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PubMed1985

Characterization of muscles from aspartic acid obese rats.

This study was undertaken to determine whether changes in muscle mass, muscle fiber diameter, or shifts in fiber type occur in the aspartic acid-injected rat, an animal model of hypothalamically induced obesity. We found that diaphragm, gastrocnemius, and soleus muscle mass was 140, 149, and 171% greater, respectively, in control compared with aspartic acid-injected rats. No differences were noted in heart weights. Significant reductions in mean fiber diameter of aspartic compared with control rats were present in each skeletal muscle. Furthermore, significant size reductions were noted for each fiber type in the diaphragm, with fast-glycolytic fibers showing the greatest reduction compared with controls at both 7 and 12 mo. Fiber type composition within the diaphragm did not differ between groups but showed a change with age. These results are compared with genetic models of obesity, the Zucker rat and the ob/ob mouse, as well as the ventromedial hypothalamic lesioned rat and the gold thioglucose mouse. Based on these results, the aspartic rat appears more similar to the two genetic models of obesity and also mimics some of the effects of malnutrition in rodents.

Age Factors↗
PubMed1996

Turnover rate and stimulus-evoked release of dopamine by progesterone and N-methyl-D-aspartic acid in rat striatum during pregnancy.

The proposed modulatory role of progesterone on dopaminergic nerve terminal activity in the striatum was examined in pregnant rats. Endogenous dopamine concentration and the in vitro effect of exogenous progesterone in association with N-methyl-D-aspartic acid (NMDA) upon [3H]dopamine release from striatal slices were determined. Striatal dopamine and 3,4-dihidroxyphenylacetic acid (Dopac) contents on day 5 of pregnancy were significantly higher than those found at the other stages of pregnancy and proestrus. On days 5 and 15 of pregnancy, progesterone (400 nM) was able to enhance [3H]dopamine release stimulated by NMDA (50 microM). A similar effect was found in striatal slices from proestrus rats. In contrast, progesterone was without an effect on days 1, 10 and 20 of pregnancy and postpartum. The results suggest that an increased synthesis and/or release of dopamine takes place on certain days of pregnancy and, simultaneously, that there is a significant increase in the responsiveness of striatal dopaminergic nerve terminals to excitatory inputs. They provide further support for a modulatory role of progesterone in relation with a glutamatergic action on dopaminergic activity in the corpus striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

The effect of peptides containing the arginine-glycine-aspartic acid sequence on the adsorption of foot-and-mouth disease virus to tissue culture cells.

Sequencing of the VP1 of a large number of subtypes of foot-and-mouth disease virus (FMDV) has revealed the presence of a conserved arginine-glycine-aspartic acid (RGD) sequence located in a highly exposed region. This sequence has been shown to be essential for the interaction of certain extracellular matrix and adhesion proteins with a superfamily of cell-surface receptors called integrins. We have examined the effects of synthetic peptides containing the RGD sequence on the binding of eight different subtypes of FMDV to tissue culture cells. The results showed that such peptides inhibited viral adsorption by 50-80%. The inhibition was dose dependent but not as great as that achieved by using a saturating amount of virus as an inhibitor. Substitution of other amino acids for any of the three main residues lowered the inhibitory properties of the peptides. These results suggest that the RGD sequence in FMDV VP1 appears to be important for the interaction of virus with cellular receptor sites.

Adsorption↗
PubMed2003

Porous polymer scaffolds surface-modified with arginine-glycine-aspartic acid enhance bone cell attachment and differentiation in vitro.

This study was designed to determine if the surface modification of porous poly(lactic acid) (PLA) scaffolds would enhance osteogenic precursor cell (OPC) attachment, growth, and differentiation. A covalently grafted amino group (-NH(2)), poly(L-lysine) (PLL), and the peptide arginine-glycine-aspartic acid (RGD) were selected for the evaluation. The hypothesis was that surface modification would have a positive impact on cell-substratum interactions. The experiment was performed by OPC cells being placed on PLA films and scaffolds modified with NH(2), PLL, or RGD in tissue culture media. OPC attachment to PLA films was assessed after 24 h of incubation. The growth and differentiation of the adherent OPCs on porous PLA scaffolds were assessed after 14 and 28 days for alkaline phosphatase (APase) activity and calcium levels, both of which increase as OPCs differentiate into mature bone cells. All assays were accomplished in triplicate, and data were tested with post hoc orthogonal contrasts (i.e., Fisher's least significant difference) at p < or = 0.05. The PLA film surface-modified with RGD showed better OPC cell attachment than the other films. The cells on the PLA scaffolds surface-modified with RGD also exhibited an increase in APase activity and calcium levels in comparison with those on other scaffolds. This difference was apparent at both time intervals and was especially evident in the tissue culture media containing an osteogenic supplement. The results of this study indicate that modifying the surface of PLA polymer scaffolds with RGD enhances bone cell attachment and differentiation and may improve their ability to regenerate bone tissue more efficiently in wound models.

