Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “GLUTAMIC ACID”

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

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

At least 1,675 records · Page 93Linked to original sources
PubMed1998

Glutamic acid and Alzheimer's disease.

Neurotoxicity mediated by glutamate is thought to play a role in neurological disorders such a stroke, ischemia and slowly progressing neurodegenerative diseases. However, the contribution of excitotoxicity in neuronal death that occurs in Alzheimer's disease is still an open question. This paper briefly reviews the main lines of evidence supporting a participation of excess glutamatergic neurotransmission in the neurodegeneration of selective groups of neurons in this disease.

Alzheimer Disease↗
PubMed1997

Glutamic acid decarboxylase antibodies in non-insulin-dependent diabetes patients with secondary sulfonylurea failure in Thailand.

The objective of this study was to determine the frequency of glutamic acid decarboxylase antibody (GAD-Ab) in Thai non-insulin-dependent diabetes (NIDDM) patients who had secondary sulfonylurea failure. Sera were collected from 40 NIDDM patients, who had history of secondary failure to treatment with sulfonylurea, for analysis of fasting c-peptide and GAD-Ab. Both c-peptide and GAD-Ab were measured using radioimmunoassay method. Of 40 patients, ten (25.0%) were positive for GAD-Ab with a mean level of 59.9 U/ml (median 58.5, range 3.4-127). Patients with (GAD-Ab (+) had a significantly lower fasting c-peptide levels than those with GAD-Ab(-) albeit shorter duration of diabetes (0.21 +/- 0.19 (S.D.) versus 0.52 +/- 0.33 nmol/l; P = 0.003). Duration of treatment with sulfonylurea in patients with GAD-Ab (+) was also shorter (4.6 +/- 3.5 versus 10.4 +/- 5.5 years; P = 0.001). Age at onset of diabetes did not differ between these two groups. Among 40% of patients who had insulin deficiency (fasting c-peptide level < 0.33 nmol/1), GAD-Ab was present in half and these GAD-Ab(+) patients had significantly shorter duration of sulfonylurea treatment (3.3 +/- 2.3 versus 10.0 +/- 7.9 years; P = 0.018). In conclusion, the frequency of GAD-Ab in Thai NIDDM patients with secondary sulfonylurea failure in this study was 25%. Almost all GAD-Ab(+) patients had insulin deficiency and most had been initially treated with sulfonylurea for a few years before depending on insulin. This group of patients represents a slowly progressive type I or latent autoimmune diabetes in adult diabetic population.

Adult↗
PubMed2005

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss.

Postmortem brain studies have shown deficits in the cortical gamma-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD67, were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n=72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5' upstream region of GAD1 showed a positive pairwise association with illness in these families (P=0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P=0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD67 may be a common risk factor for schizophrenia.

5' Flanking Region↗
PubMed2001

Quantitative analysis of glutamic acid decarboxylase-immunoreactive neurons in the anterior thalamus of the human brain.

Local circuit neurons in the human anterior thalamus (AT) were identified on the basis of glutamic acid decarboxylase immunoreactivity (GAD-IR). GAD-IR neurons of the AT displayed small diameter somas with thin, sparsely-branching dendrites, consistent with the morphological characteristics of local circuit neurons found in the thalami of other mammals. Sampling techniques revealed an average of 42% of all neurons within the AT were GAD-IR, one of the highest reported percentages of local circuit neurons in the mammalian thalamus. The presence of high proportion of local circuit neurons in the AT may indicate the extent to which the Papez circuit has evolved within the human brain in comparison to other mammals.

Adult↗
PubMed1984

Quantitative autoradiography of binding sites for [3H]AMPA, a structural analogue of glutamic acid.

Binding sites for the potent glutamate agonist [3H] alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were localized in rat brain frozen sections by quantitative autoradiography. Highest levels of binding were seen in stratum radiatum and stratum oriens of the CA1 hippocampal subfield and in the dorsal subiculum. Substantially less but still high amounts of [3H]AMPA binding occurred in other hippocampal subfields and in rostral forebrain structures. The heterogeneous nature of [3H]AMPA binding is discussed in relation to [3H]glutamate binding visualized by similar methods. From these data it is suggested that [3H]AMPA may label a particular subclass of the glutamate receptor population which exhibits a high affinity for quisqualic acid.

