Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “GLUTAMATES”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 235 records · Page 13Linked to original sources
PubMed1993

MK-801 and memantine protect cultured neurons from glutamate toxicity induced by glutamate carboxypeptidase-mediated cleavage of methotrexate.

Cleavage of methotrexate into glutamate and diaminomethylpteroate by intrathecal glutamate carboxypeptidase is a new approach to the treatment of acute methotrexate neurotoxicity. The simulation of glutamate carboxypeptidase rescue from high-dose methotrexate in neuron astrocyte cocultures of rat cerebellum or cerebral cortex resulted in a selective, concentration-dependent neurotoxicity. The neurotoxicity was caused by the enzymatic release of glutamate from methotrexate at lower concentrations of methotrexate, and by both glutamate and diaminomethylpteroate at concentrations of methotrexate exceeding 200 microM. The good neuroprotection afforded by MK-801 and memantine suggested that glutamate toxicity was mediated by N-methyl-D-aspartate receptors. Methotrexate alone was not toxic to astrocytes, neurons, or the neurite networking. [3H]thymidine and [3H]deoxyuridine incorporation studies showed that astrocyte proliferation in the presence of methotrexate was maintained by the reutilization of pyrimidine bases for DNA synthesis. N-methyl-D-asparate receptor antagonists should be coadministered in future experimental and clinical trials examining intrathecal glutamate carboxypeptidase rescue of methotrexate toxicity.

Animals↗
PubMedDate not supplied

Reactive amino acid residues involved in glutamate-binding of human glutamate dehydrogenase isozymes.

In the present study, the cassette mutagenesis at several putative positions (K94, G96, K118, K130, or D172) was performed to examine the residues involved in the glutamate-binding of the human glutamate dehydrogenase isozymes (hGDH1 and hGDH2). None of the mutations tested affected the expression or stability of the proteins. There was dramatic reduction in the catalytic efficiency in mutant proteins at K94, G96, K118, or K130 site, but not at D172 site. The K(M) values for glutamate were 4-10-fold greater for the mutants at K94, G96, or K118 site than for the wild-type hGDH1 and hGDH2, whereas no differences in the K(M) values for NAD(+) were detected between the mutant and wild-type enzymes. For K130Y mutant, the K(M) value for glutamate increased 1.6-fold, whereas the catalytic efficiency (k(cat)/K(M)) showed only 2-3% of the wild-type. Therefore, the decreased catalytic efficiency of the K130 mutant mainly results from the reduced k(cat) value, suggesting a possibility that the K130Y residue may be involved in the catalysis rather than in the glutamate-binding. The D172Y mutant did not show any changes in k(cat) value and K(M) values for glutamate and NAD(+), indicating that D172Y is not directly involved in catalysis and substrates binding of the hGDH isozymes. For sensitivity to ADP activation, only the D172Y mutant showed a reduced sensitivity to ADP activation. The reduction of ADP activation in D172Y mutant was more profoundly observed in hGDH2 than in hGDH1. There were no differences in their sensitivities to GTP inhibition between the wild-type and mutant GDHs at all positions tested. Our results suggest that K94, G96, and K118 residues play an important role, although at different degrees, in the binding of glutamate to hGDH isozymes.

Adenosine Diphosphate↗
PubMed2001

The anion conductance of the glutamate transporter EAAC1 depends on the direction of glutamate transport.

The steady-state and pre-steady-state kinetics of glutamate transport by the neuronal glutamate transporter EAAC1 were determined under conditions of outward glutamate transport and compared to those found for the inward transport mode. In both transport modes, the glutamate-induced current is composed of two components, the coupled transport current and the uncoupled anion current, and inhibited by a specific non-transportable inhibitor. Furthermore, the glutamate-independent leak current is observed in both transport modes. Upon a glutamate concentration jump outward transport currents show a distinct transient phase that deactivates within 15 ms. The results demonstrate that the general properties of EAAC1 are symmetric, but the rates of substrate transport and anion flux are asymmetric with respect to the orientation of the substrate binding site in the membrane. Therefore, the EAAC1 anion conductance differs from normal ligand-gated ion channels in that it can be activated by glutamate and Na(+) from both sides of the membrane.

