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PubMed2004

Detection of autoreactive T cells in type 1 diabetes using coded autoantigens and an immunoglobulin-free cytokine ELISPOT assay: report from the fourth immunology of diabetes society T cell workshop.

The "gold standard" for evaluation of immunoassays is blinded testing, using coded samples and antigens. Although assays for autoreactive T cells are no exception to this rule, it is nonetheless rarely applied in this context. To facilitate such investigations, we coded a panel of 10 peptides representing T cell epitopes reported to be of relevance to islet autoimmunity. These were deployed in a novel cytokine ELISPOT assay, in which the use of immunoglobulin-free medium reduces background reactivity and thus potentially enhances the specificity and sensitivity of detection of autoreactive T cells. Significant IFN-gamma production against GAD65 (554-575), insulin (B9-23), and IA-2 (709-736) peptides were observed in type 1 diabetic patients, whereas no significant changes from background were detected in healthy controls. These results confirm the utility of the blinded performance of T cell assays as the most robust platform for assessing technologies to T cell autoreactivity.

Adolescent↗
PubMed2005

Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia.

Dysfunction of inhibitory neurons in the prefrontal cortex (PFC), represented by decreased expression of GABA-related genes such as the 67 kDa isoform of glutamate decarboxylase (GAD67) and parvalbumin (PV), appears to contribute to cognitive deficits in subjects with schizophrenia. We investigated the involvement of signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in producing the altered GABA-related gene expression in schizophrenia. In 15 pairs of subjects with schizophrenia and matched control subjects, both BDNF and TrkB mRNA levels, as assessed by in situ hybridization, were significantly decreased in the PFC of the subjects with schizophrenia, whereas the levels of mRNA encoding the receptor tyrosine kinase for neurotrophin-3, TrkC, were unchanged. In this cohort, within-pair changes in TrkB mRNA levels were significantly correlated with those in both GAD67 and PV mRNA levels. Decreased BDNF, TrkB, and GAD67 mRNA levels were replicated in a second cohort of 12 subject pairs. In the combined cohorts, the correlation between within-pair changes in TrkB and GAD67 mRNA levels was significantly stronger than the correlation between the changes in BDNF and GAD67 mRNA levels. Neither BDNF nor TrkB mRNA levels were changed in the PFC of monkeys after a long-term exposure to haloperidol. Genetically introduced decreases in TrkB expression, but not in BDNF expression, also resulted in decreased GAD67 and PV mRNA levels in the PFC of adult mice; in addition, the cellular pattern of altered GAD67 mRNA expression paralleled that present in schizophrenia. Decreased TrkB signaling appears to underlie the dysfunction of inhibitory neurons in the PFC of subjects with schizophrenia.

Adult↗
PubMed2001

International Workshop on Lessons From Animal Models for Human Type 1 Diabetes: identification of insulin but not glutamic acid decarboxylase or IA-2 as specific autoantigens of humoral autoimmunity in nonobese diabetic mice.

Several self-antigens have been reported as targets of the autoimmune response in nonobese diabetic (NOD) mice. The aim of this workshop was to identify autoantibody assays that could provide useful markers of autoimmunity in this animal model for type 1 diabetes. More than 400 serum samples from NOD (4, 8, and 12 weeks of age and at diabetes onset), BALB/c, and B6 mice were collected from six separate animal facilities, coded, and distributed to five laboratories for autoantibody measurement. Insulin autoantibodies (IAA) were measured by radiobinding assay (RBA) by four laboratories and by enzyme-linked immunosorbent assay (ELISA) in one laboratory. Using the 99th percentile of BALB/c and B6 control mice as the threshold definition of positivity, IAA by RBA were detected in NOD mice at frequencies ranging from 10 to 30% at age 4 weeks, from 26 to 56% at 8 weeks, from 42 to 56% at 12 weeks, and from 15 to 75% at diabetes onset. With ELISA, IAA signals differed significantly between control mouse strains and increased with age in both control and NOD mice, with frequencies in NOD animals being 0% at 4 weeks, 14% at 8 weeks, 19% at 12 weeks, and 42% at diabetes onset. For IAA, the ELISA results were relatively discordant with those of RBA. GAD autoantibody (GADA) and IA-2 autoantibody (IA-2A) signals obtained by RBA were low (maximum 2.5% of total) but were increased in NOD mice compared with control mice at diabetes onset (GADA 29-50%; IA-2A 36-47%). ELISA also detected GADA (42%) and IA-2A (50%) at diabetes onset, with results concordant with those of RBA. Remarkably, GADA and IA-2A frequencies varied significantly with respect to the source colony of NOD mice. Furthermore, whereas neither GADA nor IA-2A correlated with IAA, there was strong concordance between GADA and IA-2A in individual mice. Sera with increased binding to GAD and IA-2 also had increased binding to the unrelated antigen myelin oligodendrocyte glycoprotein, and binding to GAD could not be inhibited with excess unlabeled antigen, suggesting nonspecific interactions. In sum, this workshop demonstrated that IAA measured by sensitive RBA are a marker of autoimmunity in NOD mice and draw into question the true nature of GADA and IA-2A in this animal model.