Animals↗
PubMed1992

Quantitative analysis of islet glutamic acid decarboxylase p64 autoantibodies in insulin-dependent diabetes mellitus.

Autoantibodies against the beta-cell M(r) 64,000 protein (p64), recently identified as an isoform of glutamic acid decarboxylase (GAD), are prevalent in patients with insulin-dependent diabetes mellitus (IDDM). Dog islets were found to represent an abundant source of native p64 allowing the study of antigen-antibody interactions in IDDM. A quantitative, standardized assay for p64 antibodies based on dog islets was developed and evaluated. Utilizing dog and human islets the p64 antibodies were detected in 17/19 (89%) new onset 15-32-year-old patients, compared to 15/19 (79%) in a rat islet assay. ICA were detected in 15/19 (79%) patients and correlated with the presence of p64 antibodies (rs = 0.59, P < 0.004) but not with age at onset, sex, or C-peptide levels. Sensitivity therefore is improved with the dog islet p64 antibody assay which will allow future studies requiring native p64 antigen in larger quantities are possible based on our findings.

Adolescent↗
PubMed1994

Role of dopamine in the plasticity of glutamic acid decarboxylase messenger RNA in the rat frontal cortex and the nucleus accumbens.

The modulatory role of dopamine (DA) on the expression of mRNA encoding the large isoform of glutamic acid decarboxylase (GAD67), the biosynthesis enzyme of gamma aminobutyric acid (GABA), was examined in GABA neurons of two structures innervated by DA neurons originating from the ventral tegmental area (VTA): the medial frontal cortex (MFC) and the nucleus accumbens (NAcc). A bilateral electrolytic lesion of VTA was performed in rats to produce a DA denervation of both the MFC and NAcc. The efficacy of VTA lesions was verified by measurement of locomotor activity and by immunohistochemical detection of tyrosine hydroxylase in the mesencephalon. GAD67 mRNA was detected by in situ hybridization histochemistry using a 35S-labelled cDNA probe. Densitometric analysis of GAD67 mRNA hybridization signals revealed in VTA-lesioned rats a significant decrease (-24%) in GAD67 mRNA levels in the prelimbic area of the MFC and no significant effect in the anterior cingulate area or the frontoparietal cortex. Single cell analyses by computer-assisted grain counting showed that the decrease in GAD67 mRNA levels in prelimbic MFC was due to a change in GAD67 mRNA expression in a subpopulation of GABA interneurons located in the deep cortical layers (V-VI). By contrast, in the NAcc of VTA-lesioned rats, GAD67 mRNA levels were significantly increased in the anterior part and in the core but were unchanged in the shell part. These results suggest that in two target structures of VTA DA neurons, GAD67 mRNA expression is, in normal conditions, under a tonic stimulatory and a tonic inhibitory DA control in the MFC and the NAcc respectively. A schematic diagram is proposed for functional interactions between these structures.

Animals↗
PubMed1996

Glutamic acid decarboxylase autoantibody assay using 125I-labelled recombinant GAD65 produced in yeast.

We describe a new method for measuring autoantibodies (Ab) to the 65 kDa isoform of glutamic acid carboxylase (GAD65). In particular, GAD65 without the hydrophobic N-terminal region has been produced in yeast, purified, labelled with 125I and reacted with GAD65 Ab. Antibody bound 125I-GAD65 is then precipitated by the addition of solid phase protein A. With the assay, GAD65 Ab were detected in 59 of 71 (83%) islet cell antibody (ICA) positive IDDM patients and in 8 of 23 (35%) ICA negative IDDM patients (overall 67 of 94 (71%) of IDDM patients). Low concentrations of GAD65 Ab were also detected in 2/98 (2%) healthy blood donors and 1/27 (4%) Graves' disease patients had a high level of antibody. GAD65 Ab were not detected in any of 10 Hashimoto's thyroiditis, 20 Addison's disease or 19 myasthenia gravis sera. There was good agreement between the 125I assay and the current reference method based on 35S-labelled full-length GAD65 (produced by in vitro transcription/translation reaction) and solid phase protein A (r = 0.91, n = 108). Overall, our 125I assay showed sensitivity, precision and disease group specificity at least as good as any assay so far described. These features, combined with a simple assay protocol and the convenience of 125I counting and handling indicate that the method is suitable for routine GAD65 Ab measurements.

