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PubMed2001

Acamprosate is neuroprotective against glutamate-induced excitotoxicity when enhanced by ethanol withdrawal in neocortical cultures of fetal rat brain.

BACKGROUND: Acamprosate reduces relapse, and the drug may interact with glutamate transmission and with glutamate/NMDA receptors. Because these systems are implicated in excess calcium entry leading to alcohol withdrawal-induced neurotoxicity, we evaluated the effects of acamprosate on these parameters in neuronal cultures. METHODS: Primary cultures of neocortical neurons from fetal Sprague-Dawley rats were maintained either in normal medium or in medium containing 100 mM ethanol for 4 days. After this time, cultures were challenged with glutamate for 10 min and then returned to medium (all in the absence of ethanol). 45Ca2+ uptake was measured during the challenge, and glutamate-induced toxicity was assessed after 20 hr. The effects of acamprosate present during the glutamate challenge were measured on both parameters. RESULTS: In controls, acamprosate did not significantly affect glutamate-induced neurotoxicity but produced a significant inhibition of calcium entry. The NMDA receptor antagonists dizocilpine and d-amino-phosphonovalerate (D-APV) inhibited both glutamate neurotoxicity and calcium entry. In cultures previously exposed to ethanol, glutamate-induced neurotoxicity and calcium entry were both significantly enhanced. Dizocilpine reduced both these parameters to unstimulated control values, and D-APV reduced both calcium entry and neurotoxicity with the same relation that we obtained in control cultures. In the ethanol-withdrawn cultures, acamprosate reduced both the enhanced glutamate-induced calcium entry and the enhanced neurotoxicity in a concentration-dependent manner. Acamprosate also significantly reduced calcium entry caused by 80 mM K+ in control and ethanol-exposed cultures. CONCLUSIONS: Acamprosate had protective effects against glutamate-induced neurotoxicity only in ethanol-withdrawn cultures. The neuroprotective effects of the drug did not correlate with its effects on calcium entry, making it unlikely that acamprosate directly affects NMDA receptors via the glutamate binding site or the receptor-operated calcium channel. The results are, however, compatible with other inhibitory effects on NMDA receptor function.

Acamprosate↗
PubMed1999

Different effects of volatile anesthetics and polyhalogenated alkanes on depolarization-evoked glutamate release in rat cortical brain slices.

UNLABELLED: Anesthetics cause a reduction in excitatory neurotransmission that may be important in the mechanisms of in vivo anesthetic action. Because glutamate is the major excitatory neurotransmitter in mammalian brain, evaluation of anesthetic effects on induced glutamate release is relevant for studying this potential mechanism of anesthetic action. In the present study, we compared the effects of anesthetics and nonanesthetics (halogenated alkanes that disobey the Meyer-Overton hypothesis) on depolarization-evoked glutamate release. Glutamate released from rat cortical brain slices after chemically induced depolarization (50 mM KCl) was measured continuously using an enzymatic fluorescence assay. The effects of the volatile anesthetics isoflurane and enflurane were compared with the effects of the transitional compound 1,1,2-trichlorotrifluoroethane, the nonanesthetic compound 1,2-dichlorohexafluorocyclobutane, and other polyhalogenated alkanes. Tested concentrations included effective anesthetic concentrations for the anesthetics and transitional compounds, and concentrations predicted to be anesthetic based on lipid solubility for the nonanesthetics. Isoflurane dose-dependently reduced depolarization-evoked glutamate release in cortical brain slices. Isoflurane and enflurane at concentrations equivalent to 1 minimum alveolar anesthetic concentration (MAC) reduced the KCl-evoked release to 20% and 17% of control, respectively. The transitional compound 1,1,2-trichlorotrifluoroethane at 210 microM (approximately 1.2 MAC) reduced glutamate release to 47%, and the nonanesthetic 1,2-dichlorohexafluorocyclobutane increased glutamate release at 70 microM (approximately 3 MAC). These findings support the hypothesis that the modulation of excitatory neurotransmission might be responsible, in part, for in vivo anesthetic action. IMPLICATIONS: The volatile anesthetics isoflurane and enflurane reduce depolarization-evoked glutamate release in rat brain slices. The transitional compound 1,1,2-trichlorotrifluoroethane reduces glutamate release to a much lesser extent, and the nonanesthetic 1,2-dichlorohexafluorocyclobutane does not reduce glutamate release. These findings support the hypothesis that the modulation of excitatory neurotransmission might be responsible, in part, for in vivo anesthetic action.

