effect of the D466E mutation is not specific to VUAA1 agonism or dependent on homomeric Orco assembly. We suggest the gain-of-activation characteristic of the D466E mutant identifies an amino acid that is likely to be important for activation of both heteromeric and homomeric insect odorant receptor channels. PMID:23894621

  17. Inhibition of antigen receptor-dependent Ca(2+) signals and NF-AT activation by P2X7 receptors in human B lymphocytes.

    Science.gov (United States)

    Pippel, Anja; Beßler, Björn; Klapperstück, Manuela; Markwardt, Fritz

    2015-04-01

    One of the first intracellular signals after antigen binding by the antigen receptor of B lymphocytes is the increased intracellular Ca(2+) concentration ([Ca(2+)]i), which is followed by several intracellular signaling events like the nuclear translocation of the transcription factor NF-AT controlling the fate of B lymphocytes after their activation. Extracellular ATP, which is released from cells under several pathological conditions, is considered a danger-associated signal serving as an immunomodulator. We investigated the interaction of antigen receptor (BCR) and P2X7 receptor (P2X7R) activation on [Ca(2+)]i signaling and on nuclear translocation of the transcription factor NF-AT in human B lymphocytes. Although the P2X7R is an ATP-gated Ca(2+)-permeable ion channel, P2X7R activation inhibits the BCR-mediated [Ca(2+)]i responses. This effect is mimicked by cell membrane depolarization induced by an increase in the extracellular K(+) concentration or by application of the Na(+) ionophore gramicidin, but is abolished by stabilization of the membrane potential using the K(+) ionophore valinomycin, by extracellular Mg(2+), which is known to inhibit P2X7R-dependent effects, or by replacing Na(+) by the less P2X7R-permeable Tris(+) ion. Furthermore, P2X7R activation by ATP inhibits the BCR-dependent translocation of the transcription factor NF-ATc1 to the nucleus. We therefore conclude that extracellular ATP via the P2X7R mediates inhibitory effects on B cell activation. This may be of relevance for understanding of the activation of the BCR under pathological conditions and for the development of therapeutic strategies targeting human B lymphocytes or P2X7 receptors.

  18. PGE2-induced hypertrophy of cardiac myocytes involves EP4 receptor-dependent activation of p42/44 MAPK and EGFR transactivation.

    Science.gov (United States)

    Mendez, Mariela; LaPointe, Margot C

    2005-05-01

    Upon induction of cyclooxygenase-2 (COX-2), neonatal ventricular myocytes (VMs) mainly synthesize prostaglandin E2 (PGE2). The biological effects of PGE2 are mediated through four different G protein-coupled receptor (GPCR) subtypes (EP(1-4)). We have previously shown that PGE2 stimulates cAMP production and induces hypertrophy of VMs. Because the EP4 receptor is coupled to adenylate cyclase and increases in cAMP, we hypothesized that PGE2 induces hypertrophic growth of cardiac myocytes through a signaling cascade that involves EP4-cAMP and activation of protein kinase A (PKA). To test this, we used primary cultures of VMs and measured [3H]leucine incorporation into total protein. An EP4 antagonist was able to partially block PGE2 induction of protein synthesis and prevent PGE2-dependent increases in cell surface area and activity of the atrial natriuretic factor promoter, which are two other indicators of hypertrophic growth. Surprisingly, a PKA inhibitor had no effect. In other cell types, G protein-coupled receptor activation has been shown to transactivate the epidermal growth factor receptor (EGFR) and result in p42/44 mitogen-activated protein kinase (MAPK) activation and cell growth. Immunoprecipitation of myocyte lysates demonstrated that the EGFR was rapidly phosphorylated by PGE2 in VMs, and the EP4 antagonist blocked this. In addition, the selective EGFR inhibitor AG-1478 completely blocked PGE2-induced protein synthesis. We also found that PGE2 rapidly phosphorylated p42/44 MAPK, which was inhibited by the EP4 antagonist and by AG-1478. Finally, the p42/44 MAPK inhibitor PD-98053 (25 micromol/l) blocked PGE2-induced protein synthesis. Altogether, we believe these are the first data to suggest that PGE2 induces protein synthesis in cardiac myocytes in part via activation of the EP4 receptor and subsequent activation of p42/44 MAPK. Activation of p42/44 MAPK is independent of the common cAMP-PKA pathway and involves EP4-dependent transactivation of EGFR.

  19. CB1 Cannabinoid Receptor-Dependent Activation of mTORC1/Pax6 Signaling Drives Tbr2 Expression and Basal Progenitor Expansion in the Developing Mouse Cortex.

    Science.gov (United States)

    Díaz-Alonso, Javier; Aguado, Tania; de Salas-Quiroga, Adán; Ortega, Zaira; Guzmán, Manuel; Galve-Roperh, Ismael

    2015-09-01

    The CB1 cannabinoid receptor regulates cortical progenitor proliferation during embryonic development, but the molecular mechanism of this action remains unknown. Here, we report that CB1-deficient mouse embryos show premature cell cycle exit, decreased Pax6- and Tbr2-positive cell number, and reduced mammalian target of rapamycin complex 1 (mTORC1) activation in the ventricular and subventricular cortical zones. Pharmacological stimulation of the CB1 receptor in cortical slices and progenitor cell cultures activated the mTORC1 pathway and increased the number of Pax6- and Tbr2-expressing cells. Likewise, acute CB1 knockdown in utero reduced mTORC1 activation and cannabinoid-induced Tbr2-positive cell generation. Luciferase reporter and chromatin immunoprecipitation assays revealed that the CB1 receptor drives Tbr2 expression downstream of Pax6 induction in an mTORC1-dependent manner. Altogether, our results demonstrate that the CB1 receptor tunes dorsal telencephalic progenitor proliferation by sustaining the transcriptional activity of the Pax6-Tbr2 axis via the mTORC1 pathway, and suggest that alterations of CB1 receptor signaling, by producing the missexpression of progenitor identity determinants may contribute to neurodevelopmental alterations.

  20. Reversibility of epithelial-mesenchymal transition (EMT) induced in breast cancer cells by activation of urokinase receptor-dependent cell signaling.

    Science.gov (United States)

    Jo, Minji; Lester, Robin D; Montel, Valerie; Eastman, Boryana; Takimoto, Shinako; Gonias, Steven L

    2009-08-21

    Hypoxia induces expression of the urokinase receptor (uPAR) and activates uPAR-dependent cell signaling in cancer cells. This process promotes epithelial-mesenchymal transition (EMT). uPAR overexpression in cancer cells also promotes EMT. In this study, we tested whether uPAR may be targeted to reverse cancer cell EMT. When MDA-MB 468 breast cancer cells were cultured in 1% O(2), uPAR expression increased, as anticipated. Cell-cell junctions were disrupted, vimentin expression increased, and E-cadherin was lost from cell surfaces, indicating EMT. Transferring these cells back to 21% O(2) decreased uPAR expression and reversed the signs of EMT. In uPAR-overexpressing MDA-MB 468 cells, EMT was reversed by silencing expression of endogenously produced urokinase-type plasminogen activator (uPA), which is necessary for uPAR-dependent cell signaling, or by targeting uPAR-activated cell signaling factors, including phosphatidylinositol 3-kinase, Src family kinases, and extracellular signal-regulated kinase. MDA-MB 231 breast cancer cells express high levels of uPA and uPAR and demonstrate mesenchymal cell morphology under normoxic culture conditions (21% O(2)). Silencing uPA expression in MDA-MB-231 cells decreased expression of vimentin and Snail, and induced changes in morphology characteristic of epithelial cells. These results demonstrate that uPAR-initiated cell signaling may be targeted to reverse EMT in cancer.

  1. Attenuation of Aβ{sub 25–35}-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Xiangbao; Wang, Min [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Sun, Guibo, E-mail: sunguibo@126.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Ye, Jingxue [Jilin Agricultural University, Changchun, Jilin 130021 (China); Zhou, Yanhui [Center of Cardiology, People' s Hospital of Jilin Province, Changchun, 130021, Jilin (China); Dong, Xi [Wenzhou Medical University, Wenzhou, Zhejiang 325035 (China); Wang, Tingting; Lu, Shan [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China); Sun, Xiaobo, E-mail: sun_xiaobo163@163.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193 (China)

    2014-08-15

    Amyloid-beta (Aβ) has a pivotal function in the pathogenesis of Alzheimer's disease. To investigate Aβ neurotoxicity, we used an in vitro model that involves Aβ{sub 25–35}-induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ{sub 25–35} (20 μM) treatment for 24 h caused apoptotic cell death, as evidenced by significant cell viability reduction, LDH release, phosphatidylserine externalization, mitochondrial membrane potential disruption, cytochrome c release, caspase-3 activation, PARP cleavage, and DNA fragmentation in PC12 cells. Aβ{sub 25–35} treatment led to autophagic cell death, as evidenced by augmented GFP-LC3 puncta, conversion of LC3-I to LC3-II, and increased LC3-II/LC3-I ratio. Aβ{sub 25–35} treatment induced oxidative stress, as evidenced by intracellular ROS accumulation and increased production of mitochondrial superoxide, malondialdehyde, protein carbonyl, and 8-OHdG. Phytoestrogens have been proved to be protective against Aβ-induced neurotoxicity and regarded as relatively safe targets for AD drug development. Gypenoside XVII (GP-17) is a novel phytoestrogen isolated from Gynostemma pentaphyllum or Panax notoginseng. Pretreatment with GP-17 (10 μM) for 12 h increased estrogen response element reporter activity, activated PI3K/Akt pathways, inhibited GSK-3β, induced Nrf2 nuclear translocation, augmented antioxidant responsive element enhancer activity, upregulated heme oxygenase 1 (HO-1) expression and activity, and provided protective effects against Aβ{sub 25–35}-induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ{sub 25–35}-induced neurotoxicity through estrogen receptor-dependent activation of PI3K/Akt pathways, inactivation of GSK-3β and activation of Nrf2/ARE/HO-1 pathways. This finding might provide novel insights into understanding the mechanism for neuroprotective effects of phytoestrogens

  2. Neuroligin-1 links neuronal activity to sleep-wake regulation

    Science.gov (United States)

    El Helou, Janine; Bélanger-Nelson, Erika; Freyburger, Marlène; Dorsaz, Stéphane; Curie, Thomas; La Spada, Francesco; Gaudreault, Pierre-Olivier; Beaumont, Éric; Pouliot, Philippe; Lesage, Frédéric; Frank, Marcos G.; Franken, Paul; Mongrain, Valérie

    2013-01-01

    Maintaining wakefulness is associated with a progressive increase in the need for sleep. This phenomenon has been linked to changes in synaptic function. The synaptic adhesion molecule Neuroligin-1 (NLG1) controls the activity and synaptic localization of N-methyl-d-aspartate receptors, which activity is impaired by prolonged wakefulness. We here highlight that this pathway may underlie both the adverse effects of sleep loss on cognition and the subsequent changes in cortical synchrony. We found that the expression of specific Nlg1 transcript variants is changed by sleep deprivation in three mouse strains. These observations were associated with strain-specific changes in synaptic NLG1 protein content. Importantly, we showed that Nlg1 knockout mice are not able to sustain wakefulness and spend more time in nonrapid eye movement sleep than wild-type mice. These changes occurred with modifications in waking quality as exemplified by low theta/alpha activity during wakefulness and poor preference for social novelty, as well as altered delta synchrony during sleep. Finally, we identified a transcriptional pathway that could underlie the sleep/wake-dependent changes in Nlg1 expression and that involves clock transcription factors. We thus suggest that NLG1 is an element that contributes to the coupling of neuronal activity to sleep/wake regulation. PMID:23716671

  3. The Cellular Mechanisms of Memory Are Modified by Experience

    Science.gov (United States)

    Wiltgen, Brian J.; Wood, Alynda N.; Levy, Brynne

    2011-01-01

    The N-methyl-D-aspartate receptor (NMDAR) is thought to be essential for synaptic plasticity and learning. However, recent work indicates that the role of this receptor depends on the prior history of the research subject. For example, animals trained on a hippocampus-dependent learning task are subsequently able to acquire new information in the…

  4. Pivotal role of tissue plasminogen activator in the mechanism of action of electroconvulsive therapy.

    Science.gov (United States)

    Hoirisch-Clapauch, Silvia; Mezzasalma, Marco A U; Nardi, Antonio E

    2014-02-01

    Electroconvulsive therapy is an important treatment option for major depressive disorders, acute mania, mood disorders with psychotic features, and catatonia. Several hypotheses have been proposed as electroconvulsive therapy's mechanism of action. Our hypothesis involves many converging pathways facilitated by increased synthesis and release of tissue-plasminogen activator. Human and animal experiments have shown that tissue-plasminogen activator participates in many mechanisms of action of electroconvulsive therapy or its animal variant, electroconvulsive stimulus, including improved N-methyl-D-aspartate receptor-mediated signaling, activation of both brain-derived neurotrophic factor and vascular endothelial growth factor, increased bioavailability of zinc, purinergic release, and increased mobility of dendritic spines. As a result, tissue-plasminogen activator helps promote neurogenesis in limbic structures, modulates synaptic transmission and plasticity, improves cognitive function, and mediates antidepressant effects. Notably, electroconvulsive therapy seems to influence tissue-plasminogen activator metabolism. For example, electroconvulsive stimulus increases the expression of glutamate decarboxylase 65 isoform in γ-aminobutyric acid-releasing neurons, which enhances the release of tissue-plasminogen activator, and the expression of p11, a protein involved in plasminogen and tissue-plasminogen activator assembling. This paper reviews how electroconvulsive therapy correlates with tissue-plasminogen activator. We suggest that interventions aiming at increasing tissue-plasminogen activator levels or its bioavailability - such as daily aerobic exercises together with a carbohydrate-restricted diet, or normalization of homocysteine levels - be evaluated in controlled studies assessing response and remission duration in patients who undergo electroconvulsive therapy.

  5. The C-Terminal Region of G72 Increases D-Amino Acid Oxidase Activity

    Directory of Open Access Journals (Sweden)

    Sunny Li-Yun Chang

    2013-12-01

    Full Text Available The schizophrenia-related protein G72 plays a unique role in the regulation of D-amino acid oxidase (DAO in great apes. Several psychiatric diseases, including schizophrenia and bipolar disorder, are linked to overexpression of DAO and G72. Whether G72 plays a positive or negative regulatory role in DAO activity, however, has been controversial. Exploring the molecular basis of the relationship between G72 and DAO is thus important to understand how G72 regulates DAO activity. We performed yeast two-hybrid experiments and determined enzymatic activity to identify potential sites in G72 involved in binding DAO. Our results demonstrate that residues 123–153 and 138–153 in the long isoform of G72 bind to DAO and enhance its activity by 22% and 32%, respectively. A docking exercise indicated that these G72 peptides can interact with loops in DAO that abut the entrance of the tunnel that substrate and cofactor must traverse to reach the active site. We propose that a unique gating mechanism underlies the ability of G72 to increase the activity of DAO. Because upregulation of DAO activity decreases d-serine levels, which may lead to psychiatric abnormalities, our results suggest a molecular mechanism involving interaction between DAO and the C-terminal region of G72 that can regulate N-methyl-d-aspartate receptor-mediated neurotransmission.

  6. PDI regulates seizure activity via NMDA receptor redox in rats.

    Science.gov (United States)

    Kim, Ji Yang; Ko, Ah-Rhem; Hyun, Hye-Won; Min, Su-Ji; Kim, Ji-Eun

    2017-02-15

    Redox modulation of cysteine residues is one of the post-translational modifications of N-methyl-D-aspartate receptor (NMDAR). Protein disulfide isomerases (PDI), an endoplasmic reticulum (ER) chaperone, plays a crucial role in catalyzing disulfide bond formation, reduction, and isomerization. In the present study, we found that PDI bound to NMDAR in the normal hippocampus, and that this binding was increased in chronic epileptic rats. In vitro thiol reductase assay revealed that PDI increased the amount of thiols on full-length recombinant NR1 protein. PDI siRNA, 5-5'-dithio-bis(2-nitrobenzoic acid) (DTNB), bacitracin and PDI antibody reduced seizure susceptibility in response to pilocarpine. In addition, PDI knockdown effectively ameliorated spontaneous seizure activity in chronic epileptic rats. Anticonvulsive effects of PDI siRNA were correlated to the reduction of the amount of free- and nitrosothiols on NMDAR, accompanied by the inhibition of PDI activity. However, PDI knockdown did not lead to alteration in basal neurotransmission or ER stress under physiological condition. These findings provide mechanistic insight into sulfhydration of disulfide bonds on NMDAR by PDI, and suggest that PDI may represent a target of potential therapeutics for epilepsy, which avoids a possible side effect on physiological receptor functionality.

  7. Activation of NR2A receptors induces ischemic tolerance through CREB signaling.

    Science.gov (United States)

    Terasaki, Yasukazu; Sasaki, Tsutomu; Yagita, Yoshiki; Okazaki, Shuhei; Sugiyama, Yukio; Oyama, Naoki; Omura-Matsuoka, Emi; Sakoda, Saburo; Kitagawa, Kazuo

    2010-08-01

    Previous exposure to a nonlethal ischemic insult protects the brain against subsequent harmful ischemia. N-methyl-D-aspartate (NMDA) receptors are a highly studied target of neuroprotection after ischemia. Recently, NMDA receptor subtypes were implicated in neuronal survival and death. We focused on the contribution of NR2A and cyclic-AMP response element (CRE)-binding protein (CREB) signaling to ischemic tolerance using primary cortical neurons. Ischemia in vitro was modeled by oxygen-glucose deprivation (OGD). Ischemic tolerance was induced by applying 45-mins OGD 24 h before 180-mins OGD. Sublethal OGD also induced cross-tolerance against lethal glutamate and hydrogen peroxide. After sublethal OGD, expression of phosphorylated CREB and CRE transcriptional activity were significantly increased. When CRE activity was inhibited by CREB-S133A, a mutant CREB, ischemic tolerance was abolished. Inhibiting NR2A using NVP-AAM077 attenuated preconditioning-induced neuroprotection and correlated with decreased CRE activity levels. Activating NR2A using bicuculline and 4-aminopiridine induced resistance to lethal ischemia accompanied by elevated CRE activity levels, and this effect was abolished by NVP-AAM077. Elevated brain-derived neurotrophic factor (BDNF) transcriptional activities were observed after sublethal OGD and administration of bicuculline and 4-aminopiridine. NR2A-containing NMDA receptors and CREB signaling have important functions in the induction of ischemic tolerance. This may provide potential novel therapeutic strategies to treat ischemic stroke.