Animals↗
PubMed1985

Partial purification and some properties of tryptophan decarboxylase from a Bacillus strain.

Bacteria of different origin were screened for tryptophan decarboxylase activity. The best producer belonged to an unidentified taxonomic entity of the genus Bacillus. In complete medium it produced tryptamine from tryptophan. The decarboxylase could partially be purified from the cells by sonication and DEAE-cellulose chromatography. The enzyme had an Mr of 150 000 and a pH optimum of about 7, was stable up to 37 degrees C, and its Km was about 0.3 mM for tryptophan. The enzyme needed pyridoxal phosphate for maximum activity.

Aromatic Amino Acid Decarboxylase Inhibitors↗
PubMed1990

Parkinsonism in monkeys produced by chronic administration of an endogenous substance of the brain, tetrahydroisoquinoline: the behavioral and biochemical changes.

We have examined the effect of chronic administration of a probable endogenous dopaminergic neurotoxin, tetrahydroisoquinoline (TIQ, 20 mg/kg per day, s.c. for up to 104 days), on squirrel monkeys. Chronically administered TIQ produced motor symptoms similar to parkinsonism in squirrel monkeys even after 7 days' discontinuation of TIQ and the symptomes were alleviated remarkably by levodopa treatment. Biochemical analysis of the brains of TIQ-treated monkeys revealed significant decrease in dopamine (DA) and total biopterin (BP) concentrations, and tyrosine hydroxylase (TH) activity in the substantia nigra, and these biochemical changes were not reversed by 7 days following the termination of chronic administration of TIQ. TIQ was identified in the brain (caudate-putamen) of saline-injected control monkeys by gas chromatography-mass spectrometry. The endogenous levels of TIQ in the caudate-putamen was about 0.15 micrograms/g, and increased up to 3-4 micrograms/g, 1 day as well as 7 days following termination of TIQ administration.

Animals↗
PubMed1980

Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization.

Various doses of 6-hydroxydopamine injected into the rat substantia nigra produced partial, dose-dependent lesions of the dopaminergic nigrostriatal tract. The resulting reduction in striatal dopamine concentrations and tyrosine hydroxylase activities tended to be proportional, allowing these measurements to serve as indices for lesion severity in any particular animal. Lesions destroying two-thirds or more of the nigrostriatal neurons accelerated dopamine's synthesis in, and release from, surviving neurons, as indicated by increased striatal levels of the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid. Formation of these metabolites was also enhanced in dendrites of dopaminergic neurons in the substantia nigra. Supersensitivity of striatal postsynaptic receptors, as judged by induction of rotational behavior after apomorphine or L-DOPA administration, occurred when 90% or more of the nigrostriatal neurons had been destroyed. In contrast, rotational behavior could be induced by amphetamine in animals with only 50% of these neurons destroyed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Increased neostriatal tyrosine hydroxylation during stress: role of extracellular dopamine and excitatory amino acids.

