[Metabolism of 1-aspartic acid by B. roseus fluorescens].
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Aspartic Acid↗
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Effects of arginine-glycine-aspartic acid (RGD) containing snake venom peptides on parthenogenetic development and in vitro fertilization of bovine oocytes.
The ability of synthetic arginine-glycine-aspartic acid (RGD)-containing peptides to induce intracellular calcium transients similar to those observed at fertilization by spermatozoa in the bovine has been reported (Campbell et al., 2000: Biol Reprod 62:1702-1709; Sessions et al., 2006. Mol Reprod Dev). These results also indicated the ability of synthetic RGD-containing peptides to induce activation and subsequent parthenogenetic development to the blastocyst stage, although, at numbers lower than observed with control in vitro fertilization (IVF). Evidence has been provided indicating the important effect of surrounding regions on the biological activity of the RGD sequence (Zhu and Evans, 2002; Sessions et al., 2006). The current experiments were designed to use natural RGD-containing sequences (disintegrins) to understand their effects. A total of three RGD-containing snake venom peptides (Kistrin (K), Elegantin (Ele), and Echistatin (Ech)) and one nonRGD-containing venom (Erabutoxin B (EB; control) were used at three concentrations (0.1, 1, and 10 micro g /ml) to induce parthenogenetic development to the blastocyst stage and in conjunction (1.0, 5.0, and 10 micro g/ml) with spermatozoa to evaluate competitive inhibition of fertilization and subsequent development. A (P < 0.01) higher number of bovine oocytes developed to the blastocyst stage after incubation with K, Ele and Ech at 1.0 micro g/ml, and was not different (P > 0.01) from IVF control. Fertilization was significantly reduced (P < 0.01) at all concentrations of K, Ele and Ech as compared to IVF control. No reduction (P > 0.05) was observed in EB (nonRGD) treated oocytes. These results support the involvement of a disintegrin-integrin interaction at fertilization in the bovine resulting in activation and subsequent development.
Amino Acid Sequence↗
Acceleration of enzymatic reaction of trypsin through the formation of water-soluble complexes with poly(ethylene glycol)-block-poly(alpha,beta-aspartic acid).
The amidase activity of bovine pancreas trypsin in water-soluble complexes with poly(ethylene glycol)-block-poly(alpha,beta-aspartic acid) (PEG-PAA) was evaluated by a colorimetric assay using L-lysine p-nitroanilide as a substrate. The enzymatic reaction of trypsin was accelerated through the complexation with PEG-PAA. By determining the kinetic parameters of the enzymatic reaction of trypsin, it was confirmed that the catalytic rate constant of the complexed trypsin was 15 times higher than that of the native trypsin. From the evaluation of pH dependence of initial reaction rate, it was indicated that this acceleration was induced by a stabilization of the imidazolium ion of the His residue in the catalytic site, the Asp-His-Ser triad, of trypsin due to the Asp units of PEG-PAA. The hydrogen bonded Asp-His pairs are critical constituents in several key enzymatic reactions including serine protease and apurinic endonucleases, and it was expected that the acceleration of the catalytic reaction might occur for other enzymes by the formation of water-soluble complexes with PEG-PAA.
Amino Acids↗
[Pharmacological studies on receptive mechanisms for N-methyl-D-aspartic acid signals].
A series of investigations has been made to analyze the receptive mechanisms for signals mediated by an N-methyl-D-aspartic acid (NMDA)-sensitive subclass of brain excitatory amino acid receptors. Treatment of synaptic membranes with a low concentration of Triton X-100 induced a drastic disclosure of NMDA-sensitive [3H]glutamic acid binding without affecting the NMDA-insensitive populations. In these Triton-treated membranes, binding of [3H]glycine (Gly) was displaced by D-serine and D-alanine, but not by strychnine. These membrane preparations were also useful for detecting the binding of noncompetitive blockers to open NMDA channels in a manner highly sensitive to potentiation by NMDA, Gly and the polyamine spermidine. Comparative studies on the binding of agonist and antagonist ligands in different central regions suggested the possible heterogeneity of the NMDA, Gly and ionophore domains. By screening more than 1000 compounds, the binding of noncompetitive blockers was completely abolished by the addition of 6,7-dichloroquinoxaline-2,3-dione, which was revealed to be a selective antagonist for the Gly domain. Binding studies using the aforementioned radioligands gave rise to the idea that both reduced and oxidized glutathione could be endogenous agonists for the NMDA domain. An i.c.v. injection of NMDA led to a marked potentiation of DNA binding activities of particular transcription factors in a manner sensitive to antagonism by antagonists at the respective domains. These results suggest that NMDA signals are indeed transduced from cell surfaces into nuclei to express nuclear transcription factors through the NMDA-sensitive subclass that is a receptor ionophore complex consisting of at least 4 different constituents including the NMDA, Gly, polyamine and ionophore domains.
