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PubMedDate not supplied

The d-wave of the rod electroretinogram of rat originates in the cone pathway.

We studied the off-response of the rat ERG evoked with long duration, mesopic stimuli during light and dark adaptation, and after intravitreal injection of aspartate and (+/-)-cis-piperidine-2,3-dicarboxylic acid (PDA). At stimulus offset, the dark-adapted ERG always showed a rapid negative deflection followed by a positive deflection after which the potential returned to baseline. When the stimulus was turned off in the presence of a background of scotopic intensity, the positive deflection consisted of two components. One component was relatively small, fast, and insensitive to rod light adaptation. It resembled the d-wave of the rod ERG. The other component was slow and its amplitude grew with rod light adaptation. In the presence of aspartate, the fast-positive component was absent from the ERG while the remaining positive-going decay of the receptor potential had a time course similar to that of the slow-positive component in the untreated eye. Scotopically matched red and blue stimuli of mesopic intensity elicited equal ERG responses from the dark-adapted eye, including the two positive components in the off-response. These stimuli were also used to assess changes in the ERG off-response during recovery from a strong bleach. Even though the cone contribution to the rat ERG is very small, the presence of a small positive-going component in the off-response following an intense bleach suggested that this response originated from the cone pathway. PDA which suppresses the light response of hyperpolarizing bipolar cells and horizontal cells selectively eliminated the fast-positive component from the ERG. The findings of this study are inconsistent with the idea that the d-wave reflects the decay of the rod receptor potential. They support the possibility that signals from rods cross rod-cone gap junctions at mesopic light intensities, and drive second-order neurons in the cone pathway.

Animals↗
PubMed1994

Comparison of the potency of competitive NMDA antagonists against the neurotoxicity of glutamate and NMDA.

The object of this investigation was to determine whether glutamate uptake affects the apparent potency of the competitive antagonists DL-2-amino-5-phosphonovalerate and CGS-19755 in blocking NMDA receptor-mediated neurotoxicity. In astrocyte-rich rat cortical cultures we observed that DL-2-amino-5-phosphonovalerate and CGS-19755 were 24 and 16 times more potent against NMDA than against glutamate-induced toxicity. In contrast, DL-2-amino-5-phosphonovalerate was equipotent against the two agonists in astrocyte-poor cultures, in which dendrites are directly exposed to the extracellular medium. With the noncompetitive NMDA antagonist MK-801, similar potencies were observed against glutamate (212 +/- 16 nM) and against NMDA (155 +/- 9 nM) neurotoxicity. These results may be explained if we assume that the neuronal cell body is less susceptible than the dendrites to NMDA receptor-mediated toxicity, and that the action of glutamate in astrocyte-rich cultures is confined to the cell body. In this case, one would expect that higher concentrations of glutamate would be needed to produce toxicity in astrocyte-rich cultures, and that higher concentrations of competitive antagonists would be needed to overcome this toxicity. Our observations help explain the pharmacology of the competitive NMDA antagonists against NMDA receptor-mediated neurotoxicity but also suggest the possibility that, because the cell body and dendrites may be distinct sites for neurotoxicity, they might also involve different mechanisms of toxicity.

2-Amino-5-phosphonovalerate↗
PubMed1989

Different classes of glutamate receptors mediate distinct behaviors in a single brainstem nucleus.

We have taken advantage of the increasing understanding of glutamate neuropharmacology to probe mechanisms of well-defined vertebrate behaviors. Here we report a set of experiments that suggests distinct roles for two major classes of glutamate receptors in a discrete premotor nucleus of the brainstem. The medullary pacemaker nucleus of weakly electric fish is an endogenous oscillator that controls the electric organ discharge (EOD). Its regular frequency of firing is modulated during several distinct behaviors. The pacemaker nucleus continues firing regularly when isolated in vitro, and modulatory behaviors can be reproduced by stimulating the descending input pathway. Glutamate agonists applied to the pacemaker in vitro produced increases in frequency, while glutamate antagonists selectively blocked stimulus-induced modulations. Experiments with glutamate antagonists in the intact animal resulted in specific effects on two well-characterized behaviors. Our data indicate that these behaviors are separately mediated in the pacemaker by receptors displaying characteristics of the kainate/quisqualate and N-methyl-D-aspartate subtypes of glutamate receptor, respectively.