Adult↗
PubMed1984

Glutamic acid decarboxylase-immunoreactive neurons and terminals in the lateral geniculate nucleus of the cat.

We have examined the distribution of neurons and terminals that are immunoreactive for glutamic acid decarboxylase (GAD), the synthesizing enzyme for the inhibitory neurotransmitter gamma-aminobutyric acid within the lateral geniculate nucleus of the cat. We estimate that GAD-positive neurons constitute approximately one-fourth of the neurons in all layers of the lateral geniculate nucleus and in the medial interlaminar nucleus (MIN). In addition, almost all of the neurons within the perigeniculate nucleus are GAD-positive. The mean size of GAD-positive cell bodies is significantly smaller than the mean size of unlabeled neurons in all subdivisions of the lateral geniculate nucleus. GAD-positive neurons have thick primary dendrites which are associated with thin lightly immunoreactive processes that give rise to clusters of GAD-positive terminals. Clusters of GAD-positive terminals are prominent in lamina A, A1, magnocellular C, and MIN but are rare in the parvocellular C laminae. Within the A laminae, GAD immunoreactivity is found within vesicle-containing profiles of the synaptic glomerulus lying postsynaptic to optic axon terminals and presynaptic to unlabeled dendritic profiles. GAD-positive neurons in the A laminae are distinguished from other small to medium-sized neurons by their failure to label following injections of HRP into visual cortex and by their lack of cytoplasmic laminated body. These results support the idea that GAD-positive neurons constitute a distinct population of neurons in the lateral geniculate nucleus of the cat; a population which has a number of features in common with previous descriptions of presumed local circuit neurons based on Golgi staining.

Animals↗
PubMed2000

Autoantibodies to glutamic acid decarboxylase in diabetic patients from a multi-ethnic Australian community: the Fremantle Diabetes Study.

AIMS: To investigate ethnic/racial differences in the prevalence of serum antibodies to glutamic acid decarboxylase (GADA) and ICA512/IA-2 in diabetic patients from a large, urban community. METHODS: A cross-sectional sample of 1,381 diabetic patients aged 11-98 years, representing 61% of those identified in a postcode-defined population base of 120,097 people were studied. Diabetes was classified on clinical grounds. Serum GADA and anti-ICA512/IA-2 were measured by radioimmunoprecipitation assay. RESULTS: Anglo-Celts formed 62% of the sample, southern Europeans 18%, other Europeans 8% and Asians 3%. GADA prevalence in Type 1 and Type 2 diabetes mellitus was 46.0% and 4.2%, respectively, amongst Anglo-Celts and 22.2% and 1.7% in southern Europeans. The prevalence of anti-ICA512/IA-2 in Type 1 diabetes was 17.4% and, in a sample of 233 patients with Type 2 diabetes, 0.8%. GADA-positive Type 2 patients had a lower body mass index and greater glycosylated haemoglobin, and were more likely to be taking insulin, than GADA-negative Type 2 diabetic subjects (P < 0.05), consistent with the phentoype of latent autoimmune diabetes of adults (LADA). In both Type 1 and Type 2 diabetes, there was a strong inverse association between GADA and serum triglycerides (P < 0.001). CONCLUSIONS: The relatively low GADA prevalence in Anglo-Celt patients with Type 1 diabetes is a feature of this community-based study and suggests that GADA levels do fall with time, given the older age of the sample and a relatively long period between diagnosis and sampling. Southern Europeans had an even lower GADA prevalence, regardless of diabetes type. Variations in GADA frequency in diabetic patients of differing European ethnicity has implications for clinical management and healthcare planning.

Adolescent↗
PubMed1998

Glutamic acid decarboxylase T lymphocyte responses associated with susceptibility or resistance to type I diabetes: analysis in disease discordant human twins, non-obese diabetic mice and HLA-DQ transgenic mice.