Animals↗
Evidence for involvement of brain dopamine and other mechanisms in the behavioral action of the N-methyl-D-aspartic acid antagonist MK-801 in control and 6-hydroxydopamine-lesioned rats.
Behavioral activation following systemic administration of the N-methyl-D-aspartic acid receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d) cyclohepten-5,10-imine; dizocilpine] was examined in unlesioned control and in neonatal-6-hydroxydopamine (OHDA) lesioned rats. Neonatal-6-OHDA lesioned animals were found more sensitive than control rats and female rats more sensitive than males to this MK-801-induced behavioral activation. CGS-19755, a competitive NMDA antagonist, also increased activity in neonatally lesioned animals. The increased activity level following MK-801 administration to neonatally lesioned rats was reduced, but not eliminated, by pretreatment with alpha-methyltyrosine, indicating that endogenous catecholamines were partially responsible for this action of MK-801. Furthermore, neither a D1- nor a D2-dopamine antagonist was totally effective alone in reducing MK-801-induced behavioral activation in the neonatally lesioned rats, but MK-801-induced activity was reduced to the level observed after alpha-methyltyrosine when both dopamine antagonists were administered in combination. In contrast to these results, alpha-methyltyrosine virtually eliminated the MK-801-induced activity in adult-lesioned rats. When individual behaviors induced by MK-801 were examined in neonatal-6-OHDA lesioned rats, MK-801 did not produce the same behaviors as L-dihydroxyphenylalanine or a D1- or D2-dopamine agonist. Whereas MK-801 had no major effect on most behaviors induced by specific D1- or D2-dopamine agonists, it blocked some behaviors produced after L-dihydroxyphenylalanine administration, including the self-injurious behavior. Repeated MK-801 treatment resulted in increasingly greater motor activity, but this was not related to increased D1-dopamine receptor sensitization. In support of a regional action of MK-801, MK-801 induced c-fos-like immunoreactivity in the cerebral cortex, but not in the nucleus accumbens or striatum. The action of MK-801 to increase c-fos-like immunoreactivity in cerebral cortex was reduced, but not blocked, by SCH-23390. Additionally, MK-801 reduced, but did not eliminate, D1-dopamine agonist induced c-fos-like immunoreactivity in striatum. These data suggest that MK-801 not only can facilitate dopamine release within specific brain regions, but has behavioral and functional actions distinct from dopamine agonists.
Animals↗
A placebo-controlled randomized crossover trial of the N-methyl-D-aspartic acid receptor antagonist, memantine, in patients with chronic phantom limb pain.
UNLABELLED: In the present study we investigated the effect of the N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine (30 mg/d) on the intensity of chronic phantom limb pain (PLP) and cortical reorganization. In 8 patients with chronic PLP, memantine was tested in a placebo-controlled double-blinded crossover trial of 4 wk duration per trial. The intensity of PLP was rated hourly by the patients on a visual analog scale during baseline and both treatment periods. At the same time points, the functional organization of the primary somatosensory cortex (SI) was determined by neuromagnetic source imaging. In comparison to baseline and placebo, the NMDA receptor antagonist had no effect on the intensity of chronic PLP. In none of the periods were significant changes in the functional organization of SI observed. Although the conclusions regarding the clinical effect are limited because of the small sample size, the data indicate that in the studied dosage the NMDA receptor antagonist memantine is ineffective in the treatment of chronic PLP and is also ineffective for the reduction of associated neural plasticity in the primary SI. IMPLICATIONS: NMDA receptors play a substantial role in central nervous system changes underlying neuropathic pain. In a placebo-controlled double-blinded study we tested the effect of 30 mg memantine on chronic phantom limb pain and pain-associated cortical reorganization.
Adult↗
The antiallodynic action target of intrathecal gabapentin: Ca2+ channels, KATP channels or N-methyl-d-aspartic acid receptors?
