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PubMedDate not supplied

Induction of ornithine decarboxylase in Reuber H35 rat hepatoma cells.

Stimuli known to induce tyrosine aminotransferase in H35 cells were tested relative to their ability to induce ornithine decarboxylase, the initial enzyme in the polyamine biosynthetic pathway. Dibutyryl cyclic AMP (0.5 mM), parachlorophenylthio-cyclic AMP (0.1 mM) and dexamethasone (1 muM) stimulated the activity of ornithine decarboxylase 7- to 8-fold by 5 hr of induction. There was a delay of 1 hr before any increase in enzyme activity was detectable. Insulin administered alone failed to significantly change ornithine decarboxylase activity. The ability of dibutyryl cyclic AMP to elevate ornithine decarboxylase activity was found to be concentration-dependent, and a dose-response relationship very similar to that for the induction of tyrosine aminotransferase by dibutyryl cyclic AMP was observed in these cells. The ability of various 8-substituted cyclic AMP analogues to increase the activity of ornithine decarboxylase was correlated with their ability to activate purified protein kinase.

Animals↗
PubMed2003

The neonatal ventral hippocampal lesion model of schizophrenia: effects on dopamine and GABA mRNA markers in the rat midbrain.

The neonatal ventral hippocampal lesion in the rat has been used as a model of schizophrenia, a human disorder associated with changes in markers of dopamine and gamma-aminobutyric acid (GABA) circuits in various regions of the brain. We investigated whether alterations in mRNA markers related to the activity of midbrain dopaminergic and GABAergic neurons are associated with this model. We used in situ hybridization histochemistry to assess expression of mRNAs for dopamine transporter (DAT), tyrosine hydroxylase (TH) and glutamate decarboxylase-67 (GAD67) in the midbrain of adult rats with neonatal and adult ibotenic acid lesions of the ventral hippocampus. Neonatally lesioned rats showed in adulthood significantly reduced expression of DAT mRNA in the substantia nigra and the ventral tegmental area but no changes in the expression of TH and GAD67 mRNAs in these midbrain regions. Adult lesioned rats showed no changes in the expression of any of these genes. As the neonatal ventral hippocampal lesion reproduces many aspects of schizophrenia and is used as an animal model of this disorder, these results suggest that the reduction in DAT mRNA could result from developmental neuropathology in the ventral hippocampus and may thus represent a molecular substrate of the disease process.

Aging↗
PubMed2006

Midkine is a potent regulator of the catecholamine biosynthesis pathway in mouse aorta.

To discover regulatory pathways dependent on midkine (Mk the gene, MK the protein) signaling, we compared the transcriptional profiles of aortae obtained from Mk -/- and wild type (WT, +/+) mice; the comparison demonstrated an extraordinary high level expression of tyrosine hydroxylase (12-fold), the rate-limiting enzyme in catecholamine biosynthesis, DOPA decarboxylase (73-fold), and dopamine beta-hydroxylase (75-fold) in aortae of Mk -/- mice compared with aortae of WT (+/+) mice. Phenylethanolamine-N-methyltransferase, the enzyme catalyzing the conversion of norepinephrine into epinephrine, was not detected in either Mk -/- and WT (+/+) mouse aorta. The protein levels of tyrosine hydroxylase, DOPA decarboxylase and dopamine beta-hydroxylase confirmed the analysis of the transcriptional profiles. Surprisingly, MK failed to regulate the enzymes of the catecholamine biosynthesis pathway in 10 other tissues studied. Furthermore, the expression levels of the enzymes of catecholamine biosynthesis in aortae of Mk -/- mice were effectively the same as those in aortae of Pleiotrophin (Ptn the gene, PTN the protein) genetically deficient (Ptn -/-) mice when compared with WT (+/+) mice. The remarkable increases in levels of expression of tyrosine hydroxylase, DOPA decarboxylase and dopamine beta-hydroxylase suggest that MK together with PTN are very important regulators of the catecholamine pathway in mouse aorta and may critically regulate catecholamine biosynthesis and function in inflammatory and the other pathological conditions in which Mk or Ptn are upregulated. The data also establish that norepinephrine is effectively the only catecholamine synthesized in mouse aorta.