Amino Acid Transport System X-AG↗
PubMed2001

Glutamate induces oxidative stress not mediated by glutamate receptors or cystine transporters: protective effect of melatonin and other antioxidants.

Glutamate is responsible for most of the excitatory synaptic activity and oxidative stress induction in the mammalian brain. This amino acid is increased in the substantia nigra in parkinsonism due to the lack of dopamine restraint to the subthalamic nucleus. Parkinson's disease also shows an increase of iron levels in the substantia nigra and a decrease of glutathione, the antioxidant responsible for the ascorbate radical recycling. Considered together, these facts could make the antioxidant ascorbate behave as a pro-oxidant in parkinsonism. Since both glutamate and ascorbate are present in the synaptosomes and neurons of substantia nigra, we tested 1) if glutamate is able to induce oxidative stress independently of its excitatory activity, and 2) if ascorbate may have synergistic effects with glutamate when these two molecules co-exist. Brains were homogenized in order to disrupt membranes and render membrane receptors and intracellular signaling pathways non-functional. In these homogenates glutamate induced lipid peroxidation, indicating that this amino acid also may cause oxidative stress not mediated by its binding to glutamate receptors or cystine transporters. Ascorbate also induced lipid peroxidation thus behaving as a pro-oxidant. Both substances together produced an additive effect but they did not synergize. Given that melatonin is a potent physiological antioxidant with protective effects in models of neurotoxicity, we tested the role of this secretory product on the pro-oxidant effect of both compounds given separately or in combination. We also checked the protective ability of several other antioxidants. Pharmacological doses of melatonin (millimolar), estrogens, pinoline and trolox (micromolar) prevented the oxidant effect of glutamate, ascorbate, and the combination of both substances. Potential therapeutic application of these results is discussed.

Acetylcysteine↗
PubMed1995

Release of glutamate and aspartate from CA1 synaptosomes: selective modulation of aspartate release by ionotropic glutamate receptor ligands.

Synaptosomes prepared from area CA1 of the rat hippocampus were used to determine (a) whether Schaffer collateral-commissural-ipsilateral associational terminals release both aspartate and glutamate in a Ca(2+)-dependent manner when reuptake of released glutamate is minimal and (b) whether autoreceptor mechanisms described in CA1 or hippocampal slices could reflect direct actions of glutamate receptor ligands on the synaptic terminal. When challenged for 1 min with either 25 mM K+ or 300 microM 4-aminopyridine, CA1 synaptosomes released both glutamate and aspartate in Ca(2+)-dependent manner. The glutamate/aspartate ratio was approximately 5:1 in each case. K(+)-evoked glutamate release was unaffected by ligands active at NMDA or (RS)-alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate (AMPA) receptors. Unlike glutamate release, the release of aspartate was enhanced by NMDA, and this effect was blocked by D-2-amino-5-phosphonovalerate (D-AP5). Kainate selectively depressed and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) selectively increased the K(+)-evoked release of aspartate. AMPA enhanced aspartate release, like the antagonist CNQX. When applied in the presence of diazoxide, which blocks the desensitization of AMPA receptors, AMPA and kainate both depressed aspartate release. These findings support the view that Schaffer collateral-commissural-ipsilateral associational terminals release aspartate as well as glutamate and that these two release processes are regulated by different autoreceptor mechanisms.

Animals↗
PubMed1985

Effect of starch ingestion on plasma glutamate concentrations in humans ingesting monosodium L-glutamate in soup.