Gabapentin is a novel analgesic whose mechanism of action is not known. We investigated in a postoperative pain model whether adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channels, N-methyl-d-aspartic acid (NMDA) receptors, and Ca2+ channels are involved in the antiallodynic effect of intrathecal gabapentin. Mechanical allodynia was induced by a paw incision in isoflurane-anesthetized rats. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before and after incision and after intrathecal drug administration. The antiallodynic effect of gabapentin (100 mug) was not affected by intrathecal pretreatment with antagonists of K(ATP) channels, NMDA receptors or gamma-aminobutyric acid (GABA)(A) receptors. K(ATP) channel openers and GABA(A) receptor agonist, per se, had little effect on the postincision allodynic response. The Ca2+ channel blocker of N-type (omega-conotoxin GVIA, 0.1-3 microg), but not of P/Q-type (omega-agatoxin IVA), L-type (verapamil, diltiazem or nimodipine), or T-type (mibefradil), attenuated the incision-induced allodynia, as did gabapentin. Both the antiallodynic effects of gabapentin and omega-conotoxin GVIA were attenuated by Bay K 8644, an L-type Ca2+ channel activator. These results provide correlative evidence to support the contention that N-type Ca2+ channels, but not K(ATP) channels or NMDA or GABA(A) receptors, might be involved in the antiallodynic effect of intrathecal gabapentin.
Adenosine Triphosphate↗
N-methyl-D-aspartic acid (NMDA) and non-NMDA receptors regulating hippocampal norepinephrine release. II. Evidence for functional cooperation and for coexistence on the same axon terminal.
The possible interactions between activation of N-methyl-D-aspartic acid (NMDA) receptors and non-NMDA receptors regulating the release of [3H]norepinephrine [( 3H]NE) have been investigated in superfused synaptosomes from rat hippocampus. NMDA--at a concentration (100 microM) which, in a medium containing 1.2 mM Mg++ ions, did not evoke [3H]NE release--acquired releasing activity in the presence of equimolar concentrations of quisqualic acid (QA), (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or kainic acid. The [3H] NE release evoked by NMDA plus QA in the presence of Mg++ ions was Ca(++)-dependent, partly tetrodotoxin-sensitive, inhibited by clonidine but insensitive to desipramine. The NMDA receptor antagonists D-2-amino-5-phosphonopentanoic acid (D-AP5) and (+)-5-methyl-10,11-dihydro-5-H-dibenzo[a,d]cycloepten-5,10-imine (MK-801) antagonized the NMDA-induced [3H]NE release in Mg(++)-free medium; the IC50 values amounted, respectively, to 81.4 microM and to 1.11 microM. When NMDA was tested in the presence of QA and Mg++ ions, the affinity of D-AP5 was enormously increased (IC50 = 40 nM; i.e., more than 6 orders of magnitude); the affinity of MK-801 was found to be augmented by 350-fold.(ABSTRACT TRUNCATED AT 250 WORDS)
2-Amino-5-phosphonovalerate↗
Poly-L-aspartic acid as a carrier for doxorubicin: a comparative in vivo study of free and polymer-bound drug.
The synthetic polypeptide, poly-L-aspartic acid (PAA, mol. wt = 20,000) has been used as a macromolecular carrier for doxorubicin. The drug may be released in vivo through hydrolysis of the ester linkage formed between the carboxyl groups of the polymer and the drug side chain. PAA has been found to be a suitable carrier since it is a soluble, biodegradable, multivalent and nontoxic polymer. The toxicity and the therapeutic efficacy of free and polymer-linked doxorubicin have been evaluated in normal and tumour-bearing mice, using a variety of experimental tumour systems. In studies on single and multiple drug administration, the results indicated that the polymeric derivative of doxorubicin had approximately 3-fold lower toxicity than did free drug. In addition, the severity of specific toxic effects, including cardio- and vesicant toxicity, were appreciably reduced following conjugation to PAA. The doxorubicin-PAA conjugate gave similar or rather greater therapeutic effects than free drug at less toxic doses. This effect, more evident in the highly sensitive tumours, suggests an improvement of the therapeutic index of the polymer-linked drug.
Animals↗
Real-time effects of N-methyl-D-aspartic acid on dopamine release in slices of rat caudate putamen: a study using fast cyclic voltammetry.