Absorbable Implants↗
PubMed1996

Opioids modulate N-methyl-D-aspartic acid (NMDA)-evoked responses of neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis).

Extracellular single unit recordings were made from 74 neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis). N-methyl-D-aspartic acid (NMDA) excited nociceptive as well as non-nociceptive neurons. NMDA receptor antagonist, DL-2-Amino-5-Phosphonovaleric acid (AP-5), blocked the NMDA-evoked excitation. Microiontophoretic application of a selective mu-opioid receptor agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO), reduced the NMDA-evoked responses of 100% of nociceptive specific (NS), 93% of wide dynamic range (WDR) and 86% of low threshold (LT) neurons in the superficial and deeper dorsal horn of the medulla. In contrast, application of a selective delta 1-opioid receptor agonist, [D-Pen2,5]enkephalin (DPDPE), reduced the NMDA-evoked responses of 90% of NS neurons, 72% of WDR neurons and 67% of LT neurons in the superficial and deeper dorsal horn of the medulla. DPDPE also produced excitatory or biphasic effects. The inhibitory actions of DAMGO and DPDPE were reversed by naloxone and/or 7-benzylidenenaltrexone (BNTX), mu- and delta 1-receptor antagonists. It is concluded that mu- and delta-opioid receptor agonists produce a predominantly inhibitory modulation of the NMDA-evoked responses of nociceptive and non-nociceptive neurons in the medullary dorsal horn.

Analgesics, Opioid↗
PubMed1995

Novel benzo[b]quinolizinium cations as uncompetitive N-methyl-D-aspartic acid (NMDA) antagonists: the relationship between log D and agonist independent (closed) NMDA channel block.

A series of permanently charged benzo[b]quinolizinium cations having lower lipophilicity than MK-801 or phencyclidine (PCP) were synthesized. Data relating agonist independent block of N-methyl-D-aspartic acid (NMDA) ion channels to log D are described. Closed channel access is predicted to result in a more noncompetitive profile of antagonism compared to selective open channel blockers, which are uncompetitive inhibitors. Reduced closed channel block may underlie the absence of PCP or MK-801-like behavioral side effects observed for benzo[b]-quinolizinium cations.

Animals↗
PubMed1993

Chronic ethanol administration sensitizes hippocampal neurons to neurotoxicity of N-methyl-D-aspartic acid.

The hyperexcitability observed following ethanol withdrawal in dependent animals is thought to be related to increased sensitivity of glutamate receptors. This may predispose to 'excitotoxic' neural damage. The aim of this study was to test this hypothesis by intrahippocampal injection of N-methyl-D-aspartic acid (NMDA) in ethanol-dependent rats and to quantify brain damage using enzymic neuronal markers, viz. choline acetyltransferase (ChAT) and glutamate decarboxylase (GAD). Specific activity of GAD but not ChAT was found to be significantly decreased in hippocampi of ethanol-dependent animals following injection of NMDA, suggesting that chronic ethanol administration sensitizes GABAergic neurons to the toxic effects of excitatory amino acid transmitters.

Alcoholism↗
PubMed2000

The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases.

Type 4 prepilins or prepilin-like-proteins are secreted by a wide range of bacterial species and are required for a variety of functions including type 4 pilus formation, toxin and other enzyme secretion, gene transfer, and biofilm formation. A distinctive feature of these proteins is the presence of a specialized leader peptide that is cleaved off by a cognate membrane-bound type 4 prepilin peptidase (TFPP) during the process of secretion. In this report we show that the TFPPs represent a novel family of bilobed aspartate proteases that is unlike any other protease. The active site pairs of aspartic acids of the two TFPPs in Vibrio cholerae are found at positions 125 and 189 of TcpJ and 147 and 212 of VcpD. Corresponding aspartate residues are completely conserved throughout this extensive peptidase family.