  8. Modulation of IκB kinase autophosphorylation and activity following brain ischemia

    Institute of Scientific and Technical Information of China (English)

    SHENWan-Hua; ZHANGHun-Yi; 等

    2003-01-01

    ATIM:To investigate the effects of different antagonists on the alteration of IκB kinase(IKK)activity in rat hipoocampus folluwing global brain ischemia,METHODS:Using 4-vessel occlusion(4-VO)as brain ischemia model,IKK protein expression was examined by immunoblotting and immunoprecipitation,and IKK activity was assayed by in vitro kinase assay.RESULTS:There was no alteration of IKK protein expression following ischemia or ischemia/reperfusion different time points,but IKK activity reached its peak level at ischemia 30min.Pretreatment with N-methyl-D-aspartate(NMDA)receptor antagonist ketamine,non-NMDA receptor antagonist DNQX,or NFκB inhibitor PDTC decreased the IKK activity following brain ischemia 30min.The increase in substrate myelin basic protein(MBP)phosphorylation by IKK is associated with an increase in autophosphorylation of IKK,which can also be antagonized by ketamine,DNQX,and PDTC,CONCLUSION:NMDA receptor and non-NMDA receptor mediate the increase of IKK activity following global brain ischemia in rat hippocampus,which contributes to the alterations of expression and activity of downstream factor NF-κB.

  9. Anticonvulsant activity of Mimosa pudica decoction.

    Science.gov (United States)

    Ngo Bum, E; Dawack, D L; Schmutz, M; Rakotonirina, A; Rakotonirina, S V; Portet, C; Jeker, A; Olpe, H-R; Herrling, P

    2004-06-01

    The decoction of Mimosa pudica leaves given intraperitoneally at dose of 1000-4000 mg/kg protected mice against pentylentetrazol and strychnine-induced seizures. M. pudica had no effect against picrotoxin-induced seizures It also antagonized N-methyl-D-aspartate- induced turning behavior. These properties could explain its use in African traditional medicine. Copyright 2004 Elsevier B.V.

  10. Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways.

    Science.gov (United States)

    Hanno-Iijima, Yoko; Tanaka, Masami; Iijima, Takatoshi

    2015-01-01

    Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.

  11. NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity.

    Science.gov (United States)

    Baron, A; Montagne, A; Cassé, F; Launay, S; Maubert, E; Ali, C; Vivien, D

    2010-05-01

    Although the molecular bases of its actions remain debated, tissue-type plasminogen activator (tPA) is a paradoxical brain protease, as it favours some learning/memory processes, but increases excitotoxic neuronal death. Here, we show that, in cultured cortical neurons, tPA selectively promotes NR2D-containing N-methyl-D-aspartate receptor (NMDAR)-dependent activation. We show that tPA-mediated signalling and neurotoxicity through the NMDAR are blocked by co-application of an NR2D antagonist (phenanthrene derivative (2S(*), 3R(*))-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid, PPDA) or knockdown of neuronal NR2D expression. In sharp contrast with cortical neurons, hippocampal neurons do not exhibit NR2D both in vitro and in vivo and are consequently resistant to tPA-promoted NMDAR-mediated neurotoxicity. Moreover, we have shown that activation of synaptic NMDAR prevents further tPA-dependent NMDAR-mediated neurotoxicity and sensitivity to PPDA. This study shows that the earlier described pro-neurotoxic effect of tPA is mediated by NR2D-containing NMDAR-dependent extracellular signal-regulated kinase activation, a deleterious effect prevented by synaptic pre-activation.

  12. Improvement of Psychotic Symptoms and the Role of Tissue Plasminogen Activator

    Directory of Open Access Journals (Sweden)

    Silvia Hoirisch-Clapauch

    2015-11-01

    Full Text Available Tissue plasminogen activator (tPA mediates a number of processes that are pivotal for synaptogenesis and remodeling of synapses, including proteolysis of the brain extracellular matrix, degradation of adhesion molecules, activation of neurotrophins, and activation of the N-methyl-d-aspartate receptor. Abnormalities in these processes have been consistently described in psychotic disorders. In this paper, we review the physiological roles of tPA, focusing on conditions characterized by low tPA activity, which are prevalent in schizophrenia. We then describe how tPA activity is influenced by lifestyle interventions and nutritional supplements that may ameliorate psychotic symptoms. Next, we analyze the role of tPA in the mechanism of action of hormones and medications effective in mitigating psychotic symptoms, such as pregnenolone, estrogen, oxytocin, dopamine D3 receptor antagonists, retinoic acid, valproic acid, cannabidiol, sodium nitroprusside, N-acetyl cysteine, and warfarin. We also review evidence that tPA participates in the mechanism by which electroconvulsive therapy and cigarette smoking may reduce psychotic symptoms.

  13. Reduced Hyperpolarization-Activated Current Contributes to Enhanced Intrinsic Excitability in Cultured Hippocampal Neurons from PrP(-/-) Mice.

    Science.gov (United States)

    Fan, Jing; Stemkowski, Patrick L; Gandini, Maria A; Black, Stefanie A; Zhang, Zizhen; Souza, Ivana A; Chen, Lina; Zamponi, Gerald W

    2016-01-01

    Genetic ablation of cellular prion protein (PrP(C)) has been linked to increased neuronal excitability and synaptic activity in the hippocampus. We have previously shown that synaptic activity in hippocampi of PrP-null mice is increased due to enhanced N-methyl-D-aspartate receptor (NMDAR) function. Here, we focused on the effect of PRNP gene knock-out (KO) on intrinsic neuronal excitability, and in particular, the underlying ionic mechanism in hippocampal neurons cultured from P0 mouse pups. We found that the absence of PrP(C) profoundly affected the firing properties of cultured hippocampal neurons in the presence of synaptic blockers. The membrane impedance was greater in PrP-null neurons, and this difference was abolished by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker ZD7288 (100 μM). HCN channel activity appeared to be functionally regulated by PrP(C). The amplitude of voltage sag, a characteristic of activating HCN channel current (I h), was decreased in null mice. Moreover, I h peak current was reduced, along with a hyperpolarizing shift in activation gating and slower kinetics. However, neither HCN1 nor HCN2 formed a biochemical complex with PrP(C). These results suggest that the absence of PrP downregulates the activity of HCN channels through activation of a cell signaling pathway rather than through direct interactions. This in turn contributes to an increase in membrane impedance to potentiate neuronal excitability.

  14. Activation and subcellular distribution of ERK1/2 following cerebral ischemia/reperfusion in rat hippocampus

    Institute of Scientific and Technical Information of China (English)

    WANG Rui-min; ZHANG Guang-yi; ZHANG Quan-guang; YANG Fang; MA Wen-dong; LI Qi-jia

    2006-01-01

    Objective:To investigate the activation (phosphorylation) and subcellular localization of extracellular signal-regulated kinase(ERK1/2), as well as the possible mechanism, following cerebral ischemia and ischemia/reperfusion in rat hippocampus. Methods: Transient brain ischemia was induced by the four-vessel occlusion method in Sprague-Dawley rats. Western blot analysis. Results: During cerebral ischemia without reperfusion ERK1/2 activation immediately increased with a peak at 5 min and then decreased in the cytosol fraction, which was paralleled by the increase of ERK1/2 activation in the nucleus fraction. During reperfusion, ERK1/2 was activated with peaks occurring at 10 min in the cytosol and at 30 min in the nucleus, respectively. Under those conditions, the protein expressions had no significant change. In order to clarify the possible mechanism of ERK1/2 activation, the rats were intraperitoneally administrated with N-methyl D aspartate (NMDA) receptor antagonist dextromethorphan(DM), L-type voltage-gated Ca2+ channel (L-VGCC) antagonist nifedipine (ND) 20 min before ischemia, finding that DM and ND markedly prevented ERK1/2 activation of nucleus fraction induced by reperfusion, not by ischemia. Conclusion: These results suggested that the nuclear translocation mainly occurred during is chemia, while ischemia-reperfusion induced ERK1/2 activation both in the cytosol and the nucleus. Two type calcium channels contributed, at least partially, to the activation of ERK1/2.

  15. Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity.

    Science.gov (United States)

    Almonte, Antoine G; Qadri, Laura H; Sultan, Faraz A; Watson, Jennifer A; Mount, Daniel J; Rumbaugh, Gavin; Sweatt, J David

    2013-01-01

    Protease-activated receptor-1 (PAR1) is an unusual G-protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. Although previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1's contribution to normal brain function. Here, we used PAR1-/- mice to investigate the contribution of PAR1 function to memory formation and synaptic function. We demonstrate that PAR1-/- mice have deficits in hippocampus-dependent memory. We also show that while PAR1-/- mice have normal baseline synaptic transmission at Schaffer collateral-CA1 synapses, they exhibit severe deficits in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). Mounting evidence indicates that activation of PAR1 leads to potentiation of NMDAR-mediated responses in CA1 pyramidal cells. Taken together, this evidence and our data suggest an important role for PAR1 function in NMDAR-dependent processes subserving memory formation and synaptic plasticity. © 2012 International Society for Neurochemistry.

  16. Long-term heavy ketamine use is associated with spatial memory impairment and altered hippocampal activation

    Directory of Open Access Journals (Sweden)

    Celia J A Morgan

    2014-12-01

    Full Text Available Ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 polydrug controls, matched for IQ, age and years in education. We used fMRI utilising an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls. Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users.

  17. Activation-induced structural change in the GluN1/GluN3A excitatory glycine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Balasuriya, Dilshan; Takahashi, Hirohide; Srivats, Shyam; Edwardson, J. Michael, E-mail: jme1000@cam.ac.uk

    2014-08-08

    Highlights: • We studied the response of the GluN1/GluN3A excitatory glycine receptor to activation. • GluN1 and GluN3A subunits interacted within transfected cells. • The GluN1/GluN3A receptor was functionally active. • Glycine or D-serine caused a ∼1 nm height reduction in bilayer-integrated receptors. • This height reduction was abolished by the glycine antagonist DCKA. - Abstract: Unlike GluN2-containing N-methyl-D-aspartate (NMDA) receptors, which require both glycine and glutamate for activation, receptors composed of GluN1 and GluN3 subunits are activated by glycine alone. Here, we used atomic force microscopy (AFM) imaging to examine the response to activation of the GluN1/GluN3A excitatory glycine receptor. GluN1 and GluN3A subunits were shown to interact intimately within transfected tsA 201 cells. Isolated GluN1/GluN3A receptors integrated into lipid bilayers responded to addition of either glycine or D-serine, but not glutamate, with a ∼1 nm reduction in height of the extracellular domain. The height reduction in response to glycine was abolished by the glycine antagonist 5,7-dichlorokynurenic acid. Our results represent the first demonstration of the effect of activation on the conformation of this receptor.

  18. Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts.

    Science.gov (United States)

    Emanuele, Marco; Esposito, Alessandro; Camerini, Serena; Antonucci, Flavia; Ferrara, Silvia; Seghezza, Silvia; Catelani, Tiziano; Crescenzi, Marco; Marotta, Roberto; Canale, Claudio; Matteoli, Michela; Menna, Elisabetta; Chieregatti, Evelina

    2016-05-01

    Alpha-synuclein (αSyn) interferes with multiple steps of synaptic activity at pre-and post-synaptic terminals, however the mechanism/s by which αSyn alters neurotransmitter release and synaptic potentiation is unclear. By atomic force microscopy we show that human αSyn, when incubated with reconstituted membrane bilayer, induces lipid rafts' fragmentation. As a consequence, ion channels and receptors are displaced from lipid rafts with consequent changes in their activity. The enhanced calcium entry leads to acute mobilization of synaptic vesicles, and exhaustion of neurotransmission at later stages. At the post-synaptic terminal, an acute increase in glutamatergic transmission, with increased density of PSD-95 puncta, is followed by disruption of the interaction between N-methyl-d-aspartate receptor (NMDAR) and PSD-95 with ensuing decrease of long term potentiation. While cholesterol loading prevents the acute effect of αSyn at the presynapse; inhibition of casein kinase 2, which appears activated by reduction of cholesterol, restores the correct localization and clustering of NMDARs.

  19. Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain.

    Science.gov (United States)

    Réus, Gislaine Z; Stringari, Roberto B; Rezin, Gislaine T; Fraga, Daiane B; Daufenbach, Juliana F; Scaini, Giselli; Benedet, Joana; Rochi, Natália; Streck, Emílio L; Quevedo, João

    2012-04-01

    Several studies have appointed for a role of glutamatergic system and/or mitochondrial function in major depression. In the present study, we evaluated the creatine kinase and mitochondrial respiratory chain activities after acute and chronic treatments with memantine (N-methyl-D: -aspartate receptor antagonist) and imipramine (tricyclic antidepressant) in rats. To this aim, rats were acutely or chronically treated for 14 days once a day with saline, memantine (5, 10 and 20 mg/kg) and imipramine (10, 20 and 30 mg/kg). After acute or chronic treatments, we evaluated mitochondrial respiratory chain complexes (I, II, II-III and IV) and creatine kinase activities in prefrontal cortex, hippocampus and striatum. Our results showed that both acute and chronic treatments with memantine or imipramine altered respiratory chain complexes and creatine kinase activities in rat brain; however, these alterations were different with relation to protocols (acute or chronic), complex, dose and brain area. Finally, these findings further support the hypothesis that the effects of imipramine and memantine could be involve mitochondrial function modulation.

  20. Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts

    Directory of Open Access Journals (Sweden)

    Marco Emanuele

    2016-05-01

    Full Text Available Alpha-synuclein (αSyn interferes with multiple steps of synaptic activity at pre-and post-synaptic terminals, however the mechanism/s by which αSyn alters neurotransmitter release and synaptic potentiation is unclear. By atomic force microscopy we show that human αSyn, when incubated with reconstituted membrane bilayer, induces lipid rafts' fragmentation. As a consequence, ion channels and receptors are displaced from lipid rafts with consequent changes in their activity. The enhanced calcium entry leads to acute mobilization of synaptic vesicles, and exhaustion of neurotransmission at later stages. At the post-synaptic terminal, an acute increase in glutamatergic transmission, with increased density of PSD-95 puncta, is followed by disruption of the interaction between N-methyl-d-aspartate receptor (NMDAR and PSD-95 with ensuing decrease of long term potentiation. While cholesterol loading prevents the acute effect of αSyn at the presynapse; inhibition of casein kinase 2, which appears activated by reduction of cholesterol, restores the correct localization and clustering of NMDARs.

  1. Evidence for glutamate-mediated activation of hippocampal neurons by glial calcium waves.

    Science.gov (United States)

    Hassinger, T D; Atkinson, P B; Strecker, G J; Whalen, L R; Dudek, F E; Kossel, A H; Kater, S B

    1995-10-01

    Communication from astrocytes to neurons has recently been reported by two laboratories, but different mechanisms were though to underlie glial calcium wave activation of associated neurons. Neuronal calcium elevation by glia observed in the present report is similar to that reported previously, where an increase in neuronal calcium was demonstrated in response to glial stimulation. In the present study hippocampal neurons plated on a confluent glial monolayer displayed a transient increase in intracellular calcium following a short delay after the passage of a wave of increased calcium in underlying glia. Activated cells displayed action potentials in response to glial waves and showed antineurofilament immunoreactivity. Finally, the N-methyl-D-aspartate glutamate receptor antagonist DL-2-amino-5-phosphonovaleric acid and the non-NMDA glutamate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione significantly reduced the responsiveness of neurons to glial calcium waves. Our results indicate that hippocampal neurons growing on hippocampal or cortical astrocytes respond to glial calcium waves with elevations in calcium and increased electrical activity. Furthermore, we show that in most cases this communication appears to be mediated by ionotropic glutamate receptor channels.

  2. Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication

    Directory of Open Access Journals (Sweden)

    Kenji Hashimoto

    2015-01-01

    Full Text Available Endoplasmic reticulum (ER protein sigma-1 receptor represents unique chaperone activity in the central nervous system, and it exerts a potent influence on a number of neurotransmitter systems. Several lines of evidence suggest that activation of sigma-1 receptor plays a role in the pathophysiology of neuropsychiatric diseases, as well as in the mechanisms of some therapeutic drugs and neurosteroids. Preclinical studies showed that some selective serotonin reuptake inhibitors (SSRIs; fluvoxamine, fluoxetine, excitalopram, donepezil, and ifenprodil act as sigma-1 receptor agonists. Furthermore, sigma-1 receptor agonists could improve the N-methyl-D-aspartate (NMDA antagonist phencyclidine (PCP-induced cognitive deficits in mice. A study using positron emission tomography have demonstrated that an oral administration of fluvoxamine or donepezil could bind to sigma-1 receptor in the healthy human brain, suggesting that sigma-1 receptor might be involved in the therapeutic mechanisms of these drugs. Moreover, case reports suggest that sigma-1 receptor agonists, including fluvoxamine, and ifenprodil, may be effective in the treatment of cognitive impairment in schizophrenia, delirium in elderly people, and flashbacks in post-traumatic stress disorder. In this review article, the author would like to discuss the clinical implication of sigma-1 receptor agonists, including endogenous neurosteroids, in the neuropsychiatric diseases.

  3. Neuronal injury induces the release of pro-interleukin-1beta from activated microglia in vitro.

    Science.gov (United States)

    Wang, Penglian; Rothwell, Nancy J; Pinteaux, Emmanuel; Brough, David

    2008-10-21

    Microglia activated after brain injury, are a major source of the pro-inflammatory cytokine interleukin-1 (IL-1), which is known to further exacerbate damage. However, the mechanisms that control IL-1 release in acute neuronal injury are unknown and the purpose of this study was to test the hypothesis that neuronal injury induces IL-1beta release from microglial cells. Here we report that lipopolysaccharide (LPS)-activated rat microglia co-cultured with healthy rat neurons express pro-IL-1beta, which in the absence of cell death accumulates in the cells. Treatment of co-cultures with the excitotoxin N-methyl-D-aspartate (NMDA) induced neuronal cell death leading to the appearance of pro-IL-1beta in the culture supernatant. This effect was reversed by the NMDA receptor antagonist MK-801, and was neuron-dependent, since NMDA had no effect on cell death or pro-IL-1beta release in mixed glial cell cultures. In addition, we show that pro-IL-1beta release from LPS-treated mixed glia or LPS-treated microglia is significantly reduced in the presence of conditioned medium from healthy co-cultures or neuronal cultures respectively. These results demonstrate that injured neurons promote the release of pro-IL-1beta from microglia, possibly by regulating microglial cell viability, and suggest an important alternative mechanism of IL-1beta release that occurs in response to neuronal injury.

  4. Activity-induced long-term potentiation of excitatory synapses in developing zebrafish retina in vivo.

    Science.gov (United States)

    Wei, Hong-ping; Yao, Yuan-yuan; Zhang, Rong-wei; Zhao, Xiao-feng; Du, Jiu-lin

    2012-08-09

    Neural activity-induced long-term potentiation (LTP) of synaptic transmission is believed to be one of the cellular mechanisms underlying experience-dependent developmental refinement of neural circuits. Although it is well established that visual experience and neural activity are critical for the refinement of retinal circuits, whether and how LTP occurs in the retina remain unknown. Using in vivo perforated whole-cell recording and two-photon calcium imaging, we find that both repeated electrical and visual stimulations can induce LTP at excitatory synapses formed by bipolar cells on retinal ganglion cells in larval but not juvenile zebrafish. LTP induction requires the activation of postsynaptic N-methyl-D-aspartate receptors, and its expression involves arachidonic acid-dependent presynaptic changes in calcium dynamics and neurotransmitter release. Physiologically, both electrical and visual stimulation-induced LTP can enhance visual responses of retinal ganglion cells. Thus, LTP exists in developing retinae with a presynaptic locus and may serve for visual experience-dependent refinement of retinal circuits.