We examined the regulation of neostriatal tyrosine hydroxylation during acute stress, testing the hypothesis that excitatory amino acids (EAAs) contribute to the stress-evoked increase in dopamine (DA) synthesis. Dialysis probes implanted into neostriatum permitted delivery of drugs and sampling of extracellular fluid. Rats were exposed to 30 min of intermittent tail shock during infusion of an inhibitor of aromatic amino acid decarboxylase (AAAD), NSD-1015 (100 microM), and DOPA was measured in the dialysate. Tail shock was applied beginning either 15 min after the onset of NSD-1015 treatment (the initial rate of DOPA accumulation) or 75 min after the onset of treatment (when DOPA had approached steady state). Tail shock increased the steady-state levels of extracellular DOPA in neostriatum (+40%). However, there was no change in the initial rate of DOPA accumulation unless animals also received the D2 receptor antagonist eticlopride (50 nM), in which case an increase was observed (+228%). The impact of tail shock on the steady-state level of DOPA was attenuated by the D2 agonist quinpirole (100 microM), or by 2-amino-5-phosphonovalerate (APV) (100 microM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (100 microM), EAA antagonists acting at NMDA or D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA) receptors, respectively. These data suggest that acute stress normally has little effect on tyrosine hydroxylation in neostriatum due to the inhibitory influence of DA in the extracellular fluid. However, when that influence is absent (e.g., during extended inhibition of DOPA decarboxylation or blockade of DA receptors), stress increases tyrosine hydroxylation via EAAs acting on NMDA and AMPA receptors. Thus, EAAs released from corticostriatal projections may stimulate DA synthesis and thereby restore dopaminergic activity under conditions in which the availability of DA for release has been compromised.

Administration, Topical↗
PubMed2006

Uptake and decarboxylation of L-3,4-dihydroxyphenylalanine in cultured monkey placenta amniotic epithelial cells.

In this study we tested the ability of monkey amniotic epithelial cells (MAEC) to take up and decarboxylate l-3,4-dihydroxyphenylalanine (l-DOPA) by incubating the cells in buffer containing l-DOPA under different experimental conditions followed by assaying cellular dopamine (DA) content using high performance liquid chromatography with electrochemical detection. Cellular contents of DA were significantly increased in a time- and l-DOPA-concentration-dependent manner, suggesting the uptake of l-DOPA by MAEC and indicating the presence of aromatic l-amino acid decarboxylase (AADC). This was confirmed by the decreased DA content in the presence of benserazide, an AADC inhibitor. Neither d-DOPA nor DA uptake blockers such as mazindol and GBR 12935 significantly affected l-DOPA uptake and hence DA levels. Further, synthesis of DA from l-DOPA was decreased in the presence of the amino acids tyrosine, phenylalanine and tryptophan, whereas the amino acids glycine and proline were without any significant effect. These findings suggest that MAEC have the capacity to selectively take up and decarboxylate l-DOPA with subsequent production of DA.

Amnion↗
PubMedDate not supplied

[Ex vivo gene therapy in the treatment of Parkinson s disease].

OBJECTIVE: Taking into account the growing development and application of in vivo and ex vivo gene therapy in neurodegenerative disorders we review this kind of therapy applications in Parkinson s disease. DEVELOPMENT: Gene therapy carried out to this illness includes the liberation of genes encoding biosynthetic enzymes for dopamine synthesis: tyrosine hydroxylase, AADC and GTP cyclohydrolase and neurotrophic factors like GDNF which promotes the survival and maintenance of dopamin rgic neurons. Ex vivo gene therapy allows the control of the gene transfer before implantation, however one of the fundamental problems of this procedure is given by the immunologic rejection, so the use of autologous sources is recommended. CONCLUSIONS: Ex vivo gene therapy is advantageous in relation to in vivo gene therapy because it allows the control of gene transfer before the implantation; looking for cellular sources of neural origin or pluripotent stem cells which can be differenciated toward a wanted cellular type in order to achieve the structural and functional integration of the cells implanted in the central nervous system are recommended; however it becomes necessary the development of vectors of new generation to avoid biosafety problems involved in the gene therapy.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1988

Catecholaminergic innervation of luteinizing hormone-releasing hormone and glutamic acid decarboxylase immunopositive neurons in the rat medial preoptic area. An electron-microscopic double immunostaining and degeneration study.