Animals↗
PubMed1977

Adrenergic, cholinergic, and inactive human neuroblastoma cell lines with the action-potential Na+ ionophore.

Cultured human neuroblastoma cell lines were assayed for biochemical characteristics of neuonal function. Cell lines studied included LA-N-1, LA-N-2, IMR-32, SK-N-SH, and SK-N-MC. Veratridine-dependent uptake of 22Na+ implied the presence of the action potential Na+ ionophore in LA-N-1, LA-N-2, IMR-32, and SK-N-SH. The time course of 22Na+ uptake and inhibition of uptake by tetrodotoxin supported this. SK-N-MC had no veratridine-dependent 22Na+ uptake. Tyrosine hydroxylase (EC 1.14.10.), glutamic acid decarboxylase (EC 4.1.1.15), and acetylcholine contents in neuroblastoma cells were compared to those in brain. LA-N-1 and IMR-32 contained 15 and 5 times as much tyrosine hydroxylase, respectively, whereas LA-N-2, SK-N-SH, and SK-N-MC contained only 0.5 to 5% of that in brain. Acetylcholine was present in -LA-N-2 in 15- to 20-fold greater quantities than in brain; other lines had only 10 to 50% of that in brain. None of the cell lines contained glutamic acid decarboxylase. Thus, continuously propogated human neuroblastoma cell lines may have the action potential Na+ ionophore and may be adrenergic (LA-N-1 and IMR-32), cholinergic (LA-N-2), or inactive (SK-N-SH and SK-N-MC). This is the first demonstration of the action potential Na+ ionophore and of acetylcholine production in human neuroblastoma cell lines.

Acetylcholine↗
PubMed2001

[Auto-antibody profile and breast feeding in type 1 diabetic patients].

BACKGROUND: Islet cell-specific autoantibodies such as islet cell antibody (ICA), antiinsulin (IAA), anti-glutamic acid decarboxylase (GAD) and anti-tyrosine phosphatase (IA2) can be present in patients with type I diabetes. Breast feeding duration and the early exposure to milk substitutes are environmental factors associated to etiology of type 1 diabetes. AIM: To study the frequency of the anti-GAD, anti-IA-2 e ICA antibodies in Chilean type 1 diabetic patients and determine the possible modulator effect of the breast feeding. PATIENTS AND METHODS: One hundred thirty four type 1 diabetic patients, aged one to 15 years old, were studied at the moment of their diagnosis. Patients were classified according to the duration of exclusive breast feeding. IA-2 and GAD were determined by radio immuno assay and ICA by means of indirect immunofluorescence. RESULTS: Subjects with three months or less and those with more than three months of breast feeding were positive for ICA in 78.8 and 90.6% of cases respectively, for GAD in 75 and 54.6% of cases respectively (p = 0.024) and for IA-2 in 73 and 43.8% of cases respectively (p = 0.001). All three antibodies were positive in 53.9 and 21.8% of children with less or more than three months of breast feeding (p = 0.001). CONCLUSION: Both IA-2 and GAD antibodies are less frequently positive in type 1 diabetic patients who have been breast fed for more than three months. These findings suggest a possible attenuating role of exclusive breast feeding on pancreatic aggression events in patients with type 1 diabetes.

Adolescent↗
PubMed2000

In vitro and in vivo characterization of hNT neuron neurotransmitter phenotypes.