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

    Science.gov (United States)

    Bak, Lasse K; Johansen, Maja L; Schousboe, Arne; Waagepetersen, Helle S

    2012-09-01

    Synthesis of neuronal glutamate from α-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 μM), which results in release of vesicular glutamate. At the end of the superfusion experiment, the vesicular pool of glutamate was released by treatment with α-latrotoxin (3 nM, 5 min). This experimental paradigm allows a separate analysis of the cytoplasmic and vesicular pools of glutamate. Amount and extent of (15) N labeling of intracellular amino acids plus vesicular glutamate were analyzed employing HPLC and LC-MS analysis. Only when [(15) N]valine served as precursor did the labeling of both cytoplasmic and vesicular glutamate increase after synaptic activity. In addition, only [(15) N]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.

  6. Co-activation of NR2A and NR2B subunits induces resistance to fear extinction.

    Science.gov (United States)

    Leaderbrand, Katherine; Corcoran, Kevin A; Radulovic, Jelena

    2014-09-01

    Unpredictable stress is known to profoundly enhance susceptibility to fear and anxiety while reducing the ability to extinguish fear when threat is no longer present. Accordingly, partial aversive reinforcement, via random exposure to footshocks, induces fear that is resistant to extinction. Here we sought to determine the hippocampal mechanisms underlying susceptibility versus resistance to context fear extinction as a result of continuous (CR) and partial (PR) reinforcement, respectively. We focused on N-methyl-D-aspartate receptor (NMDAR) subunits 2A and B (NR2A and NR2B) as well as their downstream signaling effector, extracellular signal-regulated kinase (ERK), based on their critical role in the acquisition and extinction of fear. Pharmacological inactivation of NR2A, but not NR2B, blocked extinction after CR, whereas inactivation of NR2A, NR2B, or both subunits facilitated extinction after PR. The latter finding suggests that co-activation of NR2A and NR2B contributes to persistent fear following PR. In contrast to CR, PR increased membrane levels of ERK and NR2 subunits after the conditioning and extinction sessions, respectively. In parallel, nuclear activation of ERK was significantly reduced after the extinction session. Thus, co-activation and increased surface expression of NR2A and NR2B, possibly mediated by ERK, may cause persistent fear. These findings suggest that patients with post-traumatic stress disorder (PTSD) may benefit from antagonism of specific NR2 subunits.

  7. Activation of InsP3 receptors is sufficient for inducing graded intrinsic plasticity in rat hippocampal pyramidal neurons

    Science.gov (United States)

    Ashhad, Sufyan; Johnston, Daniel

    2014-01-01

    The synaptic plasticity literature has focused on establishing necessity and sufficiency as two essential and distinct features in causally relating a signaling molecule to plasticity induction, an approach that has been surprisingly lacking in the intrinsic plasticity literature. In this study, we complemented the recently established necessity of inositol trisphosphate (InsP3) receptors (InsP3R) in a form of intrinsic plasticity by asking if InsP3R activation was sufficient to induce intrinsic plasticity in hippocampal neurons. Specifically, incorporation of d-myo-InsP3 in the recording pipette reduced input resistance, maximal impedance amplitude, and temporal summation but increased resonance frequency, resonance strength, sag ratio, and impedance phase lead. Strikingly, the magnitude of plasticity in all these measurements was dependent on InsP3 concentration, emphasizing the graded dependence of such plasticity on InsP3R activation. Mechanistically, we found that this InsP3-induced plasticity depended on hyperpolarization-activated cyclic nucleotide-gated channels. Moreover, this calcium-dependent form of plasticity was critically reliant on the release of calcium through InsP3Rs, the influx of calcium through N-methyl-d-aspartate receptors and voltage-gated calcium channels, and on the protein kinase A pathway. Our results delineate a causal role for InsP3Rs in graded adaptation of neuronal response dynamics, revealing novel regulatory roles for the endoplasmic reticulum in neural coding and homeostasis. PMID:25552640

  8. Neuroprotective effects of Asiaticoside.

    Science.gov (United States)

    Qi, Feng-Yan; Yang, Le; Tian, Zhen; Zhao, Ming-Gao; Liu, Shui-Bing; An, Jia-Ze

    2014-07-01

    In the central nervous system, Asiaticoside has been shown to attenuate in vitro neuronal damage caused by exposure to β-amyloid. In vivo studies demonstrated that Asiaticoside could attenuate neurobehavioral, neurochemical and histological changes in transient focal middle cerebral artery occlusion animals. In addition, Asiaticoside showed anxiolytic effects in acute and chronic stress animals. However, its potential neuroprotective properties in glutamate-induced excitotoxicity have not been fully studied. We investigated the neuroprotective effects of Asiaticoside in primary cultured mouse cortical neurons exposed to glutamate-induced excitotoxicity invoked by N-methyl-D-aspartate. Pretreatment with Asiaticoside decreased neuronal cell loss in a concentration-dependent manner and restored changes in expression of apoptotic-related proteins Bcl-2 and Bax. Asiaticoside pretreatment also attenuated the upregulation of NR2B expression, a subunit of N-methyl-D-aspartate receptors, but did not affect expression of NR2A subunits. Additionally, in cultured neurons, Asiaticoside significantly inhibited Ca(2+) influx induced by N-methyl-D-aspartate. These experimental findings provide preliminary evidence that during excitotoxicity induced by N-methyl-D-aspartate exposure in cultured cortical neurons, the neuroprotective effects of Asiaticoside are mediated through inhibition of calcium influx. Aside from its anti-oxidant activity, down-regulation of NR2B-containing N-methyl-D-aspartate receptors may be one of the underlying mechanisms in Asiaticoside neuroprotection.

  9. Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice

    Institute of Scientific and Technical Information of China (English)

    ZHU Yong-ping; LONG Zai-hao; ZHENG Ming-lan; BINSACK Ralf

    2006-01-01

    Objective: To study the effect of glycine site/NMDA (N-methyl-D-aspartate) receptor antagonist MRZ2/576 on the conditioned place preference (CPP) and locomotor activity induced by morphine in mice. Methods: Different doses (1.25, 2.5 and 5 mg/kg, i.p.) of MRZ2/576 were used to evaluate the effect of MRZ2/576 on the acquisition and expression of CPP induced by morphine (5 mg/kg) in mice. In addition, we examined the locomotor activity of mice in conditioning and testing phase of CPP paradigm. Results: MRZ2/576 alone could not establish place preference, but a 5 mg/kg dose of MRZ2/576 could block both acquisition and expression of morphine-induced CPP. In testing phase of CPP, there was no statistical difference for locomotor activity between the groups; injection of MRZ2/576 showed a dose-dependent decrease of locomotor activity on both control and morphine-treated mice, especially 5 mg/kg of MRZ2/576 significantly suppressed the locomotor activity of mice. Conclusion:Based on the present results, we assume that MRZ2/576 can antagonize the rewarding effect of morphine, suggesting that this glycine site/NMDA receptor antagonist could be used to treat addictions due to its light side effect profile.

  10. GDNF selectively induces microglial activation and neuronal survival in CA1/CA3 hippocampal regions exposed to NMDA insult through Ret/ERK signalling.

    Directory of Open Access Journals (Sweden)

    Francesca Boscia

    Full Text Available The glial cell line-derived neurotrophic factor (GDNF is a potent survival factor for several neuronal populations in different brain regions, including the hippocampus. However, no information is available on the: (1 hippocampal subregions involved in the GDNF-neuroprotective actions upon excitotoxicity, (2 identity of GDNF-responsive hippocampal cells, (3 transduction pathways involved in the GDNF-mediated neuroprotection in the hippocampus. We addressed these questions in organotypic hippocampal slices exposed to GDNF in presence of N-methyl-D-aspartate (NMDA by immunoblotting, immunohistochemistry, and confocal analysis. In hippocampal slices GDNF acts through the activation of the tyrosine kinase receptor, Ret, without involving the NCAM-mediated pathway. Both Ret and ERK phosphorylation mainly occurred in the CA3 region where the two activated proteins co-localized. GDNF protected in a greater extent CA3 rather than CA1 following NMDA exposure. This neuroprotective effect targeted preferentially neurons, as assessed by NeuN staining. GDNF neuroprotection was associated with a significant increase of Ret phosphorylation in both CA3 and CA1. Interestingly, confocal images revealed that upon NMDA exposure, Ret activation occurred in microglial cells in the CA3 and CA1 following GDNF exposure. Collectively, this study shows that CA3 and CA1 hippocampal regions are highly responsive to GDNF-induced Ret activation and neuroprotection, and suggest that, upon excitotoxicity, such neuroprotection involves a GDNF modulation of microglial cell activity.

  11. Endogenous nitric oxide induces activation of apoptosis signal-regulating kinase 1 via S-nitrosylation in rat hippocampus during cerebral ischemia-reperfusion.

    Science.gov (United States)

    Liu, D-H; Yuan, F-G; Hu, S-Q; Diao, F; Wu, Y-P; Zong, Y-Y; Song, T; Li, C; Zhang, G-Y

    2013-01-15

    Apoptosis signal-regulating kinase 1 (ASK1) is a general mediator of cell death in response to a variety of stimuli, including reactive oxygen species, tumor necrosis factor α, lipopolysaccharide, endoplasmic reticulum stress, calcium influx and ischemia. Here we reported ASK1 was activated by nitric oxide (NO) through S-nitrosylation during cerebral ischemia-reperfusion. The reagents that abrogate neuronal nitric oxide synthase (nNOS) activity such as nNOS inhibitor 7NI and N-methyl-D-aspartate receptor antagonist MK801 prevented ASK1 activation via decreasing ASK1 S-nitrosylation. In HEK293 cells, over-expressed ASK1 could be S-nitrosylated by both exogenous and endogenous NO and Cys869 was identified as the site of ASK1 S-nitrosylation. S-nitrosylation increased the level of ASK1 phosphorylation at Thr845, which represents ASK1 activation. Our results further confirmed that S-nitrosylation led to the increment of ASK1 dimerization. S-nitrosylation of ASK1 also activated the downstream JNK signaling and JNK-mediated nucleic pathway. The exogenous NO (SNP and GSNO) reversed the effect of endogenous NO by suppressing S-nitrosylation of ASK1 and exerted neuroprotection during ischemia-reperfusion. These results suggest that inhibiting ASK1 S-nitrosylation may be a novel approach for stroke therapy. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Comparison of the MK-801-induced increase in non-rewarded appetitive responding with dopamine agonists and locomotor activity in rats.

    Science.gov (United States)

    Davis-MacNevin, Parnell L; Dekraker, Jordan; LaDouceur, Liane; Holahan, Matthew R

    2013-09-01

    Systemic administration of the noncompetitive N-methyl-D-aspartate (NMDA)- receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. Evidence has shown that MK-801 increases the probability of operant responding during extinction, possibly modeling perseveration, as would be seen in patients with schizophrenia. This MK-801-induced behavioral perseveration is reversed by dopamine receptor antagonism. To further explore the role of dopamine in this behavioral change, the current study sought to determine if the MK-801-induced increase in non-rewarded operant responding could be mimicked by dopamine agonism and determine how it was related to locomotor activity. Male Long Evans rats were treated systemically with MK-801, cocaine, GBR12909 or apomorphine (APO) and given a single trial operant extinction session, followed by a separate assessment of locomotor activity. Both MK-801 (0.05 mg/kg) and cocaine (10 mg/kg) significantly increased responding during the extinction session and both increased horizontal locomotor activity. No dose of GBR-12909 (5, 10 or 20 mg/kg) was found to effect non-rewarded operant responding or locomotor activity. APO (0.05, 0.5, 2 or 5 mg/kg) treatment produced a dose-dependent decrease in both operant responding and locomotor activity. These results suggest the possibility that, rather than a primary influence of increased dopamine concentration on elevating bar-pressing responses during extinction, other neurotransmitter systems may be involved.

  13. Molecular structure and physiological function of N-methyl-D-aspartic acid receptor%N-甲基-D-天氡氨酸受体的分子结构与生理功能

    Institute of Scientific and Technical Information of China (English)

    林奕斌; 赵同军; 展永

    2007-01-01

    NMDA(N-甲基-D-天氡氨酸)受体是离子型谷氨酸受体的一种亚型,在中枢神经系统的突触传递和突触可塑性调节中起着重要的作用.生物体内已经发现了三种NMDA受体亚基,通过基因的选择性剪切可产生多种亚单位.NMDA受体是一个具有多个结合位点的大分子复合物,其生理特性同异聚体通道的装配密切相关.NMDA受体的异常会导致一些认知功能的缺失,这为治疗性药物开发提供了靶点.

  14. Quantitative determination of free D-Asp, L-Asp and N-methyl-D-aspartate in mouse brain tissues by chiral separation and Multiple Reaction Monitoring tandem mass spectrometry.

    Science.gov (United States)

    Fontanarosa, Carolina; Pane, Francesca; Sepe, Nunzio; Pinto, Gabriella; Trifuoggi, Marco; Squillace, Marta; Errico, Francesco; Usiello, Alessandro; Pucci, Piero; Amoresano, Angela

    2017-01-01

    Several studies have suggested that free d-Asp has a crucial role in N-methyl d-Asp receptor-mediated neurotransmission playing very important functions in physiological and pathological processes. This paper describes the development of an analytical procedure for the direct and simultaneous determination of free d-Asp, l-Asp and N-methyl d-Asp in specimens of different mouse brain tissues using chiral LC-MS/MS in Multiple Reaction Monitoring scan mode. After comparing three procedures and different buffers and extraction solvents, a simple preparation procedure was selected the analytes of extraction. The method was validated by analyzing l-Asp, d-Asp and N-methyl d-Asp recovery at different spiked concentrations (50, 100 and 200 pg/μl) yielding satisfactory recoveries (75-110%), and good repeatability. Limits of detection (LOD) resulted to be 0.52 pg/μl for d-Asp, 0.46 pg/μl for l-Asp and 0.54 pg/μl for NMDA, respectively. Limits of quantification (LOQ) were 1.57 pg/μl for d-Asp, 1.41 pg/μl for l-Asp and 1.64 pg/μl for NMDA, respectively. Different concentration levels were used for constructing the calibration curves which showed good linearity. The validated method was then successfully applied to the simultaneous detection of d-Asp, l-Asp and NMDA in mouse brain tissues. The concurrent, sensitive, fast, and reproducible measurement of these metabolites in brain tissues will be useful to correlate the amount of free d-Asp with relevant neurological processes, making the LC-MS/MS MRM method well suited, not only for research work but also for clinical analyses.

  15. 抗NMDA受体脑炎1例报道并文献复习%One case of anti-N-methyl-D-aspartate receptor encephalitis was reported and literature were reviewed

    Institute of Scientific and Technical Information of China (English)

    李庭毅; 李睿; 李文辉; 王小平; 盛飞; 胡松; 王丽

    2014-01-01

    目的 探讨抗NMDA受体脑炎的发病机制、临床表现、辅助检查、及治疗方法.方法 报道本院确诊的1例患者的临床资料并复习国内外相关文献.结果 本例患者以发热为首发症状,后出现癫痫、精神行为异常、意识障碍、口-面-舌部的异常运动,经脑脊液和血液检测出抗NMDAR抗体,确诊为抗NMDA受体脑炎,经激素及丙种球蛋白治疗后患者基本恢复正常.结论 抗NMDA受体脑炎是一种少见的新型自身免疫性脑炎,好发于青年女性,主要表现为癫痫、精神症状、意识障碍、口-面-舌的异常运动等,脑脊液抗NMDAR抗体检测阳性可确诊本病,激素、丙种球蛋白、血浆置换为该病的一线治疗,早诊断、早治疗后大多患者预后良好.

  16. Severity anti-N-methyl-D-aspartate receptor encephalitis:review of clinical presentation,imaging and electroencephalogram%重症抗NMDAR脑炎临床、影像学及脑电图特征研究

    Institute of Scientific and Technical Information of China (English)

    陈萍; 杜芳; 刘之荣; 王津存; 吴中亮; 赵钢

    2016-01-01

    Objective To analysis the clinical presentation,imaging and electroencephalogram of severity anti NMDA receptor encephalitis.Method Twenty three patients were confirmed to have serum or cerebrospinal fluid (CSF) antibodies to the NMDA receptor,Modified Rankin Scale(MRS) were 4-5 scores.To analysis the charactor of white blood cells in CSF,severity of disturbance of consciousness,failure of respiration, head MRI and 24 hour long-term video electroencephalogram(VEEG).Results In the twenty three patients with severity anti NMDA receptor encephalitis,nineteen patients showed psychiatric disorder(82.6%),twenty patients showed disturbance of consciousness(87%).White blood cells in CSF of severe anti NMDA receptor encephalitis had no different with that of in mild anti NMDA receptor encephalitis(P<0.05). Seventeen cases of seizure(73.9%)including thirteen cases of status epileptics(56.5%).By 24hVEEG ,fifteen patients showed wide slow wave including twelve cases of θ wave ,five cases of δ wave. Two patients showed 10-20 HZ fast wave background.Six patients showed spike wave,sharp wave,spike slow wave.Only one case was normal VEEG.Fourteen patients were abnormal signals in MRI including six cases of cortex of frontal , temporal,parietal and occipital, five cases of subcortical white matter,five cases of hippocampus,two cases of brain stem, MRI showed normal in 9 cases. In ten cases with respiratory failure (43.5%), six cases were type I and four cases were type Ⅱ respiratory failure.Conclusion Severity ,white blood cells in CSF and degree of disturbance of consciousness has nothing to do with the titer of anti NMDA receptor antibody ,the status of epilepsy is easy to occur and the respiratory failure caused by central ventilation is insufficient in severity anti NMDA receptor encephalitis.%目的:分析重症抗NMDAR脑炎临床,影像学及脑电图(EEG)特征。方法23例血清和/或脑脊液(CSF)抗NMDAR抗体阳性、MRS评分4-5分的重症抗NMDAR脑炎,分析CSF白细胞数、意识障碍严重程度、呼吸功能衰竭特点及头颅MRI、24h长程视频脑电图(VEEG)特点。结果23例重症抗NMDAR脑炎中,精神行为异常19例(82.6%),意识障碍20例(87%)。CSF白细胞数增高19例(82.6%),与轻症抗NMDAR脑炎差异无统计学意义(P<0.05)。癫痫发作17例(73.9%),其中癫痫持续状态13例(56.5%)。24hVEEG监测,广泛慢波15例,其中θ波为主调12例,δ波为主调3例。14~20HZ快波背景2例,额顶枕颞导棘波、尖波或尖慢综合波发放6例,未见异常1例。头颅MRI异常14例(60.9%),其中累及额、颞、顶枕叶皮质6例,皮质下白质多发异常信号5例,累及海马5例,累及脑干2例,未见异常9例。呼吸功能衰竭10例(43.5%),Ⅰ型呼吸功能衰竭6例,Ⅱ型呼吸功能衰竭4例。结论重症抗NMDAR脑炎疾病的严重程度、CSF白细胞数量、意识障碍程度与抗NMDAR抗体的滴度无关,重症抗NMDAR脑炎易出现癫痫持续状态和中枢性通气不足所致呼吸功能衰竭。

  17. Maternal magnesium sulfate fetal neuroprotective effects to the fetus: inhibition of neuronal nitric oxide synthase and nuclear factor kappa-light-chain-enhancer of activated B cells activation in a rodent model.