The functional role of N-methyl-D-aspartic acid (NMDA) glutamate receptors in the real-time regulation of single electrical pulse (1 p)-stimulated endogenous dopamine release was investigated in slices of rat caudate putamen using fast cyclic voltammetry at a carbon fibre electrode. In the presence of Mg2+, 20 microM NMDA had a weak effect on background signals but did not affect 1 p-stimulated dopamine release. Removal of Mg2+ increased the background and doubled 1 p-stimulated dopamine release. In the absence of Mg2+, 20 microM NMDA caused a transient "release" of dopamine and decreased the background signal. The 1 p-stimulated dopamine release was subsequently reduced. In the presence of 1 microM (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), superfusion with 20 microM NMDA did not cause a transient "release" of dopamine, and 1 p-stimulated dopamine release was not subsequently attenuated. In the presence of 1 microM tetrodotoxin, 1 p-stimulated dopamine release was abolished, but 20 microM NMDA still caused a transient "release" of dopamine. Removal of Ca2+ from the artificial CSF abolished 1 p-stimulated dopamine release and resulted in a decline in the baseline but did not affect dopamine "release" when 20 microM NMDA was added. The dopamine release-inducing effect of 20 microM NMDA was less pronounced in sites in the caudate putamen where dopamine release increased with frequency of electrical stimulation (hot spots) than in sites where there was little frequency-dependent dopamine release (cold spots). Subsequent 1 p-stimulated dopamine release was less attenuated in cold spots than in hot spots. We conclude that in the absence of Mg2+, NMDA induces release of dopamine by acting at CPP-sensitive NMDA receptors in a Ca(2+)-independent manner. This transient release depletes dopamine from a storage site from which dopamine is released by 1 p electrical stimulation. These real-time observations of the effects of NMDA on electrical stimulus-independent and -dependent dopamine release may explain the apparently conflicting observations of the effects of NMDA on dopamine release made in previous studies. They also indicate that dopamine release and storage are heterogeneous at different sites in the rat caudate putamen.
Animals↗
Pantothenate studies. I. Interference by D-serine and L-aspartic acid with pantothenate synthesis in Escherichia coli.
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Aspartic Acid↗
Surface Electrical Properties of Barium Sulfate Modified by Adsorption of Poly alpha, beta Aspartic Acid.
The surface electrical properties of precipitated barium sulfate in aqueous solution have been probed in the presence and absence of synthetic poly alpha, beta aspartic acid. The effect of cation type, ion concentration, and pH on the electrokinetic properties of barite with and without adsorbed polyaspartic acid has been analyzed to afford insights into the mechanism by which polyaspartic acid acts as an inhibitor of barium sulfate precipitation. In addition, vibrational spectroscopy has been employed to monitor bond changes within polyaspartic acid molecules adsorbed on precipitated barium sulfate. These studies have indicated that the surface electrical charge of "pure" barite differs significantly from that of barite precipitated in the presence of calcium ions. Moreover, the presence of the cations Ca2+ and Mg2+ in the suspending liquor has a marked influence of the measured electrokinetic properties. The infrared spectral studies strongly suggest that polyaspartic acid is bound to the barite via the backbone nitrogen atoms. This proposal in conjunction with the electrokinetic and adsorption data has allowed a tentative model of barium sulfate inhibition to be proposed; viz, calcium ions are needed to complex with the polyaspartic acid, first, to reduce the molecules electrical charge in order to promote adsorption onto a charged surface; second, to induce a conformational change in the molecule in order to allow optimal anchoring via the backbone nitrogen atoms; and, third, to reduce the solubility of the molecule in order to increase its surface activity. Copyright 1999 Academic Press.
Journal Article↗
The gene for indole-3-acetyl-L-aspartic acid hydrolase from Enterobacter agglomerans: molecular cloning, nucleotide sequence, and expression in Escherichia coli.
A 5.5-kb DNA fragment containing the indole-3-acetyl-aspartic acid (IAA-asp) hydrolase gene (iaaspH) was isolated from Enterobacter agglomerans strain GK12 using a hybridization probe based on the N-terminal amino acid sequence of the protein. The DNA sequence of a 2.4-kb region of this fragment was determined and revealed a 1311-nucleotide ORF large enough to encode the 45-kDa IAA-asp hydrolase. A 1.5-kb DNA fragment containing iaaspH was subcloned into the Escherichia coli expression plasmid pTTQ8 to yield plasmid pJCC2. Extracts of IPTG-induced E. coli cultures containing the pJCC2 recombinant plasmid showed IAA-asp hydrolase levels 5 to 10-fold higher than those in E. agglomerans extracts. Homology searches revealed that the IAA-asp hydrolase was similar to a variety of amidohydrolases. In addition, IAA-asp hydrolase showed 70% sequence identity to a putative thermostable carboxypeptidase of E. coli.
Amidohydrolases↗
Acute immobilization stress alters LH and ACTH release in response to administration of N-methyl-D,L-aspartic acid in peripubertal and adult male rats.