2-Amino-5-phosphonovalerate↗
PubMed1999

Administration of either non-NMDA receptor agonists or NMDA receptor antagonists into the substantia nigra or the globus pallidus reduces the psychostimulant effect of high helium pressure on locomotor activity in rats.

Helium pressure of >2 MPa is a well known factor underlying pressure-dependent central neuroexcitatory disorders that include locomotor and motor activity (LMA) and myoclonia. We investigated the effects of bilateral injection in either the substantia nigra (SN) or the globus pallidus (GP) of the AMPA receptor agonist (+/-)AMPA, the kainate receptor agonist kainic acid, the NMDA receptor agonist (+/-)-cis-piperidine-2,3-dicarboxylic acid (PDA), and the NMDA receptor antagonist (+/-)-2-amino-7-phosphono-heptanoic acid (AP-7) in the occurrence of helium pressure-induced LMA and myoclonia. Administration of AMPA, kainate, or AP-7 in either the SN or the GP significantly reduced high helium pressure-induced LMA, whereas the NMDA receptor agonist showed no significant effect. Injection in the SN of the non-NMDA receptor agonist AMPA and the NMDA receptor agonist PDA increased the development of high helium pressure-induced myoclonia, whereas injection of the NMDA receptor antagonist AP-7 into the SN or the GP decreased it. This confirms that NMDA transmission in the SN and the GP would play a major role in the development of helium pressure-induced LMA; manipulation of AMPA and kainate systems may have therapeutic potential. The opposite effects of AMPA on LMA and myoclonia also confirm the neural substrates involved in the motor disorder produced by helium pressure differ substantially between LMA and myoclonia.

2-Amino-5-phosphonovalerate↗
PubMed1993

Effects of LY274614, a competitive NMDA receptor antagonist, on the micturition reflex in the urethane-anaesthetized rat.

1. The effects of 3 competitive N-methyl-D-aspartate (NMDA) receptor antagonists, LY274614, LY233536 and LY235723, on the micturition reflex and external urethral sphincter EMG activity, were examined either under isovolumetric conditions or during continuous filling cystometry in urethane-anaesthetized (1.2 g kg-1, s.c.) rats. 2. Intravenous administration of LY274614 (3-30 mg kg-1) inhibited in a dose-dependent fashion both bladder and sphincter activity in the intact rats. In addition, the volume threshold for inducing micturition was increased and voided volume was decreased. 3. Intrathecal administration of LY274614 (0.06-30 micrograms) similarly inhibited bladder and sphincter activity during cystometry in intact rats. 4. In chronic spinal cord (T6-T8) transected rats LY274614 (0.1-30 mg kg-1, i.v.) did not alter bladder activity under isovolumetric conditions but decreased the amplitude of micturition contractions and sphincter EMG activity during cystometry at a dose of 10-30 mg kg-1. 5. The inhibitory effects of i.v. administration of LY274614, on bladder and sphincter activity induced by infusion of chemical irritant (0.1% acetic acid) or saline, were similar; except that a slightly larger dose was needed to inhibit sphincter activity during acetic acid infusion. 6. Peak amplitude of micturition contractions recovered to 50% of control 3 h following i.v. (30 mg kg-1) or i.t. (6 micrograms) administration of LY274614. 7. Two other chemically related NMDA antagonists, LY233536 and LY235723 produced similar but less potent effects than LY274614 when given i.v. 8. These data indicate that glutamatergic transmitter mechanisms at the level of the spinal cord are important in modulating bladder activity in the intact animal, but that these mechanisms do not contribute to bladder reflexes in the chronic spinal rat. These mechanisms may, however, contribute to sphincter activity in both intact or chronic spinal rats.