Alkanes↗
PubMed1992

Enflurane-induced release of an excitatory amino acid, glutamate, from mouse brain synaptosomes.

To clarify the mechanisms of enflurane-induced convulsions, we examined the effects of enflurane, halothane, and diethyl ether on the release of an excitatory neurotransmitter, glutamate, from isolated pinched-off nerve terminals (synaptosomes) of the mouse cerebral cortex. At concentrations corresponding to those used clinically (0.75 and 1.25 mM), enflurane released more glutamate than did halothane. Diethyl ether (10 and 58 mM) had no effect on glutamate release. Enflurane (0.75-15 mM) increased glutamate and aspartate release in a dose-dependent manner but had little effect on the release of the inhibitory neurotransmitters glycine and gamma-aminobutyric acid or on the release of glutamine. A glutamate uptake inhibitor, kainic acid (1 mM), did not affect enflurane-induced glutamate release. Replacement of the medium's Ca2+ by Co2+, or exposure to cold (about 2 degrees C), suppressed the enflurane-induced glutamate release. Depolarization caused by 40 mM K+ increased the basal level of glutamate released, and enflurane-induced glutamate release was lower after depolarization. Enflurane had no effect in synaptosomes prepared from the cerebellum, diencephalon and pons, or medulla oblongata. Thus, enflurane increased Ca(2+)- and temperature-dependent glutamate release, especially from synaptosomes of the cerebral cortex. These data provide a pathophysiologic explanation for enflurane-induced convulsions.

Animals↗
PubMed1994

Effects of isoflurane and hypothermia on glutamate receptor-mediated calcium influx in brain slices.

BACKGROUND: To understand how volatile anesthetics protect neurons during cerebral ischemia, we studied the effects of isoflurane on cerebral glutamate receptor-mediated calcium influx. Calcium influx via these key excitatory receptors may mediate pain transmission, memory, and the pathophysiologic sequelae of cerebral anoxia or ischemia. Because cerebral protection by hypothermia may involve a decrease in glutamate receptor activity, we also examined the interaction of temperature and isoflurane on glutamate receptor inhibition. METHODS: We measured glutamate receptor-mediated changes in cytosolic calcium in 300-microns-thick rat cortical brain slices. Temperature was varied to 28, 34, 37, or 39 degrees C and isoflurane partial pressure to 0.016-0.019 atm (equivalent to 1.16 minimum alveolar concentration [MAC], adjusted for temperature and age). Brain slices were loaded with fura-2 to permit measurement of cytosolic free calcium. Calcium changes due to the glutamate receptor agonist N-methyl-D-aspartate (NMDA) (50 microM), to ischemia levels of L-glutamate (1.0 mM) or to simulated ischemia (1.0 mM glutamate, 100 microM NaCN, and 3.5 mM iodoacetate) was then measured. Slice lactate dehydrogenase leakage and adenosine triphosphate were measured as indices of cellular integrity. RESULTS: Isoflurane reduced both L-glutamate and NMDA-mediated calcium fluxes by approximately 60%. Neither the activity of the NMDA receptor nor its inhibition by isoflurane was altered by temperature. The rate of calcium influx during ischemia was significantly reduced both by temperature and by isoflurane (P < 0.05). Adenosine triphosphate loss and lactate dehydrogenase leakage were reduced by isoflurane during simulated ischemia by 37% and 73% (P < 0.05), respectively. CONCLUSIONS: (1) At 1.16 MAC, isoflurane potently inhibits glutamate receptors and delays cellular injury induced by simulated ischemia, and (2) hypothermia does not reduce the intrinsic activity of cortical glutamate receptors but delays calcium accumulation during simulated ischemia. Isoflurane reduces the severity of key pathophysiologic events in an in vitro model of simulated cerebral ischemia.

Adenosine Triphosphate↗
PubMed1996

Evidence against high extracellular glutamate promoting the elicitation of spreading depression by potassium.