    Science.gov (United States)

    Beloosesky, Ron; Khatib, Nizar; Ginsberg, Yuval; Anabosy, Saja; Shalom-Paz, Einat; Dahis, Masha; Ross, Michael G; Weiner, Zeev

    2016-09-01

    Maternal magnesium administration has been shown to protect the preterm fetus from white- and gray-matter injury, although the mechanism is unknown. The purpose of the study is to test the following hypotheses: (1) maternal infections/inflammation activate fetal neuronal N-methyl-D-aspartate receptors that up-regulate neuronal nitric oxide synthase and nuclear factor kappa-light-chain-enhancer of activated B cells pathways; and (2) maternal magnesium sulfate attenuates fetal brain neuronal nitric oxide synthase and nuclear factor kappa-light-chain-enhancer of activated B cells activation through N-methyl-D-aspartate receptors. Pregnant rats at embryonic day 16 and embryonic day 18 (n = 6, 48 total) received injections of intraperitoneal lipopolysaccharide 500 μg/kg or saline at time 0. Dams were randomized for treatment with subcutaneous magnesium sulfate (270 mg/kg) or saline for 2 hours prior to and following lipopolysaccharide/saline injections. At 4 hours after lipopolysaccharide administration, fetal brains were collected from the 4 treatment groups (lipopolysaccharide/saline, lipopolysaccharide/magnesium sulfate, saline/magnesium sulfate, saline/saline), and phosphoneuronal nitric oxide synthase, nuclear factor kappa-light-chain-enhancer of activated B cells p65, and chemokine (C-C motif) ligand 2 protein levels were determined by Western blot. An additional group of pregnant rats (n = 5) received N-methyl-D-aspartate-receptor antagonist following the lipopolysaccharide injection to study magnesium sulfate protective mechanism. Lipopolysaccharide (lipopolysaccharide/saline) significantly increased fetal brain phosphoneuronal nitric oxide synthase, nuclear factor kappa-light-chain-enhancer of activated B cells p65, and chemokine (C-C motif) ligand 2 protein levels compared to the saline/saline group at both embryonic day 16 (phosphoneuronal nitric oxide synthase 0.23 ± 0.01 vs 0.11 ± 0.01 U; nuclear factor kappa-light-chain-enhancer of activated B cells

  18. Activation of AMPA receptors in the suprachiasmatic nucleus phase-shifts the mouse circadian clock in vivo and in vitro.

    Directory of Open Access Journals (Sweden)

    Yasutaka Mizoro

    Full Text Available The glutamatergic neurotransmission in the suprachiasmatic nucleus (SCN plays a central role in the entrainment of the circadian rhythms to environmental light-dark cycles. Although the glutamatergic effect operating via NMDAR (N-methyl D-aspartate receptor is well elucidated, much less is known about a role of AMPAR (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor in circadian entrainment. Here we show that, in the mouse SCN, GluR2 and GluR4 AMPAR subtypes are abundantly expressed in the retinorecipient area. In vivo microinjection of AMPA in the SCN during the early subjective night phase-delays the behavioral rhythm. In the organotypic SCN slice culture, AMPA application induces phase-dependent phase-shifts of core-clock gene transcription rhythms. These data demonstrate that activation of AMPAR is capable of phase-shifting the circadian clock both in vivo and in vitro, and are consistent with the hypothesis that activation of AMPA receptors is a critical step in the transmission of photic information to the SCN.

  19. Free D-aspartate regulates neuronal dendritic morphology, synaptic plasticity, gray matter volume and brain activity in mammals.

    Science.gov (United States)

    Errico, F; Nisticò, R; Di Giorgio, A; Squillace, M; Vitucci, D; Galbusera, A; Piccinin, S; Mango, D; Fazio, L; Middei, S; Trizio, S; Mercuri, N B; Teule, M A; Centonze, D; Gozzi, A; Blasi, G; Bertolino, A; Usiello, A

    2014-01-01

    D-aspartate (D-Asp) is an atypical amino acid, which is especially abundant in the developing mammalian brain, and can bind to and activate N-methyl-D-Aspartate receptors (NMDARs). In line with its pharmacological features, we find that mice chronically treated with D-Asp show enhanced NMDAR-mediated miniature excitatory postsynaptic currents and basal cerebral blood volume in fronto-hippocampal areas. In addition, we show that both chronic administration of D-Asp and deletion of the gene coding for the catabolic enzyme D-aspartate oxidase (DDO) trigger plastic modifications of neuronal cytoarchitecture in the prefrontal cortex and CA1 subfield of the hippocampus and promote a cytochalasin D-sensitive form of synaptic plasticity in adult mouse brains. To translate these findings in humans and consistent with the experiments using Ddo gene targeting in animals, we performed a hierarchical stepwise translational genetic approach. Specifically, we investigated the association of variation in the gene coding for DDO with complex human prefrontal phenotypes. We demonstrate that genetic variation predicting reduced expression of DDO in postmortem human prefrontal cortex is mapped on greater prefrontal gray matter and activity during working memory as measured with MRI. In conclusion our results identify novel NMDAR-dependent effects of D-Asp on plasticity and physiology in rodents, which also map to prefrontal phenotypes in humans.

  20. Effects of Ketamine on Resting-State EEG Activity and Their Relationship to Perceptual/Dissociative Symptoms in Healthy Humans

    Science.gov (United States)

    de la Salle, Sara; Choueiry, Joelle; Shah, Dhrasti; Bowers, Hayley; McIntosh, Judy; Ilivitsky, Vadim; Knott, Verner

    2016-01-01

    N-methyl-D-aspartate (NMDA) receptor antagonists administered to healthy humans results in schizophrenia-like symptoms, which preclinical research suggests are due to glutamatergically altered brain oscillations. Here, we examined resting-state electroencephalographic activity in 21 healthy volunteers assessed in a placebo-controlled, double-blind, randomized study involving administration of either a saline infusion or a sub-anesthetic dose of ketamine, an NMDA receptor antagonist. Frequency-specific current source density (CSD) was assessed at sensor-level and source-level using eLORETA within regions of interest of a triple network model of schizophrenia (this model posits a dysfunctional switching between large-scale Default Mode and Central Executive networks by the monitor-controlling Salience Network). These CSDs were measured in each session along with subjective symptoms as indexed with the Clinician Administered Dissociative States Scale. Ketamine-induced CSD reductions in slow (delta/theta and alpha) and increases in fast (gamma) frequencies at scalp electrode sites were paralleled by frequency-specific CSD changes in the Default Mode, Central Executive, and Salience networks. Subjective symptoms scores were increased with ketamine and ratings of depersonalization in particular were associated with alpha CSD reductions in general and in specific regions of interest in each of the three networks. These results tentatively support the hypothesis that pathological brain oscillations associated with hypofunctional NMDA receptor activity may contribute to the emergence of the perceptual/dissociate symptoms of schizophrenia. PMID:27729865

  1. 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.

  2. ATP Induces NO Production in Hippocampal Neurons by P2X7 Receptor Activation Independent of Glutamate Signaling

    Science.gov (United States)

    Codocedo, Juan Francisco; Godoy, Juan Alejandro; Poblete, Maria Ines; Inestrosa, Nibaldo C.; Huidobro-Toro, Juan Pablo

    2013-01-01

    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 Nω-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. PMID:23472093

  3. Forgetting of long-term memory requires activation of NMDA receptors, L-type voltage-dependent Ca2+ channels, and calcineurin

    Science.gov (United States)

    Sachser, Ricardo Marcelo; Santana, Fabiana; Crestani, Ana Paula; Lunardi, Paula; Pedraza, Lizeth Katherine; Quillfeldt, Jorge Alberto; Hardt, Oliver; de Oliveira Alvares, Lucas

    2016-01-01

    In the past decades, the cellular and molecular mechanisms underlying memory consolidation, reconsolidation, and extinction have been well characterized. However, the neurobiological underpinnings of forgetting processes remain to be elucidated. Here we used behavioral, pharmacological and electrophysiological approaches to explore mechanisms controlling forgetting. We found that post-acquisition chronic inhibition of the N-methyl-D-aspartate receptor (NMDAR), L-type voltage-dependent Ca2+ channel (LVDCC), and protein phosphatase calcineurin (CaN), maintains long-term object location memory that otherwise would have been forgotten. We further show that NMDAR activation is necessary to induce forgetting of object recognition memory. Studying the role of NMDAR activation in the decay of the early phase of long-term potentiation (E-LTP) in the hippocampus, we found that ifenprodil infused 30 min after LTP induction in vivo blocks the decay of CA1-evoked postsynaptic plasticity, suggesting that GluN2B-containing NMDARs activation are critical to promote LTP decay. Taken together, these findings indicate that a well-regulated forgetting process, initiated by Ca2+ influx through LVDCCs and GluN2B-NMDARs followed by CaN activation, controls the maintenance of hippocampal LTP and long-term memories over time. PMID:26947131

  4. Induction of long-term oscillations in the γ frequency band by nAChR activation in rat hippocampal CA3 area.

    Science.gov (United States)

    Zhang, X; Ge, X Y; Wang, J G; Wang, Y L; Wang, Y; Yu, Y; Li, P P; Lu, C B

    2015-08-20

    The hippocampal neuronal network oscillation at γ frequency band (γ oscillation) is generated by the precise interaction between interneurons and principle cells. γ oscillation is associated with attention, learning and memory and is impaired in the diseased conditions such as Alzheimer's disease (AD) and schizophrenia. Nicotinic acetylcholine receptor (nAChR) plays an important role in the regulation of hippocampal neurotransmission and network activity. It is not known whether nicotine modulates plasticity of network activity at γ oscillations in the hippocampus. In this study we investigated the effects of nicotine on the long-term changes of KA-induced γ oscillations. We found that hippocampal γ oscillations can be enhanced by a low concentration of nicotine (1μM), such an enhancement lasts for hours after washing out of nicotine, suggesting a form of synaptic plasticity, named as long-term oscillation at γ frequency band (LTOγ). Nicotine-induced LTOγ was mimicked by the selective α4β2 but not by α7 nAChR agonist and was involved in N-methyl-d-aspartate (NMDA) receptor activation as well as depended on excitatory and inhibitory neurotransmission. Our results indicate that nAChR activation induced plasticity in γ oscillation, which may be beneficial for the improvement of cognitive deficiency in AD and schizophrenia.

  5. Forgetting of long-term memory requires activation of NMDA receptors, L-type voltage-dependent Ca2+ channels, and calcineurin.

    Science.gov (United States)

    Sachser, Ricardo Marcelo; Santana, Fabiana; Crestani, Ana Paula; Lunardi, Paula; Pedraza, Lizeth Katherine; Quillfeldt, Jorge Alberto; Hardt, Oliver; Alvares, Lucas de Oliveira

    2016-03-07

    In the past decades, the cellular and molecular mechanisms underlying memory consolidation, reconsolidation, and extinction have been well characterized. However, the neurobiological underpinnings of forgetting processes remain to be elucidated. Here we used behavioral, pharmacological and electrophysiological approaches to explore mechanisms controlling forgetting. We found that post-acquisition chronic inhibition of the N-methyl-D-aspartate receptor (NMDAR), L-type voltage-dependent Ca(2+) channel (LVDCC), and protein phosphatase calcineurin (CaN), maintains long-term object location memory that otherwise would have been forgotten. We further show that NMDAR activation is necessary to induce forgetting of object recognition memory. Studying the role of NMDAR activation in the decay of the early phase of long-term potentiation (E-LTP) in the hippocampus, we found that ifenprodil infused 30 min after LTP induction in vivo blocks the decay of CA1-evoked postsynaptic plasticity, suggesting that GluN2B-containing NMDARs activation are critical to promote LTP decay. Taken together, these findings indicate that a well-regulated forgetting process, initiated by Ca(2+) influx through LVDCCs and GluN2B-NMDARs followed by CaN activation, controls the maintenance of hippocampal LTP and long-term memories over time.

  6. Phosphorylated Histone 3 at Serine 10 Identifies Activated Spinal Neurons and Contributes to the Development of Tissue Injury-Associated Pain

    Science.gov (United States)

    Torres-Pérez, Jose Vicente; Sántha, Péter; Varga, Angelika; Szucs, Peter; Sousa-Valente, Joao; Gaal, Botond; Sivadó, Miklós; Andreou, Anna P; Beattie, Sara; Nagy, Bence; Matesz, Klara; C. Arthur, J. Simon; Jancsó, Gábor; Nagy, Istvan

    2017-01-01

    Transcriptional changes in superficial spinal dorsal horn neurons (SSDHN) are essential in the development and maintenance of prolonged pain. Epigenetic mechanisms including post-translational modifications in histones are pivotal in regulating transcription. Here, we report that phosphorylation of serine 10 (S10) in histone 3 (H3) specifically occurs in a group of rat SSDHN following the activation of nociceptive primary sensory neurons by burn injury, capsaicin application or sustained electrical activation of nociceptive primary sensory nerve fibres. In contrast, brief thermal or mechanical nociceptive stimuli, which fail to induce tissue injury or inflammation, do not produce the same effect. Blocking N-methyl-D-aspartate receptors or activation of extracellular signal-regulated kinases 1 and 2, or blocking or deleting the mitogen- and stress-activated kinases 1 and 2 (MSK1/2), which phosphorylate S10 in H3, inhibit up-regulation in phosphorylated S10 in H3 (p-S10H3) as well as fos transcription, a down-stream effect of p-S10H3. Deleting MSK1/2 also inhibits the development of carrageenan-induced inflammatory heat hyperalgesia in mice. We propose that p-S10H3 is a novel marker for nociceptive processing in SSDHN with high relevance to transcriptional changes and the development of prolonged pain. PMID:28120884

  7. Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator

    Science.gov (United States)

    Jin, Rong; Yang, Guojun; Li, Guohong

    2010-01-01

    Blood-brain barrier (BBB) disruption, mediated through matrix metalloproteinases (MMPs) and other mechanisms, is a critical event during ischemic stroke. Tissue plasminogen activator (tPA) is the only FDA-approved thrombolytic therapy for acute ischemic stroke, but the efficacy and safety of its therapeutic application is limited by narrow treatment time windows and side effects. Thus, there is a pressing need to develop combinational therapy that could offset tPA side effects and improve efficacy in clinical practice. Recent experimental studies indicate that tPA has previously unidentified functions in the brain beyond its well established thrombolytic activity, which might contribute to tPA-related side effects through MMPs (mainly MMP-9) and several signaling pathways involved in LDL receptor-related protein (LRP), activated protein C (APC) and protease-activated receptor 1 (PAR-1), platelet-derived growth factor C (PDGF-C), and N-methyl-D-aspartate (NMDA) receptor. Therapeutic targeting of MMPs and/or tPA-related signaling pathways might offer promising new approaches to combination therapies for ischemic stroke. This review provides an overview of the relationship between structural components and function of the BBB/neurovascular unit with respect to ischemic stroke. We discuss how MMPs and tPA contribute to BBB disruption during ischemic stroke and highlight recent findings of molecular signaling pathways involved in neurotoxicity of tPA therapy. PMID:20302940

  8. Frequency-dependent associative long-term potentiation at the hippocampal mossy fiber-CA3 synapse.

    Science.gov (United States)

    Derrick, B E; Martinez, J L

    1994-10-25

    The mossy fiber-CA3 synapse displays an N-methyl-D-aspartate-receptor-independent mu-opioid-receptor-dependent form of long-term potentiation (LTP) that is thought not to display cooperativity or associativity with coactive afferents. However, because mossy fiber LTP requires repetitive synaptic activity for its induction, we reevaluated cooperativity and associativity at this synapse by using trains of mossy fiber stimulation. Moderate-, but not low-, intensity trains induced mossy fiber LTP, indicating cooperativity. Low-intensity mossy fiber trains that were normally ineffective in inducing LTP could induce mossy fiber LTP when delivered in conjunction with trains delivered to commissural-CA3 afferents. Associative mossy fiber LTP also could be induced with single mossy fiber pulses when delivered with commissural trains in the presence of a mu-opioid-receptor agonist. Our findings suggest a frequency-dependent variation of Hebbian associative LTP induction that is regulated by the release of endogenous opioid peptides.

  9. Pharmacological activation/inhibition of the cannabinoid system affects alcohol withdrawal-induced neuronal hypersensitivity to excitotoxic insults.

    Directory of Open Access Journals (Sweden)

    Marina Rubio

    Full Text Available Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716 during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal.

  10. Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.

    Directory of Open Access Journals (Sweden)

    Zhao Han

    Full Text Available Excessive activation of the N-methyl-D-aspartic acid (NMDA type glutamate receptors (NMDARs causes excitotoxicity, a process important in stroke-induced neuronal death. Drugs that inhibit NMDA receptor-mediated [Ca(2+]i influx are potential leads for development to treat excitotoxicity-induced brain damage. Our previous studies showed that 2-(2-benzofu-ranyl-2-imidazoline (2-BFI, an immidazoline receptor ligand, dose-dependently protects rodent brains from cerebral ischemia injury. However, the molecular mechanisms remain unclear. In this study, we found that 2-BFI transiently and reversibly inhibits NMDA, but not AMPA currents, in a dose-dependent manner in cultured rat cortical neurons. The mechanism of 2-BFI inhibition of NMDAR is through a noncompetitive fashion with a faster on (Kon = 2.19±0.33×10(-9 M(-1 sec(-1 and off rate (Koff = 0.67±0.02 sec(-1 than those of memantine, a gold standard for therapeutic inhibition NMDAR-induced excitotoxicity. 2-BFI also transiently and reversibly blocked NMDA receptor-mediated calcium entry to cultured neurons and provided long-term neuroprotection against NMDA toxicity in vitro. Collectively, these studies demonstrated a potential mechanism of 2-BFI-mediated neuroprotection and indicated that 2-BFI is an excellent candidate for repositioning as a drug for stroke treatment.

  11. Differential involvement of glutamatergic and catecholaminergic activity within the amygdala during taste aversion retrieval on memory expression and updating.

    Science.gov (United States)

    Daniel, Osorio-Gómez; Kioko, Guzmán-Ramos; Federico, Bermúdez-Rattoni

    2016-07-01

    During memory retrieval, consolidated memories are expressed and destabilized in order to maintain or update information through a memory reconsolidation process. Despite the key role of the amygdala during memory acquistion and consolidation, the participation of neurotransmitter signals in memory retrieval is poorly understood. Hence, we used conditioned taste aversion and in vivo microdialysis to evaluate changes in glutamate, norepinephrine and dopamine concentrations within the amygdala during memory retrieval. We observed that exposure to an aversive-conditioned stimulus induced an augmentation in glutamate, norepinephrine and dopamine levels within the amygdala, while exposure to a familiar and safe stimulus did not induce changes in these neurotransmitters levels. Also, we evaluated the amygdalar blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-d-aspartate (NMDA), β-adrenergic and dopamine D1 receptors in memory retrieval and updating. Results showed that during retrieval, behavioural expression was impaired by intra-amygdalar blockade of AMPA and β-adrenergic receptors, whereas NMDA, D1 and β-adrenergic receptors blockade hindered memory updating. In summary, during conditioned taste aversion retrieval there was an increase in the extracellular levels of glutamate, norepinephrine and dopamine within the amygdala, and their receptors activity were differentially involved in the behavioural expression and memory updating during retrieval.

