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PubMed1996

Development and pharmacokinetics of galactosylated poly-L-glutamic acid as a biodegradable carrier for liver-specific drug delivery.

PURPOSE: A biodegradable carrier for the liver-specific delivery of drugs was developed using poly-L-glutamic acid (PLGA) modified with galactose (galactosylated PLGA or Gal-PLGA), and its feasibility was investigated in mice. METHODS: 111In-PLGA and 111In-Gal-PLGAs were injected in mice and their distribution and biodegradation properties were studied. RESULTS: After intravenous injection. 111In-PLGA was rapidly eliminated from the plasma and recovered mainly in the kidneys and urine. Approximately 15% of the dose was recovered in the liver, predominantly in the nonparenchymal cells. 111In-Gal-PLGAs were taken up by the liver parenchymal cells. Derivatives having 16 or more galactose residues were taken up by the liver to a higher extent (> 60% of the dose). The hepatic clearance of 111In-Gal-PLGAs correlated with their number of galactose residues. 111In-Gal18-PLGA was degraded into low-molecular weight products in the liver. CONCLUSIONS: The advantageous in vivo properties of Gal-PLGA as a liver-specific biodegradable carrier of drugs were demonstrated in mice.

Animals↗
PubMed1984

Carcinogenicity in mice of mutagenic compounds from glutamic acid and soybean globulin pyrolysates.

2-Amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole and 2- aminodipyrido [1,2-a:3',2'-d]imidazole, potent mutagens from glutamic acid pyrolysate, were given orally to CDF1 mice of both sexes at concentrations of 0.05% in pellet diet. 2-Amino-3-methyl-9H-pyrido[2,3-b]indole and 2-amino-9H-pyrido[2,3-b]indole, potent mutagens from soybean globulin pyrolysate, were given to CDF1 mice of both sexes at concentrations of 0.08%. Hepatocellular carcinomas and hemangioendothelial sarcomas in the brown adipose tissue were induced in high incidence by all these compounds.

Animals↗
PubMed1989

Characterization of striatal neurons expressing high levels of glutamic acid decarboxylase messenger RNA.

Two types of labelled cells are detected in sections of rat and mouse striata processed for in situ hybridization histochemistry with 35S-radiolabelled RNA probes complementary to the messenger RNA (mRNA) encoding glutamic acid decarboxylase (GAD), the synthesis enzyme for gamma-aminobutyric acid (GABA): numerous lightly, and fewer very densely labelled neurons. In order to determine whether the densely labelled cells correspond to the striatal somatostatinergic neurons with which they share morphological characteristics, the presence of GAD mRNA was examined in brain sections processed successively for dihydronicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry, a marker of striatal somatostatinergic neurons, and in situ hybridization histochemistry. In addition, the distribution of GABAergic interneurons was analyzed with regard to striatal compartments (striosomes) indicated by patches of dense opiate binding sites. The results show that NADPH diaphorase activity and GAD mRNA do not co-exist in striatal neurons. Furthermore, in contrast to the somatostatinergic neurons which are almost exclusively located in the extrastriosomal matrix, densely labelled GAD cells were present both in the striosomes and the matrix, further suggesting that GABAergic and somatostatinergic neurons form two distinct interneuronal systems in the striatum of rats and mice.

Animals↗
PubMed1991

Striatal glutamic acid decarboxylase immunoreactivity is increased after dopaminergic deafferentation: densitometric analysis.

Several lines of evidence suggest that dopamine exerts a chronic inhibitory action on GABAergic cells in the striatum, and striatal glutamic acid decarboxylase (GAD) mRNA levels are increased after ipsilateral dopaminergic denervation. In the present study we have used GAD immunocytochemistry to assess whether dopaminergic denervation results in an increase in GAD protein synthesis. In three 6-hydroxydopamine-lesioned animals, there was a perceptible increase in the density of GAD-immunoreactive (ir)staining on the side ipsilateral to the lesion. Computer-assisted densitometric analysis showed a significant increase in GAD-ir staining in the ipsilateral striatum compared to the contralateral (control) side. These data suggest that removal of striatal dopaminergic innervation results in an increase in the amount of immunoreactive GAD, the rate limiting enzyme in the synthesis of GABA.

Afferent Pathways↗
PubMed1975

Release of (3H)GABA and (14C)glutamic acid from rat cortex slices: the relationship between the tissue pool size and rates of spontaneous and electrically induced release.