Acetates↗
PubMed1992

NMDA-receptor blockers but not NBQX, an AMPA-receptor antagonist, inhibit spreading depression in the rat brain.

The effect of different glutamate-receptor antagonists on the induction of cortical spreading depression of Leao and of cortical anoxic membrane depolarization were investigated in the anaesthetized rat. Spreading depression (SD), elicited by mechanical stimulation of the cortical surface, was inhibited by the non-competitive N-methyl-D-aspartate (NMDA)-receptor blocker, (+-)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclo-hepten-5,10-imi ne maleate (dizocilpine or MK-801), (0.30 mumol kg-1 (0.10 mg kg-1)), and the competitive NMDA-receptor antagonists; cis-4-phosphonomethyl-2-piperidine carboxylate (CGS 19755), (3.36 mumol kg-1 (0.75 mg kg-1)), D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), (1.20 mumol kg-1 (0.25 mg kg-1)) and its carboxylester CGP 43487, (6.30 mumol kg-1 (1.50 mg kg-1)). The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepripriate (AMPA)-receptor blocker, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F) quinoxaline (NBQX), administered as an intravenous dose of 29.76 and 89.29 mumol kg-1 (10 & 30 mg kg-1), which is sufficient to block seizures and protect against ischaemic brain damage, did not inhibit spreading depression. None of the drugs utilized inhibited the anoxic membrane depolarization. The data demonstrate that NMDA-receptor activation is essential for the initiation and propagation of spreading depression, while activation of AMPA-receptors is not obligatory. The observed initiation and propagation of SD, during AMPA-receptor blockade, suggest that activation of voltage-operated ion channels may contribute to release the magnesium block of the NMDA-receptor operated channel and to the initiation of SD.

2-Amino-5-phosphonovalerate↗
PubMed1995

Strategies for neuroprotection with glutamate antagonists. Extrapolating from evidence taken from the first stroke and head injury studies.

Over fifty patients with severe head injury, and one hundred with stroke, have now been treated with the competitive NMDA antagonist CGS 19755 (selfotel). Preliminary analysis has shown possible evidence of benefit for both these clinical indications, and several other glutamate antagonists are now being evaluated for these indications in Phase II trials. The optimal dose of CGS 19755 (selfotel) for efficacy for severe head trauma has not yet been identified, but may be > 3 mg/kg, as at this dose there was evidence of an ICP lowering effect and improved CPP. For stroke, however, the maximal tolerated dose was 1.5 mg/kg, because these conscious patients developed hallucinations and agitation. There were no other significant drug-associated adverse events in either of these studies. It is difficult to determine the "neuroprotective" dose for this compound in humans. By extrapolating from animal studies the "best estimate" would be around 5 mg/kg in patients with severe head trauma. For stroke, behavioral side effects were the major limiting factor for dosing. Although several NMDA antagonists, including CGS 19755 (selfotel), are currently entering efficacy trials for stroke, based upon their tremendous potency in animal models, the problem of psychomimetic effects may necessitate the use of additional management strategies, e.g., more intensive monitoring and concomitant medications.

Brain↗
PubMed1980

L-lysine epsilon-aminotransferase involved in cephamycin C synthesis in Streptomyces lactamdurans.

In Streptomyces lactamdurans, the precursor of the alpha-aminoadipoyl side-chain of cephamycin C is L-lysine. In this regard, streptomycetes differ strikingly from the fungi, which produce alpha-aminoadipic acid during the synthesis, rather than the breakdown, of L-lysine. Studies using a cell-free system showed that an aminoadipic acid. The product of this reaction was trapped and subsequently purified by ion-exchange chromatography. Thin-layer chromatography, spectrophotometry, and amino acid oxidase digestion studies identified the reaction product as L-1-piperideine-6-carboxylate, implying enzymatic removal of the epsilon amino group of L-lysine. This enzymatic activity (E.C. 2.6.1.36; L-lysine: 2-oxoglutarate 6-aminotransferase) is highly unusual and was previously conclusively demonstrated only in the genus Flavobacterium. In S. lactamdurans, the specific activity of this enzyme reaches a peak early in the fermentation (approximately 20 h) and decreases as the antibiotic begins to appear.