Plasma glutamate concentrations in human subjects are markedly lower when monosodium L-glutamate is ingested in a water solution containing partially hydrolyzed starch than when ingested in water alone. This study was carried out to investigate whether starch ingested as crackers had a similar effect. Eight normal adult subjects (four male, four female) ingested three servings of a beef consommé providing 50 mg/kg body weight monosodium L-glutamate. One serving was consommé alone, the other two were accompanied by sufficient crackers to provide 0.25 or 0.5 g starch per kilogram body weight, respectively. Ingestion of consommé containing glutamate significantly increased the mean plasma glutamate concentration above baseline to a mean peak value 30 min later. The peak after consumption of 0.5 g starch per kilogram body weight, but not 0.25 g/kg body weight, was significantly lower than when consommé alone was ingested. These data indicate that simultaneous ingestion of metabolizable carbohydrate with glutamate has a marked effect on the plasma glutamate response and indicate that the threshold value for carbohydrate is greater than 0.25 g/kg body weight.

Adult↗
PubMed1996

Glutamate depresses release by activating non-conventional glutamate receptors at crayfish nerve terminals.

The present study shows that release of glutamate from crayfish nerve terminals is inhibited at low depolarizing current pulses by glutamate, N-methyl-D-aspartate (NMDA) and quisqualate. These agonists elicit inhibitory effects at concentrations as low as 10(-8) M (quisqualate) and 10(-7) M (glutamate and NMDA). The NMDA-mediated inhibition is blocked by (+/-)-2-amino-5-phosphonovaleric acid (APV). The quisqualate-mediated inhibition is blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Both CNQX and APV are needed to block glutamate-mediated inhibition. The inhibition of release is not accompanied by a detectable change in presynaptic membrane conductance at the secondary branch. Using fura-2, Ca2+ accumulation during repetitive stimulation (100 Hz) was monitored in single release boutons. Inhibition of release, elicited by 10(-4) M glutamate, was not associated with a reduction in the accumulation of Ca2+. We show that the glutamate released from a single or a few release boutons during normal activity acts similarly to glutamate added externally, i.e. it inhibits its own release.

2-Amino-5-phosphonovalerate↗
PubMed1988

Glucose and synaptosomal glutamate metabolism: studies with [15N]glutamate.

The metabolism of [15N]glutamate was studied with gas chromatography-mass spectrometry in rat brain synaptosomes incubated with and without glucose. [15N]Glutamate was taken up rapidly by the preparation, reaching a steady-state level in less than 5 min. 15N was incorporated predominantly into aspartate and, to a much lesser extent, into gamma-aminobutyrate. The amount of [15N]ammonia formed was very small, and the enrichment of 15N in alanine and glutamine was below the level of detection. Omission of glucose substantially increased the rate and amount of [15N]aspartate generated. It is proposed that in synaptosomes (a) the predominant route of glutamate nitrogen disposal is through the aspartate aminotransferase reaction; (b) the aspartate aminotransferase pathway generates 2-oxoglutarate, which then serves as the metabolic fuel needed to produce ATP; (c) utilization of glutamate via transamination to aspartate is greatly accelerated when flux through the tricarboxylic acid cycle is diminished by the omission of glucose; (d) the metabolism of glutamate via glutamate dehydrogenase in intact synaptosomes is slow, most likely reflecting restriction of enzyme activity by some unknown factor(s), which suggests that the glutamate dehydrogenase reaction may not be near equilibrium in neurons; and (e) the activities of alanine aminotransferase and glutamine synthetase in synaptosomes are very low.

Amino Acids↗
PubMed1993

Inhibition of glutamate uptake with L-trans-pyrrolidine-2,4-dicarboxylate potentiates glutamate toxicity in primary hippocampal cultures.

