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NMDA Receptor Antagonists (nmda + receptor_antagonist)

Distribution by Scientific Domains

Life Sciences	67%
Medical Sciences	21%

Selected Abstracts

ChemInform Abstract: Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3-benzazepine as Novel NMDA Receptor Antagonist.

CHEMINFORM, Issue 27 2010
Syed Masood Husain
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source]

Oxamides as Novel NR2B Selective NMDA Receptor Antagonists

CHEMINFORM, Issue 47 2004
Gyoergy Domany
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

Novel N1 -(Benzyl)cinnamamidine Derived NR2B Subtype-Selective NMDA Receptor Antagonists.

CHEMINFORM, Issue 25 2003
Neil R. Curtis
Abstract For Abstract see ChemInform Abstract in Full Text. [source]

Persistent rhythmic oscillations induced by nicotine on neonatal rat hypoglossal motoneurons in vitro

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2006
Nerijus Lamanauskas
Abstract Patch-clamp recording from hypoglossal motoneurons in neonatal Wistar rat brainstem slices was used to investigate the electrophysiological effects of bath-applied nicotine (10 µm). While nicotine consistently evoked membrane depolarization (or inward current under voltage clamp), it also induced electrical oscillations (3,13 Hz; lasting for , 8.5 min) on 40% of motoneurons. Oscillations required activation of nicotinic receptors sensitive to dihydro-,-erythroidine (0.5 µm) or methyllycaconitine (5 nm), and were accompanied by enhanced frequency of spontaneous glutamatergic events. The slight voltage dependence of oscillations and their block by the gap junction blocker, carbenoxolone, suggest they originate from electrically coupled neurons. Network nicotinic receptors desensitized more slowly than motoneuron ones, demonstrating that network receptors remained active longer to support heightened release of the endogenous glutamate necessary for enhancing the network excitability. The ionotropic glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and the group I metabotropic receptor antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), suppressed oscillations, while the NMDA receptor antagonist, d -amino-phosphonovaleriate (APV), produced minimal depression. Nicotine-evoked oscillations constrained spike firing at low rates, although motoneurons could still generate high-frequency trains of action potentials with unchanged gain for input depolarization. This is the first demonstration that persistent activation of nicotinic receptors could cause release of endogenous glutamate to evoke sustained oscillations in the theta frequency range. As this phenomenon likely represented a powerful process to coordinate motor output to tongue muscles, our results outline neuronal nicotinic acetylcholine receptors (nAChRs) as a novel target for pharmacological enhancement of motoneuron output in motor dysfunction. [source]

Bi-directional regulation of postsynaptic cortactin distribution by BDNF and NMDA receptor activity

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2005
Junko Iki
Abstract Cortactin is an F-actin-associated protein which interacts with the postsynaptic scaffolding protein Shank at the SH3 domain and is localized within the dendritic spine in the mouse neuron. Green fluorescent protein (GFP)-based time-lapse imaging revealed cortactin redistribution from dendritic cytoplasm to postsynaptic sites by application of brain-derived neurotrophic factor (BDNF). This response was mediated by mitogen-activated protein (MAP) kinase activation and was dependent on the C-terminal SH3 domain. In contrast, activation of N -methyl- d -aspartate (NMDA) receptors induced loss of cortactin from postsynaptic sites. This NMDA-dependent redistribution was blocked by an Src family kinase inhibitor. Conversely, increasing Src family kinase activity induced cortactin phosphorylation and loss of cortactin from the postsynaptic sites. Finally, blocking of endogenous BDNF reduced the amount of cortactin at the postsynaptic sites and an NMDA receptor antagonist prevented this reduction. These results indicate the importance of counterbalance between BDNF and NMDA receptor-mediated signalling in the reorganization of the postsynaptic actin cytoskeleton during neuronal development. [source]

Immune-related mechanisms participating in resistance and susceptibility to glutamate toxicity

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2002
Hadas Schori
Abstract Glutamate is an essential neurotransmitter in the CNS. However, at abnormally high concentrations it becomes cytotoxic. Recent studies in our laboratory showed that glutamate evokes T cell-mediated protective mechanisms. The aim of the present study was to examine the nature of the glutamate receptors and signalling pathways that participate in immune protection against glutamate toxicity. We show, using the mouse visual system, that glutamate-induced toxicity is strain dependent, not only with respect to the amount of neuronal loss it causes, but also in the pathways it activates. In strains that are genetically endowed with the ability to manifest a T cell-dependent neuroprotective response to glutamate insult, neuronal losses due to glutamate toxicity were relatively small, and treatment with NMDA-receptor antagonist worsened the outcome of exposure to glutamate. In contrast, in mice devoid of T cell-dependent endogenous protection, NMDA receptor antagonist reduced the glutamate-induced neuronal loss. In all strains, blockage of the AMPA/KA receptor was beneficial. Pharmacological (with ,2 -adrenoceptor agonist) or molecular intervention (using either mice overexpressing Bcl-2, or DAP-kinase knockout mice) protected retinal ganglion cells from glutamate toxicity but not from the toxicity of NMDA. The results suggest that glutamate-induced neuronal toxicity involves multiple glutamate receptors, the types and relative contributions of which, vary among strains. We suggest that a multifactorial protection, based on an immune mechanism independent of the specific pathway through which glutamate exerts its toxicity, is likely to be a safer, more comprehensive, and hence more effective strategy for neuroprotection. It might suggest that, because of individual differences, the pharmacological use of NMDA-antagonist for neuroprotective purposes might have an adverse effect, even if the affinity is low. [source]

Reducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitro

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000
Ashley K. Pringle
Abstract Inappropriate activation of NMDA receptors during a period of cerebral ischaemia is a crucial event in the pathway leading to neuronal degeneration. However, significant research has failed to deliver a clinically active NMDA receptor antagonist, and competitive NMDA antagonists are ineffective in many experimental models of ischaemia. The NMDA receptor itself has a number of modulatory sites which may affect receptor function under ischaemic conditions. Using rat organotypic hippocampal slice cultures we have investigated whether the redox modulatory site affects the neuroprotective efficacy of NMDA receptor antagonists against excitotoxicity and experimental ischaemia (OGD). NMDA toxicity was significantly enhanced in cultures pretreated with a reducing agent. The noncompetitive antagonist MK-801 and a glycine-site blocker were equally neuroprotective in both normal and reduced conditions, but there was a significant rightward shift in the dose,response curves of the competitive antagonists APV and CPP and the uncompetitive antagonist memantine. OGD produced neuronal damage predominantly in the CA1 region, which was prevented by MK-801 and memantine, but not by APV or CPP. Inclusion of an oxidizing agent during the period of OGD had no effect alone, but significantly enhanced the neuroprotective potency of the competitive antagonists. These data clearly demonstrate that chemical reduction of the redox modulatory site of the NMDA receptor decreases the ability of competitive antagonists to block NMDA receptor-mediated neuronal damage, and that the reducing conditions which occur during simulated ischaemia are sufficient to produce a similar effect. This may have important implications for the design of future neuroprotective agents. [source]

N-methyl- d -aspartate enhancement of the glycine response in the rat sacral dorsal commissural neurons

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2000
Tian-.
Abstract The effect of N-methyl- d -aspartate (NMDA) on the glycine (Gly) response was examined in neurons acutely dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin-perforated patch-recording configuration under voltage-clamp conditions. The application of 100 ,m NMDA to SDCN neurons reversibly potentiated Gly-activated Cl, currents (IGly) without affecting the Gly binding affinity and the reversal potential of IGly. A selective NMDA receptor antagonist, APV (100 ,m), blocked the NMDA-induced potentiation of IGly, whereas 50 ,m CNQX, a non-NMDA receptor antagonist, did not. The potentiation effect was reduced when NMDA was applied in a Ca2+ -free extracellular solution or in the presence of BAPTA AM, and was independent of the activation of voltage-dependent Ca2+ channels. Pretreatment with KN-62, a selective Ca2+,calmodulin-dependent protein kinase II (CaMKII) inhibitor, abolished the NMDA action. Inhibition of calcineurin (CaN) further enhanced the NMDA-induced potentiation of IGly. In addition, the GABAA receptor-mediated currents were suppressed by NMDA receptor activation in the SDCN neurons. The present results show that Ca2+ entry through NMDA receptors modulates the Gly receptor function via coactivation of CaMKII and CaN in the rat SDCN neurons. This interaction may represent one of the important regulatory mechanisms of spinal nociception. The results also suggest that GABAA and Gly receptors may be subject to different intracellular modulatory pathways. [source]

2-Deoxyglucose and NMDA inhibit protein synthesis in neurons and regulate phosphorylation of elongation factor-2 by distinct mechanisms

JOURNAL OF NEUROCHEMISTRY, Issue 3 2006
M. Maus
Abstract Cerebral ischaemia is associated with brain damage and inhibition of neuronal protein synthesis. A deficit in neuronal metabolism and altered excitatory amino acid release may both contribute to those phenomena. In the present study, we demonstrate that both NMDA and metabolic impairment by 2-deoxyglucose or inhibitors of mitochondrial respiration inhibit protein synthesis in cortical neurons through the phosphorylation of eukaryotic elongation factor (eEF-2), without any change in phosphorylation of initiation factor eIF-2,. eEF-2 kinase may be activated both by Ca2+ -independent AMP kinase or by an increase in cytosolic Ca2+. Although NMDA decreases ATP levels in neurons, only the effects of 2-deoxyglucose on protein synthesis and phosphorylation of elongation factor eEF-2 were reversed by Na+ pyruvate. Protein synthesis inhibition by 2-deoxyglucose was not as a result of a secondary release of glutamate from cortical neurons as it was not prevented by the NMDA receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo-(a,d)-cyclohepten-5,10-imine hydrogen maleate (MK 801), nor to an increase in cytosolic-free Ca2+. Conversely, 2-deoxyglucose likely activates eEF-2 kinase through a process involving phosphorylation by AMP kinase. In conclusion, we provide evidence that protein synthesis can be inhibited by NMDA and metabolic deprivation by two distinct mechanisms involving, respectively, Ca2+ -dependent and Ca2+ -independent eEF-2 phosphorylation. [source]