  12. 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…

  13. 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…

  14. Long-term heavy ketamine use is associated with spatial memory impairment and altered hippocampal activation

    NARCIS (Netherlands)

    Morgan, C.J.A.; Dodds, C.M.; Furby, H.; Pepper, F.; Johnson, F.; Freeman, T.P.; Hughes, E.; Doeller, C.F.; King, J.; Howes, O.; Stone, J.M.

    2014-01-01

    Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to

  15. Long-term heavy ketamine use is associated with spatial memory impairment and altered hippocampal activation

    NARCIS (Netherlands)

    Morgan, C.J.A.; Dodds, C.M.; Furby, H.; Pepper, F.; Johnson, F.; Freeman, T.P.; Hughes, E.; Doeller, C.F.; King, J.; Howes, O.; Stone, J.M.

    2014-01-01

    Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to exam

  16. Holographic Quantitative Structure-Activity Relationships of Tryptamine Derivatives at NMDA, 5HT1A and 5HT2A Receptors

    Directory of Open Access Journals (Sweden)

    Peter Wolschann

    2013-07-01

    Full Text Available Tryptamine derivatives (Ts were found to inhibit the binding of [3H]MK-801, [3H]ketanserin and [3H]8-OH-DPAT to rat brain membranes. [3H]MK-801 labels the NMDA (N-methyl-D-aspartate receptor, a ionotropic glutamate receptor which controls synaptic plasticity and memory function in the brain, whereas [3H]ketanserin and [3H]8-OH-DPAT label 5HT2A and 5HT1A receptors, respectively. The inhibitory potencies of 64 Ts (as given by IC50 values were correlated with their structural properties by using the Holographic QSAR procedure (HQSAR. This method uses structural fragments and connectivities as descriptors which were encoded in a hologram thus avoiding the usual problems with conformation and alignment of the structures. Four correlation equations with high predictive ability and appropriate statistical test values could be established. The results are visualized by generation of maps reflecting the contribution of individual structural parts to the biological activities.

  17. Oxygen/Glucose Deprivation and Reperfusion Cause Modifications of Postsynaptic Morphology and Activity in the CA3 Area of Organotypic Hippocampal Slice Cultures.

    Science.gov (United States)

    Jung, Yeon Joo; Suh, Eun Cheng; Lee, Kyung Eun

    2012-12-01

    Brain ischemia leads to overstimulation of N-methyl-D-aspartate (NMDA) receptors, referred as excitotoxicity, which mediates neuronal cell death. However, less attention has been paid to changes in synaptic activity and morphology that could have an important impact on cell function and survival following ischemic insult. In this study, we investigated the effects of reperfusion after oxygen/glucose deprivation (OGD) not only upon neuronal cell death, but also on ultrastructural and biochemical characteristics of postsynaptic density (PSD) protein, in the stratum lucidum of the CA3 area in organotypic hippocampal slice cultures. After OGD/reperfusion, neurons were found to be damaged; the organelles such as mitochondria, endoplasmic reticulum, dendrites, and synaptic terminals were swollen; and the PSD became thicker and irregular. Ethanolic phosphotungstic acid staining showed that the density of PSD was significantly decreased, and the thickness and length of the PSD were significantly increased in the OGD/reperfusion group compared to the control. The levels of PSD proteins, including PSD-95, NMDA receptor 1, NMDA receptor 2B, and calcium/calmodulin-dependent protein kinase II, were significantly decreased following OGD/reperfusion. These results suggest that OGD/reperfusion induces significant modifications to PSDs in the CA3 area of organotypic hippocampal slice cultures, both morphologically and biochemically, and this may contribute to neuronal cell death and synaptic dysfunction after OGD/reperfusion.

  18. SUN11602 has basic fibroblast growth factor-like activity and attenuates neuronal damage and cognitive deficits in a rat model of Alzheimer's disease induced by amyloid β and excitatory amino acids.

    Science.gov (United States)

    Ogino, Ryoko; Murayama, Norihito; Noshita, Takafumi; Takemoto, Naohiro; Toba, Tetsuya; Oka, Tetsushi; Narii, Nobuhiro; Yoshida, Sayaka; Ueno, Nobuhiro; Inoue, Teruyoshi

    2014-10-17

    Basic fibroblast growth factor (bFGF/FGF-2) is known to possess neuroprotective and neurite outgrowth activity properties. In this study, the effects of a novel synthetic compound that mimics the neuroprotective properties of bFGF - SUN11602 - were examined in vitro and in vivo. SUN11602 promoted neurite outgrowth of primarily cultured rat hippocampal neurons. For the in vivo study, an Alzheimer's disease (AD) model with severe damage to the hippocampal tissue was constructed by injecting the hippocampi of rats with aggregated Aβ1-40, followed 48 h later by an injection of ibotenate [an agonist for N-methyl-d-aspartate (NMDA) receptor]. Oral administration of SUN11602 at the midpoint of Aβ1-40 and ibotenate injections attenuated short-term memory impairment in the Y-maze test, as well as spatial learning deficits in the water maze task. In addition, the SUN11602 treatment inhibited the increase of peripheral-type benzodiazepine-binding sites (PTBBS), which are a marker for gliosis. A negative correlation was found between PTBBS numbers and learning capacity in the water maze task. These results suggest that SUN111602 improved memory and learning deficits in the hippocampally lesioned rats by preventing neuronal death and/or promotion of neurite outgrowth. Taken together, these results indicate that SUN11602, a bFGF-like compound with neuroprotective and neurite outgrowth activity, may be beneficial for the treatment of progressive neurodegenerative diseases such as AD.

  19. 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-isox...

  20. A non-opioid pathway for dynorphin-caused spinal cord injury in rats

    Institute of Scientific and Technical Information of China (English)

    Yu Chen; Liangbi Xiang; Jun Liu; Dapeng Zhou; Hailong Yu; Qi Wang; Wenfeng Han; Mingming Guo

    2012-01-01

    Intrathecal injection of dynorphin into rats via subarachnoid catheter induces damage to spinal cord tissue and motor function. Injection of the kappa opioid receptor antagonist nor-binaltorphine, or the excitatory amino acid N-methyl-D-aspartate receptor antagonist MK-801 into rats alleviated the pathological changes of dynorphin-caused spinal cord tissue injury and reduced the acid phosphatase activity in the spinal cord. The experimental findings indicate that there are opioid and non-opioid pathways for dynorphin-induced spinal cord injury, and that the non-opioid receptor pathway may be mediated by the excitatory amino acid N-methyl-D-aspartate receptor.

  1. Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation.

    Science.gov (United States)

    Lambe, E K; Aghajanian, G K

    2007-03-30

    The fine-tuning of network activity provides a modulating influence on how information is processed and interpreted in the brain. Here, we use brain slices of rat prefrontal cortex to study how recurrent network activity is affected by neuromodulators known to alter normal cortical function. We previously determined that glutamate spillover and stimulation of extrasynaptic N-methyl-d-aspartic acid (NMDA) receptors are required to support hallucinogen-induced cortical network activity. Since microdialysis studies suggest that psychedelic hallucinogens and dopamine D1/D5 receptor agonists have opposite effects on extracellular glutamate in prefrontal cortex, we hypothesized that these two families of psychoactive drugs would have opposite effects on cortical network activity. We found that network activity can be enhanced by 2,5-dimethoxy-4-iodoamphetamine (DOI) (a psychedelic hallucinogen that is a partial agonist of 5-HT(2A/2C) receptors) and suppressed by the selective D1/D5 agonist SKF 38393. This suppression could be mimicked by direct activation of adenylyl cyclase with forskolin or by addition of a cAMP analog. These findings are consistent with previous work showing that activation of adenylyl cyclase can upregulate neuronal glutamate transporters, thereby decreasing synaptic spillover of glutamate. Consistent with this hypothesis, a low concentration of the glutamate transporter inhibitor threo-beta-benzoylaspartic acid (TBOA) restored electrically-evoked recurrent activity in the presence of a selective D1/D5 agonist, whereas recurrent activity in the presence of a low level of the GABA(A) antagonist bicuculline was not resistant to suppression by the D1/D5 agonist. The tempering of network UP states by D1/D5 receptor activation may have implications for the proposed use of D1/D5 agonists in the treatment of schizophrenia.

  2. Opposing action of conantokin-G on synaptically and extrasynaptically-activated NMDA receptors.

    Science.gov (United States)

    Balsara, Rashna; Li, Neill; Weber-Adrian, Danielle; Huang, Louxiu; Castellino, Francis J

    2012-06-01

    Synaptic and extrasynaptic activation of the N-methyl-D-aspartate receptor (NMDAR) has distinct consequences on cell signaling and neuronal survival. Since conantokin (con)-G antagonism is NR2B-selective, which is the key subunit involved in extrasynaptic activation of the receptor, its ability to specifically elicit distinct signaling outcomes in neurons with synaptically or extrasynaptically-activated NMDARs was evaluated. Inhibition of Ca(2+) influx through extrasynaptic NMDAR ion channels was neuroprotective, as it effectively enhanced levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), activated cAMP response element binding protein (CREB), enhanced mitochondrial viability, and attenuated the actin disorganization observed by extrasynaptic activation of NMDARs. Conversely, the pro-signaling pathways stimulated by synaptically-induced Ca(2+) influx were abolished by con-G. Furthermore, subunit non-selective con-T was unable to successfully redress the impairments in neurons caused by extrasynaptically-activated NMDARs, thus indicating that NR2B-specific antagonists are beneficial for neuron survival. Neurons ablated for the NR2B subunit showed weak synaptic Ca(2+) influx, reduced sensitivity to MK-801 blockage, and diminished extrasynaptic current compared to WT and NR2A(-/-) neurons. This indicates that the NR2B subunit is an integral component of both synaptic and extrasynaptic NMDAR channels. Altogether, these data suggest that con-G specifically targets the NR2B subunit in the synaptic and extrasynaptic locations, resulting in the opposing action of con-G on differentially activated pools of NMDARs.

  3. Soybean-derived Bowman-Birk inhibitor inhibits neurotoxicity of LPS-activated macrophages

    Directory of Open Access Journals (Sweden)

    Persidsky Yuri

    2011-02-01

    Full Text Available Abstract Background Lipopolysaccharide (LPS, the major component of the outer membrane of gram-negative bacteria, can activate immune cells including macrophages. Activation of macrophages in the central nervous system (CNS contributes to neuronal injury. Bowman-Birk inhibitor (BBI, a soybean-derived protease inhibitor, has anti-inflammatory properties. In this study, we examined whether BBI has the ability to inhibit LPS-mediated macrophage activation, reducing the release of pro-inflammatory cytokines and subsequent neurotoxicity in primary cortical neural cultures. Methods Mixed cortical neural cultures from rat were used as target cells for testing neurotoxicity induced by LPS-treated macrophage supernatant. Neuronal survival was measured using a cell-based ELISA method for expression of the neuronal marker MAP-2. Intracellular reactive oxygen species (ROS production in macrophages was measured via 2', 7'-dichlorofluorescin diacetate (DCFH2DA oxidation. Cytokine expression was determined by quantitative real-time PCR. Results LPS treatment of macrophages induced expression of proinflammatory cytokines (IL-1β, IL-6 and TNF-α and of ROS. In contrast, BBI pretreatment (1-100 μg/ml of macrophages significantly inhibited LPS-mediated induction of these cytokines and ROS. Further, supernatant from BBI-pretreated and LPS-activated macrophage cultures was found to be less cytotoxic to neurons than that from non-BBI-pretreated and LPS-activated macrophage cultures. BBI, when directly added to the neuronal cultures (1-100 μg/ml, had no protective effect on neurons with or without LPS-activated macrophage supernatant treatment. In addition, BBI (100 μg/ml had no effect on N-methyl-D-aspartic acid (NMDA-mediated neurotoxicity. Conclusions These findings demonstrate that BBI, through its anti-inflammatory properties, protects neurons from neurotoxicity mediated by activated macrophages.

  4. Long Term Depression in the CA1 field is associated with a transient decrease in Pre-and Post-synaptic PKC substrate phosphorylation

    NARCIS (Netherlands)

    Gispen, W.H.; Ramakers, G.J.A.; Heinen, K.; Graan, P.N.E. de

    2000-01-01

    Induction of homosynaptic long term depression (LTD) in the CA1 field of the hippocampus is thought to require activation of N-methyl-D-aspartate receptors, an elevation of postsynaptic Ca2+ levels, and a subsequent increase in phosphatase activity. To investigate the spatial and temporal changes in

  5. Matrix Metalloprotease 3 Activity Supports Hippocampal EPSP-to-Spike Plasticity Following Patterned Neuronal Activity via the Regulation of NMDAR Function and Calcium Flux.

    Science.gov (United States)

    Brzdąk, Patrycja; Włodarczyk, Jakub; Mozrzymas, Jerzy W; Wójtowicz, Tomasz

    2017-01-01

    Matrix metalloproteases (MMPs) comprise a family of endopeptidases that are involved in remodeling the extracellular matrix and play a critical role in learning and memory. At least 24 different MMP subtypes have been identified in the human brain, but less is known about the subtype-specific actions of MMP on neuronal plasticity. The long-term potentiation (LTP) of excitatory synaptic transmission and scaling of dendritic and somatic neuronal excitability are considered substrates of memory storage. We previously found that MMP-3 and MMP-2/9 may be differentially involved in shaping the induction and expression of excitatory postsynaptic potential (EPSP)-to-spike (E-S) potentiation in hippocampal brain slices. MMP-3 and MMP-2/9 proteolysis was previously shown to affect the integrity or mobility of synaptic N-methyl-D-aspartate receptors (NMDARs) in vitro. However, the functional outcome of such MMP-NMDAR interactions remains largely unknown. The present study investigated the role of these MMP subtypes in E-S plasticity and NMDAR function in mouse hippocampal acute brain slices. The temporal requirement for MMP-3/NMDAR activity in E-S potentiation within the CA1 field largely overlapped, and MMP-3 but not MMP-2/9 activity was crucial for the gain-of-function of NMDARs following LTP induction. Functional changes in E-S plasticity following MMP-3 inhibition largely correlated with the expression of cFos protein, a marker of activity-related gene transcription. Recombinant MMP-3 promoted a gain in NMDAR-mediated field potentials and somatodendritic Ca(2+) waves. These results suggest that long-term hippocampal E-S potentiation requires transient MMP-3 activity that promotes NMDAR-mediated postsynaptic Ca(2+) entry that is vital for the activation of downstream signaling cascades and gene transcription.

  6. Growth hormone rescues hippocampal synaptic function after sleep deprivation

    OpenAIRE

    Kim, EunYoung; Grover, Lawrence M; Bertolotti, Don; Green, Todd L.

    2010-01-01

    Sleep is required for, and sleep loss impairs, normal hippocampal synaptic N-methyl-d-aspartate (NMDA) glutamate receptor function and expression, hippocampal NMDA receptor-dependent synaptic plasticity, and hippocampal-dependent memory function. Although sleep is essential, the signals linking sleep to hippocampal function are not known. One potential signal is growth hormone. Growth hormone is released during sleep, and its release is suppressed during sleep deprivation. If growth hormone l...

  7. Local NMDA receptor blockade attenuates chronic tinnitus and associated brain activity in an animal model.

    Directory of Open Access Journals (Sweden)

    Thomas J Brozoski

    Full Text Available Chronic tinnitus has no broadly effective treatment. Identification of specific markers for tinnitus should facilitate the development of effective therapeutics. Recently it was shown that glutamatergic blockade in the cerebellar paraflocculus, using an antagonist cocktail was successful in reducing chronic tinnitus. The present experiment examined the effect of selective N-methyl d-aspartate (NMDA receptor blockade on tinnitus and associated spontaneous brain activity in a rat model. The NMDA antagonist, D(--2-amino-5-phosphonopentanoic acid (D-AP5 (0.5 mM, was continuously infused for 2 weeks directly to the ipsilateral paraflocculus of rats with tinnitus induced months prior by unilateral noise exposure. Treated rats were compared to untreated normal controls without tinnitus, and to untreated positive controls with tinnitus. D-AP5 significantly decreased tinnitus within three days of beginning treatment, and continued to significantly reduce tinnitus throughout the course of treatment and for 23 days thereafter, at which time testing was halted. At the conclusion of psychophysical testing, neural activity was assessed using manganese enhanced magnetic resonance imaging (MEMRI. In agreement with previous research, untreated animals with chronic tinnitus showed significantly elevated bilateral activity in their paraflocculus and brainstem cochlear nuclei, but not in mid or forebrain structures. In contrast, D-AP5-treated-tinnitus animals showed significantly less bilateral parafloccular and dorsal cochlear nucleus activity, as well as significantly less contralateral ventral cochlear nucleus activity. It was concluded that NMDA-mediated glutamatergic transmission in the paraflocculus appears to be a necessary component of chronic noise-induced tinnitus in a rat model. Additionally, it was confirmed that in this model, elevated spontaneous activity in the cerebellar paraflocculus and auditory brainstem is associated with tinnitus.

  8. Daidzein stimulates osteogenesis facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via estrogen receptor-dependent MEK/ERK and PI3K/Akt activation.

    Science.gov (United States)

    Jin, Xin; Sun, Jing; Yu, Bo; Wang, Yue; Sun, Wei Jia; Yang, Jing; Huang, Su Hui; Xie, Wen Li

    2017-06-01

    Daidzein, a natural soy isoflavone, has a structure similar to estradiol and exhibiting bone-sparing effects against osteoporosis. However, the molecular mechanisms of osteogenesis remain unclear. We hypothesized that daidzein stimulates osteogenesis through estrogen receptor (ER)-dependent signal pathways. To test this hypothesis, we investigated the effects of daidzein compared with 17β-estradiol on proliferation, differentiation, and cisplatin-induced apoptosis in human osteoblast-like MG-63 cells containing 2 ER isoforms. The results showed that daidzein stimulated cell proliferation by altering cell cycle distribution, promoted cell differentiation by increasing the alkaline phosphatase activity and collagen content, and reduced cell apoptosis associated by up-regulating the expression of Bcl-xL. The above actions of daidzein were prevented by cotreatment with the ER antagonist ICI 182780. Using small interfering RNA technology, we further demonstrated that the effects of daidzein on alkaline phosphatase activity, collagen content, and cell apoptosis are mediated by both ERα and ERβ, whereas the effects on cell proliferation are primarily mediated by ERα. However, the effects of 17β-estradiol on osteoblastic proliferation and survival are mediated by both ER isotypes, and the effects on osteoblastic differentiation are primarily mediated by ERα. The use of specific inhibitors indicated that activation of the mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) and phosphoinositide 3-kinase/protein kinase B or PKB (PI3K/Akt) signaling pathway at least partially accounts for these effects of daidzein. Taken together, the results indicate that daidzein stimulates osteogenesis through facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via activation of MEK/ERK and PI3K/Akt in an ER-dependent manner. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Receptor-Dependent Coronavirus Infection of Dendritic Cells

    Science.gov (United States)

    Turner, Brian C.; Hemmila, Erin M.; Beauchemin, Nicole; Holmes, Kathryn V.