Sodium-dependent, high-affinity glutamate transport is generally assumed to limit the toxicity of glutamate in vivo and in vitro, but there is very little direct evidence to support this hypothesis. In the present study, the effects of the specific uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate on the toxicity and clearance of glutamate were examined in hippocampal neuronal cultures. At a concentration that was not toxic by itself, L-trans-pyrrolidine-2,4-dicarboxylate increased the toxicity of glutamate approximately fivefold and slowed the clearance of glutamate from the extracellular space. This toxicity was almost completely blocked by the N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonopentanoate. These studies provide direct evidence that sodium-dependent, high-affinity glutamate transport limits glutamate toxicity in vitro.

Animals↗
PubMed2005

Regulation of glutamate carboxypeptidase II hydrolysis of N-acetylaspartylglutamate (NAAG) in crayfish nervous tissue is mediated by glial glutamate and acetylcholine receptors.

Glutamate carboxypeptidase II (GCPII), a glial ectoenzyme, is responsible for N-acetylaspartylglutamate (NAAG) hydrolysis. Its regulation in crayfish nervous tissue was investigated by examining uptake of [3H]glutamate derived from N-acetylaspartyl-[3H]glutamate ([3H]NAAG) to measure GCPII activity. Electrical stimulation (100 Hz, 10 min) during 30 min incubation with [3H]NAAG increased tissue [3H]glutamate tenfold. This was prevented by 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a GCPII inhibitor, suggesting that stimulation increased the hydrolysis of [3H]NAAG and metabolic recycling of [3H]glutamate. Antagonists of glial group II metabotropic glutamate receptors (mGLURII), NMDA receptors and acetylcholine (ACh) receptors that mediate axon-glia signaling in crayfish nerve fibers decreased the effect of stimulation by 58-83%, suggesting that glial receptor activation leads to stimulation of GCPII activity. In combination, they reduced [3H]NAAG hydrolysis during stimulation to unstimulated control levels. Agonist stimulation of mGLURII mimicked the effect of electrical stimulation, and was prevented by antagonists of GCPII or mGLURII. Raising extracellular K+ to three times the normal level stimulated [3H]NAAG release and GCPII activity. These effects were also blocked by antagonists of GCPII and mGLUR(II). No receptor antagonist or agonist tested or 2-PMPA affected uptake of [3H]glutamate. We conclude that NAAG released from stimulated nerve fibers activates its own hydrolysis via stimulation of GCPII activity mediated through glial mGLURII, NMDA and ACh receptors.

Animals↗
PubMed1991

Activation of glutamate receptors and glutamate uptake in identified macroglial cells in rat cerebellar cultures.

1. Patch-clamp methods have been used to examine the action of excitatory amino acids on three types of glial cell in cultures of rat cerebellum, namely type-1-like astrocytes, type-2 astrocytes and oligodendrocytes. In addition we have examined glutamate sensitivity of the precursor cell (the O-2A progenitor) that gives rise to type-2 astrocytes and oligodendrocytes. 2. Glutamate (30 microM), quisqualate (3-100 microM), (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA, 10-30 microM) and kainate (10-500 microM) were applied to cerebellar type-2 astrocytes examined under whole-cell voltage clamp. Each of these agonists induced inward currents in cells held at negative membrane potentials. The currents reversed direction near 0 mV holding potential. N-Methyl-D-aspartate (NMDA, 30-100 microM) or aspartate (30 microM) in the presence of glycine (1 microM) did not evoke any whole-cell current changes in type-2 astrocytes. 3. The distribution of glutamate receptors in type-2 astrocytes was mapped with single- or double-barrelled ionophoretic pipettes containing quisqualate or kainate. Application of these agonists (current pulses 100 ms, 50-100 nA) to cells held at -60 mV evoked inward currents of 20-120 pA in the cell soma and 10-80 pA in the processes. Responses could also be obtained at the extremities of processes (approximately 60 microns from the soma). 4. Quisqualate or kainate (at 30 microM) applied to O-2A progenitor cells from rat cerebellum or optic nerve induced whole-cell currents (quisqualate 20-30 pA; kainate 20-50 pA, holding potential, Vh = -60 mV) that reversed near 0 mV. In common with type-2 astrocytes, the progenitor cells did not respond to NMDA (30 microM). 5. Type-1-like astrocytes produced large inward currents to glutamate (30 microM). These currents remained inward-going at holding potentials as positive as +80 mV and were not accompanied by any apparent noise increase. This result can be explained by the presence of an electrogenic glutamate uptake carrier. In cells kept up to 4 days in vitro, quisqualate, kainate and NMDA each failed to produce any whole-cell current changes, indicating the absence of receptors in type-1-like astrocytes at this stage in culture. Furthermore the glutamate uptake currents in type-1-like astrocytes were inhibited when external Na+ was replaced by Li+, although Li+ was found to pass through the glutamate channel in type-2 astrocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Overexpression of constitutively activated glutamate dehydrogenase induces insulin secretion through enhanced glutamate oxidation.