Glutamic acid decarboxylase (GAD65) has been implicated as a targeted self antigen in the immune destruction of pancreatic beta cells. T cell responses to GAD65 peptides have been detected in both patients with type I diabetes and in the non-obese diabetic (NOD) mouse. To establish which GAD65 epitopes are important in the immunopathogenesis of disease we initially compared T cell responses to GAD65 epitopes in conditions of disease susceptibility and protection. T cell responses to GAD65 peptides were measured in monozygotic twin pairs selected on the basis of disease discordance and T cell recognition of immunogenic regions of GAD65. Peptides of interest were then used to immunize susceptible NOD mice and H2-E transgenic NOD mice which are protected from diabetes. A differential response to the epitope GAD65 521-535 discriminated diabetic from non-diabetic human twins as well as susceptible from protected mice. This epitope as well as GAD 505-519 induces T cell responses despite binding the type I diabetes associated HLA-DQA1*0301/DQB1*0302 product with low affinity. Since DQ-restricted T cell responses are difficult to study in humans, HLA-DQ8 transgenic mice were then used: GAD epitopes 521-535 and 505-519 induced responses in DQ8 transgenic mice and T cell lines were established. Long-term T cell lines against GAD 505-519 were HLA-DQ restricted, and responded to peptide with a strong IFN-gamma and IL-10 response. The findings implicate GAD 521-535 as a possible target peptide in pathogenesis and are compatible with a model whereby self-reactive T cells specific for low-affinity peptide-MHC complexes may escape thymic negative selection.

Adult↗
PubMed1992

Is there a high molecular weight glutamic acid decarboxylase?

Gel-filtration chromatography from crude extracts of mouse brain indicates the presence of a high molecular weight (HMW) (more than 750 kd) and a low molecular weight (LMW) (87.5 Kd) glutamic acid decarboxylase (GAD) when they are concentrated prior chromatography either by precipitation with salts or ethanol. Kinetically both peaks of GAD-activity exhibit an almost identical Km for L-glutamate. Only LMW-GAD appears if the concentration step is carried out by ultrafiltration or if the extract is chromatographied without the concentrating step. HMW-GAD disappears from the chromatographic profiles if ethanolic extracts of GAD are treated with Triton X-100 before the chromatographic procedure. The sodium sulfate precipitation of a previously separated LMW-GAD gives rise to the reappearance of a HMW-GAD peak. Apparently HMW-GAD does not exist as a different molecular entity; indeed it may be an artefactual aggregation of LMW-GAD.

Animals↗
PubMed1989

Amygdaloid kindling of rats increases preprosomatostatin mRNA and somatostatin without affecting glutamic acid decarboxylase (GAD) mRNA or GAD.

The levels of preprosomatostatin (preproSS) mRNA, somatostatin-like immunoactivity (SS-LI) (also known as somatotropin-release inhibitory factor, or SRIF), glutamic acid decarboxylase (GAD) activity and GAD mRNA were determined in several brain regions of amygdaloid-kindled rats. SS mRNA and SS increased in the cortex and striatum, while only SS increased in the hippocampus. No changes were detected in either GAD activity or GAD mRNA in any brain region. The data suggest that somatostatin may be one of the factors involved in the chain of events leading to kindled seizures.

Amygdala↗
PubMed1999

Intra-accumbens infusions of antisense oligodeoxynucleotides to one isoform of glutamic acid decarboxylase mRNA, GAD65, but not to GAD67 mRNA, impairs sustained attention performance in the rat.

The effects of bilateral infusions of antisense oligodeoxynucleotides (ODNs) for the two isoforms of glutamic acid decarboxylase (GAD65; GAD67) into the nucleus accumbens on the performance of intact rats in a task designed to assess sustained attention were tested. The task required the animals to discriminate between signal and non-signal events. Signals and non-signals were presented randomly and unpredictably. The task generated all four response types of a sustained attention task, i.e., hits, misses, correct rejections, false alarms. Infusions of the scrambled sequence ODNs did not affect performance. Likewise, infusions of the GAD67 ODNs failed to produce any effect. However, infusions of the GAD65 ODNs into the nucleus accumbens resulted in a robust and reliable decrease in the relative number of hits. Similarly, the combined infusion of GAD65+67 ODNs impaired the hit rate but did not affect the animals' ability to reject non-signals. Following each treatment series, performance rapidly returned to baseline, further indicating the specificity and reversibility of the effects of the infusions of the ODNs. While these data suggest that translation arrest of specifically the GAD65 isoform of the enzyme in the nucleus accumbens impairs attentional performance, the neuronal mechanisms mediating these effects remain unsettled.