This study ascertains whether high extracellular glutamate contributes to the initiation of spreading depression (SD) by K+. Two microdialysis probes, each incorporating an electrode to record the extracellular direct current (DC) potential at the elicitation site, were implanted symmetrically in the cortex of anesthetized rats. Recurrent SD was triggered by perfusion of 130 mM K+ through the microdialysis probe for 20 min. On one side, this medium was supplemented with increasing concentrations of glutamate (0.1-1 mM) or of the selective glutamate uptake inhibitor 1-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC: 1-10 mM). The effects of L-trans-PDC on extracellular glutamate and basal DC potential were studied in separate experiments. Application of K+ for 20 min consistently elicited five to seven waves of SD. Increasing the concentration of glutamate in the perfusion medium did not alter SD elicitation. Application of L-trans-PDC concentration dependently increased the dialysate levels of glutamate (by approximately 19-fold with 10 mM L-trans-PDC) but, unexpectedly, reduced SD elicitation. These data do not support the hypothesis that SD is elicited because high extracellular glutamate resulting from exocytosis and/or reversal of glutamate uptake depolarizes adjacent neurons. As SD elicitation requires activation of N-methyl-D-aspartate (NMDA) receptors, these results also illustrate that sensitivity of a pathological or experimental event to NMDA receptor antagonists does not necessarily imply involvement of increased extracellular glutamate. This does not rule out a selective action of glutamate, transiently released from presynaptic vesicles, on immediately juxtaposed postsynaptic receptors.

Animals↗
PubMed2002

TACE/ADAM17-TNF-alpha pathway in rat cortical cultures after exposure to oxygen-glucose deprivation or glutamate.

The role of the tumor necrosis factor (TNF)-alpha convertase (TACE/ADAM17) in the adult nervous system remains poorly understood. The authors have previously demonstrated that TACE is upregulated in rat forebrain slices exposed to oxygen-glucose deprivation (OGD). They have now used rat mixed cortical cultures exposed to OGD or glutamate to study (1) TACE expression and localization, and (2) the effects of TNF-alpha release on cell viability. OGD-or glutamate-caused TNF-alpha release, an effect that was blocked by the TACE inhibitor BB3103 (BB) (0.1-1 micromol/L; control: 1.67 +/- 0.59; OGD: 6.59 +/- 1.52; glutamate: 3.38 +/- 0.66; OGD +/- BB0.1: 3.23 +/- 0.67; OGD +/- BB1: 1.33 +/- 0.22 pg/mL, n = 6, P < 0.05). Assay of TACE activity as well as Western blot showed that TACE expression is increased in OGD-or glutamate-exposed cells. In control cultures, TACE immunoreactivity was present in some microglial cells, whereas, after OGD or glutamate, TACE immunostaining appeared in most microglial cells and in some astrocytes. Conversely, BB3103 (0.1 micromol/L) caused apoptosis after glutamate exposure as shown by annexin and Hoechst 33342 staining and caspase-3 activity, an effect mimicked by the proteasome inhibitor MG-132 (caspase activity: glutamate: 5.1 +/- 0.1; glutamate + BB: 7.8 +/- 0.8; glutamate + MG: 11.9 +/- 0.5 pmol. min(-1) mg(-1) protein, n = 4, P < 0.05), suggesting that translocation of the transcription factor NF-kappaB mediates TNF-alpha-induced antiapoptotic effect. Taken together, these data demonstrate that, in rat mixed neuronal-glial cortical cultures exposed to OGD or glutamate, (1) TACE/ADAM17 activity accounts for the majority of TNF-alpha shedding, (2) an increase in glial TACE expression contributes to the rise in TNF-alpha, and (3) TNF-alpha release in this setting inhibits apoptosis via activation of the transcription factor NF-kappaB.

ADAM Proteins↗
PubMed2002

Mouse cerebellar adenosine-glutamate interactions and modulation of ethanol-induced motor incoordination.