Dextromethorphan and Quinidine Combination for Heroin Detoxification

THE AMERICAN JOURNAL ON ADDICTIONS, Issue 3 2008
Evaristo Akerele MD
Dextromethorphan (DM) is a low-affinity, non-competitive NMDA receptor antagonist that has shown promise in preclinical and preliminary clinical studies for the reduction of opioid withdrawal symptoms, but when used at higher doses, it is associated with deleterious side effects attributed to its metabolite, dextrorphan. A clinical trial was therefore conducted to test the withdrawal-suppressant effect of a combination of dextromethorphan with quinidine (DM/Q). Quinidine inhibits the metabolism of dextromethorphan, reducing dextrorphan levels. Opioid-dependent patients were admitted to an inpatient unit, stabilized for three days on morphine (25 mg, sc, every six hours), and randomly assigned on day 2 to DM/Q (30 mg/30 mg, twice a day) (n = 22) or matching placebo (n = 9) prior to the discontinuation of morphine on day 4. Withdrawal symptoms, measured with the Modified Himmelsbach Opioid Withdrawal Scale (MHOWS), increased significantly on days 4 and 5 (Z = 3.70, p = .0002), and by day 6, 90% of the sample (28/31) had dropped out of the study. There were no differences between treatment groups on either outcome measure. The combination of dextromethorphan and quinidine appears ineffective as a primary treatment for opioid withdrawal. Future studies should examine dextromethorphan as an adjunct to other anti-withdrawal medications and focus more on the relationship between dextrorphan levels and withdrawal suppression. [source]

Protein kinase A-dependent enhanced NMDA receptor function in pain-related synaptic plasticity in rat amygdala neurones

THE JOURNAL OF PHYSIOLOGY, Issue 3 2005
Gary C. Bird
Mechanisms of pain-related plasticity in the amygdala, a key player in emotionality, were studied at the cellular and molecular levels in a model of arthritic pain. The influence of the arthritis pain state induced in vivo on synaptic transmission and N -methyl- d -aspartate (NMDA) receptor function was examined in vitro using whole-cell voltage-clamp recordings of neurones in the latero-capsular part of the central nucleus of the amygdala (CeA), which is now defined as the ,nociceptive amygdala'. Synaptic transmission was evoked by electrical stimulation of afferents from the pontine parabrachial area (part of the spino-parabrachio-amygdaloid pain pathway) in brain slices from control rats and from arthritic rats. This study shows that pain-related synaptic plasticity is accompanied by protein kinase A (PKA)-mediated enhanced NMDA-receptor function and increased phosphorylation of NMDA-receptor 1 (NR1) subunits. Synaptic plasticity in the arthritis pain model, but not normal synaptic transmission in control neurones, was inhibited by a selective NMDA receptor antagonist. Accordingly, an NMDA receptor-mediated synaptic component was recorded in neurones from arthritic animals, but not in control neurones, and was blocked by inhibition of PKA but not protein kinase C (PKC). Exogenous NMDA evoked a larger inward current in neurones from arthritic animals than in control neurones, indicating a postsynaptic effect. Paired-pulse facilitation, a measure of presynaptic mechanisms, was not affected by an NMDA-receptor antagonist. Increased levels of phosphorylated NR1 protein, but not of total NR1, were measured in the CeA of arthritic rats compared to controls. Our results suggest that pain-related synaptic plasticity in the amygdala involves a critical switch of postsynaptic NMDA receptor function through PKA-dependent NR1 phosphorylation. [source]

Blockade of the central generator of locomotor rhythm by noncompetitive NMDA receptor antagonists in Drosophila larvae

