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PubMed1977

In vivo studies on the conversion of m-tyrosine to 3,4-dihydroxyphenylalanine in the rat.

The question whether m-tyrosine can give rise to catechols in vivo has been investigated using labelled precursor. DL-[2-14C]m-tyrosine (38 muCi/mmol (1 Ci = 37 GBq)) was synthesized from [2-14C]glycine. Radioactive catechols in rat brain, liver, and kidneys were examined 15 min after intraperitoneal administration of DL-[2-14C]m-tyrosine (100 mg/kg). The kidney was the only organ which showed demonstrable amounts of radioactive catechols, and about 14% of the catechols formed was identified as 3,4-dihydroxyphenylalanine (dopa), 22% as 3,4-dihydroxyphenylacetic acid, and 56% as dopamine. However, when the animals were pretreated with dopa decarboxylase inhibitor, labelled catechols were also observed in liver and brain, and dopa accounted for over 95% of the catechols formed in all three organs examined. Thus it is clear that m-tyrosine can by hydroxylated in vivo. Results from experiments using [2-14C]m-tyrosine enantiomers and specific enzyme inhibitors suggest that phenylalanine hydroxylase could be the enzyme catalyzing this reaction.

Animals↗
PubMed1990

Enhancement of in vivo tyrosine hydroxylation in the rat adrenal gland under hypoxic conditions.

We examined the effects of hypoxia (8% O2) on in vivo tyrosine hydroxylation, a rate-limiting step for catecholamine synthesis, in the rat adrenal gland. The hydroxylation rate was determined by measuring the rate of accumulation of 3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition. One hour after hypoxic exposure, DOPA accumulation decreased to 60% of control values, but within 2 h it doubled. At 2 h, the apparent Km values for tyrosine and for biopterin cofactor of tyrosine hydroxylase (TH) in the soluble fraction were unchanged, whereas the Vmax value increased by 30%. The content of total or reduced biopterin was unchanged, but the content of tyrosine increased by 80%. Tyrosine administration had little effect on DOPA accumulation under room air conditions but enhanced DOPA accumulation under hypoxia. After denervation of the adrenal gland, the hypoxia-induced increase in DOPA accumulation and in the Vmax value was abolished, whereas the hypoxia-induced increase in tyrosine content was persistent. These results suggest that in vivo tyrosine hydroxylation is enhanced under hypoxia, although availability of oxygen is reduced. The enhancement is the result of both an increase in tyrosine content coupled with increased sensitivity of TH to changes in tyrosine tissue content and of an increase in dependence of TH on tyrosine levels. The increase in the sensitivity of TH and in the Vmax value is neurally induced, whereas the increase in tyrosine content is regulated by a different mechanism.

Adrenal Glands↗
PubMed2000

Hypertrophic effect of selective beta(1)-adrenoceptor stimulation on ventricular cardiomyocytes from adult rat.

We investigated whether selective beta(1)-adrenoceptor stimulation causes hypertrophic growth on isolated ventricular cardiomyocytes from adult rat. As parameters for the induction of hypertrophic growth, the increases of [(14)C]phenylalanine incorporation, protein and RNA mass, and cell size were determined. Isoproterenol (Iso, 10 microM) alone had no growth effect. In the presence of the beta(2)-adrenoceptor antagonist ICI-118551 (ICI, 10 microM), Iso caused an increase in [(14)C]phenylalanine incorporation, protein and RNA mass, cell volume, and cross-sectional area. We showed for phenylalanine incorporation that the growth effect of Iso+ICI could be antagonized by beta(1)-adrenoceptor blockade with atenolol (10 microM) or metoprolol (10 microM), indicating that it was caused by selective beta(1)-adrenoceptor stimulation. The growth response to Iso+ICI was accompanied by an increase in ornithine decarboxylase (ODC) activity and expression. Inhibition of ODC by the ODC antagonist difluoromethylornithine (1 mM) attenuated this hypertrophic response, indicating that ODC induction is causally involved. The growth response to Iso+ICI was found to be cAMP independent but was sensitive to genistein (100 microM) or rapamycin (0.1 microM). The reaction was enhanced in the presence of pertussis toxin (10 microM). We conclude that selective beta(1)-adrenoceptor stimulation causes hypertrophic growth of ventricular cardiomyocytes by a mechanism that is independent of cAMP but dependent on a tyrosine kinase and ODC.

Adrenergic beta-Antagonists↗
PubMed1988

Mass and activity of tyrosine hydroxylase in tuberoinfundibular dopaminergic neurons of the aged brain. Control by prolactin and ovarian hormones.

The roles of prolactin (PRL) and the ovarian hormones, estradiol and progesterone, in the control of tuberoinfundibular dopaminergic neurons of aged female rats were investigated. The in situ molar activity of tyrosine hydroxylase (TH) in neurites of these neurons was assayed by measuring the rate of accumulation of L-dihydroxyphenylalanine in the median eminence following the administration of a L-dihydroxiphenylalanine decarboxylase inhibitor. The TH mass was measured by an immunoblot assay using rat TH as the standard. Pituitary implants in aged ovariectomized animals resulted in a significant increase in the median eminence of both the mass and in situ molar activity of TH. When circulating PRL of aged rats was neutralized by administration of antiserum against rat PRL, the activity of TH was reduced significantly compared to that of animals treated with preimmune serum. In aged ovariectomized rats treated with both estradiol and progesterone, the in situ molar activity of TH increased significantly compared to animals treated only with the solvent vehicle, estradiol, or progesterone. The stimulatory effect of estradiol and progesterone appeared to be mediated through a mechanism that did not involve PRL, since neutralization of circulating PRL failed to prevent an increase in TH activity in estradiol-progesterone-treated animals. None of these treatments affected the in situ activity of TH in the superior cervical ganglion. We conclude that PRL as well as combined estradiol-progesterone treatment have important roles in the maintenance of TH activity in aged tuberoinfundibular dopaminergic neurons.