2-Aminoadipic Acid↗
PubMed1994

Catabolism of lysine in Penicillium chrysogenum leads to formation of 2-aminoadipic acid, a precursor of penicillin biosynthesis.

Penicillium chrysogenum L2, a lysine auxotroph blocked in the early steps of the lysine pathway before 2-aminoadipic acid, was able to synthesize penicillin when supplemented with lysine. The amount of penicillin produced increased as the level of lysine in the media was increased. The same results were observed in resting-cell systems. Catabolism of [U-14C]lysine by resting cells and batch cultures of P. chrysogenum L2 resulted in the formation of labeled saccharopine and 2-aminoadipic acid. Formation of [14C]saccharopine was also observed in vitro when cell extracts of P. chrysogenum L2 and Wis 54-1255 were used. Saccharopine dehydrogenase and saccharopine reductase activities were found in cell extracts of P. chrysogenum, which indicates that lysine catabolism may proceed by reversal of the two last steps of the lysine biosynthetic pathway. In addition, a high lysine:2-ketoglutarate-6-aminotransferase activity, which converts lysine into piperideine-6-carboxylic acid, was found in cell extracts of P. chrysogenum. These results suggest that lysine is catabolized to 2-aminoadipic acid in P. chrysogenum by two different pathways. The relative contribution of lysine catabolism in providing 2-aminoadipic acid for penicillin production is discussed.

2-Aminoadipic Acid↗
PubMed1996

Effect of N-methyl-D-aspartate-receptor blockade on hypoxic ventilatory response in unanesthetized piglets.

The central excitatory amino acid (EAA) neurotransmitter glutamate has been shown to mediate the ventilatory response to hypoxia through N-methyl-D-aspartate (NMDA) receptors in anesthetized adult animals. To determine the role of the EAA glutamate in the neonatal ventilatory response to hypoxia, 19 unanesthetized chronically instrumented piglets were studied. Minute ventilation (VE), oxygen consumption (VO2), arterial blood pressure (ABP), heart rate (HR), and blood gases were measured in room air (RA) and after 1, 5, and 10 min of hypoxia (inspired oxygen fraction = 0.10) before and after an infusion of saline or CGS-19755, a competitive NMDA-receptor blocker (10 mg/kg i.v.). Nine control piglets [age 6 +/- 1 (SD) days; weight 2.02 +/- 0.40 kg] and 10 CGS-19755-treated animals (age 6 +/- 1 days; weight 1.90 +/- 0.66 kg) were studied during quiet sleep and in a thermoneutral environment. There was a marked decrease in the VE response to hypoxia after the administration of CGS-19755. The ventilatory response to hypoxia was not modified by saline infusion. Changes in ABP and arterial PO2 during hypoxia were similar between groups, whereas the decrease in arterial PCO2 was significantly less after CGS-19755 administration. The increase in HR with hypoxia was eliminated by the NMDA-receptor blocker administration. VO2 decreased with hypoxia in both groups, but this decrease was more marked after the NMDA-receptor blockade. These results suggest that the central EAA glutamate mediates, at least in part, the hypoxic hyperventilation in unanesthetized newborn piglets.

Animals↗
PubMed1994

Glutamatergic antagonism: effects on lidocaine-induced seizures in the rat.