BACKGROUND: It was demonstrated previously that cerebellar adenosine modulates ethanol-induced motor incoordination via A(1) subtype of adenosine receptors. Several reports suggest the involvement of brain glutamate mechanisms, in particular N-methyl-d-aspartate (NMDA) receptor sites, in the central nervous system (CNS) actions of ethanol. Mutually antagonistic functional responses as a result of glutamate and adenosine within the brain regions have also been well documented. METHODS: With the use of rotorod performance as the test response, this study was conducted to evaluate possible functional interactions between cerebellar adenosine and glutamate and its consequence on ethanol-induced motor incoordination. Except for ethanol, which was injected intraperitoneally, all drugs used were microinfused directly into the cerebellum. RESULTS: Direct intracerebellar microinfusion of glutamate (125, 250, and 500 ng) and the antagonist l-glutamic acid diethyl-ester (125, 250, and 500 ng) markedly and dose-dependently attenuated and accentuated, respectively, ethanol-induced motor incoordination, suggesting an involvement of glutamate. Subsequently, intracerebellar microinfusions of NMDA (125, 250, and 500 ng) and its antagonists AP-5 [(+)-2-amino-5-phosphoropentanoic acid; 125, 250, and 500 ng] and (+)-MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclo-hepten-5,10-imine hydrogen maleate; 25, 50, and 100 ng] significantly attenuated and accentuated, respectively, ethanol-induced motor incoordination in a dose-related manner, indicating participation of NMDA receptor. The attenuation of ethanol-induced motor incoordination by glutamate and NMDA was receptor mediated as it was antagonized by their receptor antagonists. Adenosine A(1) -selective agonist N(6) -cyclohexyladenosine and antagonist 8-cyclopentyl-1,3-dipropylxanthine functionally opposed the attenuation by glutamate and NMDA and the accentuation by L-glutamic acid diethyl-ester, AP-5, and (+)-MK-801, respectively, of ethanol-induced motor incoordination. CONCLUSIONS: These results suggest a functional antagonism between glutamate NMDA and adenosine A(1) receptors exhibiting a co-modulation of ethanol-induced motor incoordination within the cerebellum.

Animals↗
PubMed2003

Long-term potentiation in the dentate gyrus of the anaesthetized rat is accompanied by an increase in extracellular glutamate: real-time measurements using a novel dialysis electrode.

We have used a glutamate-specific dialysis electrode to obtain real-time measurements of changes in the concentration of glutamate in the extracellular space of the hippocampus during low-frequency stimulation and following the induction of long-term potentiation (LTP). In the dentate gyrus, stimulation of the perforant path at 2 Hz for 2 min produced a transient increase in glutamate current relative to the basal value at control rates of stimulation (0.033 Hz). This activity-dependent glutamate current was significantly enhanced 35 and 90 min after the induction of LTP. The maximal 2 Hz signal was obtained during post-tetanic potentiation (PTP). There was also a more gradual increase in the basal level of extracellular glutamate following the induction of LTP. Both the basal and activity-dependent increases in glutamate current induced by tetanic stimulation were blocked by local infusion of the N-methyl-D-aspartate receptor antagonist D-APV. In areas CA1 and CA3 we were unable to detect a 2 Hz glutamate signal either before or after the induction of LTP, possibly owing to a more avid uptake of glutamate in the pyramidal cell fields. These results demonstrate that LTP in the dentate gyrus is associated with a greater concentration of extracellular glutamate following activation of potentiated synapses, either because potentiated synapses release more transmitter per impulse, or because of reduced uptake by glutamate transporters. We present arguments favouring increased release rather than decreased uptake.

Animals↗
PubMed2004

Roles and regulation of the glutamate racemase isogenes, racE and yrpC, in Bacillus subtilis.