DEVELOPMENTAL NEUROBIOLOGY, Issue 1 2001
Daniel Cattaert
Abstract The noncompetitive antagonists of the vertebrate N -methyl- D -aspartate (NMDA) receptor dizocilpine (MK 801) and phencyclidine (PCP), delivered in food, were found to induce a marked and reversible inhibition of locomotor activity in Drosophilamelanogaster larvae. To determine the site of action of these antagonists, we used an in vitro preparation of the Drosophila third-instar larva, preserving the central nervous system and segmental nerves with their connections to muscle fibers of the body wall. Intracellular recordings were made from ventral muscle fibers 6 and 7 in the abdominal segments. In most larvae, long-lasting (>1 h) spontaneous rhythmic motor activities were recorded in the absence of pharmacological activation. After sectioning of the connections between the brain and abdominal ganglia, the rhythm disappeared, but it could be partially restored by perfusing the muscarinic agonist oxotremorine, indicating that the activity was generated in the ventral nerve cord. MK 801 and PCP rapidly and efficiently inhibited the locomotor rhythm in a dose-dependent manner, the rhythm being totally blocked in 2 min with doses over 0.1 mg/mL. In contrast, more hydrophilic competitive NMDA antagonists had no effect on the motor rhythm in this preparation. MK 801 did not affect neuromuscular glutamatergic transmission at similar doses, as demonstrated by monitoring the responses elicited by electrical stimulation of the motor nerve or pressure applied glutamate. The presence of oxotremorine did not prevent the blocking effect of MK 801. These results show that MK 801 and PCP specifically inhibit centrally generated rhythmic activity in Drosophila, and suggest a possible role for NMDA-like receptors in locomotor rhythm control in the insect CNS. © 2001 John Wiley & Sons, Inc. J Neurobiol 48: 58,73, 2001 [source]

Impairment of CaMKII activation and attenuation of neuropathic pain in mice lacking NR2B phosphorylated at Tyr1472

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2010
Shinji Matsumura
Abstract Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key mediator of long-term potentiation (LTP), which can be triggered by N -methyl- d -aspartate (NMDA) receptor-mediated Ca2+ influx. We previously demonstrated that Fyn kinase-mediated phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 in the dorsal horn was involved in a neuropathic pain state even 1 week after nerve injury. Here we show that Y1472F-KI mice with a knock-in mutation of the Tyr1472 site to phenylalanine did not exhibit neuropathic pain induced by L5 spinal nerve transection, whereas they did retain normal nociceptive responses and induction of inflammatory pain. Phosphorylation of NR2B at Tyr1472 was only impaired in the spinal cord of Y1472F-KI mice among the major phosphorylation sites. There was no difference in the Ca2+ response to glutamate and sensitivity to NMDA receptor antagonists between naive wild-type and Y1472F-KI mice, and the Ca2+ response to glutamate was attenuated in the Y1472F-KI mice after nerve injury. Autophosphorylation of CaMKII at Thr286 was markedly impaired in Y1472F-KI mice after nerve injury, but there was no difference in phosphorylation of CaMKII at Thr305 or protein kinase C, at Thr674, and activation of neuronal nitric oxide synthase and microglia in the superficial layer of spinal cord between wild-type and Y1472F-KI mice after the operation. These results demonstrate that the attenuation of neuropathic pain is caused by the impaired NMDA receptor-mediated CaMKII signaling in Y1472F-KI mice, and suggest that autophosphorylation of CaMKII at Thr286 plays a central part not only in LTP, but also in persistent neuropathic pain. [source]

Glutamate enhances proliferation and neurogenesis in human neural progenitor cell cultures derived from the fetal cortex

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2006
Masatoshi Suzuki
Abstract Excitatory amino acids such as glutamate play important roles in the central nervous system. We previously demonstrated that a neurosteroid, dehydroepiandrosterone (DHEA), has powerful effects on the cell proliferation of human neural progenitor cells (hNPC) derived from the fetal cortex, and this effect is modulated through NMDA receptor signaling. Here, we show that glutamate can significantly increase the proliferation rates of hNPC. The increased proliferation could be blocked by specific NMDA receptor antagonists, but not other glutamate antagonists for kainate,AMPA or metabotropic receptors. The NR1 subunit of the NMDA receptor was detectable in elongated bipolar or unipolar cells with small cell bodies. These NR1-positive cells were colocalized with GFAP immunoreactivity. Detection of the phosphorylation of cAMP response element-binding protein (pCREB) revealed that a subset of NR1-positive hNPC could respond to glutamate. Furthermore, we hypothesized that glutamate treatment may affect mainly the hNPC with a radial morphology and found that glutamate as well as DHEA selectively affected elongated hNPC; these elongated cells may be a type of radial glial cell. Finally we asked whether the glutamate-responsive hNPC had an increased potential for neurogenesis and found that glutamate-treated hNPC produced significantly more neurons following differentiation. Together these data suggest that glutamate stimulates the division of human progenitor cells with neurogenic potential. [source]

AMPA/kainate and NMDA-like glutamate receptors at the chromatophore neuromuscular junction of the squid: role in synaptic transmission and skin patterning