We tested the hypothesis that glutamate receptor antagonists increase the dose of lidocaine required to induce seizure activity. Sprague-Dawley rats were anesthetized with halothane in 40% O2/balance N2 and mechanically ventilated. After surgical preparation, halothane was discontinued. Normocapnia, normoxia, and normothermia were maintained. The electroencephalogram (EEG) and arterial blood pressure were monitored continuously. Rats were then randomized to one of six groups (control, one of three intravenous [i.v.] bolus doses of the competitive glutamate N-methyl-D-aspartate [NMDA] receptor antagonist CGS 19755, or one of two i.v. bolus and continuous infusion regimens of the competitive glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)quinoxalline [NBQX]). Thirty minutes after onset of CGS 19755 or NBQX administration (end-tidal halothane < 0.2%), rats received a continuous i.v. infusion of 1.5% lidocaine until EEG seizures occurred. The duration of the infusion (min) and total lidocaine dose (mg/kg) administered were recorded. CGS 19755 increased the lidocaine seizure threshold in a log-linear dose-dependent fashion (P < 10(-6)). The largest dose of CGS 19755 (112.5 mg/kg) increased the time to initial EEG seizure activity more than twofold (e.g., control = 12.6 +/- 2.6 min; CGS 19755 = 28.6 +/- 6.9 min). The effect of AMPA receptor antagonism was less obvious because treatment resulted in an EEG morphology dissimilar to that observed in the CGS 19755 or control groups. Our findings indicate that competitive NMDA receptor antagonists (e.g., CGS 19755) increase the dose of lidocaine required for seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Glutamate release through volume-activated channels during spreading depression.

Volume-sensitive organic anion channels (VSOACs) in astrocytes are activated by cell swelling and are permeable to organic anions, such as glutamate and taurine. We have examined the release of glutamate through VSOACs during the propagation of spreading depression (SD). SD was induced by bath application of ouabain in hippocampal brain slices and was monitored by imaging intrinsic optical signals, a technique that provides a measure of cellular swelling. The onset of SD was associated with increased light transmittance, confirming previous studies that cellular swelling occurs during SD. NMDA receptor antagonists, either noncompetitive (MK-801, 10-50 microM) or competitive (CGS-17355, 100 microM), reduced the rate of propagation of SD, indicating that glutamate release contributes to SD onset. SD still occurred in zero Ca(2+)-EGTA (0-Ca(2+)-EGTA) solution, a manipulation that depresses synaptic transmission. HPLC measurements indicated that, even in this solution, there was significant glutamate release. Two lines of experiments indicated that glutamate was released through VSOACs during SD. First, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), a blocker of VSOACs, depressed the rate of propagation of SD in a manner similar to NMDA antagonists. Second, NPPB inhibited the release of glutamate during SD in 0-Ca(2+)-EGTA external solution. These results indicate that cellular swelling during SD causes the activation of VSOACs and the release of glutamate by permeation through this channel. Cellular swelling is a result of neuronal activity and is observed during excitotoxicity. Therefore, glutamate release from VSOAC activation could occur under conditions of cell swelling and contribute to excitotoxic damage.

Animals↗
PubMed1990

Stereoselectivity and mode of inhibition of phosphoinositide-coupled excitatory amino acid receptors by 2-amino-3-phosphonopropionic acid.

DL-2-Amino-3-phosphonopropionic acid, a phosphonate-substituted derivative of aspartic acid, has been shown to be an inhibitor of excitatory amino acid-stimulated phosphoinositide hydrolysis in rat brain slices. In this study, the enantiomers of 2-amino-3-phosphonopropionic acid were synthesized and used to further characterize the stereoselectivity and mechanism of interaction of this compound for inhibiting phosphoinositide-coupled (metabotropic) excitatory amino acid receptors. L-2-Amino-3-phosphonopropionic acid was 3-5 times more potent than D-2-amino-3-phosphonopropionic acid as an inhibitor of ibotenate-stimulated [3H]inositol monophosphate formation in slices of the rat hippocampus or quisqualate-stimulated [3H]inositol monophosphate formation in neonatal rat cerebral cortical slices. Carbachol-stimulated phosphoinositide hydrolysis was not inhibited by L-2-amino-3-phosphonopropionic acid, and L-2-amino-3-phosphonopropionic acid had no appreciable affinity for ionotropic excitatory amino acid receptors at concentrations required to inhibit metabotropic excitatory amino acid responses. The inhibitory effects of L-2-amino-3-phosphonopropionic acid or L-2-amino-4-phosphonobutyric acid on phosphoinositide hydrolysis were not competitive, because they could not be surmounted by increasing concentrations of ibotenate or quisqualate. L-2-Amino-3-phosphonopropionic acid inhibition also could not be prevented by washing the tissue before incubation with ibotenate. Thus, L-2-amino-3-phosphonopropionic acid is a stereoselective inhibitor of metabotropic excitatory amino acid receptors with little affinity for ionotropic receptors. However, the inhibitory effects of L-2-amino-3-phosphonopropionic acid or L-2-amino-4-phosphonobutyric acid were not readily reversed, and the site at which they act to inhibit metabotropic excitatory amino acid receptors remains to be determined.