The hNT neuron exhibits many characteristics of neuroepithelial precursor cells, making them an excellent model to study neuronal plasticity in vitro and in vivo. These cells express a number of neurotransmitters in vitro, including dopamine, gamma-aminobutyric acid and acetylcholine. However, there have been few reports of the neurotransmitters that hNT neurons express in vivo. The present study examined whether hNT neurons express the same neurotransmitters in vivo as they do in vitro. First, the expression of tyrosine hydroxylase (TH), glutamic acid decarboxylase (GAD), choline acetyltransferase (ChAT) and the human specific nuclear marker NuMA by hNT neurons was confirmed. Nineteen normal animals were then transplanted with 80,000 hNT neurons aimed at the striatum, hippocampus or cerebral cortex. Five additional animals received injections of medium. All animals received daily intraperitoneal injections of cyclosporine (10 mg/kg) and survived 30 days. Sections through the transplants were examined for NuMA-positive hNT neurons, and for the presence of the three neurotransmitter markers: TH, GAD and ChAT. The hNT neurons were found in the striatum and cortex. Of the hNT neurons found within the rat striatum, 33% were ChAT-positive. In the cortex, only 4% of the neurons expressed ChAT. No GAD-positive hNT neurons were detected at either site. No NuMA-positive neurons were found in the hippocampus. The implanted hNT neurons did not induce activation of astrocytes as determined by immunocytochemistry for glial fibrillary acidic protein (GFAP). Moreover, no hNT neuron was found to express GFAP in vivo. Together, these data suggest that the hNT neurons engraft in the new host tissue, maintain their neuronal identity and may be guided in differentiation according to local environmental cues.

Animals↗
PubMed2006

Clinical phenotype and beta-cell autoimmunity in Italian patients with adult-onset diabetes.

OBJECTIVE: To characterize the phenotype of a large population of Italian patients with adult onset (> or =40 years) diabetes who were attending outpatient clinics and who were screened for glutamic acid decarboxylase 65 autoantibodies (GADA), protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA). DESIGN AND METHODS: This was a cross-sectional study comprising a total of 881 patients, aged < or = 70 years, diagnosed with type 2 diabetes after the age of 40 years, and consecutively recruited in five clinics located in different geographic areas of Italy (Milan, Florence, Rome, Naples and Catania). Their mean disease duration was 8.1 (6.9; s.d.) years. GADA, IA-2A and IA-2betaA were measured with radiobinding assays with in vitro translated S-methionine-labelled glutamic acid decarboxylase 65 (GAD65) or IA-2 or IA-2beta. Anthropometric and clinical data were collected and compared amongst patients with or without autoantibodies. RESULTS: Sixty-three (7.1%) patients had one or more autoantibodies, 58 (6.6%) had GADA, 22 (2.5%) had IA-2A, six (0.7%) had IA-2betaA and 19 (2.15%) had two or more autoantibodies. IA-2A or IA-2betaA, in the absence of GADA, were found in only five patients. Autoantibody-positive patients were more often female (63.5 vs 36.5%; P < 0.009), had higher glycated haemoglobin (Hb A1c) (P < 0.001), lower body mass index (BMI; P < 0.0005) and waist/hip ratio (WHR; P < 0.01); female gender being the main contributor to BMI and WHR. We did not observe any differences in age at diagnosis or duration of disease with respect to the presence or absence of islet autoantibodies. The proportion of patients on insulin therapy was higher in patients with two or more antibodies, compared with those with one antibody only, and no antibodies (P for trend < 0.001), and among patients with GADA, in those with higher antibody titre (73.9% in those with > 10 units vs 42.0% in those with < or = 10 units; P < 0.007). CONCLUSIONS: Patients with adult onset diabetes characterized by autoimmunity to beta-cells showed a clinical phenotype with anthropometric features that differed from those classically observed in patients with type 2 diabetes. The number and titre of autoantibodies, which reflect the severity of autoimmunity and beta-cell impairment, amplified this difference. The usefulness of autoantibody screening in adult-onset diabetes is further emphasized by these findings.

Aged↗
PubMed2000

Evaluation of T-cell receptor CD3+ gamma delta in gestational diabetes mellitus.