A constant fraction of the existing tissue pool of (3H)GABA or (14C)glutamic acid was released during electrical stimulation of rat cortex slices. The sum of the amounts of labeled amino acids released spontaneously and by electrical stimulation was constant when stimulated slices were superfused with normal medium or media containing ouabain or a high K+ concentration. The fraction of the total amount released that was attributable to electrical stimulation varied inversely with the amount released spontaneously. Pentobarbital inhibited the accelerated spontaneous release produced by ouabain or high K+ and restored the ability of the slice to respond to electrical stimulation. Electrically induced release was felt to be limited by a theoretical maximum transport velocity of efflux of approximately 5.5% per min.

Aminobutyrates↗
PubMed2001

Enantiomeric crystallization from DL-aspartic and DL-glutamic acids: implications for biomolecular chirality in the origin of life.

Amino acids in living systems consist almost exclusively of the L-enantiomer. How and when this homochiral characteristic of life came to be has been a matter of intense investigation for many years. Among the hypotheses proposed to explain the appearance of chiral homogeneity, the spontaneous resolution of conglomerates seems one of the most plausible. Racemic solids may crystallize from solution either as racemic compounds (both enantiomeric molecules in the same crystal), or less commonly as conglomerates (each enantiomer molecule separate in different enantiomeric crystals). Only conglomerates can develop a spontaneous resolution (one of the enantiomeric molecule crystallizes preferentially, the other one remains in solution). Most of natural amino acids are racemic compounds at moderate temperatures. How can we expect a hypothetical spontaneous resolution of these amino acids if they are not conglomerates? In this paper we show how DL-aspartic and DL-glutamic amino acids (racemic compounds), crystallize at ambient conditions as true conglomerates. The experimental conditions here described, that allows this 'anomalous' behaviour, could be also found in natural sedimentary environments. We suggest that these experimental procedures and its natural equivalents, have a potential interest for the investigation of the spontaneous resolution of racemic compounds comprising molecules associated with the origin of life.

Aspartic Acid↗
PubMed1992

Antibodies to glutamic acid decarboxylase discriminate major types of diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is marked by circulating antibodies to a 64,000-M(r) islet cell antigen identified as glutamic acid decarboxylase (GAD). We describe a radioimmunoprecipitation assay with GAD isolated from pig brain. The sera tested were from 80 patients with IDDM including 26 with disease of recent onset and 54 with disease of longer duration (3-42 yr), 20 with non-insulin-dependent diabetes mellitus (NIDDM), and 55 nondiabetic subjects. Conventional assays for islet cell cytoplasmic antibodies were performed concurrently. The level of antibody in serum was expressed in units based on percentage reactivity of a standard reference serum. The frequency of antibody to GAD in IDDM was 69% in short-duration cases and 59% in long-duration cases. The latter was substantially higher than the frequency of islet cell cytoplasmic antibody. Antibodies to GAD were elevated (means +/- 3 SD) in 5% NIDDM cases and in none of the nondiabetic subjects. A simple laboratory test with a defined autoantigen has substantial implications for population screening and early diagnosis of IDDM and for better understanding of its pathogenesis.

Adolescent↗
PubMed1985

Immunocytochemical localization of glutamic acid decarboxylase and substance P in the lateral cervical nucleus: a light and electron microscopic study in the cat.

Using immunocytochemical technique, the light and electron microscopic localization of substance P and glutamic acid decarboxylase (GAD) immunoreactivity in the feline lateral cervical nucleus (LCN) has been investigated. A dense substance P labeling, confined mainly to boutons contacting dendritic profiles, was demonstrated in the ventromedial part of the LCN. GAD-positive boutons, frequently in contact with cell bodies, were found scattered throughout the nucleus. The results suggest that gamma-aminobutyric acid is an inhibitory transmitter in the LCN. The role of the substance P is unclear. Its distribution, however, supports the concept of a separate function of the ventromedial part of the LCN.

Animals↗
PubMed2003

Disturbance of neural respiratory control in neonatal mice lacking GABA synthesizing enzyme 67-kDa isoform of glutamic acid decarboxylase.