Glutamate dehydrogenase (GDH) catalyzes reversible oxidative deamination of l-glutamate to alpha-ketoglutarate. Enzyme activity is regulated by several allosteric effectors. Recognition of a new form of hyperinsulinemic hypoglycemia, hyperinsulinism/hyperammonemia (HI/HA) syndrome, which is caused by gain-of-function mutations in GDH, highlighted the importance of GDH in glucose homeostasis. GDH266C is a constitutively activated mutant enzyme we identified in a patient with HI/HA syndrome. By overexpressing GDH266C in MIN6 mouse insulinoma cells, we previously demonstrated unregulated elevation of GDH activity to render the cells responsive to glutamine in insulin secretion. Interestingly, at low glucose concentrations, basal insulin secretion was exaggerated in such cells. Herein, to clarify the role of GDH in the regulation of insulin secretion, we studied cellular glutamate metabolism using MIN6 cells overexpressing GDH266C (MIN6-GDH266C). Glutamine-stimulated insulin secretion was associated with increased glutamine oxidation and decreased intracellular glutamate content. Similarly, at 5 mmol/l glucose without glutamine, glutamine oxidation also increased, and glutamate content decreased with exaggerated insulin secretion. Glucose oxidation was not altered. Insulin secretion profiles from GDH266C-overexpressing isolated rat pancreatic islets were similar to those from MIN6-GDH266C, suggesting observation in MIN6 cells to be relevant in native beta-cells. These results demonstrate that, upon activation, GDH oxidizes glutamate to alpha-ketoglutarate, thereby stimulating insulin secretion by providing the TCA cycle with a substrate. No evidence was obtained supporting the hypothesis that activated GDH produced glutamate, a recently proposed second messenger of insulin secretion, by the reverse reaction, to stimulate insulin secretion.

Animals↗
PubMed1994

Glutamate in pyridoxine-dependent epilepsy: neurotoxic glutamate concentration in the cerebrospinal fluid and its normalization by pyridoxine.

BACKGROUND: Pyridoxine-dependent epilepsy is a rare autosomal recessive disorder. Untreated patients suffer from a progressive encephalopathy with mental retardation, intractable epilepsy, and progressive neurological signs and symptoms. Lifelong supplementation with vitamin B6 is the treatment of choice. However, despite early treatment, many patients develop mental retardation. OBJECTIVES: To assess the role of glutamate as an excitatory neurotransmitter and neurotoxin in pyridoxine-dependent epilepsy. METHODS: We examined cerebrospinal fluid (CSF) levels of glutamate, gamma-aminobutyric acid, and pyridoxal-5'-phosphate in a patient with pyridoxine dependency while on and off vitamin B6 treatment. RESULTS: Off vitamin B6 the glutamate level was two hundred times normal. An intermediate dose of vitamin B6 (5 mg/kg BW/day) caused normalization of the EEG and remission of the seizures, but the CSF glutamate concentration was still ten times normal. With a higher dose of pyridoxine (10 mg/kg BW/day) the CSF glutamic acid normalized. CONCLUSIONS: The results indicate that control of epilepsy might not suffice as the therapeutic aim in treating of pyridoxine dependency. In view of the evidence for the role of excitatory amino acids in destruction of CNS nerve cells, the optimal treatment must counteract the raised levels of CSF glutamate and the dosage of vitamin B6 must be adjusted accordingly. The development of mental retardation might theoretically be prevented by adjusting the dose of vitamin B6 to achieve not only remission of epilepsy but also normalization of CSF glutamate.