Few studies have shown a significant increase of CD3+ T-cell receptor (TCR) gamma delta in the early phases of type 1 diabetes. We wished to determine if CD3+ TCR gamma delta is involved in the pathogenesis of gestational diabetes mellitus (GDM). We studied 29 GDM patients and 21 normal pregnant women. Lymphocyte subpopulations (CD3+ TCR alpha beta, CD3+ TCR gamma delta), islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GAD) and protein tyrosine phosphatase antibodies (IA2-Ab) were evaluated in all patients. The percentage of CD3+ TCR gamma delta was significantly higher in GDM women than in the control group (5.1 +/- 2.9% vs 3.7 +/- 1.7%; p < 0.05). No abnormalities of the other lymphocyte subpopulations were found. All subjects were negative for ICA; 2 GDM patients were positive for GAD, but no relationship was found between GAD positivity and CD3+ gamma delta levels in these 2 patients. Further follow-up studies of these patients are required to verify if the CD3+ TCR gamma delta receptor is a useful marker for diabetes development.

Adult↗
PubMed2005

Catecholamine-synthesizing enzymes in the adult and prenatal human testis.

Catecholamines play functional roles in the mature and developing mammalian testis but the cell types responsible for their local synthesis are still controversially discussed. Here, we demonstrate that four enzymes involved in the biosynthesis of catecholamines, namely, tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DBH) and phenylethanolamine- N-methyltransferase (PNMT), are expressed in Leydig cells of the human testis. Tyrosine hydroxylase, the key enzyme of the biosynthesis of catecholamines, was localized to Leydig cells both at the transcript level (by RT-PCR analyses and by in situ hybridization assays) and at the protein level (by immunoblotting and by immunohistochemistry). The other enzymes were also demonstrated in Leydig cells by RT-PCR and immunohistochemical analyses. The presence of TH, AADC, DBH, and PNMT in human Leydig cells was found, in addition, by immunohistochemical approaches carried out on sections from prenatal human testes. Thus, the present study identifies the Leydig cells as the presumed sites of catecholamine production in both the mature and fetal human testes and further supports the previously recognized neuroendocrine characteristics of this cell type.

Aged↗
PubMed1990

Effect of trimipramine, an atypical tricyclic antidepressant, on the activities of various enzymes involved in the metabolism of biogenic amines.

1. The mechanism of action of trimipramine, a clinically efficacious tricyclic antidepressant, is not well understood. In order to investigate whether it might affect the activities of different enzymes involved in biogenic amine metabolism we have undertaken a comparative study of it along with amitriptyline. 2. Neither trimipramine nor amitriptyline, at concentrations up to 1 mM, exhibited any significant effect on phenylalanine hydroxylase, tyrosine hydroxylase, L-aromatic amino acid decarboxylase, dopamine-beta-hydroxylase, phenylethanolamine-N-methyltransferase, catechol-O-methyltransferase, phenylsulfotransferase or tyrosine aminotransferase. 3. Monoamine oxidase, however, was inhibited by both drugs with the greatest effect being on MAO-B. The inhibition was reversible, non-competitive and relatively weak.

Adrenal Glands↗
PubMed1987

Neurotoxic effects of low-level chronic acephate exposure in rats.

Rats were administered the organophosphorus insecticide acephate at 1.0 or 10.0 mg/kg.day for 15 weeks. Blood and brain samples were collected at the end of the treatment and analyzed for cholinesterase, acetylcholinesterase, and glutamic acid decarboxylase activities and catecholamine and amino acid levels. No significant inhibition in the activity of brain AChE was noted at doses of 1.0 or 10.0 mg/kg.day. Low levels of acephate exposure (1.0 mg/kg.day), which did not alter plasma cholinesterase or RBC acetylcholinesterase activity levels, resulted in a significant elevation of plasma epinephrine and norepinephrine levels. Decreased GABA, dopamine, and tyrosine levels and glutamic acid decarboxylase activity were observed in brains of these rats. Similar changes occurred in rats exposed to 10 mg of acephate/kg.day; however, plasma cholinesterase and RBC acetylcholinesterase activities were inhibited. These observations suggest that chronic exposure to acephate altered the activity of the noncholinergic system without altering the cholinergic activity, and that low-level chronic exposure to organophosphorous compounds cannot be predicted by measuring the ChE or AChE enzyme activities.

Acetylcholinesterase↗
PubMed1994

GABA-ergic and substance P-ergic double-innervation to noradrenergic neurons in the rat locus coeruleus.