To examine the role of GABA in the respiratory rhythm and pattern generation in neonatal mice, we analyzed the function of the respiratory control system of 67-kDa isoform of glutamic acid decarboxylase (GAD67)-deficient neonatal mice. In these mutant (GAD67-/-) mice, GABA levels in the brainstem were reduced to about 30% of those in wild-type (GAD67+/+) mice. In in vivo preparations, ventilatory parameters were analyzed by whole body plethysmography and electromyography of intercostal muscles. GAD67-/- mice exhibited abnormal respiratory patterns, i.e. irregular respiratory rhythm, and periodic gasp-like respiration followed by shallow breathing with short inspiratory duration and apnea. In in vitro GAD67-/- brainstem-spinal cord preparations, inspiratory C4 burst duration was shorter than that in GAD67+/+ preparations. Whole cell recordings revealed that activities of inspiratory neurons in the ventral medulla of GAD67-/- mice were characterized by a short depolarization period and a paucity of firing during the inspiratory phase. Superfusion of the in vitro GAD67-/- preparation with 10 microM GABA prolonged C4 burst duration and partly restored a normal pattern of inspiration, although the restoration was limited. These results indicate that reduced GABA levels during the perinatal period induce malfunction in the respiratory control system. We suggest that GABAergic transmission is not essential for basic respiratory rhythm generation but plays an important role in the maintenance of regular respiratory rhythm and normal inspiratory pattern in neonatal mice.

Animals↗
PubMed1997

Antibodies to glutamic acid decarboxylase in Japanese diabetic patients with secondary failure of oral hypoglycaemic therapy.

Some patients with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) are positive for antibodies to glutamic acid decarboxylase (anti-GAD), which have been shown to be a useful marker for the diagnosis and prediction of insulin-dependent (Type 1) diabetes mellitus (IDDM). Anti-GAD positive NIDDM patients tend to develop insulin deficiency. We investigated the prevalence of anti-GAD in 200 NIDDM with secondary failure of oral hypoglycaemic therapy (SF) and 200 NIDDM well controlled by diet and/or sulphonylurea agents (NSF). Twenty-two of 200 (11%, p < 0.05) SF patients and 6 of 200 (3%) NSF patients were anti-GAD positive. The positive. The positive rate for anti-GAD was as high as 23.8% in the non-obese and insulin deficient SF patients. The SF patients with anti-GAD tended to be non-obese and to have an impaired release of endogenous insulin. The internal before development of secondary failure was not associated with the presence of anti-GAD in this study. In conclusion we found that anti-GAD was positive in as many as 11% of the SF patients, suggesting that autoimmune mechanisms may play an important role in the pathogenesis of secondary failure or sulphonylurea therapy.

Analysis of Variance↗
PubMed1996

T cell clones to epitopes of glutamic acid decarboxylase 65 raised from normal subjects and patients with insulin-dependent diabetes.

Insulin-dependent diabetes (IDDM) is probably mediated by T lymphocytes recognizing critical beta cell autoantigens. Glutamic acid decarboxylase (GAD) 65 is a major antigen in IDDM. T cells in both IDDM patients and controls respond to GAD 65 and certain epitopes of this molecule. To clarify the immune response to GAD 65 we established T cell clones specifically recognizing epitopes of GAD 65. We obtained T cells clones to GAD 65 peptides 161-175 (from a healthy individual), and 505-519 and 521-535 (from two IDDM patients). On extensive screening T cells responsive to peptide 161-175 were found only in controls, while T cells responsive to peptide 521-535 were found only in IDDM patients; T cells from both IDDM patients and controls responded to peptide 505-519. We could exclude simple genetic shaping of these T cell responses since the responses differed between genetically identical twins discordant for IDDM. Reactivity of T cell clones from the control to peptide 161-175 was restricted by HLA DR1 but promiscuous for HLA DR4 as DR4+ EBV transformed B cells and DR4+ mouse L-transfectants could present the peptide. As DR4+ antigen presenting cells of diabetics could present peptide 161-175 to some clones, the lack of response to this epitope in diabetic patients cannot be due to inadequate antigen presentation but is probably due to deletion of these cells either centrally or peripherally. Reactivity of clones to peptide 505-519 was either HLA DR1 or DQ1 restricted. In conclusion, T cell clones to specific epitopes of GAD 65 provide a model to clarify those differences in the immune response to this autoantigen between controls and IDDM patients.

Antibody Formation↗
PubMed1996

Murine monoclonal glutamic acid decarboxylase (GAD)65 antibodies recognize autoimmune-associated GAD epitope regions targeted in patients with type 1 diabetes mellitus and stiff-man syndrome.