Adrenocorticotropic Hormone↗
PubMed1996

Glutamate-induced swelling of cultured astrocytes is mediated by metabotropic glutamate receptor.

The effects of glutamate and its agonists and antagonists on the swelling of cultured astrocytes were studied. Swelling of astrocytes was measured by [3H]-O-methyl-D-glucose uptake. Glutamate at 0.5, 1 and 10 mmol/L and trans-1-aminocyclopentane-1, 3-dicarboxylic acid (trans-ACPD), a metabotropic glutamate receptor (mGluR) agonist, at 1 mmol/L caused a significant increase in astrocytic volume, whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) was not effective. L-2-amino-3-phosphonopropionic acid (L-AP3), an antagonist of mGluR, blocked the astrocytic swelling induced by trans-ACPD or glutamate. In Ca(2+)-free condition, glutamate was no longer effective. Swelling of astrocytes induced by glutamate was not blocked by CdCl2 at 20 mumol/L, but significantly reduced by CdCl2 at 300 mumol/L and dantrolene at 30 mumol/L. These findings indicate that mGluR activation results in astrocytic swelling and both extracellular calcium and internal calcium stores play important roles in the genesis of astrocytic swelling induced by glutamate.

Animals↗
PubMed1999

Recurrent glutamate stimulations potentiate the hydroxyl radicals response to glutamate.

Neurotoxicity induced by hydroxyl radicals (OH) release is thought to be involved in a number of acute and chronical neuropathologies of the central nervous system. As far as neurodegenerative processes are concerned, the possible mechanisms giving rise to such OH releases remain poorly understood. In the present study, unanesthetized rats were perfused with a low salicylate solution through a chronic microdialysis cannula implanted into the striatum, and the OH responses to glutamate were analyzed. A single bolus of 3 mM glutamate elicited only minute releases of OH in naive rats. By contrast, recurrent infusions at 1-week intervals of the same glutamate concentration induced a robust OH response. Similar potentiation of the initial response also occurred for a larger glutamate concentration (30 mM). Oppositely, multiple injections of a high (300 mM) glutamate concentration resulted in a slow down of the initial OH response recorded in naive animals. The mechanisms giving rise to such effects are presently unknown. It is, however, clear that repetitive dysfunctions of the glutamate neurotransmission may be sufficient to promote the release of significant amounts of hydroxyl radicals, resulting in a progressive impairment of the astrocytic glutamate transporter, leading to neurodegenerative processes.

Animals↗
PubMed1987

Single glutamate-gated synaptic channels at the crayfish neuromuscular junction. II. Dependence of channel open time on glutamate concentration.

Single, glutamate activated ionic channel currents were recorded from crayfish muscle in the cell attached mode. Different concentrations of glutamate were present in the patch clamp pipette. Bursts of openings were observed with a concentration dependent number of short gaps per burst. Also the mean burst length was concentration dependent and varied between 0.3 ms (100 microM) and 1.3 ms (20 mM). Even with the highest concentrations of glutamate the channel activations were well separated and the beginning and the end of a burst could be defined. The distributions of open times and of burst lengths could be fitted well with a single exponential component for all studied concentrations of glutamate. The distributions of closed times were composed of two or three exponential components (with possibly more than one channel contributing). The mean burst length was compared with the time constants of decay of synaptic currents (0.8-3.0 ms at 19 degrees C) which were measured either with the same pipette as the single channel currents or with a macro patch technique. An estimation of the glutamate concentration at the receptors during synaptic transmission gave values in the millimolar range. The most simple model of glutamate-receptor interaction contains two binding sites for glutamate but no singly liganded open states. Rate constants were estimated for this model.