Synaptic contacts between noradrenaline (NA) neurons and GABA (gamma-aminobutyric acid) afferents and/or substance P (SP) afferents in the locus coeruleus (LC) were examined by a combination of immunoelectron microscopic mirror method and double-immunostaining method. For visualization of NA and GABA, we used antibodies against NA and GABA synthesizing enzymes, i.e., tyrosine hydroxylase (TH) and glutamic acid decarboxylase (GAD). GAD-immunoreactive (IR) and SP-IR axon terminals often made synaptic contacts with NA neurons, respectively. Furthermore, we identified that a single NA neuron simultaneously receives synaptic inputs from GAD-IR and SP-IR afferents. These NA neurons made symmetrical synaptic contacts with GAD-IR axon terminals and asymmetrical contacts with SP-IR axon terminals. This suggests that central NA neuronal mechanisms are affected by GABA and SP neurons in a different manner.

Animals↗
PubMed1996

Molecular analysis of a new member of the opium poppy tyrosine/3,4-dihydroxyphenylalanine decarboxylase gene family.

An aromatic amino acid decarboxylase DNA fragment was generated from opium poppy (Papaver somniferum L.) genomic DNA by the PCR using primers designed from conserved amino acid sequences of other aromatic amino acid decarboxylase genes. Using this fragment as a probe, a genomic clone was isolated that encodes a new member of the opium poppy tyrosine/3,4-dihydroxyphenylalanine decarboxylase gene family (TyDC5). The predicted TyDC5 amino acid sequence shares extensive identity with other opium poppy tyrosine/3,4-dihydroxyphenylalanine decarboxylases (84%), and when expressed in Escherichia coli, it is active against tyrosine and to a lesser extent against 3,4-dihydroxyphenylalanine. Ribonuclease protection assays indicate that TyDC5 is expressed primarily in the roots of mature poppy plants. A peak of TyDC5 expression was also observed during germination, coincident with the emergence of the radicle from the seed coat. Parallel results were obtained in transgenic tobacco using a TyDC5 promoter fragment (-2060) translationally fused to the beta-glucuronidase reporter gene (GUS). IN TyDC5::GUS tobacco, GUS activity transiently appeared in all parts of the seedling during germination, but was limited to the roots in older plants. These results indicate that TyDC5 expression is transcriptionally regulated and suggest that the TyDC5 enzyme may play an important role in providing precursors for alkaloid synthesis in the roots and germinating seedlings of opium poppy.

Amino Acid Sequence↗
PubMed1983

Age and strain comparisons of neurotransmitter synthetic enzyme activities in the mouse.

Activities of the neurotransmitter synthetic enzymes, choline acetyltransferase (EC 2.3.1.6; ChAT), glutamic acid decarboxylase (EC 4.1.1.15; GAD), and tyrosine hydroxylase (EC 1.14.3.2; TH), were assayed in four brain regions of A/J and C57BL/6J mice at three ages (4, 18, and 24 months). The brain regions assayed were the fronto-parietal cortex, hippocampus, striatum, and cerebellum. Strain effects: In some brain regions, at several ages, ChAT activity did not differ among the two strains. However, ChAT was higher in the C57BL/6J strain in the cortex at 18 months, the hippocampus at 18 and 24 months, the striatum at 24 months, and the cerebellum at 4 months. The reverse was true in the cerebellum at 24 months, where ChAT was higher in A/J mice. GAD activity in C57BL/6J mice compared to that of A/J mice was higher in the striatum and cortex, and lower in the hippocampus and cerebellum. TH activities in all four regions were generally higher in C57BL/6J mice than in A/J mice. Age effects: Age differences in enzyme activities varied with the genetic strain. ChAT activity generally was higher in brain regions of older mice of both strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1997

Combined analysis and single-step detection of GAD65 and IA2 autoantibodies in IDDM can replace the histochemical islet cell antibody test.