Amino Acid Sequence↗
PubMed1992

3-(2-Carboxyindol-3-yl)propionic acid-based antagonists of the N-methyl-D-aspartic acid receptor associated glycine binding site.

A series of substituted 3-(2-carboxyindol-3-yl)propionic acids was synthesized and tested as antagonists for the strychnine-insensitive glycine binding site of the NMDA receptor. Chlorine, and other small electron-withdrawing substituents in the 4- and 6-positions of the indole ring, greatly enhanced binding and selectivity for the glycine site over the glutamate site of the NMDA receptor; one of the most potent compounds is 3-(4,6-dichloro-2-carboxyindol-3-yl)propionic acid (IC50 = 170 nM; greater than 2100-fold selective for glycine). The importance of a heteroatom NH and the enhancing effect of the propionic acid side chain were demonstrated and are consistent with previous results which suggest the presence of a pocket on the receptor which can accept an acidic side chain. Substitution of a sulfur at C3 led to the most potent compound 3-[(carboxymethyl)thio]-2-carboxy-4,6-dichloroindole (IC50 = 100 nM).

Animals↗
PubMed2004

Cloning and heterologous expression of a beta-fructofuranosidase gene from Arthrobacter globiformis IFO 3062, and site-directed mutagenesis of the essential aspartic acid and glutamic acid of the active site.

We have cloned the gene encoding a beta-fructofuranosidase from Arthrobacter globiformis IFO 3062, and subsequently, the gene was heterologously expressed in Escherichia coli. This beta-fructofuranosidase gene encodes a protein of 548 amino acid residues with a calculated molecular mass of 60,519 Da. We have examined the roles of three residues of A. globiformis IFO 3062 beta-fructofuranosidase by site-directed mutagenesis, and found that aspartic acid 130 and glutamic acid 392, which are two of the apparent catalytic residues, are essential for hydrolase activity. This study provides the first experimental evidence showing that these two amino acid residues of beta-fructofuranosidase play a critical role in hydrolyzing sucrose.

Journal Article↗
PubMed2002

Allopregnanolone increase in striatal N-methyl-D-aspartic acid evoked [3H]dopamine release is estrogen and progesterone dependent.

1. The neurosteroids are compounds derived from steroid hormones and synthesized in the nervous system. They can modulate different neurotransmitter pathways. In previous work we demonstrated that progesterone modulates dopamine release induced by the glutamatergic agonist N-methyl-D-aspartic acid (NMDA). 2. The aim of this work was to evaluate a possible modulatory role of the progesterone metabolite allopregnanolone on NMDA-evoked [3H]dopamine release from corpus striatum slices obtained from cycling and ovariectomized female rats. 3. We used a dynamic superfusion method to evaluate the release of [3H]dopamine. Allopregnanolone at 50-600 nM was added to the superfusion buffer (Krebs-Ringer-bicarbonate-glucose. pH 7.4. with constant O2/CO2 gassing). The results are expressed as a percentage over basal [3H]dopamine loaded by the tissue. 4. Allopregnanolone (50 and 100 nM) increased the NMDA-evoked [3H]dopamine release from estrus rats. The remaining doses did not show significant changes in the pattern of release. This effect was not observed in diestrus rats. The ovariectomy abolished the facilitatory effect of allopregnanolone on NMDA-evoked 2 [3H]dopamine release. 5. Subcutaneous administration of exogenous estrogen (25 mg/rat) and progesterone (1 mg/rat) restored the facilitatory effect on dopaminergic input. 6. These results suggest that allopregnanolone is a neurosteroid able to modulate dopamine release in an ovarian-hormone-fluctuation-dependent manner and provide further support for a role of allopregnanolone as a modulator of glutamatergic-dopaminergic interaction in the corpus striatum.

Animals↗
PubMed1988

Anticonvulsant effects of phencyclidine-like drugs: relation to N-methyl-D-aspartic acid antagonism.

Various compounds that have been identified in the literature as binding to the [3H]phencyclidine receptor site and as producing behavioral effects similar to phencyclidine (phencyclidine-like) protected mice from maximal electric shock-induced tonic-extensor seizures. These anticonvulsant effects appear to be due to blockade of the N-methyl-D-aspartic acid receptor, as recently reported for phencyclidine-like compounds. Phencyclidine-like compounds produced their anticonvulsant effects at doses that were also neurologically impairing.