Many bacteria, including Escherichia coli, have a unique gene that encodes glutamate racemase. This enzyme catalyses the formation of d-glutamate, which is necessary for cell wall peptidoglycan synthesis. However, Bacillus subtilis has two glutamate racemase genes, named racE and yrpC. Since racE appears to be indispensable for growth in rich medium, the role of yrpC in d-amino acid synthesis is vague. Experiments with racE- and yrpC-knockout mutants confirmed that racE is essential for growth in rich medium but showed that this gene was dispensable for growth in minimal medium, where yrpC executes the anaplerotic role of racE. LacZ fusion assays demonstrated that racE was expressed in both types of media but yrpC was expressed only in minimal medium, which accounted for the absence of yrpC function in rich medium. Neither racE nor yrpC was required for B. subtilis cells to synthesize poly-gamma-dl-glutamate (gamma-PGA), a capsule polypeptide of d- and l-glutamate linked through a gamma-carboxylamide bond. Wild-type cells degraded the capsule during the late stationary phase without accumulating the degradation products, d-glutamate and l-glutamate, in the medium. In contrast, racE or yrpC mutant cells accumulated significant amounts of d- but not l-glutamate. Exogenous d-glutamate utilization was somewhat defective in the mutants and the double mutation of race and yrpc severely impaired d-amino acid utilization. Thus, both racemase genes appear necessary to complete the catabolism of exogenous d-glutamate generated from gamma-PGA.

Adaptation, Physiological↗
PubMed2005

Myocardial interstitial choline and glutamate levels during acute myocardial ischaemia and local ouabain administration.

AIM: Noradrenaline (NA) uptake transporters are known to reverse their action during acute myocardial ischaemia and to contribute to ischaemia-induced myocardial interstitial NA release. By contrast, functional roles of choline and glutamate transporters during acute myocardial ischaemia remain to be investigated. Because both transporters are driven by the normal Na+ gradient across the plasma membrane in a similar manner to NA transporters, the loss of Na+ gradient would affect the transporter function, which would in turn alter myocardial interstitial choline and glutamate levels. The aim of the present study was to examine the effects of acute myocardial ischaemia and the inhibition of Na+,K+-ATPase on myocardial interstitial glutamate and choline levels. METHODS: In anaesthetized cats, we measured myocardial interstitial glutamate and choline levels while inducing acute myocardial ischaemia or inhibiting Na+,K+-ATPase by local administration of ouabain. RESULTS: The choline level was not changed significantly by ischaemia (from 0.93 +/- 0.06 to 0.82 +/- 0.13 microm, mean +/- SE, n = 6) and was decreased slightly by ouabain (from 1.30 +/- 0.06 to 1.05 +/- 0.07 microm, P < 0.05, n = 6). The glutamate level was significantly increased from 9.5 +/- 1.9 to 34.7 +/- 6.1 microm by ischaemia (P < 0.01, n = 6) and from 8.9 +/- 1.0 to 15.9 +/- 2.3 microm by ouabain (P < 0.05, n = 6). Inhibition of glutamate transport by trans-L-pyrrolidine-2,4-dicarboxylate (t-PDC) suppressed ischaemia- and ouabain-induced glutamate release. CONCLUSION: Myocardial interstitial choline level was not increased by acute myocardial ischaemia or by Na+,K+-ATPase inhibition. By contrast, myocardial interstitial glutamate level was increased by both interventions. The glutamate transporter contributed to glutamate release via retrograde transport.

Acetylcholine↗
PubMed1976

1. Membrane vesicles of Escherichia coli K-12 CS7, a strain gentically derepressed for glutamate permease, maintain low aspartate transport activity, like that of prep.

1. Membrane vesicles of Escherichia coli K-12 CS7, a strain gentically derepressed for glutamate permease, maintain low aspartate transport activity, like that of preparations of the wild-type parent. Growth of the parent CS101 on aspartate as the source of carnon or nitrogen results in derepression of both asparatate and glytamate transport. Growth of strain CS7 on aspartate derepresses aspartate transport to the same extent as in strains CS101, but only slightly increases the derepressed level of glutamate transport activity. 2. The affinity of the membrane transport system for glutamate is enhanced by sodium, while that for asparate is not. 3. Although the affinities for glutamate (23 muM) and aspartate (12 muM) are similar, aspartate does not inhibit glutamate transport, while glutamate competitively inhibits aspartate transport. 4. Aspartate transport, but not glutamate transport, is competitively inhibited by C4 dicarboxylic acids, whereas 2-oxoglutarate competitively inhibits glutamate transport, but not aspartate transport. 5. Competitive inhibition of L-aspartate transport by L-glutamate and by the 5-methyl ester of L-glutamate is abolished in the presence of 2-oxoglutarate. However, 2-oxoglutarate does not affect the competitive inhibition of L-aspartate transport by D-aspartate and by DL-threo-3-hydroxyaspartate. The relationship between the two dicarboxylic amino acid transport systems and the spatial characteristics of the aspartate carrier are discussed in the light of these findings.