    2004-01-01

    In several mammalian species, including humans, coronavirus infection can modulate the host immune response. We show a potential role of dendritic cells (DC) in murine coronavirus-induced immune modulation and pathogenesis by demonstrating that the JAW SII DC line and primary DC from BALB/c mice and p/p mice with reduced expression of the murine coronavirus receptor, murine CEACAM1a, are susceptible to murine coronavirus infection by a receptor-dependent pathway. PMID:15113927

  10. Synaptic activity protects neurons against calcium-mediated oxidation and contraction of mitochondria during excitotoxicity.

    Science.gov (United States)

    Depp, Constanze; Bas-Orth, Carlos; Schroeder, Lisa; Hellwig, Andrea; Bading, Hilmar

    2017-10-07

    Excitotoxicity triggered by extrasynaptic N-methyl-D-aspartate-type glutamate receptors (NMDARs) has been implicated in many neurodegenerative conditions, including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke. Mitochondrial calcium overload leading to mitochondrial dysfunction represents an early event in excitotoxicity. Neurons are rendered resistant to excitotoxicity by previous periods of synaptic activity that activates a nuclear calcium-driven neuroprotective gene program. This process, termed acquired neuroprotection, involves transcriptional repression of the mitochondrial calcium uniporter leading to a reduction in excitotoxcity-associated mitochondrial calcium load. As mitochondrial calcium and the production of reactive oxygen species (ROS) may be linked, we monitored excitotoxicity-associated changes in the mitochondrial redox status using the ratiometric glutathione redox potential indicator, Grx1-roGFP2, targeted to the mitochondrial matrix. Aim of this study was to investigate if suppression of oxidative stress underlies mitoprotection afforded by synaptic activity. We found that synaptic activity protects primary rat hippocampal neurons against acute excitotoxicity-induced mitochondrial oxidative stress and mitochondrial contraction associated with it. Downregulation of the mitochondrial uniporter by genetic means mimics the protective effect of synaptic activity on mitochondrial redox status. These findings indicate that oxidative stress acts downstream of mitochondrial calcium overload in excitotoxicity. Innovation and conclusion: We established mito-Grx1-roGFP2 as a reliable and sensitive tool to monitor rapid redox changes in mitochondria during excitotoxicity. Our results highlight the importance of developing means of blocking mitochondrial calcium overload for therapeutic targeting of oxidative stress and mitochondrial dysfunction in neurodegenerative diseases.

  11. S-ketamine modulates hyperalgesia in patients with chronic pancreatitis pain

    NARCIS (Netherlands)

    Bouwense, S.A.W.; Buscher, H.C.J.L.; Goor, H. van; Wilder-Smith, O.H.G.

    2011-01-01

    BACKGROUND AND OBJECTIVES: Upper abdominal pain is a dominant feature of chronic pancreatitis. A key phenomenon in this context is hyperalgesia, typically associated with N-methyl-d-aspartate receptor activation. This exploratory study evaluates acute effects of S-ketamine, a noncompetitive N-methyl

  12. SRC Inhibition Reduces NR2B Surface Expression and Synaptic Plasticity in the Amygdala

    Science.gov (United States)

    Sinai, Laleh; Duffy, Steven; Roder, John C.

    2010-01-01

    The Src protein tyrosine kinase plays a central role in the regulation of N-methyl-d-aspartate receptor (NMDAR) activity by regulating NMDAR subunit 2B (NR2B) surface expression. In the amygdala, NMDA-dependent synaptic plasticity resulting from convergent somatosensory and auditory inputs contributes to emotional memory; however, the role of Src…

  13. Genetic Inactivation of D-Amino Acid Oxidase Enhances Extinction and Reversal Learning in Mice

    Science.gov (United States)

    Labrie, Viviane; Duffy, Steven; Wang, Wei; Barger, Steven W.; Baker, Glen B.; Roder, John C.

    2009-01-01

    Activation of the N-methyl-d-aspartate receptor (NMDAR) glycine site has been shown to accelerate adaptive forms of learning that may benefit psychopathologies involving cognitive and perseverative disturbances. In this study, the effects of increasing the brain levels of the endogenous NMDAR glycine site agonist D-serine, through the genetic…

  14. NR2A- and NR2B-Containing NMDA Receptors in the Prelimbic Medial Prefrontal Cortex Differentially Mediate Trace, Delay, and Contextual Fear Conditioning

    Science.gov (United States)

    Gilmartin, Marieke R.; Kwapis, Janine L.; Helmstetter, Fred J.

    2013-01-01

    Activation of "N"-methyl-D-aspartate receptors (NMDAR) in the prelimbic medial prefrontal cortex (PL mPFC) is necessary for the acquisition of both trace and contextual fear memories, but it is not known how specific NR2 subunits support each association. The NR2B subunit confers unique properties to the NMDAR and may differentially…

  15. Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells

    NARCIS (Netherlands)

    Bozic, M.; de Rooij, J.; Parisi, E.; Ortega, M.R.; Fernandez, E.; Valdivielso, J.M.

    2011-01-01

    Epithelial-mesenchymal transition (EMT) contributes to the progression of renal tubulointerstitial fibrosis. The N-methyl-d-aspartate receptor (NMDAR), which is present in proximal tubular epithelium, is a glutamate receptor that acts as a calcium channel. Activation of NMDAR induces actin rearrange

  16. NR2A- and NR2B-Containing NMDA Receptors in the Prelimbic Medial Prefrontal Cortex Differentially Mediate Trace, Delay, and Contextual Fear Conditioning

    Science.gov (United States)

    Gilmartin, Marieke R.; Kwapis, Janine L.; Helmstetter, Fred J.

    2013-01-01

    Activation of "N"-methyl-D-aspartate receptors (NMDAR) in the prelimbic medial prefrontal cortex (PL mPFC) is necessary for the acquisition of both trace and contextual fear memories, but it is not known how specific NR2 subunits support each association. The NR2B subunit confers unique properties to the NMDAR and may differentially…

  17. Feedback inactivation of D-serine synthesis by NMDA receptor-elicited translocation of serine racemase to the membrane

    DEFF Research Database (Denmark)

    Balan, Livia; Foltyn, Veronika N; Zehl, Martin;

    2009-01-01

    D-serine is a physiological coagonist of N-methyl D-aspartate receptors (NMDARs) that plays a major role in several NMDAR-dependent events. In this study we investigate mechanisms regulating D-serine production by the enzyme serine racemase (SR). We now report that NMDAR activation promotes trans...

  18. The combination of glutamate receptor antagonist MK-801 with tamoxifen and its active metabolites potentiates their antiproliferative activity in mouse melanoma K1735-M2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Mariana P.C. [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal); Nunes-Correia, Isabel [Center for Neuroscience and Cell Biology, Flow Cytometry Unit, University of Coimbra, 3000-354 Coimbra (Portugal); Santos, Armanda E., E-mail: aesantos@ci.uc.pt [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal); Custódio, José B.A. [Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra (Portugal)

    2014-02-15

    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.

  19. Histamine H{sub 3} receptor activation selectively inhibits dopamine D{sub 1} receptor-dependent [{sup 3}H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata

    Energy Technology Data Exchange (ETDEWEB)

    Aceves, J. [Departmento de Fisiologia, Biofisica y Neurociencias, Centro de Investigacion y de Estudios Avanzados del IPN, Apartado postal 14-740, 07000 Mexico (Mexico); Young, J.M. [Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge (United Kingdom); Arias-Montano, J.A.; Floran, B.; Garcia, M. [Departmento de Fisiologia, Biofisica y Neurociencias, Centro de Investigacion y de Estudios Avanzados del IPN, Apartado postal 14-740, 07000 Mexico (Mexico)

    1997-06-25

    The release of [{sup 3}H]GABA from slices of rat substantia nigra pars reticulata induced by increasing extracellular K{sup +} from 6 to 15 mM in the presence of 10 {mu}M sulpiride was inhibited by 73{+-}3% by 1 {mu}M SCH 23390, consistent with a large component of release dependent upon D{sub 1} receptor activation. The histamine H{sub 3} receptor-selective agonist immepip (1 {mu}M) and the non-selective agonist histamine (100 {mu}M) inhibited [{sup 3}H]GABA release by 78{+-}2 and 80{+-}2%, respectively. The inhibition by both agonists was reversed by the H{sub 3} receptor antagonist thioperamide (1 {mu}M). However, in the presence of 1 {mu}M SCH 23390 depolarization-induced release of [{sup 3}H]GABA was not significantly decreased by 1 {mu}M immepip. In rats depleted of dopamine by pretreatment with reserpine, immepip no longer inhibited control release of [{sup 3}H]GABA, but in the presence of 1 {mu}M SKF 38393, which produced a 7{+-}1-fold stimulation of release, immepip reduced the release to a level not statistically different from that in the presence of immepip alone. Immepip (1 {mu}M) also inhibited the depolarization-induced release of [{sup 3}H]dopamine from substantia nigra pars reticulata slices, by 38{+-}3%.The evidence is consistent with the proposition that activation of histamine H{sub 3} receptors leads to the selective inhibition of the component of depolarization-induced [{sup 3}H]GABA release in substantia nigra pars reticulata slices which is dependent upon D{sub 1} receptor activation. This appears to be largely an action at the terminals of the striatonigral GABA projection neurons, which may be enhanced by a partial inhibition of dendritic [{sup 3}H]dopamine release. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  20. Activation of JNK pathway in spinal astrocytes contributes to acute ultra-low-dose morphine thermal hyperalgesia.

    Science.gov (United States)

    Sanna, Maria Domenica; Ghelardini, Carla; Galeotti, Nicoletta

    2015-07-01

    Accumulating evidence suggests that opioid analgesics can lead to paradoxical sensitization to pain when delivered in different administration patterns. Although opioid tolerance-induced hyperalgesia is largely studied, little is known about the mechanisms underlying acute ultra-low-dose morphine hyperalgesia. Activation of spinal glial cells is reported to regulate pain hypersensitivity. To elucidate the mechanism involved in acute ultra-low-dose morphine hyperalgesia, we tested whether an opioid agonist promoted the activation of spinal astrocytes and microglia and investigated the cellular pathways involved. Ultra-low-dose morphine activated spinal astrocytes with no effect on microglia. The astrocyte activation was selectively prevented by the opioid antagonist naloxone, the μ-opioid receptor (MOR) silencing and the JNK inhibitor SP600125. Morphine elevated spinal JNK1, JNK2, and c-Jun phosphorylation. Conversely, phosphorylation of cAMP response element-binding protein (CREB) and signal transducer and activator of transcription-1 (STAT-1) was not elevated, and nuclear factor kappa B (NF-κB) levels remained unmodified. Administration of SP600125 and the N-methyl-D-aspartate (NMDA) antagonist MK801 prevented morphine hyperalgesia. Ultra-low-dose morphine increased protein kinase C (PKC) γ phosphorylation. Pretreatment with a PKC inhibitor prevented morphine hyperalgesia and JNK and c-Jun overphosphorylation, indicating PKC is a JNK upstream modulator and illustrating the presence of a pathway involving PKC, NMDA, and JNK activated by morphine. Immunofluorescence experiments indicated the neuronal localization of spinal MOR. However, JNK was not detected in MOR-expressing cells, showing the presence of a neuron-astrocyte signaling pathway. These results illustrate the selective activation of an astrocyte JNK pathway after the stimulation of neuronal MOR, which contributes to ultra-low-dose morphine hyperalgesia.

  1. S-Nitrosylation of proline-rich tyrosine kinase 2 involves its activation induced by oxygen-glucose deprivation.

    Science.gov (United States)

    Yan, Xian-Liang; Liu, Dong-Hai; Zhang, Gong-Liang; Hu, Shu-Qun; Chen, Yu-Guo; Xu, Tie

    2015-06-15

    Previous studies have demonstrated that activation of proline-rich tyrosine kinase 2 (PYK2) in cerebral ischemia is involved in the modulation of N-methyl-d-aspartate-type (NMDA) glutamate receptor activity and Ca(2+) dynamics, resulting in ischemic neuron death ultimately. A number of reports indicate that PYK2 is a redox sensitive kinase that must be activated by an estrogen-induced reactive oxygen species (ROS). However, the mechanism of PYK2 activation remains incompletely illustrated. Accumulating attention is focused on nitric oxide (NO, a free radical) which plays a critical role in cellular signal transduction through stimulus-coupled S-nitrosylation of cysteine residues. Here we reported that PYK2 over-expressed in human embryonic kidney (HEK293) cells was S-nitrosylated (forming SNO-PYK2) by reacting with GSNO, an exogenous NO donor, at one critical cysteine residue (Cys534) with a biotin switch assay. Moreover, our results showed that S-nitrosylation and phosphorylation of PYK2 over-expressed in SH-SY5Y cells was significantly increased after oxygen-glucose deprivation (OGD). We further investigated whether the activation (phosphorylation) of PYK2 was associated with S-nitrosylation following SH-SY5Y cells OGD. Our results showed that the cysteine534 residue (site of S-nitrosylation) mutant PYK2 over-expressed in SH-SY5Y cells diminished S-nitrosylation of PYK2 and inhibited its phosphorylation induced by OGD. In addition, overexpression of the mutant PYK2 protein could prevent nuclear accumulation and abrogate neuronal cell death compared to wild type PYK2 in SH-SY5Y cells induced by OGD. These data suggest that the activation of PYK2 following OGD may be modulated by S-nitrosylation, which provides a new avenue for stroke therapy by targeting the post-translational modification machinery.

  2. Depletion of arginine by recombinant arginine deiminase induces nNOS-activated neurotoxicity in neuroblastoma cells.

    Science.gov (United States)

    Lin, Shan-Erh; Wu, Fe-Lin Lin; Wei, Ming-Feng; Shen, Li-Jiuan

    2014-01-01

    The abnormal regulation of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) is associated with neurodegenerative disorders. Recombinant arginine deiminase (rADI) is a selective NO modulator of iNOS and eNOS in endothelial cells, and it also exhibits neuroprotective activity in an iNOS-induced neuron-microglia coculture system. However, the effect of rADI on nNOS remains unknown. Addressing this issue is important for evaluating the potential application of rADI in neurodegenerative diseases. SH-SY5Y cells were treated with N-methyl-D-aspartic acid (NMDA) to activate nNOS. NMDA increased NO production by 39.7 ± 3.9% via nNOS under arginine-containing conditions, but there was no significant increase in both arginine-free and rADI pretreated arginine-containing (citrulline) buffer. Subsequently, neither NMDA nor rADI alone caused cytotoxicity, whereas cotreatment with NMDA and rADI resulted in dissipation of the cell mitochondrial membrane potential and decreased cell viability. The mechanism of rADI cytotoxicity in the presence of NMDA is caused by the inhibition of NO production via nNOS mediated by the NMDA receptor, which was abolished when extracellular arginine was absent, even in the presence of citrulline. rADI not only reduced NO production but also caused cellular toxicity in nNOS-activated SH-SY5Y cells, suggesting a dual role for rADI in NOS-mediated neurotoxicity.

  3. Depletion of Arginine by Recombinant Arginine Deiminase Induces nNOS-Activated Neurotoxicity in Neuroblastoma Cells

    Directory of Open Access Journals (Sweden)

    Shan-Erh Lin

    2014-01-01

    Full Text Available The abnormal regulation of inducible nitric oxide synthase (iNOS and neuronal nitric oxide synthase (nNOS is associated with neurodegenerative disorders. Recombinant arginine deiminase (rADI is a selective NO modulator of iNOS and eNOS in endothelial cells, and it also exhibits neuroprotective activity in an iNOS-induced neuron-microglia coculture system. However, the effect of rADI on nNOS remains unknown. Addressing this issue is important for evaluating the potential application of rADI in neurodegenerative diseases. SH-SY5Y cells were treated with N-methyl-D-aspartic acid (NMDA to activate nNOS. NMDA increased NO production by 39.7 ± 3.9% via nNOS under arginine-containing conditions, but there was no significant increase in both arginine-free and rADI pretreated arginine-containing (citrulline buffer. Subsequently, neither NMDA nor rADI alone caused cytotoxicity, whereas cotreatment with NMDA and rADI resulted in dissipation of the cell mitochondrial membrane potential and decreased cell viability. The mechanism of rADI cytotoxicity in the presence of NMDA is caused by the inhibition of NO production via nNOS mediated by the NMDA receptor, which was abolished when extracellular arginine was absent, even in the presence of citrulline. rADI not only reduced NO production but also caused cellular toxicity in nNOS-activated SH-SY5Y cells, suggesting a dual role for rADI in NOS-mediated neurotoxicity.

  4. mGluR5 positive modulators both potentiate activation and restore inhibition in NMDA receptors by PKC dependent pathway

    Directory of Open Access Journals (Sweden)

    Liao Pei-Fei

    2011-02-01

    Full Text Available Abstract Background In order to understand the interaction between the metabotropic glutamate subtype 5 (mGluR5 and N-methyl-D-aspartate (NMDA receptors, the influence of mGluR5 positive modulators in the inhibition of NMDA receptors by the noncompetitive antagonist ketamine, the competitive antagonist D-APV and the selective NR2B inhibitor ifenprodil was investigated. Methods This study used the multi-electrode dish (MED system to observe field potentials in hippocampal slices of mice. Results Data showed that the mGluR5 agonist (RS-2-chloro-5-hydroxyphenylglycine (CHPG, as well as the positive allosteric modulators 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl benzamide (CDPPB and 3,3'-difluorobenzaldazine (DFB alone did not alter the basal field potentials, but enhanced the amplitude of field potentials induced by NMDA. The inhibitory action of ketamine on NMDA-induced response was reversed by CHPG, DFB, and CDPPB, whereas the blockade of NMDA receptor by D-APV was restored by CHPG and CDPPB, but not by DFB. Alternatively, activation of NMDA receptors prior to the application of mGluR5 modulators, CHPG was able to enhance NMDA-induced field potentials and reverse the suppressive effect of ketamine and D-APV, but not ifenprodil. In addition, chelerythrine chloride (CTC, a protein kinase C (PKC inhibitor, blocked the regulation of mGluR5 positive modulators in enhancing NMDA receptor activation and recovering NMDA receptor inhibition. The PKC activator (PMA mimicked the effects of mGluR5 positive modulators on enhancing NMDA receptor activation and reversing NMDA antagonist-evoked NMDA receptor suppression. Conclusion Our results demonstrate that the PKC-dependent pathway may be involved in the positive modulation of mGluR5 resulting in potentiating NMDA receptor activation and reversing NMDA receptor suppression induced by NMDA antagonists.