To study the immune response to glutamic acid decarboxylase (GAD) in insulin-dependent diabetes mellitus, monoclonal GAD antibodies after fusion of splenocytes from a nondiabetes-susceptible BALB/c mouse immunized with human recombinant GAD65 were generated. Of the 44 monoclonals, 35 are specific for the GAD65 isoform, whereas 9 also react with GAD67. Some 37 monoclonals, including all GAD65/67 reactive antibodies, react with GAD by Western blot analysis. The remaining 7 GAD65 monoclonals bind GAD only in an immunoprecipitation assay, which implies that they target epitopes dependent on the conformation of the GAD molecule. The 125I-GAD binding of the GAD65 monoclonals reactive on Western blotting was significantly diminished by all 3 sera from Stiff-man syndrome patients but only by 3/30 (10%) sera from type 1 diabetic patients. In contrast, the 7 monoclonal antibodies reactive with a conformation-dependent GAD epitope were competitive with 83% of GAD-autoantibody-positive sera from these diabetic patients. Using chimeric GAD65/67 proteins, the epitope region targeted by these monoclonals was mapped to the middle of GAD65 (amino acids 221-442). This central conformation-dependent GAD region was also targeted by sera from patients with type 1 diabetes. In conclusion, our data show that even after common immunization of a nondiabetes-susceptible mouse strain, monoclonal were obtained which preferentially react with the GAD65 linear amino-terminus (amino acids 4-17) and a conformation-dependent region located in the middle of GAD targeted by autoantibodies, indicating that this GAD region is not restricted to the autoimmune response associated with the Stiff-man syndrome and the beta-cell destruction in type 1 diabetes mellitus.

Animals↗
PubMed2001

Glutamic acid decarboxylase-immunoreactivity of bulbar respiratory neurons identified by intracellular recording and labeling in rats.

To distinguish the GABAergic neuron in the ventral respiratory group (VRG) of rats, immunohistochemical staining of glutamic acid decarboxylase (GAD) was performed in neurons that had been individually identified by in vivo intracellular recording and labeling with neurobiotin. A total of five types of respiratory neurons were identified and labeled; augmenting inspiratory (aug-I, n=12), decrementing or early inspiratory (early-I, n=3), inspiration-expiration phase spanning or late inspiratory (late-I, n=3), decrementing expiratory or postinspiratory (PI, n=8), and augmenting or stage 2 expiratory (E2, n=3). In addition, expiration-inspiration phase-spanning or pre-inspiratory neurons (pre-I, n=2) were recorded, but not labeled. The membrane potential trajectory of each neuron type resembled that previously described in cat, suggesting a comparable neuronal organization between the two species. According to the axonal arborization, those labeled neurons were further classified as propriobulbar (6 aug-I, all early-I, all late-I, and 3 PI), bulbospinal (2 aug-I and all E2) and cranial-motor neurons (4 aug-I and 5 PI). GAD-immunoreactivity was consistently detected in the propriobulbar neurons, while it was not seen in cranial-motor and bulbospinal neurons. In addition, GAD-immunoreactive varicosities were found surrounding the somatic and dendritic surface of all labeled neurons. The present results illustrate that the propriobulbar types of early-I, aug-I, late-I and PI neurons are GABAergic inhibitory neurons and virtually all types of respiratory neurons receive GABAergic inputs in the rat's VRG.

Action Potentials↗
PubMed2006

Partial poly(glutamic acid) <--> poly(aspartic acid) exchange in layer-by-layer polyelectrolyte films. Structural alterations in the three-component architectures.

Layer-by-layer (LBL) polyelectrolyte films were constructed from poly(L-glutamic acid) (PGA) and poly(L-aspartic acid) (PAA) as polyanions, and from poly(L-lysine) (PLL) as the polycation. The terminating layer of the films was always PLL. According to attenuated total reflection Fourier transform infrared measurements, the PGA/PLL and PAA/PLL films, despite their chemical similarity, had largely different secondary structures. Extended beta-sheets dominated the PGA/PLL films, while alpha-helices and intramolecular beta-sheets dominated the PAA/PLL films. The secondary structure of the polyelectrolyte film affected the adsorption of human serum albumin (HSA) as well. HSA preserved its native secondary structure on the PGA/PLL film, but it became largely deformed on PAA/PLL films. Both PGA and PAA were able to extrude to a certain extent the other polyanion from the films, but the structural consequences were different. Adding PAA to a (PGA/PLL)5-PGA film resulted in a simple exchange and incorporation: PGA/PLL and PAA/PLL complexes coexisted with their unaltered secondary structures in the mixed film. The incorporation of PGA into a (PAA/PLL)5-PAA film was up to 50% and caused additional beta-structure increase in the secondary structure of the film. The proportions of the two polyanions were roughly the same on the surfaces and in the interiors of the films, indicating practically free diffusion for both polyanions. The abundance of PAA/PLL and PGA/PLL domains on the film surfaces was monitored by the analysis of the amide I region of the infrared spectrum of a reporter molecule, HSA, adsorbed onto the three-component polyelectrolyte films.

Adsorption↗
PubMed1978

Structure and enzymic activity of ribonuclease-A esterified at glutamic acid-49 and aspartic acid-53.