Aspartic Acid↗
PubMed1995

Glutamate induces c-fos proto-oncogene expression and inhibits proliferation in oligodendrocyte progenitors: receptor characterization.

The effect of glutamate on c-fos expression in oligodendrocyte progenitors was investigated by Northern blot analysis. Glutamate caused rapid and transient induction. Both 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX), two competitive non-NMDA ionotropic receptor antagonists, reduced glutamate-induced c-fos expression, whereas the NMDA antagonist MK-801 was ineffective. In addition, the glutamate receptor agonists (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) and kainate strongly induced c-fos. However, the metabotropic receptor agonist trans-(+/-)-1-amino-(1S,3R)-cyclopentanedicarboxylic acid (trans-(+/-)-ACPD) did not increase c-fos mRNA level and the antagonist L-(+)-2-amino-3-phosphonopropionic acid did not block glutamate-induced c-fos mRNA. These findings indicate that c-fos induction in oligodendrocyte progenitors is mediated through the AMPA/kainate receptors, while NMDA and metabotropic receptor subtypes are not involved. Chelation of extracellular calcium by EDTA prevented glutamate-induced c-fos expression. Similarly, the protein kinase C inhibitor 1-(5-isoquinoline-sulphonyl)-2-methylpiperazine dihydrochloride (H7) and down-regulation of protein kinase C by prolonged exposure to phorbol-12-myristate 13-acetate blocked c-fos induction. These results suggest that induction of c-fos through AMPA/kainate receptors is dependent on extracellular calcium influx and involves downstream activation of phorbol ester-sensitive protein kinase C. The effect of glutamate on oligodendrocyte progenitor proliferation was assessed by [3H]thymidine incorporation. Glutamate and the agonists kainate and AMPA, but not trans-(+/-)-ACPD, caused a dose-dependent decrease in [3H]thymidine incorporation. All these pharmacological agents were not toxic to oligodendrocyte progenitors. CNQX reversed the inhibitory effects produced by glutamate and the various agonists. These results suggest that glutamate may modulate the growth and differentiation of oligodendrocytes in the central nervous system.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1996

Immunocytochemical evidence that glutamate is a neurotransmitter in the cochlear nerve: a quantitative study in the guinea-pig anteroventral cochlear nucleus.

The large so-called type I afferents of the cochlear nerve carry the majority of the auditory input from the cochlea to the cochlear nuclei in the brainstem. These fibres are excitatory and previous studies have suggested they may use glutamate as their neurotransmitter. In the present investigation therefore, antibodies to glutamate and to the glutamate precursor, glutamine, were applied to resin sections of perfusion-fixed brains and of in vitro brain slices subjected to depolarizing levels of potassium before fixation to study glutamate handling and synaptic release. Ultrathin sections were labelled by the immunogold technique, and the immunoreactivity was quantified by recording the density of gold particles over the various tissue profiles. Non-primary, presumably inhibitory, terminals and glial processes were used as reference structures. The cochlear primary terminals proved to be strongly immunoreactive for glutamate. The density of glutamate labelling was higher in primary terminals than in non-primary ones, and lowest in glial processes. The ratio between the mean glutamate and glutamine labelling densities was also higher in primary terminals than in non-primary ones, and lowest in glial processes in each case. In the primary terminals, the glutamate immunoreactivity was higher over vesicle-containing regions than over vesicle-free regions, whilst glutamine was evenly distributed throughout. The in vitro brain slices showed a potassium-induced, partly calcium-dependent depletion of glutamate from the primary terminals but not from the non-primary ones. These observations strongly support the conclusion that glutamate is a neurotransmitter of type I cochlear afferents.

Afferent Pathways↗
PubMed2003

Glutamate activates NF-kappaB through calpain in neurons.