  5. BHT blocks NF-kappaB activation and ethanol-induced brain damage.

    Science.gov (United States)

    Crews, Fulton; Nixon, Kimberly; Kim, Daniel; Joseph, James; Shukitt-Hale, Barbara; Qin, Liya; Zou, Jian

    2006-11-01

    Binge ethanol administration causes corticolimbic brain damage that models alcoholic neurodegeneration. The mechanism of binge ethanol-induced degeneration is unknown, but is not simple glutamate-N-methyl-D-aspartate (NMDA) excitotoxicity. To test the hypothesis that oxidative stress and inflammation are mechanisms of binge ethanol-induced brain damage, we administered 4 antioxidants, e.g., butylated hydroxytoluene (BHT), ebselen (Eb), vitamin E (VE), and blueberry (BB) extract, during binge ethanol treatment and assessed various measures of neurodegeneration. Adult Sprague-Dawley rats were treated with intragastric ethanol 3 times per day (8-12 g/kg/d) alone or in combination with antioxidants or isocaloric diet for 4 days. Animals were killed, and brains were perfused and extracted for histochemical silver stain determination of brain damage, markers of neurogenesis, or other immunohistochemistry. Some animals were used for determination of nuclear factor kappa B (NF-kappaB)-DNA binding by electrophoretic mobility shift assay (EMSA) or for reverse transcription-polymerase chain reaction (RT-PCR) of cyclooxygenase 2 (COX2). Binge ethanol induced corticolimbic brain damage and reduced neurogenesis. Treatment with BHT reversed binge induced brain damage and blocked ethanol inhibition of neurogenesis in all regions studied. Interestingly, the other antioxidants studied, e.g., Eb, VE, and BB, did not protect against binge-induced brain damage. Binge ethanol treatment also caused microglia activation, increased NF-kappaB-DNA binding and COX2 expression. Butylated hydroxytoluene reduced binge-induced NF-kappaB-DNA binding and COX2 expression. Binge-induced brain damage and activation of NF-kappaB-DNA binding are blocked by BHT. These studies support a neuroinflammatory mechanism of binge ethanol-induced brain damage.

  6. Nerve growth factor alters the sensitivity of rat masseter muscle mechanoreceptors to NMDA receptor activation.

    Science.gov (United States)

    Wong, Hayes; Dong, Xu-Dong; Cairns, Brian E

    2014-11-01

    Intramuscular injection of nerve growth factor (NGF) into rat masseter muscle induces a local mechanical sensitization that is greater in female than in male rats. The duration of NGF-induced sensitization in male and female rats was associated with an increase in peripheral N-methyl-d-aspartate (NMDA) receptor expression by masseter muscle afferent fibers that began 3 days postinjection. Here, we investigated the functional consequences of increased NMDA expression on the response properties of masseter muscle mechanoreceptors. In vivo extracellular single-unit electrophysiological recordings of trigeminal ganglion neurons innervating the masseter muscle were performed in anesthetized rats 3 days after NGF injection (25 μg/ml, 10 μl) into the masseter muscle. Mechanical activation threshold was assessed before and after intramuscular injection of NMDA. NMDA injection induced mechanical sensitization in both sexes that was increased significantly following NGF injection in the male rats but not in the female rats. However, in female but not male rats, further examination found that preadministration of NGF induced a greater sensitization in slow Aδ-fibers (2-7 m/s) than fast Aδ-fibers (7-12 m/s). This suggests that preadministration of NGF had a different effect on slowly conducting mechanoreceptors in the female rats compared with the male rats. Although previous studies have found an association between estrogenic tone and NMDA activity, no correlation was observed between NMDA-evoked mechanical sensitization and plasma estrogen level. This study suggests NGF alters NMDA-induced mechanical sensitization in the peripheral endings of masseter mechanoreceptors in a sexually dimorphic manner.

  7. Neuroprotective activity of stiripentol with a possible involvement of voltage-dependent calcium and sodium channels.

    Science.gov (United States)

    Verleye, Marc; Buttigieg, Dorothée; Steinschneider, Rémy

    2016-02-01

    A growing body of data has shown that recurrent epileptic seizures may be caused by an excessive release of the excitatory neurotransmitter glutamate in the brain. Glutamatergic overstimulation results in massive neuronal influxes of calcium and sodium through N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainic acid glutamate subtype receptors and also through voltage-gated calcium and sodium channels. These persistent and abnormal sodium and calcium entry points have deleterious consequences (neurotoxicity) for neuronal function. The therapeutic value of an antiepileptic drug would include not only control of seizure activity but also protection of neuronal tissue. The present study examines the in vitro neuroprotective effects of stiripentol, an antiepileptic compound with γ-aminobutyric acidergic properties, on neuronal-astroglial cultures from rat cerebral cortex exposed to oxygen-glucose deprivation (OGD) or to glutamate (40 µM for 20 min), two in vitro models of brain injury. In addition, the affinity of stiripentol for the different glutamate receptor subtypes and the interaction with the cell influx of Na(+) and of Ca(2+) enhanced by veratridine and NMDA, respectively, are assessed. Stiripentol (10-100 µM) included in the culture medium during OGD or with glutamate significantly increased the number of surviving neurons relative to controls. Stiripentol displayed no binding affinity for different subtypes of glutamate receptors (IC50  >100 µM) but significantly blocked the entry of Na(+) and Ca(2+) activated by veratridine and NMDA, respectively. These results suggest that Na(+) and Ca(2+) channels could contribute to the neuroprotective properties of sitiripentol.

  8. Calcium-dependent phosphorylation regulates neuronal stability and plasticity in a highly precise pacemaker nucleus.

    Science.gov (United States)

    George, Andrew A; Macleod, Gregory T; Zakon, Harold H

    2011-07-01

    Specific types of neurons show stable, predictable excitability properties, while other neurons show transient adaptive plasticity of their excitability. However, little attention has been paid to how the cellular pathways underlying adaptive plasticity interact with those that maintain neuronal stability. We addressed this question in the pacemaker neurons from a weakly electric fish because these neurons show a highly stable spontaneous firing rate as well as an N-methyl-D-aspartate (NMDA) receptor-dependent form of plasticity. We found that basal firing rates were regulated by a serial interaction of conventional and atypical PKC isoforms and that this interaction establishes individual differences within the species. We observed that NMDA receptor-dependent plasticity is achieved by further activation of these kinases. Importantly, the PKC pathway is maintained in an unsaturated baseline state to allow further Ca(2+)-dependent activation during plasticity. On the other hand, the Ca(2+)/calmodulin-dependent phosphatase calcineurin does not regulate baseline firing but is recruited to control the duration of the NMDA receptor-dependent plasticity and return the pacemaker firing rate back to baseline. This work illustrates how neuronal plasticity can be realized by biasing ongoing mechanisms of stability (e.g., PKC) and terminated by recruiting alternative mechanisms (e.g., calcineurin) that constrain excitability. We propose this as a general model for regulating activity-dependent change in neuronal excitability.

  9. Analgesic activity and safety of ash of silver used in Indian system of medicine in mice: A reverse pharmacological study

    Directory of Open Access Journals (Sweden)

    Deep Inder

    2012-01-01

    Full Text Available Objective: To study the analgesic activity of ash of silver used in Indian system of medicine and to explore its safety. Materials and Methods: Albino mice of either sex (20-30 gm were used to investigate the role of ash of silver against noxious stimuli: thermal (Eddy′s hot plate and analgesiometer, mechanical (tail clip, and chemical (0.6% acetic acid induced writhing. An effort was made to find nature and site of action of ash of silver following naloxone pre-treatment. Maximum tolerated dose (MTD and lethal dosage 50 (LD50 were also studied along with toxicological aspects of ash of silver. Results: Test drug (ash of silver at a dose of 50 mg/kg p.o exhibited analgesic activity against thermal, mechanical, and chemical stimuli. Analgesic effects were compared with the standard drug, morphine, in thermal and mechanical noxious stimuli and to aspirin in chemical stimulus. Analgesic activity of the test drug was reduced following naloxone pre-treatment. MTD was found out to be greater than 1.5 g/kg p.o. LD50 was 2 g/kg p.o. Fraction of mice showed symptoms of argyria as explained by autopsy reports. Conclusion: Test drug exhibited moderate analgesic activity at 50 mg/kg p.o against all type of noxious stimuli, also suggesting a role of opioidergic system. The ash of silver was been found to be safe upto a dose of 1.5 g/kg p.o. in mice without any untoward toxicity. Further studies are required to explore the effect of ash of silver on pain mediators and excitatory neurotransmitters like glutamate, aspartate, or N-methyl-D-aspartic acid (NMDA.

  10. Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus.

    Science.gov (United States)

    Weichel, O; Hilgert, M; Chatterjee, S S; Lehr, M; Klein, J

    1999-12-01

    In rat hippocampal slices superfused with magnesium-free buffer, glutamate (1 mM) caused the release of large amounts of choline due to phospholipid breakdown. This phenomenon was mimicked by N-methyl-D-aspartate (NMDA) in a calcium-sensitive manner and was blocked by NMDA receptor antagonists such as MK-801 and 7-chlorokynurenate. The NMDA-induced release of choline was not caused by activation of phospholipase D but was mediated by phospholipase A2 (PLA2) activation as the release of choline was accompanied by the formation of lyso-phosphatidylcholine (lyso-PC) and glycerophospho-choline (GPCh) and was blocked by 5-[2-(2-carboxyethyl)-4-dodecanoyl-3,5-dimethylpyrrol-1-yl]pentano ic acid, a PLA2 inhibitor. Bilobalide, a constituent of Ginkgo biloba, inhibited the NMDA-induced efflux of choline with an IC50 value of 2.3 microM and also prevented the formation of lyso-PC and GPCh. NMDA also caused a release of choline in vivo when infused into the hippocampus of freely moving rats by retrograde dialysis. Again, the effect was completely inhibited by bilobalide which was administered systemically (20 mg/kg i.p.). Interestingly, convulsions which were observed in the NMDA-treated rats were almost totally suppressed by bilobalide. We conclude that release of choline is a sensitive marker for NMDA-induced phospholipase A2 activation and phospholipid breakdown. Bilobalide inhibited the glutamatergic excitotoxic membrane breakdown both in vitro and in vivo, an effect which may be beneficial in the treatment of brain hypoxia and/or neuronal hyperactivity.

  11. Antidepressant-like activity of magnesium in the chronic mild stress model in rats: alterations in the NMDA receptor subunits.

    Science.gov (United States)

    Pochwat, Bartłomiej; Szewczyk, Bernadeta; Sowa-Kucma, Magdalena; Siwek, Agata; Doboszewska, Urszula; Piekoszewski, Wojciech; Gruca, Piotr; Papp, Mariusz; Nowak, Gabriel

    2014-03-01

    Recent data suggests that the glutamatergic system is involved in the pathophysiology and treatment of major depressive disorder (MDD) and that the N-methyl-D-aspartate (NMDA) receptor is a potential target for antidepressant drugs. The magnesium ion blocks the ion channel of the NMDA receptor and prevents its excessive activation. Some preclinical and clinical evidence suggests also that magnesium may be useful in the treatment of depression. The present study investigated the effect of magnesium treatment (10, 15 and 20 mg/kg, given as magnesium hydroaspartate) in the chronic mild stress (CMS) model of depression in rats. Moreover, the effect of CMS and magnesium (with an effective dose) on the level of the proteins related to the glutamatergic system (GluN1, GluN2A, GluN2B and PSD-95) in the hippocampus, prefrontal cortex (PFC) and amygdala were examined. A significant reduction in the sucrose intake induced by CMS was increased by magnesium treatment at a dose of 15 mg/kg, beginning from the third week of administration. Magnesium did not affect this behavioural parameter in the control animals. CMS significantly increased the level of the GluN1 subunit in the amygdala (by 174%) and GluN2A in the hippocampus (by 191%), both of which were significantly attenuated by magnesium treatment. Moreover, magnesium treatment in CMS animals increased the level of GluN2B (by 116%) and PSD-95 (by 150%) in the PFC. The present results for the first time demonstrate the antidepressant-like activity of magnesium in the animal model of anhedonia (CMS), thus indicating the possible involvement of the NMDA/glutamatergic receptors in this activity.

  12. Activation and involvement of JNK1 / 2 in hydrogen peroxide- induced neurotoxicity in cultured rat cortical neurons

    Institute of Scientific and Technical Information of China (English)

    Wei WANG; Can GAO; Xiao-yu HOU; Yong LIU; Yan-yan ZONG; Guang-yi ZHANG

    2004-01-01

    AIM: To investigate the role of c-Jun N-terminal protein kinase 1 and 2 (JNK1/2) and the main signal pathway for its activation in hydrogen peroxide (H2O2) induced apoptotic-like cortical cell death. METHODS: Using the model of oxidative stress induced by H2O2, the expression and diphosphorylation of JNK1/2 was examined by immunoblotting analysis, and neuronal apoptotic like cell death was determined by 4',6-diamidino-2-phenylindole (DAPI) staining.RESULTS: The elevation in diphosphorylation level of JNK1/2 (4.40-/5.61-fold vs sham control) was associated with the concentration of H2O2 (0-100 μmol/L) and the development of apoptotic-like cell death (11.04 %-81.01%).There was no alteration of JNK1/2 protein expression following H2O2 treatment and recovery at different time points. Administration with JNK1/2 antisense oligonucleotides not only significantly decreased JNK1/2 protein expression and activation level, but also significantly reduced cortical cell death induced by H2O2 exposure.Furthermore, both JNK1/2 diphosphorylation and apoptotic-like cell death were largely prevented by pretreatment with (5S, l0R)-(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801)or omission of Ca2+ in incubation medium with ethylene glycol-bis(2-aminoethylether)-N,N,N',N-tetraacetic acid (EGTA). CONCLUSION: JNK1/2 is activated and participates in H2O2-induced apoptotic-like death in cultured rat cortical neurons mainly via N-methyl-D-aspartate (NMDA) receptor-mediated influx of extracellular Ca2+.

  13. Dehydroepiandrosterone (DHEA)--a precursor steroid or an active hormone in human physiology.

    Science.gov (United States)

    Traish, Abdulmaged M; Kang, H Paco; Saad, Farid; Guay, Andre T

    2011-11-01

    The circulation of large amounts of dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEA-S) suggests a physiological role in human physiology. In the central nervous system, DHEA is considered a neurosteroid with a wide range of functions. The goal of this review is to discuss metabolism, biochemical, and physiological mechanism of DHEA action and the potential role of DHEA in aging and in ameliorating a host of pathological conditions, associated with aging. We examined preclinical and clinical data reported in various studies from the available literature concerning the effects of DHEA in normal and pathological conditions. Data reported in the literature were analyzed, reviewed, and discussed. DHEA mediates its action via multiple signaling pathways involving specific membrane receptors and via transformation into androgen and estrogen derivatives (e.g., androgens, estrogens, 7α and 7β DHEA, and 7α and 7β epiandrosterone derivatives) acting through their specific receptors. These pathways include: nitric oxide synthase activation, modulation of γ-amino butyric acid receptors, N-methyl D-aspartate, receptors sigma receptors (Sigma-1), differential expression of inflammatory factors, adhesion molecules and reactive oxygen species, among others. Clinical and epidemiological studies suggested that low DHEA levels might be associated with ischemic heart disease, endothelial dysfunction, atherosclerosis, bone loss, inflammatory diseases, and sexual dysfunction. Most importantly, no significant adverse or negative side effects of DHEA were reported in clinical studies of men and women. DHEA modulates endothelial function, reduces inflammation, improves insulin sensitivity, blood flow, cellular immunity, body composition, bone metabolism, sexual function, and physical strength in frailty and provides neuroprotection, improves cognitive function, and memory enhancement. DHEA possesses pleiotropic effects and reduced levels of DHEA and DHEA-S may be

  14. 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation.

    Science.gov (United States)

    Samarajeewa, Anshula; Goldemann, Lolita; Vasefi, Maryam S; Ahmed, Nawaz; Gondora, Nyasha; Khanderia, Chandni; Mielke, John G; Beazely, Michael A

    2014-01-01

    The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the cortex and hippocampus. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF) receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA)-induced toxicity. The tropomyosin-related kinase B (TrkB) receptor is one of the receptors for brain-derived neurotrophic factor (BDNF) and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins toward the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands.

  15. 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

    Directory of Open Access Journals (Sweden)

    Anshula eSamarajeewa

    2014-11-01

    Full Text Available The serotonin (5-HT type 7 receptor is expressed throughout the CNS including cortical neurons. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA-induced toxicity. The tropomyosin-related kinase B (TrkB receptor is one of the receptors for brain-derived neurotrophic factor (BDNF and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins towards the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands.

  16. 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

    Science.gov (United States)

    Samarajeewa, Anshula; Goldemann, Lolita; Vasefi, Maryam S.; Ahmed, Nawaz; Gondora, Nyasha; Khanderia, Chandni; Mielke, John G.; Beazely, Michael A.

    2014-01-01

    The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the cortex and hippocampus. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF) receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA)-induced toxicity. The tropomyosin-related kinase B (TrkB) receptor is one of the receptors for brain-derived neurotrophic factor (BDNF) and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins toward the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands. PMID:25426041

  17. Increased Na+/Ca2+ exchanger activity promotes resistance to excitotoxicity in cortical neurons of the ground squirrel (a Hibernator.

    Directory of Open Access Journals (Sweden)

    Juan-Juan Zhao

    Full Text Available Ground squirrel, a hibernating mammalian species, is more resistant to ischemic brain stress than rat. Gaining insight into the adaptive mechanisms of ground squirrels may help us design treatment strategies to reduce brain damage in patients suffering ischemic stroke. To understand the anti-stress mechanisms in ground squirrel neurons, we studied glutamate toxicity in primary cultured neurons of the Daurian ground squirrel (Spermophilus dauricus. At the neuronal level, for the first time, we found that ground squirrel was more resistant to glutamate excitotoxicity than rat. Mechanistically, ground squirrel neurons displayed a similar calcium influx to the rat neurons in response to glutamate or N-methyl-D-aspartate (NMDA perfusion. However, the rate of calcium removal in ground squirrel neurons was markedly faster than in rat neurons. This allows ground squirrel neurons to maintain lower level of intracellular calcium concentration ([Ca2+]i upon glutamate insult. Moreover, we found that Na+/Ca2+ exchanger (NCX activity was higher in ground squirrel neurons than in rat neurons. We also proved that overexpression of ground squirrel NCX2, rather than NCX1 or NCX3, in rat neurons promoted neuron survival against glutamate toxicity. Taken together, our results indicate that ground squirrel neurons are better at maintaining calcium homeostasis than rat neurons and this is likely achieved through the activity of ground squirrel NCX2. Our findings not only reveal an adaptive mechanism of mammalian hibernators at the cellular level, but also suggest that NCX2 of ground squirrel may have therapeutic value for suppressing brain ischemic damage.