Animals↗
PubMed1983

Biochemical effects of a quinazoline inhibitor of thymidylate synthetase, N-(4-(N-(( 2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoyl)-L-glutamic acid (CB3717), on human lymphoblastoid cells.

The biochemical effects of the antitumor agent N-(4-(N-(( 2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoyl)-L -glutamic acid (CB3717) were studied in WI-L2 cultured human lymphoblastoid cells. CB3717 was a potent inhibitor of human thymidylate synthetase; the inhibition was competitive with 5,10-methylenetetrahydrofolate (Ki = 4.9 X 10(-9) M). CB3717 also inhibited human dihydrofolate reductase, competitively with dihydrofolate (Ki = 2.3 X 10(-8) M). The growth-inhibitory effect of CB3717 could be prevented completely by 10 microM thymidine. Administration of thymidine could be delayed for up to 8 hr after CB3717 treatment without cytotoxicity but, if thymidine was delayed for 24 hr, severe toxicity resulted. Incubation for 16 hr in the presence of a growth-inhibitory concentration of CB3717 did not result in the appearance of dihydrofolate in WI-L2 cells. These results indicate that, in the presence of CB3717, thymidylate synthetase, rather than dihydrofolate reductase, became rate-limiting for the cycle of dihydrofolate oxidation and reduction. Treatment of cells for 16 hr at an IC50 concentration of CB3717 caused a decrease of 88% in cellular dTTP and a 2,300% increase in dUMP. The level of dUDP also increased, and traces of dUTP appeared in treated cells. No large changes were seen in ribonucleotide pools. A kinetic analysis was made, by computer simulation, of predicted consequences of metabolic effects of compounds that inhibit both dihydrofolate reductase and thymidylate synthetase. It was concluded that, even if the Ki of the inhibitor for thymidylate synthetase were 3 orders of magnitude higher (weaker) than the Ki for dihydrofolate reductase, thymidylate synthetase could still become rate-limiting.

Animals↗
PubMed2003

Poly(L-glutamic acid)-paclitaxel conjugate is a potent enhancer of tumor radiocurability.

PURPOSE: Conjugating drugs with polymeric carriers is one way to improve selective delivery to tumors. Poly (L-glutamic acid)-paclitaxel (PG-TXL) is one such conjugate. Compared with paclitaxel, its uptake, tumor retention, and antitumor efficacy are increased. Initial studies showed that PG-TXL given 24 h before or after radiotherapy enhanced tumor growth delay significantly more than paclitaxel. To determine if PG-TXL-induced enhancement is obtained in a more clinically relevant setting, we investigated PG-TXL effects on tumor cure. METHODS AND MATERIALS: Mice bearing 7-mm-diameter ovarian carcinomas were treated with PG-TXL at an equivalent paclitaxel dose of 80 mg/kg, single dose or 5 daily fractions of radiation or both PG-TXL and radiation. Treatment endpoint was TCD(50) (radiation dose yielding tumor control in 50% of mice). Acute radioresponse of jejunum, skin, and hair was determined for all treatments. RESULTS: PG-TXL dramatically improved tumor radioresponse, reducing TCD(50) of single-dose irradiation from 53.9 (52.2-55.5) Gy to 7.5 (4.5-10.7) Gy, an enhancement factor (EF) of 7.2. The drug improved the efficacy of fractionated irradiation even more, reducing the TCD(50) of 66.6 (62.8-90.4) Gy total fractionated dose to only 7.9 (4.3-11.5) Gy, for an EF of 8.4. PG-TXL did not affect normal tissue radioresponse resulting from either single or fractionated irradiation. CONCLUSION: PG-TXL dramatically potentiated tumor radiocurability after single-dose or fractionated irradiation without affecting acute normal tissue injury. To our knowledge, PG-TXL increased the therapeutic ratio of radiotherapy more than that previously reported for other taxanes, thus, PG-TXL has a high potential to improve clinical radiotherapy.

Adenocarcinoma↗