Glutamate induces gene transcription in numerous physiological and pathological conditions. Among the glutamate-responsive transcription factors, NF-kappaB has been mainly implicated in neuronal survival and death. Recent data also suggest a role of NF-kappaB in neural development and memory formation. In non-neuronal cells, degradation of the inhibitor IkappaBalpha represents a key step in NF-kappaB activation. However, little is known of how glutamate activates NF-kappaB in neurons. To investigate the signalling cascade involved we used primary murine cerebellar granule cells. Glutamate induced a rapid reduction of IkappaBalpha levels and nuclear translocation of the NF-kappaB subunit p65. The glutamate-induced reduction of IkappaBalpha levels was blocked by the N-methyl-d-aspartate inhibitor MK801. Specific inhibitors of the proteasome, caspase 3, and the phosphoinositide 3-kinase had no effect on glutamate-induced IkappaBalpha degradation. However, inhibition of the glutamate-activated Ca2+-dependent protease calpain by calpeptin completely blocked IkappaBalpha degradation and reduced the nuclear translocation of p65. Calpeptin also partially blocked glutamate-induced cell death. Our data indicate that the Ca2+-dependent protease calpain is involved in the NF-kappaB activation in neurons in response to N-methyl-d-aspartate receptor occupancy by glutamate. NF-kappaB activation by calpain may mediate the long-term effects of glutamate on neuron survival or memory formation.

Active Transport, Cell Nucleus↗
PubMed2004

Cerebrospinal fluid glutamate levels in chronic migraine.

Both preclinical and clinical data link glutamate to the migraine pathophisiology. Altered plasma, platelets and cerebrospinal (CSF) glutamate levels have been reported in migraine patients. Chronic migraine is comorbid with several conditions. It has been recently shown chronic migraine comorbidity with fibromyalgia. The objective of this study was to study cerebrospinal fluid glutamate levels in chronic migraine patients with and without fibromyalgia. We studied 20 chronic migraine patients, with and without fibromyalgia, compared to age-sex matched controls. CSF glutamate levels were measured by HPLC. CSF glutamate demonstrated significantly higher levels in patients with fibromyalgia compared to those without fibromyalgia. Patients overall had higher CSF glutamate levels than controls. Mean pain score correlated with glutamate levels in chronic migraine patients. Tender points, the hallmark of fibromyalgia, can be considered as pressure allodynia, and is probably mediated by central sensitization, with increase in CSF glutamate levels. We postulate chronic migraine patients with fibromyalgia, in addition to have more disabling headaches, suffer from a more severe central sensitization process. This subtype of patients may respond to medications modulating glutamate receptors. Headache intensity correlate with glutamate levels in chronic migraine patients.

Adult↗
PubMed1980

Structure-activity studies on an excitatory receptor for glutamate on leech Retzius neurones.

1 Intracellular recordings were made from Retzius cells from the segmental ganglia of Hirudo medicinalis and Haemopis sanguisuga. Glutamate had a direct excitatory effect on the leech Retzius cells. 2 L-Glutamate was 25 times more potent than D-glutamate. 3 L-Glutamate was approximately equipotent with ibotenic acid and 11.2 times more potent than L-aspartic acid. 4 Quisqualic acid and kainic acid were both approximately 100 times more potent than L-glutamate. DL-1-Amino-cis-1-3-dicarboxyclyclopentane was approximately 5 times more potent than L-glutamate, while the trans isomer was 105 times less potent. 5 alpha-NH2-pimelic acid and beta-CH3-glutamic acid reduced the response to L-glutamate. 6 It is suggested that glutamic acid may interact with the Retzius cell glutamate receptor in an extended conformation.

Animals↗
PubMed1995

Neuroprotective use-dependent blockers of Na+ and Ca2+ channels controlling presynaptic release of glutamate.