  18. Increased Na+/Ca2+ Exchanger Activity Promotes Resistance to Excitotoxicity in Cortical Neurons of the Ground Squirrel (a Hibernator)

    Science.gov (United States)

    Zhao, Juan-Juan; Gao, Shan; Jing, Jun-Zhan; Zhu, Ming-Yue; Zhou, Chen; Chai, Zhen

    2014-01-01

    Ground squirrel, a hibernating mammalian species, is more resistant to ischemic brain stress than rat. Gaining insight into the adaptive mechanisms of ground squirrels may help us design treatment strategies to reduce brain damage in patients suffering ischemic stroke. To understand the anti-stress mechanisms in ground squirrel neurons, we studied glutamate toxicity in primary cultured neurons of the Daurian ground squirrel (Spermophilus dauricus). At the neuronal level, for the first time, we found that ground squirrel was more resistant to glutamate excitotoxicity than rat. Mechanistically, ground squirrel neurons displayed a similar calcium influx to the rat neurons in response to glutamate or N-methyl-D-aspartate (NMDA) perfusion. However, the rate of calcium removal in ground squirrel neurons was markedly faster than in rat neurons. This allows ground squirrel neurons to maintain lower level of intracellular calcium concentration ([Ca2+]i) upon glutamate insult. Moreover, we found that Na+/Ca2+ exchanger (NCX) activity was higher in ground squirrel neurons than in rat neurons. We also proved that overexpression of ground squirrel NCX2, rather than NCX1 or NCX3, in rat neurons promoted neuron survival against glutamate toxicity. Taken together, our results indicate that ground squirrel neurons are better at maintaining calcium homeostasis than rat neurons and this is likely achieved through the activity of ground squirrel NCX2. Our findings not only reveal an adaptive mechanism of mammalian hibernators at the cellular level, but also suggest that NCX2 of ground squirrel may have therapeutic value for suppressing brain ischemic damage. PMID:25415196

  19. Indicaxanthin from Opuntia ficus-indica Crosses the Blood-Brain Barrier and Modulates Neuronal Bioelectric Activity in Rat Hippocampus at Dietary-Consistent Amounts.

    Science.gov (United States)

    Allegra, Mario; Carletti, Fabio; Gambino, Giuditta; Tutone, Marco; Attanzio, Alessandro; Tesoriere, Luisa; Ferraro, Giuseppe; Sardo, Pierangelo; Almerico, Anna Maria; Livrea, Maria Antonia

    2015-08-26

    Indicaxanthin is a bioactive and bioavailable betalain pigment from the Opuntia ficus-indica fruits. In this in vivo study, kinetic measurements showed that indicaxanthin is revealed in the rat brain within 1 h from oral administration of 2 μmol/kg, an amount compatible with a dietary consumption of cactus pear fruits in humans. A peak (20 ± 2.4 ng of indicaxanthin per whole brain) was measured after 2.5 h; thereafter the molecule disappeared with first order kinetics within 4 h. The potential of indicaxanthin to affect neural activities was in vivo investigated by a microiontophoretic approach. Indicaxanthin, administered in a range between 0.085 ng and 0.34 ng per neuron, dose-dependently modulated the rate of discharge of spontaneously active neurons of the hippocampus, with reduction of the discharge and related changes of latency and duration of the effect. Indicaxanthin (0.34 ng/neuron) showed inhibitory effects on glutamate-induced excitation, indicating activity at the level of glutamatergic synapses. A molecular target of indicaxanthin is suggested by in silico molecular modeling of indicaxanthin with N-methyl-D-aspartate receptor (NMDAR), the most represented of the glutamate receptor family in hippocampus. Therefore, at nutritionally compatible amounts indicaxanthin (i) crosses the rat BBB and accumulates in brain; (ii) can affect the bioelectric activity of hippocampal neurons locally treated with amounts comparable with those measured in the brain; and (iii) modulates glutamate-induced neuronal excitation. The potential of dietary indicaxanthin as a natural neuromodulatory agent deserves further mechanistic and neurophysiologic investigation.

  20. Activity-dependent release of endogenous BDNF from mossy fibers evokes a TRPC3 current and Ca2+ elevations in CA3 pyramidal neurons.

    Science.gov (United States)

    Li, Yong; Calfa, Gaston; Inoue, Takafumi; Amaral, Michelle D; Pozzo-Miller, Lucas

    2010-05-01

    Multiple studies have demonstrated that brain-derived neurotrophic factor (BDNF) is a potent modulator of neuronal structure and function in the hippocampus. However, the majority of studies to date have relied on the application of recombinant BDNF. We herein report that endogenous BDNF, released via theta burst stimulation of mossy fibers (MF), elicits a slowly developing cationic current and intracellular Ca(2+) elevations in CA3 pyramidal neurons with the same pharmacological profile of the transient receptor potential canonical 3 (TRPC3)-mediated I(BDNF) activated in CA1 neurons by brief localized applications of recombinant BDNF. Indeed, sensitivity to both the extracellular BDNF scavenger tropomyosin-related kinase B (TrkB)-IgG and small hairpin interference RNA-mediated TRPC3 channel knockdown confirms the identity of this conductance as such, henceforth-denoted MF-I(BDNF). Consistent with such activity-dependent release of BDNF, these MF-I(BDNF) responses were insensitive to manipulations of extracellular Zn(2+) concentration. Brief theta burst stimulation of MFs induced a long-lasting depression in the amplitude of excitatory postsynaptic currents (EPSCs) mediated by both AMPA and N-methyl-d-aspartate (NMDA) receptors without changes in the NMDA receptor/AMPA receptor ratio, suggesting a reduction in neurotransmitter release. This depression of NMDAR-mediated EPSCs required activity-dependent release of endogenous BDNF from MFs and activation of Trk receptors, as it was sensitive to the extracellular BDNF scavenger TrkB-IgG and the tyrosine kinase inhibitor k-252b. These results uncovered the most immediate response to endogenously released--native--BDNF in hippocampal neurons and lend further credence to the relevance of BDNF signaling for synaptic function in the hippocampus.

  1. Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

    Science.gov (United States)

    Schwieler, Lilly; Larsson, Markus K.; Skogh, Elisabeth; Kegel, Magdalena E.; Orhan, Funda; Abdelmoaty, Sally; Finn, Anja; Bhat, Maria; Samuelsson, Martin; Lundberg, Kristina; Dahl, Marja-Liisa; Sellgren, Carl; Schuppe-Koistinen, Ina; Svensson, Camilla I.; Erhardt, Sophie; Engberg, Göran

    2015-01-01

    Background Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway. Methods We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were analyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry. Results We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA. Limitations The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age. Conclusion We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-d-aspartate receptor antagonist KYNA in patients with schizophrenia. PMID:25455350

  2. Differential expression of brain-derived neurotrophic factor transcripts after pilocarpine-induced seizure-like activity is related to mode of Ca2+ entry.

    Science.gov (United States)

    Poulsen, F R; Lauterborn, J; Zimmer, J; Gall, C M

    2004-01-01

    Activity-dependent brain-derived neurotrophic factor (BDNF) expression is Ca2+-dependent, yet little is known about the Ca2+ channel contributions that might direct selective expression of the multiple BDNF transcripts. Here, effects of pilocarpine-induced seizure activity on total BDNF expression and on the individual sensitivity of BDNF transcripts to glutamate receptor and Ca2+ channel blockers were evaluated using hippocampal slice cultures and in situ hybridization of transcript-specific cRNA probes directed against mRNAs for the four 5' exons (I-IV) of the BDNF gene. mRNAs for nerve growth factor (NGF) and tyrosine kinase B (trkB) also were studied. Pilocarpine (5 mM) induced a dose- and time-dependent increase in total BDNF (exon V) mRNA expression in the dentate granule cells and CA3-CA1 pyramidal cells with maximal effects at 6 and 24 h, respectively. Increases were blocked by co-treatment with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX: 25 microM) and the N-methyl-d-aspartic acid receptor antagonist 2-amino-5-phosphonovaleric acid (APV; 25 microM), whereas the L-type voltage sensitive Ca2+ channel blocker nifedipine (20 microM) was without detectable effect. Maximal NGF and trkB mRNA expression was induced by pilocarpine at 4 and 12 h, respectively. For the individual BDNF transcripts, APV blocked pilocarpine-induced increases in transcript II, whereas nifedipine blocked increases in transcripts I and III. Transcript IV levels were not altered by treatment. These results indicate that transcript II makes the greatest contribution to pilocarpine effects on total BDNF mRNA content in this model and provides evidence for regional and Ca2+ channel-specific differences in activity-dependent regulation of the different BDNF transcripts in hippocampus.

  3. What is the new target inhibiting the progression of Alzheimer’s disease?

    Institute of Scientific and Technical Information of China (English)

    Lin Zhang; Jing Yang; Yunpeng Cao

    2013-01-01

    To stop the progression of Alzheimer’s disease in the early stage, it is necessary to identify new therapeutic targets. We examined striatal-enriched phosphatase 61 expression in the brain tissues of 12-month-old APPswe/PSEN1dE9 transgenic mice. Immunohistochemistry showed that al-enriched phosphatase 61 protein expression was significantly increased but phosphorylated N-methyl-D-aspartate receptor 2B levels were significantly decreased in the cortex and hippocam-pus of APPswe/PSEN1dE9 transgenic mice. Western blotting of a cel model of Alzheimer’s disease consisting of amyloid-beta peptide (1-42)-treated C57BL/6 mouse cortical neurons in vitro showed that valeric acid (AP5), an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloid-beta 1-42-induced increased activity of striatal-enriched phosphatase 61. In addition, the phos-phorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-beta 1-42-treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B. Col ectively, these findings indicate that striatal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer’s disease. Thus, al-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alzheimer’s disease.

  4. Melamine Alters Glutamatergic Synaptic Transmission of CA3-CA1 Synapses Presynaptically Through Autophagy Activation in the Rat Hippocampus.

    Science.gov (United States)

    Zhang, Hui; Wang, Hui; Xiao, Xi; Zhang, Tao

    2016-01-01

    Melamine is an industrial chemical that can cause central nervous system disorders including excitotoxicity and cognitive impairment. Its illegal use in powdered baby formula was the focus of a milk scandal in China in 2008. One of our previous studies showed that melamine impaired glutamatergic transmission in rat hippocampal CA1 pyramidal cells. However, the underlying mechanism of action of melamine is unclear, and it is unknown if the CA3-CA1 pathway is directly involved. In the present study, a whole-cell patch-clamp technique was employed to investigate the effect of melamine on the hippocampal CA3-CA1 pathway in vitro. Both the evoked excitatory postsynaptic current (eEPSC) and the paired-pulse ratio (PPR) were recorded. Furthermore, we examined whether autophagy was involved in glutamatergic transmission alterations induced by melamine. Our data showed that melamine significantly increased the amplitude of eEPSCs in a dose-dependent manner. Inhibition of the N-methyl-D-aspartic acid receptor did not prevent the increase in eEPSC amplitude. In addition, the PPR was remarkably decreased by a melamine concentration of 5 × 10(-5) g/mL. It was found that autophagy could be activated by melamine and an autophagy inhibitor, 3-MA, prevented the melamine-induced increase in eEPSC amplitude. Overall, our results show that melamine presynaptically alters glutamatergic synaptic transmission of hippocampal CA3-CA1 synapses in vitro and this is likely associated with autophagy alteration.

  5. Natural Products based P-glycoprotein Activators for Improved β-amyloid Clearance in Alzheimer's Disease: An in silico Approach.

    Science.gov (United States)

    Shinde, Pravin; Vidyasagar, Nikhil; Dhulap, Sivakami; Dhulap, Abhijeet; Hirwani, Raj

    2015-01-01

    Alzheimer's disease is an age related disorder and is defined to be progressive, irreversible neurodegenerative disease. The potential targets which are associated with the Alzheimer's disease are cholinesterases, N-methyl-D-aspartate receptor, Beta secretase 1, Pregnane X receptor (PXR) and P-glycoprotein (Pgp). P-glycoprotein is a member of the ATP binding cassette (ABC) transporter family, which is an important integral of the blood-brain, blood-cerebrospinal fluid and the blood-testis barrier. Reports from the literature provide evidences that the up-regulation of the efflux pump is liable for a decrease in β -amyloid intracellular accumulation and is an important hallmark in Alzheimer's disease (AD). Thus, targeting β-amyloid clearance by stimulating Pgp could be a useful strategy to prevent Alzheimer's advancement. Currently available drugs provide limited effectiveness and do not assure to cure Alzheimer's disease completely. On the other hand, the current research is now directed towards the development of synthetic or natural based therapeutics which can delay the onset or progression of Alzheimer's disease. Since ancient time medicinal plants such as Withania somnifera, Bacopa monieri, Nerium indicum have been used to prevent neurological disorders including Alzheimer's disease. Till today around 125 Indian medicinal plants have been screened on the basis of ethnopharmacology for their activity against neurological disorders. In this paper, we report bioactives from natural sources which show binding affinity towards the Pgp receptor using ligand based pharmacophore development, virtual screening, molecular docking and molecular dynamics simulation studies for the bioactives possessing acceptable ADME properties. These bioactives can thus be useful to treat Alzheimer's disease.

  6. Deletion of striatal adenosine A(2A) receptor spares latent inhibition and prepulse inhibition but impairs active avoidance learning.

    Science.gov (United States)

    Singer, Philipp; Wei, Catherine J; Chen, Jiang-Fan; Boison, Detlev; Yee, Benjamin K

    2013-04-01

    Following early clinical leads, the adenosine A(2A)R receptor (A(2A)R) has continued to attract attention as a potential novel target for treating schizophrenia, especially against the negative and cognitive symptoms of the disease because of A(2A)R's unique modulatory action over glutamatergic in addition to dopaminergic signaling. Through (i) the antagonistic interaction with the dopamine D(2) receptor, and (ii) the regulation of glutamate release and N-methyl-d-aspartate receptor function, striatal A(2A)R is ideally positioned to fine-tune the dopamine-glutamate balance, the disturbance of which is implicated in the pathophysiology of schizophrenia. However, the precise function of striatal A(2A)Rs in the regulation of schizophrenia-relevant behavior is poorly understood. Here, we tested the impact of conditional striatum-specific A(2A)R knockout (st-A(2A)R-KO) on latent inhibition (LI) and prepulse inhibition (PPI) - behavior that is tightly regulated by striatal dopamine and glutamate. These are two common cross-species translational tests for the assessment of selective attention and sensorimotor gating deficits reported in schizophrenia patients; and enhanced performance in these tests is associated with antipsychotic drug action. We found that neither LI nor PPI was significantly affected in st-A(2A)R-KO mice, although a deficit in active avoidance learning was identified in these animals. The latter phenotype, however, was not replicated in another form of aversive conditioning - namely, conditioned taste aversion. Hence, the present study shows that neither learned inattention (as measured by LI) nor sensory gating (as indexed by PPI) requires the integrity of striatal A(2A)Rs - a finding that may undermine the hypothesized importance of A(2A)R in the genesis and/or treatment of schizophrenia.

  7. Activation of 5-HT and NR2B contributes to visceral hypersensitivity in irritable bowel syndrome in rats

    Science.gov (United States)

    Chen, Ming-Xian; Chen, Yu; Fu, Rui; Liu, Sai-Yue; Yang, Qin-Qin; Shen, Tang-Biao

    2016-01-01

    The roles of 5-hydroxytryptamine (5-HT) and spinal N-methyl-D-aspartic acid receptor 2B (NR2B) in visceral hypersensitivity were investigated. A rat model with irritable bowel syndrome (IBS) was established by intracolonic injections of acetic acid onpost-natal days 8-21. Rats were randomly divided into five groups: normal intact (control) group, IBS model group, Ro25-6981-treated IBS rats (Ro25-6981, a NR2B antagonist) group, amitriptyline-treated IBS rats (amitriptyline, a 5-HT antagonist) and Ro25-6981 plus amitriptyline-treated IBS rats (Ro25-6981+amitriptyline) group. The expressions of 5-HT, NR2B, 5-HT2AR, 5-HT7R, SERT, TNF-α and IL-1β in colon, dorsal root ganglion (DRG) and hypothalamus, respectively, were measured by Immunohistochemical staining, Real-Time Reverse Transcription-PCR and Western blotting. Our results showed increased DRG and hypothalamus expression of 5-HT, NR2B, 5-HT2AR, 5-HT7R in IBS model group and decreased expression of those in Ro25-6981 and amitriptyline alone or both treatment groups. Moreover, SERT expression was decreased in colorectal, DRG and hypothalamus of ISB model rats, but increased by Ro25-6981 and amitriptyline alone or both treatments. Ro25-6981 and amitriptyline treatment also decreased colorectal expression of TNF-α and IL-1β induced by IBS model. In conclusion, activation of 5-HT and NR2B may play a crucial role in visceral hypersensitivity in irritable bowel syndrome in rats. PMID:28078028

  8. Dietary omega-3 deficiency reduces BDNF content and activation NMDA receptor and Fyn in dorsal hippocampus: implications on persistence of long-term memory in rats.

    Science.gov (United States)

    Bach, Simone Azevedo; de Siqueira, Letícia V; Müller, Alexandre P; Oses, Jean P; Quatrim, Andreia; Emanuelli, Tatiana; Vinadé, Lúcia; Souza, Diogo O; Moreira, Júlia D

    2014-07-01

    Omega-3 (n-3) fatty acids are important for adequate brain function and cognition. The aim of the present study was to evaluate how n-3 fatty acids influence the persistence of long-term memory (LTM) in an aversive memory task and to explore the putative mechanism involved. Female rats received isocaloric diets that included n-3 (n-3 group) or not (D group). The adult litters were subjected to an inhibitory avoidance task (0.7 mA, 1.0 seconds foot shock) to elicit persistent LTM. Twelve hours after the training session, the fatty acid profile and the brain derived neurotrophic factor (BDNF) content of the dorsal hippocampus were assessed. In addition, we measured the activation of the NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor and the SRC family protein Fyn. Despite pronounced learning in both groups, the persistence of LTM was abolished in the D group 7 days after the training session. We also observed that the D group presented reductions in hippocampal DHA (22:6 n-3) and BDNF content. Twelve hours after the training session, the D group showed decreased NR2B and Fyn phosphorylation in the dorsal hippocampus, with no change in the total content of these proteins. Further, there was a decrease in the interaction of Fyn with NR2B in the D group, as observed by co-immunoprecipitation. Taken together, these data suggest that n-3 fatty acids influence the persistence of LTM by maintaining adequate levels of DHA and BDNF as well as by influencing the activation of NR2B and Fyn during the period of memory formation.

  9. Electroacupuncture activates corticotrophin-releasing hormone-containing neurons in the paraventricular nucleus of the hypothalammus to alleviate edema in a rat model of inflammation

    Directory of Open Access Journals (Sweden)

    Berman Brian M

    2008-05-01

    Full Text Available Abstract Background Studies show that electroacupuncture (EA has beneficial effects in patients with inflammatory diseases. This study investigated the mechanisms of EA anti-inflammation, using a rat model of complete Freund's adjuvant (CFA-induced hind paw inflammation and hyperalgesia. Design Four experiments were conducted on male Sprague-Dawley rats (n = 6–7/per group. Inflammation was induced by injecting CFA into the plantar surface of one hind paw. Experiment 1 examined whether EA increases plasma adrenocorticotropic hormone (ACTH levels. Experiments 2 and 3 studied the effects of the ACTH and corticotropin-releasing hormone (CRH receptor antagonists, ACTH(11–24 and astressin, on the EA anti-edema. Experiment 4 determined whether EA activates CRH neurons in the paraventricular nucleus of the hypothalammus. EA treatment, 10 Hz at 3 mA and 0.1 ms pulse width, was given twice for 20 min each, once immediately post and again 2 hr post-CFA. Plasma ACTH levels, paw thickness, and paw withdrawal latency to a noxious thermal stimulus were measured 2 h and 5 h after the CFA. Results EA significantly increased ACTH levels 5 h (2 folds after CFA compared t