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2003
Pedro A. Lima
Abstract Glutamate receptor types were examined at the chromatophore synapses of the squids Alloteuthis subulata and Loligo vulgaris, where nerve-induced muscle contraction causes chromatophore expansion. Immunoblotting with antibody raised against a squid AMPA receptor (sGluR) demonstrated that AMPA/kainate receptors are present in squid skin. Application of l -glutamate evoked chromatophore muscle contractions in both ventral and dorsal skins, while NMDA was only active on a subpopulation of dorsal chromatophores. In dorsal skin, neurotransmission was partly blocked by either AMPA/kainate receptor antagonists (CNQX and DNQX) or NMDA receptor antagonists (AP-5 and MK-801) or completely blocked by simultaneous application of both classes of antagonists. In isolated muscle fibres, ionophoretic application of l -glutamate evoked fast inward CNQX- and DNQX-sensitive currents with reversal potentials around +14 mV and a high conductance to Na+. In fibres from dorsal skin only, a slower outward glutamate-sensitive current appeared at positive holding potentials. At negative potentials, currents were potentiated by glycine or by removing external Mg2+ and were blocked by AP-5 and MK-801. Glutamate caused a fast, followed by a slow, transient increase in cytoplasmic Ca2+. The slow component was increased in amplitude and duration by glycine or by lowering external Mg2+ and decreased by AP-5 and MK-801. In cells from ventral skin, no ,NMDA-like responses' were detected. Thus, while AMPA/kainate receptors mediated fast excitatory synaptic transmission and rapid colour change over the whole skin, activation of both AMPA/kainate and NMDA-like receptors in a subpopulation of dorsal chromatophores prolonged the postsynaptically evoked Ca2+ elevation causing temporally extended colour displays with behavioural significance. [source]

Reducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitro

Routes of zinc entry in mouse cortical neurons: role in zinc-induced neurotoxicity

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2000
Philippe Marin
Abstract Exposure of central neurons to Zn2+ triggers neuronal death. The routes of Zn2+ entry were investigated in living cortical neurons from the mouse using the specific Zn2+ fluorescent dye N-(6-methoxy-8-quinolyl)-p-toluene sulphonamide (TSQ), which preferentially detects membrane-bound Zn2+. Exposure of cortical neurons to increasing concentrations of Zn2+ (1,100 ,m) induced a progressive increase in the fluorescence of TSQ. This fluorescence signal was not attenuated by the permeation of plasma membrane with digitonin. Accordingly, the major part of TSQ fluorescence (two-thirds) was associated to the particulate fraction of cortical neurons exposed to Zn2+. These results suggest that Zn2+ detected with TSQ in neurons is mainly bound to membranes. TSQ fluorescence measured in neurons exposed to 3 ,m Zn2+ was enhanced by Na+ -pyrithione, a Zn2+ ionophore, ,-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-methyl- d -aspartate (NMDA) or KCl-induced depolarization. However, in the absence of any treatment, TSQ labelling of neurons exposed to 3 ,m Zn2+ was only decreased by NMDA receptor antagonists, whereas it remained unaltered in the presence of antagonists of AMPA receptors or L-type voltage-gated Ca2+ channels. Zn2+ entry through NMDA receptors did not contribute to Zn2+ -induced neuronal death, as it was prevented by antagonists of NMDA receptors only when they were added after the Zn2+ exposure. Finally, Zn2+ induced a delayed accumulation of extracellular glutamate which might be responsible for the delayed NMDA receptor activation that leads to neuronal death. [source]

A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory, and impairment of synaptic plasticity in rats

HIPPOCAMPUS, Issue 2 2008
Denise Manahan-Vaughan
Abstract Schizophrenia is mostly a progressive psychiatric illness. Although cognitive changes in chronic schizophrenia have been investigated, little is known about the consequences of a single psychotic episode on memory mechanisms and formation. We investigated changes in hippocampal long-term potentiation (LTP) and spatial memory in a rat model of an acute psychotic episode. Application of NMDA receptor antagonists, such as MK801 (dizolcilpine) in rats, have been shown to give rise to an acute and short-lasting behavioral state, which mirrors many symptoms of schizophrenia. Furthermore, NMDA antagonist-intake in humans elicits symptoms of schizophrenia such as hallucinations, delusions, and affective blunting. We therefore treated animals with a single systemic injection of MK801 (5 mg/kg). Increased stereotypy, locomotion, and ataxia were evident immediately after MK801-treatment, with effects disappearing within 24 h. MK801-treatment caused a disruption of prepulse inhibition of the acoustic startle reflex, 1 day but not 7 or 28 days after treatment. These effects were consistent with the occurrence of an acute psychotic episode. LTP was profoundly impaired in freely moving rats 7 days after MK801 application. Four weeks after treatment, a slight recovery of LTP was seen, however marked deficits in long-term spatial memory were evident. These data suggest that treatment with MK801 to generate an acute psychotic episode in rats, gives rise to grave disturbances in synaptic plasticity and is associated with lasting impairments with the ability to form spatial memory. © 2007 Wiley-Liss, Inc. [source]