We have originated a family of N,N'-disubstituted guanidines that block the voltage-activated Ca2+ and Na+ channels governing glutamate release. These compounds, CNS 1237 (N-acenaphthyl-N'-methoxynaphthyl guanidine) and its analogues, are "use dependent" in their ability to attenaute neurotransmitter release: they block glutamate release with greater efficacy under conditions of persistent or repetitive depolarization, as would be encountered under pathophysiological circumstances, relative to their ability to block glutamate release elicited by brief, transient depolarizations more characteristic of normal physiological release events in nonischemic brain. Using electrophysiological and rapid kinetic methods, we have differentiated the use-dependent block of the relevant Na+ and Ca2+ channels governing neurotransmitter release from the mechanism of channel antagonism exhibited by, respectively, the substituted guanidine Na+ channel blocker tetrodotoxin (TTX) and venom peptide Ca2+ antagonists. To characterize use-dependent Na+ channel block by CNS 1237, we have employed whole-cell voltage-clamp recordings from a Chinese hamster ovary (CHO) cell line expressing cloned mammalian type II Na+ channels. These experiments demonstrated that, in contrast to the actions of TTX under the same conditions, the potency of Na+ channel block by CNS 1237 is greatly enhanced by depolarizing stimuli in a frequency-dependent manner. Ca2+ channel-activated glutamate release from brain nerve terminal preparations was measured with approximately 300 msec time resolution over a 5-second period of high K(+)-depolarization, using a rapid superfusion technique. CNS 1237 and analogues, at 1-3 microM, accelerated the decay of glutamate release by 40-70%, reflecting depolarization-induced enhancement of block. In contrast, blockade of glutamate release by the Ca2+ channel antagonist peptide toxins omega-aga IV-A (from spider venom) and omega-conotoxin M-VII-C (from cone snail venom) exhibited "reverse-use-dependence:" at concentrations of 0.3 microM, which blocked the initial amplitude of glutamate release by 40-60%, the decay time constant for glutamate release was significantly increased, indicating depolarization-induced relief of block. These findings establish that CNS 1237 and other members of this compound series are use-dependent blockers of the voltage-activated ion channels governing glutamate release. Studies of CNS 1237 in the rat middle cerebral artery occlusion (MCAO) focal stroke model have indicated infarct size reduction comparable to that observed by the same investigators for the glutamate release blocker (BW 619C89 (Burroughs-Wellcome, now in clinical development). Maximal infarct size reduction is achieved with a 3-mg/kg bolus followed by a 4-hour infusion of 0.75 mg/kg/hr.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Nicotine-induced protection against glutamate cytotoxicity. Nicotinic cholinergic receptor-mediated inhibition of nitric oxide formation.

Cortical neurodegeneration in Alzheimer's disease (AD) is suggested to be attributable not only to beta-protein but also to glutamate. Although degeneration of cholinergic projection to the cerebral cortex is recognized to be one of the most prominent pathological changes in AD, there is only limited information concerning the cholinergic interaction with the cortical neurodegeneration. This study was performed to examine the protective effect of nicotine against glutamate-induced cytotoxicity using rat cultured cortical neurons. The cell viability was significantly reduced when cultures were briefly exposed to glutamate or N-methyl-D-aspartate (NMDA). The simultaneous addition of nicotine did not reduce glutamate cytotoxicity. In contrast, the simultaneous application of NMDA receptor antagonists such as MK-801 reduced glutamate cytotoxicity. Incubating the cultures with nicotine (10 microM) for 0.5-24 h prior to glutamate exposure reduced its cytotoxicity. Neuroprotection by nicotine was dependent on both the concentration and incubation period. In contrast to nicotine, muscarine (10 microM) weakly potentiated glutamate cytotoxicity. The neuroprotective effect of nicotine against glutamate cytotoxicity was antagonized by hexamethonium but not by artopine. Nicotine prevented NMDA cytotoxicity but did not affect cytotoxicity induced by either kainate or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). Cell viability was significantly reduced by a brief exposure of cultures to ionomycin, a calcium ionophore. Ionomycin-induced cytotoxicity was abolished by removing Ca2+ from incubating medium. S-nitrosocysteine (SNOC), which spontaneously releases nitric oxide (NO), also induced delayed cell death. Nicotine prevented ionomycin-induced cytotoxicity without affecting SNOC-induced cytotoxicity. These results suggest that nicotinic cholinergic receptor stimulation induces neuroprotection against glutamate cytotoxicity by its inhibitory action on NO-formation. Therefore, we propose that acetylcholine, acting through nicotinic cholinergic receptors, can function as a putative neuroprotective factor against neurodegeneration caused by the excessive release of glutamate and/or NMDA receptor activation.

Animals↗