Animals↗
PubMedDate not supplied

Molecular modeling of arginine-glycine-aspartic acid (RGD) analogs: relevance to transepithelial transport.

PURPOSE: The aim of this research is to model the effect of methylation on hydrogen bonding ability, surface area, polar surface area, volume, lipophilicity, charge, and cross-sectional diameters of a series of mono-, di-, and tri- methyl substituted analogs of arginine-glycine-aspartic acid (RGD) and compare these parameters to in vitro transport properties across Caco-2 monolayers. METHODS: Molecular modeling was used to investigate the structural parameters that may influence the transport properties of RGD and its methyl analogs at pH 7.4. Log P was experimentally determined using a potentiometric method and compared to cLogP. Transport studies were carried out using Caco-2 cell monolayers. RESULTS: Parameters such as polar and total surface area, volume, and Log P were found to vary with both the number and the sites of methyl substitution on the RGD molecule. The calculated as well as the experimental Log P values were found to be less than minus 2. The calculated maximum cross-sectional diameters ranged from 9 to 12 A. No detectable transport was noted. CONCLUSIONS: Results of our study indicate that in the design considerations for the development of new peptidomimetic RGD analogs with enhanced oral bioavailability, an important parameter to consider is the three dimensional conformation of the peptides which influences their hydrogen bonding ability, polarity and molecular geometry.

Biological Transport↗
PubMed2003

Nicotine-induced neuroprotection against N-methyl-D-aspartic acid or beta-amyloid peptide occur through independent mechanisms distinguished by pro-inflammatory cytokines.

Nicotine, the causative agent of addiction to tobacco, can also be a neuroprotectant. Nicotine-induced neuroprotection against different toxins is imparted through pharmacologically distinct neuronal nicotinic acetylcholine receptors (nAChR) where protection against chronic N-methyl-d-aspartic acid (NMDA) exposure is through nAChRalpha7 but protection against the toxic peptide of amyloid precursor protein, Abeta25-35, is through nAChRalpha4beta2. The inflammatory cytokine tumor necrosis factor alpha (TNFalpha) is also neuroprotective, however, in the presence of nicotine, neuroprotection against NMDA is abolished. The specificity of nicotine-TNFalpha antagonism was further refined using a mouse transgenic dominant negative of nAChRalpha7 in which nicotine failed to induce neuroprotection against NMDA and antagonism of TNFalpha was absent. However, nicotine-mediated neuroprotection against Abeta25-35 was unaffected and, therefore, did not require the expression of functional nAChRalpha7s. The mechanism of TNFalpha-mediated neuroprotection and antagonism by nicotine was independent of caspase 8 activation or nuclear factor kappa B translocation in neurons but C6-ceramide addition to neuronal cultures subsequently exposed to NMDA mimicked the neuroprotective effect of TNFalpha and, like TNFalpha, it was antagonized by cotreatment with nicotine. Therefore, the neuroprotective effects of nicotine against differing toxic assaults requires distinct nAChR subtypes and proceeds through intracellular pathways that overlap with similarly different mechanisms initiated by pro-inflammatory cytokines. These results provide insight into how nicotine imparts neuroprotection and modulates inflammatory responses.

Amyloid beta-Peptides↗
PubMed2002

Presence of the N-methyl-D-aspartic acid R1 glutamatergic receptor subunit in the lumbosacral spinal cord of male rats.

The lumbosacral spinal cord contains neurones that control the lower urogenital and digestive tracts. Spinal neurones respond to activation from the periphery and supraspinal nuclei. Glutamate, acting through a variety of receptors, is an established transmitter of excitatory pathways to the spinal cord. Using immunohistochemical methods, we reveal the presence of the N-methyl-D-aspartic acid R1 (NMDAR1) glutamatergic receptor subunit in the lumbosacral spinal network that controls urogenital and digestive functions: the dorsal horn; the area around the central canal including the dorsal grey commissure; the sacral parasympathetic nucleus; and pudendal motoneurones. A complete thoracic spinal section did not alter labelling. Using retrograde labelling techniques, we identify sacral preganglionic neurones and pudendal neurones that are NMDAR1 immunoreactive. Glutamate, acting at NMDA receptors, can therefore co-ordinate the activity of the autonomic and somatic outflows to the pelvic organs.

Animals↗