Alanine↗
PubMedDate not supplied

Antiepileptic effects of the excitatory amino acid antagonist cis-2,3 piperidine-dicarboxylic acid depend on non-N-methyl-d-aspartate receptors.

The effects of the broad spectrum antagonist of the excitatory amino acid neurotransmission, the cis-2,3 piperidine-dicarboxylic acid (cis-2,3 PDA) were investigated on the epileptiform activity induced in vitro by different treatments on rat hippocampal slices. The drug reduced the bursting duration by 45% and the occurrence of the additional population spikes by 50% compared with controls using 1 microM kainic acid to induce epileptiform bursting. At the same concentrations (50-100 microM) cis-2,3 PDA did not significantly affect the magnesium free-induced epileptiform activity. At higher concentrations (200-400 microM), the drug was able to reduce by 25% the bursting duration and the occurrence of the additional population spikes using 1 mM penicillin to induce epileptiform bursting. Our data indicate that the broad spectrum antagonist of the excitatory amino acid transmission, cis-2,3 PDA, presents a low antiepileptic activity that could be related to an influence on "non N-methyl-d-aspartate" (NMDA) receptors.

Animals↗
PubMedDate not supplied

Synthesis, preliminary evaluation and molecular modeling studies of new, conformationally constrained analogues of the competitive NMDA receptor antagonist 4-(phosphonomethyl)-2-piperidinecarboxylic acid (CGS 19755).

Two new spirobicyclophosphonate isomers (19 and 20), conformationally constrained analogues of the potent competitive NMDA antagonist CGS 19755 (4), have been designed and synthetized with the aim of gaining insight into the conformational preference of the crucial distal phosphonate moiety at the antagonist NMDA binding site. The preliminary biological evaluation reveals that the activity as NMDA antagonist resides only in the (1R,5S,7R)-isomer (19), characterized by a (-)-gauche disposition around the C1-C5 bond, thus confirming previously reported pharmacophore models.

Binding Sites↗
PubMed1991

Accumulation of extracellular glutamate and neuronal death in astrocyte-poor cortical cultures exposed to glutamine.

The function of astrocytes in cerebral cortex may be studied by comparing the properties of conventional, astrocyte-rich cultures with astrocyte-poor cultures in which astrocyte proliferation has been stringently suppressed. Exposure of astrocyte-poor, but not astrocyte-rich, cultures to fresh medium containing 2 mM glutamine resulted in the death of most neurons within 24 h. This study was undertaken to understand the basis for the apparent toxicity of glutamine in astrocyte-poor cultures. The toxicity of glutamine was found to be mediated by glutamate, which demonstrated an LD50 as a neurotoxin in astrocyte-poor cultures of 2 microM. Exposure of astrocyte-poor (but not astrocyte-rich) cultures to fresh medium containing glutamine for 17.5-24 h resulted in the accumulation of substantial quantities of glutamate (255 +/- 158 microM; mean +/- standard deviation) coincident with the death of neurons in the cultures. Exposure of astrocyte-poor cultures to glutamate in the absence of glutamine did not result in the accumulation of extracellular glutamate. Both the neuronal death and the extracellular glutamate accumulation in astrocyte-poor cultures exposed to glutamine could be blocked by N-methyl-D-aspartate (NMDA) antagonists. These observations suggest that astrocytes as well as glutamine may play an important role in the pathogenesis of glutamate neurotoxicity in the central nervous system.

2-Amino-5-phosphonovalerate↗