The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue S1 2003
Wojciech Danysz
Abstract There is increasing evidence for the involvement of glutamate-mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD). We suggest that glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner in this disorder. This continuous mild activation may lead to neuronal damage and impairment of synaptic plasticity (learning). It is likely that under such conditions Mg2+ ions, which block NMDA receptors under normal resting conditions, can no longer do so. We found that overactivation of NMDA receptors using a direct agonist or a decrease in Mg2+ concentration produced deficits in synaptic plasticity (in vivo: passive avoidance test and/or in vitro: LTP in the CA1 region). In both cases, memantine,an uncompetitive NMDA receptor antagonists with features of an ,improved' Mg2+ (voltage-dependency, kinetics, affinity),attenuated this deficit. Synaptic plasticity was restored by therapeutically-relevant concentrations of memantine (1,,M). Moreover, doses leading to similar brain/serum levels provided neuroprotection in animal models relevant for neurodegeneration in AD such as neurotoxicity produced by inflammation in the NBM or ,-amyloid injection to the hippocampus. As such, if overactivation of NMDA receptors is present in AD, memantine would be expected to improve both symptoms (cognition) and to slow down disease progression because it takes over the physiological function of magnesium. Copyright © 2003 John Wiley & Sons, Ltd. [source]

Dose-dependent effect of S(+) ketamine on post-ischemic endogenous neurogenesis in rats

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2009
U. WINKELHEIDE
Background: Ketamine is a non-competitive antagonist at N -methyl- d -aspartate (NMDA) receptors and reduces neuronal injury after cerebral ischemia by blocking the excitotoxic effects of glutamate. However, cerebral regeneration by means of endogenous neurogenesis may be impaired with blockade of NMDA receptors. The effects of S(+) ketamine on post-ischemic neurogenesis are unknown and investigated in this study. Methods: Thirty-two male Sprague,Dawley rats were randomly assigned to the following treatment groups with intravenous S(+) ketamine anesthesia: S(+) ketamine 0.75 mg/kg/min with or without cerebral ischemia and S(+) ketamine 1.0 mg/kg/min with or without cerebral ischemia. Eight non-anesthetized, non-ischemic animals were investigated as naïve controls. Forebrain ischemia was induced by bilateral common carotid artery occlusion in combination with hemorrhagic hypotension. 5-bromo-2-deoxyuridine (BrdU) was injected intraperitoneally for seven consecutive post-operative days. BrdU-positive neurons in the dentate gyrus and histopathological damage of the hippocampus were analyzed after 28 days. Results: The number of new neurons was not affected by S(+) ketamine in the absence of cerebral ischemia. The ischemia-induced increase in neurogenesis was reduced by high-dose S(+) ketamine. Cell death of ischemic animals did not vary between low- and high-dose S(+) ketamine. Conclusion: While low concentrations of S(+) ketamine allow an ischemia-induced increase in the number of new neurons, high S(+) ketamine concentrations block the post-ischemic increase in newly generated neurons. This effect is irrespective of the extent of other histopathological damage and in line with studies showing that NMDA receptor antagonists like MK-801 inhibit neurogenesis after cerebral ischemia. [source]

Comparison of the pharmacological properties of GK11 and MK801, two NMDA receptor antagonists: towards an explanation for the lack of intrinsic neurotoxicity of GK11

JOURNAL OF NEUROCHEMISTRY, Issue 4 2007
D. Vandame
Abstract Over-stimulation of NMDA receptors (NMDARs) is involved in many neurodegenerative disorders. Thus, developing safe NMDAR antagonists is of high therapeutic interest. GK11 is a high affinity uncompetitive NMDAR antagonist with low intrinsic neurotoxicity, shown to be promising for treating CNS trauma. In the present study, we investigated the molecular basis of its interaction with NMDARs and compared this with the reference molecule MK801. We show, on primary cultures of hippocampal neurons, that GK11 exhibits neuroprotection properties similar to those of MK801, but in contrast with MK801, GK11 is not toxic to neurons. Using patch-clamp techniques, we also show that on NR1a/NR2B receptors, GK11 totally blocks the NMDA-mediated currents but has a six-fold lower IC50 than MK801. On NR1a/NR2A receptors, it displays similar affinity but fails to totally prevent the currents. As NR2A is preferentially localized at synapses and NR2B at extrasynaptic sites, we investigated, using calcium imaging and patch-clamp approaches, the effects of GK11 on either synaptic or extrasynaptic NMDA-mediated responses. Here we demonstrate that in contrast with MK801, GK11 better preserve the synaptic NMDA-mediated currents. Our study supports that the selectivity of GK11 for NR2B containing receptors accounts contributes, at least partially, for its safer pharmacological profile. [source]