The dimethyl ester of bovine pancreatic ribonuclease-A (dimethyl RNAase-A), the initial product of esterification of RNAase-A in anhydrous methanolic HCl, was isolated in a homogeneous form. The two carboxy functions esterified in this derivative are those of glutamic acid-49 and aspartic acid-53. There were no changes in the u.v.-absorption spectral characteristics, the accessibility of the methionine residues, the resistance of the protein to proteolysis by trypsin and the antigenic behaviour of RNAase-A as a result of the esterification of these two carboxy groups. Dimethyl RNAase-A exhibited only 65% of the specific activity of RNAase-A, but still had the same K(m) value for both RNA and 2':3'-cyclic CMP. However, the V(max.) was decreased by about 35%. On careful hydrolysis of the methyl ester groups at pH9.5, dimethyl RNAase-A was converted back into RNAase-A. Limited proteolysis of dimethyl RNAase-A by subtilisin resulted in the formation of an active RNAase-S-type derivative, namely dimethyl RNAase-S, which was chromatographically distinct from dimethyl RNAase-A and had very nearly the same enzymic activity as dimethyl RNAase-A. Fractionation of dimethyl RNAase-S by trichloroacetic acid yielded dimethyl RNAase-S-protein and dimethyl RNAase-S-peptide, both of which were inactive by themselves but regenerated dimethyl RNAase-S when mixed together. Dimethyl RNAase-A-peptide was identical with RNAase-S-peptide. RNAase-S-protein could be generated from dimethyl RNAase-S-protein by careful hydrolysis of the methyl ester groups at pH9.5. The interaction of dimethyl RNAase-S-protein with RNAase-S-peptide appears to be about 4-fold weaker than that between the RNAase-S-protein and RNAase-S-peptide. Conceivably, the binding of the S-peptide ;tail' of dimethyl RNAase-A with the remainder of the molecule is similarly weaker than that in RNAase-A, and this brings about subtle changes in the geometrical orientation of the active-site amino acid residues of these modified methyl ester derivatives. It is suggested that these changes could be responsible for the generation of the catalytically less-efficient RNAase-A and RNAase-S molecules (dimethyl RNAase-A and dimethyl RNAase-S respectively).

Antigens↗
PubMedDate not supplied

Horizontal cells in cat and monkey retina express different isoforms of glutamic acid decarboxylase.

The neurotransmitter used by horizontal cells in mammals has not been identified. GABA has been the leading candidate, but doubt has remained because of failure to clearly demonstrate the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) in these cells. Because GAD was recently shown to exist as two isoforms, 65 kDa and 67 kDa, we considered whether there might be a mismatch between the forms of GAD expressed in horizontal cells and the probes used to detect it. Accordingly, we stained sections of mammalian retina with antibodies specific for each isoform. Cat horizontal cells of both types (A and B) were immunoreactive for GAD67 but negative for GAD65; monkey horizontal cells of both types (H(I) and HII) were positive for GAD65 and negative for GAD67. The findings reconcile previous, apparently conflicting, observations and strengthen considerably the hypothesis that mammalian horizontal cells are GABAergic.

Animals↗
PubMed1990

Parallel increases in striatal glutamic acid decarboxylase activity and mRNA levels in rats with lesions of the nigrostriatal pathway.

Adult male rats were lesioned with 6-hydroxydopamine in order to destroy the nigrostriatal dopaminergic projections. In rats with such a lesion, we found a parallel increase in glutamic acid decarboxylase (GAD) activity and GAD mRNA in the striatum ipsilateral to the lesion at 4 weeks and 4 months after the lesion. These observations support the proposal that nigral dopaminergic neurons exert a tonic inhibitory control over the striatal GABAergic neurons. Our observations also suggest that the dopaminergic neurons can inhibit gene expression in striatal GABAergic neurons and that the enhanced striatal GAD activity following lesions of the dopaminergic projections is due to 'de novo' synthesis of the enzyme.

Animals↗
PubMed1995

Glutamic acid decarboxylase and other autoantigens in IDDM.

Autoantigens in insulin-dependent diabetes serve as diagnostic markers and as potential therapeutic immunomodulators. Recent studies have focused particularly on two well studied molecules, glutamic acid decarboxylase and insulin, as well as several new antigens that have been recently identified, recognized by antibody and/or cell-mediated immune responses in diabetic patients. Temporal aspects of antigen exposure, antigen processing of specific peptide antigens, and the interplay between specific antigens, MHC genetics, and host T-cell responses remain to be explored.

Animals↗