Cytoplasmic islet cell antibodies (ICAs) are the classical serological markers for diagnosis and prediction of IDDM, but high technical demands have limited the widespread use of the histochemical ICA test. To investigate whether combined analysis of autoantibodies to two defined islet antigens can replace the histochemical ICA test, we established quantitative radioimmunoassays for autoantibodies to glutamate decarboxylase (GAD65-A), the tyrosine phosphatase IA2/ICA512 (IA2-A), and the cytoplasmic part of IA2 (IA2c-A). The GAD65-A and IA2c-A profiles of 920 sera from healthy individuals and from patients with IDDM, other organ-specific autoimmune diseases, and polyendocrine autoimmune syndrome were compared with the ICA profiles from these same individuals. Combined analysis of GAD65-A and IA2c-A detected 93-100% of the ICA+ sera, and, at equal specificity, improved the diagnostic sensitivity (85%) for IDDM compared with that of ICA (74%). This effect was especially pronounced in children with disease onset before 16 years of age (91% sensitivity). To replace ICA testing in risk assessment for IDDM, we designed a strategy adapted to study groups with low antibody prevalence. A combined radioimmunoassay for single-step detection of GAD65-A and IA2c-A was developed, and positive sera were reanalyzed to define their single autoantibody specificity. We identified 93% of the ICA+ sera from 204 first-degree relatives of IDDM patients. Single-step detection reduced costs and effort by more than 40% compared with separate testing, allowing an efficient large-scale screening of sera for GAD65-A and IA2c-A in IDDM. In sum, GAD65-A and IA2c-A detected much ICA reactivity, and their combined evaluation and detection is suitable to replace the histochemical ICA test.

Adolescent↗
PubMed1983

Some neurons of the rat central nervous system contain aromatic-L-amino-acid decarboxylase but not monoamines.

Neurons containing the enzyme aromatic-L-amino-acid decarboxylase (AADC) but lacking either tyrosine hydroxylase or serotonin were found in the spinal cord of neonatal and adult rats by light and electron microscopic immunocytochemistry. The majority of these neurons localized to area X of Rexed contact ependyma. Thus, spinal AADC neurons have the enzymatic capacity to catalyze directly the conversion of the amino acids tyrosine, tryptophan, or phenylalanine to their respective amines tyramine, tryptamine, or phenylethylamine. These amines normally present in the central nervous system may be of potential clinical significance as endogenous psychotomimetics.

Animals↗
PubMed2005

Environmental factors related to the induction of beta-cell autoantibodies in 1-yr-old healthy children.

We studied environmental risk factors which might contribute to the development of beta-cell autoantibodies in healthy children. Here, we investigated 6000 randomly selected children from the large All Babies in Southeast Sweden (ABIS) cohort, including 17 055 newborns recruited between 1997 and 1999. Questionnaires at birth and at 1 yr of age and the levels of autoantibodies to glutamic acid decarboxylase (GADA) and autoantibodies to tyrosine phosphatase (IA-2A) at 1 yr of age were analyzed. The 99th percentile cutoff for autoantibodies was proposed to identify children at risk of type 1 diabetes (T1D) and the 90th percentile cutoff to identify children in whom beta-cell autoimmunity has been induced. Using the 90th percentile cutoff level, 1156 children had either IA-2A (n = 574) or GADA (n = 582), while 126 children had both GADA and IA-2A. When the 99th percentile cutoff level was used, 114 children had either IA-2A (n = 57) or GADA (n = 57), and six children had both GADA and IA-2A. In logistic regression analysis, celiac disease in grandparents [odds ratio (OR) 2.2] and maternal gastrointestinal infection (OR 1.1) represented a risk for simultaneous occurrence of both IA-2A and GADA above the 90th percentile. Birth in spring (March to May) (OR 1.5) and male gender (OR 1.3) were risk factors for induction of IA-2A. Mother's low education represented a risk for induction of IA-2A (OR 1.5) and GADA (OR 1.4). T1D in first-degree relatives increased the risk for beta-cell autoimmunity above the 99th percentile (OR 2.6), whereas type 2 diabetes in grandparents was associated with GADA (OR 2.1). Exposure to cow's milk formulas <2 months of age implied an OR of 2.9 for IA-2A above the 99th percentile.

Animals↗