Catecholaminergic innervation of luteinizing hormone-releasing hormone (LHRH) and glutamic acid decarboxylase (GAD) immunoreactive neurons in the rat medial preoptic area (MPO) was studied using electron-microscopic (EM) double-label immunostaining and combinations of single- and double-label immunostaining with acute axonal degeneration. The EM double-immunostaining experiments included double staining for either tyrosine hydroxylase (TH) and LHRH, or TH and GAD. Analysis of TH and LHRH double-immunostained material revealed synaptic connections between TH immunoreactive axons and LHRH immunopositive neurons. The TH and GAD double-staining experiments also demonstrated synaptic connections between axons immunoreactive for TH and GAD immunopositive neurons. Two days following unilateral surgical transection of the ventral and dorsal noradrenergic bundles, synaptic connections were found between degenerated boutons and GAD immunoreactive neurons in the ipsilateral MPO. However, no synapses could be observed in the same area between degenerated axons and the LHRH immunopositive neurons. Following the same operation and immunostaining for TH, a moderate number of degenerating TH axons as well as a large number of nondegenerated TH immunoreactive boutons were observed. Double immunostaining for TH and GAD in MPO sections ipsilateral to the operation revealed synaptic connections between the degenerating TH immunopositive axons and GAD immunoreactive neurons. These results suggest that there are direct synaptic connections between catecholaminergic axons and GAD and LHRH immunoreactive neurons in the medial preoptic area of the rat. Some of the connections between TH immunopositive afferents and GAD immunoreactive neurons may represent connections from noradrenergic neurons in the brain stem, while the majority of TH-GAD and TH-LHRH connections may represent innervation of GABA and LHRH neurons from local dopamine-containing cells.

Adrenergic Fibers↗
PubMed1988

Inhibition of catechol-O-methyltransferase activity by two novel disubstituted catechols in the rat.

Catechol-O-methyltransferase (COMT) has an important role in the extraneuronal inactivation of catecholamine neurotransmitters and drugs with a catechol structure. Two novel COMT inhibitors, OR-462 and OR-486, were highly effective (IC50 = 18 and 12 nM, respectively) and selective in inhibiting COMT activity in vitro. Tyrosine hydroxylase was not inhibited until micromolar concentrations of these compounds were used: the IC50 values for OR-462 and OR-486 were 10 and 14 microM, respectively. The IC50 values for dopamine-beta-hydroxylase, dopa-decarboxylase and monoamine oxidase forms A and B were greater than 50 microM. In studies ex vivo oral OR-462 inhibited mainly the COMT activity in the duodenum while OR-486 inhibited COMT activity in the liver and red blood cells as well. Oral OR-462 did not penetrate into the brain in doses up to 30 mg/kg while the same dose of OR-486 had some effect on striatal COMT activity. When tested in combination with levodopa-carbidopa, orally administered OR-462 and OR-486 were more effective in reducing the formation of 3-O-methyldopa from levodopa than was the levodopa-carbidopa treatment alone. These results indicate that OR-462 and OR-486 are effective and long-lasting inhibitors of COMT activity.

Animals↗
PubMed1995

Neurotransmitter synthesis by SN6 cell lines, a family of hybrid cell lines of embryonic septal origin.

Previously, we reported the presence of multiple neurotransmitters in subclones of SN6, a septal cholinergic hybrid cell line. To obtain information concerning the functionality of these transmitters, we measured transmitter contents, activities of transmitter-producing enzymes, and the effect of serum-free culture medium in two different batches (SN6.1.6 and SN6.10.2.2) and two subclones of the SN6 cell line (SN6.2a and SN6.1b). Except for SN6.1b, SN6 cell lines and subclones had basically the same neurotransmitter characteristics. Among the transmitters, only acetylcholine seemed to be functional. Monoamine oxidase was missing and activity of aromatic amino acid decarboxylase was diminished in SN6 cell lines. Even in serum-containing medium, SN6.1b had a more mature morphology than the other cell lines, and it contained choline acetyltransferase and acetylcholine but not tyrosine hydroxylase or catecholamines. Similar characteristics were acquired by the mother cell line in response to serum-free conditions. Thus, SN6.1b is the most mature of these central cholinergic neuronal cell lines, at least with regard to neurotransmitter profiles.

Animals↗

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