We have evaluated the effects of stress on the pituitary hormone response to N-methyl-D,L aspartic acid (NMA) in peripubertal (43 day old) and adult (80 day old) male rats. Animals were stressed by immobilization for 3 h. Fifteen min prior to the end of the stress period, animals were injected sc with either vehicle or increasing doses of NMA (10, 30 or 60 mg/kg BW). Animals were sacrificed 15 minutes later. A significant rise in plasma LH in response to NMA occurred at a lower dose (10 versus 60 mg/kg BW), and the magnitude of the response was greater overall in peripubertal than in adult unstressed rats. Stress altered the LH response to NMA in both age groups. In peripubertal stressed rats, NMA did not induce a rise in plasma LH levels. In adult rats exposed to stress, the magnitude of the LH response to 60 mg/kg BW of NMA was lower than in unstressed animals. NMA administration triggered a rise in plasma ACTH levels in unstressed rats of both age groups, but the magnitude of the rise was greater in adults than in peripubertal animals. Stress reduced the ACTH response to NMA administration in both age groups. Plasma FSH concentrations were higher in peripubertal animals than in adults. NMA and stress were without major effect on plasma FSH levels in either age group. These data suggest that excitatory amino acids (EAA) form an important component in the regulatory processes governing the release of LH and ACTH, and that the maturational stage of the central nervous system and exposure to stress alter the LH and ACTH response to EAA.
Adrenocorticotropic Hormone↗
A glycine site associated with N-methyl-D-aspartic acid receptors: characterization and identification of a new class of antagonists.
Membranes from rat telencephalon contain a single class of strychnine-insensitive glycine sites. That these sites are associated with N-methyl-D-aspartic acid (NMDA) receptors is indicated by the observations that [3H]glycine binding is selectively modulated by NMDA receptor ligands and, conversely, that several amino acids interacting with the glycine sites increase [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding to the phencyclidine site of the NMDA receptor. The endogenous compound kynurenate and several related quinoline and quinoxaline derivatives inhibit glycine binding with affinities that are much higher than their affinities for glutamate binding sites. In contrast to glycine, kynurenate-type compounds inhibit [3H]TCP binding and thus are suggested to form a novel class of antagonists of the NMDA receptor acting through the glycine site. These results suggest the existence of a dual and opposite modulation of NMDA receptors by endogenous ligands.
Animals↗
N-methyl-D-aspartic acid stimulation of vasopressin release: role in osmotic regulation and modulation by gonadal steroids.
Previous experiments demonstrated that excitatory amino acids participate in the osmotic regulation of vasopressin secretion, but the specific involvement of N-methyl-D-aspartic acid (NMDA) receptors was not evaluated. This was demonstrated in the present studies. NMDA stimulated vasopressin release from perifused explants of the hypothalamo-neurohypophyseal system (HNS), and osmotic stimulation of vasopressin release was inhibited by MK-801 (10 microM) and AP5 (100 microM) NMDA receptor antagonists. The effective concentration of NMDA was dependent upon the Mg2+ concentration of the perifusate with stimulation observed at 1 microM NMDA in Mg2+-replete compared with 5 microM in low-Mg2+ medium. Previous experiments also demonstrated that estradiol and dihydrotestosterone (DHT) inhibited osmotically stimulated vasopressin secretion, and a nongenomic mechanism of action was suggested by the ability of steroids conjugated to bovine serum albumin to replicate the effect. Experiments were performed to explore the potential role of NMDA receptors in this mechanism. Estradiol (50 pg/ml) and DHT (3 ng/ml) inhibited NMDA stimulated vasopressin release in perifused HNS explants. These results suggest a role of NMDA receptors in the mediation of vasopressin secretion in osmotically stimulated release. Furthermore, estradiol and DHT may exert their inhibitory effect on osmotically stimulated vasopressin release via the NMDA receptor.
Animals↗
Studies on the distribution of N-acetyl-L-aspartic acid in brain.
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Aspartic Acid↗
Analysis of micelle formation of an adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer by gel permeation chromatography.
The micelle-forming behavior of a drug-block copolymer conjugate (adriamycin-conjugated poly(ethylene glycol)-poly(aspartic acid) block copolymer; PEG-P[Asp(ADR)]) was analyzed by gel permeation chromatography (GPC). Four compositions of the conjugates were observed to form micellar structures in aqueous media, and their micelle-forming behavior was found to be dependent on the composition and media. These micelles did not reach equilibrium within short time periods like low molecular weight surfactants. One composition formed stable micelles in the presence of serum.
Animals↗