Pregnenolone Sulfate, a Naturally Occurring Excitotoxin Involved in Delayed Retinal Cell Death

JOURNAL OF NEUROCHEMISTRY, Issue 6 2000
C. Cascio
Abstract: The present study was designed to investigate the neurosteroid pregnenolone sulfate (PS), known for its ability to modulate NMDA receptors and interfere with acute excitotoxicity, in delayed retinal cell death. Three hours after exposure of the isolated and intact retina to a 30-min PS pulse, DNA fragmentation as assessed by genomic DNA gel electrophoresis and a modified in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method appeared concurrently with an increase in superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBARS) levels. At 7 h, the increased amount of DNA laddering was accompanied by a higher number of TUNEL-positive cells in the inner nuclear and ganglion cell layers. Necrotic signs were characterized by DNA smear migration, lactate dehydrogenase (LDH) release, and damage mainly in the inner nuclear layer. PS-induced delayed cell death was markedly reduced by the NMDA receptor antagonists 4-(3-phosphonopropyl)-2-piperazinecarboxylic acid and 3,-hydroxy-5,-pregnan-20-one sulfate but completely blocked after concomitant addition of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Steroids with antioxidant properties (progesterone, dehydroepiandrosterone and its sulfate ester, and 17,-estradiol) differently prevented PS-induced delayed cell death. Cycloheximide treatment protected against DNA fragmentation and LDH release but failed to prevent the rise in SOD activity and TBARS level. We conclude that a brief PS pulse causes delayed cell death in a slowly evolving apoptotic fashion characterized by a cycloheximide-sensitive death program downstream of reactive oxygen species generation and lipid peroxidation, turning into secondary necrosis in a retinal cell subset. [source]

Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord. (National Medical Defense Center, Taipei, Taiwan) Br J Anaesth 2000;85:587,591.

PAIN PRACTICE, Issue 2 2001
Chih-Shung Wong
N -Methyl-D-aspartate (NMDA) receptor antagonists and nitric oxide synthase (NOS) inhibitors inhibit morphine tolerance. In the present study, a lumbar subarachnoid polyethylene (PE10) catheter was implanted for drug administration to study alterations in NMDA receptor activity and NOS protein expression in a morphine-tolerant rat spinal model. Antinociceptive tolerance induced by intrathecal morphine infusion (10 ,g h,1) for 5 days. Co-administered MK801 with morphine was used to inhibit the development of morphine tolerance. Lumbar spinal cord segments were removed and prepared for [3H]MK-801 binding assays and NOS western blotting. The binding affinity of [3H]MK-801 was higher in spinal cords of morphine-related rats than in control rats. There was no difference in Bmax. Western blot analysis showed that constitutive expression of neuronal NOS protein in the morphine-tolerant group was twice that in the control group. This up-regulation was partially prevented by MK-801. The results suggest that morphine tolerance affects NMDA receptor binding activity and increases nNOS expression in the rat spinal cord. Comment by Octavio Calvillo, M.D., Ph.D. Morphine tolerance may be due to receptor down-regulation or receptor uncoupling; activation of the NMDA-dependent pain-facilitatory system may also play a role. It has been proposed that NMDA receptor activation may play a role in morphine tolerance. NMDA receptor antagonists and nitric oxide synthase [NOS] inhibitors may prevent morphine tolerance. Tolerance was induced in rats by intrathecal injection of morphine [10 ug/h] for 5 days, co-administration of MK801 [NMDA antagonist] with morphine was used to prevent morphine tolerance. Lumbar spinal cord segments were removed and prepared for [H3]MK801 binding assays and NOS western blotting. The binding affinity of labeled MK801 was higher in spinal cords of morphine tolerant rats than in control rats. Western blot analysis showed that constitutive expression of neuronal NOS protein in the morphine tolerant rats was twice that in the control group, thus, up-regulation was prevented by MK801. The results suggest that morphine tolerance affect NMDA receptor binding activity and increase neuronal protein expression in rat the spinal cord. [source]

Learning to breathe: control of the inspiratory,expiratory phase transition shifts from sensory- to central-dominated during postnatal development in rats