Animals↗
PubMed1998

The role of glutamate in the locus coeruleus during opioid withdrawal and effects of H-7, a protein kinase inhibitor, on the action of glutamate in rats.

To investigate the role of glutamate in the locus coeruleus (LC) during opioid withdrawal, rats were continuously infused with morphine (a mu-opioid receptor agonist, 26 nmol/microl/h) or butorphanol (a mu/delta/kappa-mixed opioid receptor agonist, 26 nmol/microl/h) intracerebroventricularly (i.c.v.) via osmotic minipumps for 3 days. A direct LC injection of glutamate (1 or 10 nmol/5 microl) or naloxone (an opioid receptor antagonist, 24 nmol/5 microl) induced withdrawal signs in morphine- or butorphanol-dependent animals. However, these agents failed to precipitate any withdrawal signs in saline-treated control animals. On the other hand, the expression of withdrawal signs precipitated by the administration of glutamate or naloxone in opioid-dependent animals was completely blocked by concomitant infusion with 1 or 10 nmol/microl/h of an inhibitor of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase and protein kinase C, H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine]. In animals that had been infused with opioids in the same manner, i.c.v. injection of naloxone (48 nmol/5 microl) precipitated withdrawal signs and increased extracellular fluid levels of glutamate in the LC of morphine- or butorphanol-dependent rats measured by in vivo microdialysis method. However, concomitant infusion with H-7 inhibited the increases of glutamate levels in the LC. These results strongly suggest that an expeditious release of glutamate in the LC region plays an important role in the expression of physical dependence on opioids. Furthermore, the action on glutamate release might be increased by the enhancement of cAMP-dependent protein kinase and/or protein kinase C activity.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

[Glutamate neurotoxicity during spinal cord ischemia--neuroprotective effects of glutamate receptor antagonists].

Evidence is accumulating that glutamate, a major neurotransmitter, exerts potent neurotoxic activity during ischemia. In our laboratory, a delayed-onset paraplegia model using rabbits has been developed and described. The severity of the ischemic event in this model, i.e., extracellular glutamate overload, is believed to influence the etiology of this borderline lesion. We hypothesized that glutamate receptor antagonists (MK-801, NBQX) would attenuate the delayed neuronal dysfunction that follows spinal cord ischemia. Infrarenal aortic segments from 18 New Zealand white rabbits were isolated for 5 minutes and infused at a rate of 2 ml/min. Group I (n = 6) received normothermic L-glutamate (20 mM). Group II (n = 6) received 3 mg of MK-801 and normothermic L-glutamate (20 mM). Group III (n = 6) received 3 mg of NBQX and normothermic L-glutamate (20 mM). Neurologic function was assessed at 6, 24, and 48 hours after surgery according to the modified Tarlov scale. After 48 hours, the rabbits were euthanized and spinal cords were harvested for histologic examination. The neurologic function of three rabbits in group I showed acure paraplegia and the other three showed delayed-onset paraplegia, whereas all group II animals had nearly intact neurologic function and all group III animals showed mild neurologic disturbance. Histologic examination of spinal cords from rabbits in group I showed evidence of moderate spinal cord injury with necrosis of central gray matter and adjacent white matter and axonal swelling, whereas spinal cords from group II showed small and localized spinal cord injuries and those from group III revealed no evidence of cord injury. These results indicate that MK-801 and NBQX exert different neuroprotective effects related to different mechanisms of glutamate neurotoxicity mediated by the NMDA receptor and non-NMDA receptor, which initiate a deleterious cascade of biochemical events that ultimately results in delayed-onset paraplegia.

Animals↗