THE JOURNAL OF PHYSIOLOGY, Issue 20 2009
Mathias Dutschmann
The hallmark of the dynamic regulation of the transitions between inspiration and expiration is the timing of the inspiratory off-switch (IOS) mechanisms. IOS is mediated by pulmonary vagal afferent feedback (Breuer,Hering reflex) and by central interactions involving the Kölliker,Fuse nuclei (KFn). We hypothesized that the balance between these two mechanisms controlling IOS may change during postnatal development. We tested this hypothesis by comparing neural responses to repetitive rhythmic vagal stimulation, at a stimulation frequency that paces baseline breathing, using in situ perfused brainstem preparations of rats at different postnatal ages. At ages < P15 (P, postnatal days), phrenic nerve activity (PNA) was immediately paced and entrained to the afferent input and this pattern remained unchanged by repetitive stimulations, indicating that vagal input stereotypically dominated the control of IOS. In contrast, PNA entrainment at > P15 was initially insignificant, but increased after repetitive vagal stimulation or lung inflation. This progressive adaption of PNA to the pattern of the sensory input was accompanied by the emergence of anticipatory centrally mediated IOS preceding the stimulus trains. The anticipatory IOS was blocked by bilateral microinjections of NMDA receptor antagonists into the KFn and PNA was immediately paced and entrained, as it was seen at ages < P15. We conclude that as postnatal maturation advances, synaptic mechanisms involving NMDA receptors in the KFn can override the vagally evoked IOS after ,training' using repetitive stimulation trials. The anticipatory IOS may imply a hitherto undescribed form of pattern learning and recall in convergent sensory and central synaptic pathways that mediate IOS. [source]

NMDA receptor antagonists: tools in neuroscience with promise for treating CNS pathologies

THE JOURNAL OF PHYSIOLOGY, Issue 1 2007
Georg Köhr
No abstract is available for this article. [source]

Effects of the Non-Competitive NMDA Receptor Antagonist Memantine on the Volitional Consumption of Ethanol by Alcohol-Preferring Rats

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2010
Gloria E. Malpass
This study examined the effects of memantine, a low-affinity, open channel NMDA antagonist, on volitional consumption of ethanol by alcohol-preferring rats and potential locomotor, sedative and hypothermic effects. Volitional consumption of ethanol in a 24-hr two-choice paradigm was determined for male Myers' high-ethanol-preferring (mHEP) rats. Effects of memantine (0.3, 1.0, 3.0 and 10.0 mg/kg, i.p., b.i.d. [twice daily] for 3 days) or vehicle on volitional consumption of ethanol, proportion of ethanol to total fluids consumed, total fluid intake and consumption of food were observed. Potential sedating and locomotor effects of memantine (10.0 mg/kg, i.p., b.i.d.) were determined using an elevated plus maze and an Auto-Track Opto-Varimex activity monitoring system. Rectal temperature was measured to determine if memantine (10.0 mg/kg, i.p.) produces a hypothermic effect. The results indicate that memantine dose-dependently decreased the amount of ethanol and proportion of ethanol to total fluids consumed daily, reaching 48% and 24%, respectively, at the highest dose. These effects did not appear to be anti-caloric. Memantine (10.0 mg/kg) partially reversed both the sedation and the reductions in locomotor activity induced by ethanol. This dose did, however, produce a small, partially reversible hypothermic effect. In conclusion, memantine may decrease ethanol consumption with fewer side effects than other NMDA receptor antagonists, such as phencyclidine (PCP), MK 801 and ketamine. [source]

Biphasic effects of NMDA on the motility of the rat portal vein

BRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2000
Z L Rossetti
The effect of NMDA on the motility of the rat portal vein was studied in an isolated preparation. NMDA induced a concentration-dependent (10,7,10,4 M) increase of the contraction frequency (maximum increase, 148±6% of control at NMDA 10,4 M). The NMDA-induced excitatory response was prevented by the competitive NMDA receptor antagonists (±)-2-Amino-5-phosphonopentanoic acid (AP-5, 5×10,4 M) or (RS)-3-(2-carboxypiperazine-4-yl) propyl-1-phosphonic acid (CPP, 10,4 M). Tetrodotoxin (TTX, 10,6 M) or atropine (10,4 M) abolished the NMDA-induced increase of the portal vein motility and reversed the excitatory effect to a concentration-dependent inhibition (maximum inhibition, 52±8 and 29±7% of controls, respectively, at NMDA 10,3 M). Removal of the endothelium abolished the NMDA-induced inhibitory response. Sodium nitroprusside concentration-dependently (10,7,10,5 M) inhibited the portal vein motility, while L -NG -nitro-arginine methyl ester (L -NAME, 10,4 M) reversed the inhibitory effect of NMDA (in the presence of TTX), restoring the portal vein spontaneous activity to control values. These results show that NMDA modulates the portal vein motility in a biphasic manner: via indirect activation, through prejunctional NMDA receptors presumably located on intrinsic excitatory neuronal afferences, or via direct inhibition, through endothelial NMDA receptors activating the nitric oxide pathway. Overall these findings support the hypothesis of the existence of a peripheral glutamatergic innervation modulating the contractile activity of the rat portal vein. British Journal of Pharmacology (2000) 129, 156,162; doi:10.1038/sj.bjp.0703002 [source]