Age Factors↗
PubMed1962

Observations on the substrate specificity of DOPA decarboxylase from ox adrenal medulla, human phaeochromocytoma and human argentaffinoma.

The substrate specificity of the dopa decarboxylases of ox adrenal medulla, human phaeochromocytoma and human argentaffinoma have been studied. The enzymes from all three tissues decarboxylated dopa, metatyrosine, orthotyrosine and 5-hydroxytryptophan. Dopa was decarboxylated most rapidly and 5-hydroxytryptophan least rapidly by the enzyme from all three tissues. Competition experiments indicate that all four substrates are decarboxylated by the one enzyme. Attempts to demonstrate decarboxylation of [C(14)]-tyrosine, [C(14)]-tryptophan or [C(14)]-histidine by these enzyme preparations were unsuccessful.

5-Hydroxytryptophan↗
PubMed1999

alpha-Difluoromethylornithine blocks thymocyte apoptosis via a reduction in tyrosine phosphorylation.

The effect of alpha-difluoromethylornithine on cell apoptosis was investigated. Freshly isolated mouse thymocytes were cultured in the medium alone or with dexamethasone, and apoptotic cell death was monitored after 6 h. A correlation was seen between cell apoptosis and a reduction in the polyamine levels of thymocytes. Addition of exogenous polyamines decreased the levels of apoptosis induced spontaneously in the culture medium or by dexamethasone. However, addition of alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, to the cultures did not enhance apoptosis but rather caused inhibition of thymocyte apoptosis. Analysis of the mechanism of alpha-difluoromethylornithine-mediated inhibition of apoptosis indicated that alpha-difluoromethylornithine treatment blocked protein tyrosine phosphorylation, which was elevated drastically during the first hour of thymocyte cultivation. Treatment with the phosphotyrosine phosphatase inhibitor phenylarsine oxide reversed this inhibitory effect of alpha-difluoromethylornithine on apoptotic cell death. Our results provide an alternative mechanism for alpha-difluoromethylornithine showing the inhibition of apoptosis via reduction of protein tyrosine phosphorylation.

Animals↗
PubMed1999

T-cell mediated autoimmunity to the insulinoma-associated protein 2 islet tyrosine phosphatase in type 1 diabetes mellitus.

The target molecules of the T-cell response in type 1 diabetes, despite their pathogenic importance, remain largely uncharacterized, especially in humans. Interestingly, molecules such as insulin and glutamic acid decarboxylase (GAD) have been shown to be a target not only of autoantibodies, but also of autoreactive T-lymphocytes both in man and in the non-obese diabetic (NOD) mouse. In the present study we aimed to determine the existence of a specific T-cell response towards the insulinoma-associated protein 2 (IA-2) islet tyrosine phosphatase, a recently identified autoantigen which is the target of autoantibodies strongly associated with diabetes development. Human recombinant IA-2 produced in Escherichia coli, was tested for its reactivity with peripheral blood lymphocytes obtained from 16 newly diagnosed type 1 diabetic patients and from 25 normal controls, 15 of whom were HLA-DR-matched. A T-cell proliferation assay was performed in triplicate employing freshly isolated cells in the absence or in the presence of the antigen to be tested (at two different concentrations: 2 microg/ml and 10 microg/ml). A specific T-cell proliferation (defined as a stimulation index (S.I.) >/=3) was observed against IA-2 used at a concentration of 10 microg/ml (but not of 2 microg/ml) in 8/16 diabetic patients, in 1/15 HLA-DR-matched control subjects (P<0.01 by Fisher exact test) and in 0/10 of the remaining normal individuals. A statistically significant difference (P<0.003 by Mann-Whitney U test) was also observed in S.I. values between patients (3.1+/-1.4) and HLA-DR-matched controls (1.7+/-0.54) employing IA-2 at a concentration of 10 microg/ml. However, when IA-2 was used at a concentration of 2 microg/ml, the difference in S. I. between patients (1.65+/-0.8) and controls (1.0+/-0.3) did not reach statistical significance. In conclusion, these data show the presence of a specific, dose-dependent T-lymphocyte response against the IA-2 islet tyrosine phosphatase at the onset of type 1 diabetes. Consequently, this molecule appears to be a target not only at the B-lymphocyte but also at the T-lymphocyte level, reinforcing the potential pathogenic role of this autoantigen in the islet destructive process.

Adolescent↗
PubMed2006

Neural precursors derived from embryonic stem cells, but not those from fetal ventral mesencephalon, maintain the potential to differentiate into dopaminergic neurons after expansion in vitro.

Neural precursors (NPs) derived from ventral mesencephalon (VM) normally generate dopaminergic (DA) neurons in vivo but lose their potential to differentiate into DA neurons during mitogenic expansion in vitro, hampering their efficient use as a transplantable and experimental cell source. Because embryonic stem (ES) cell-derived NPs (ES NP) do not go through the same maturation process during in vitro expansion, we hypothesized that expanded ES NPs may maintain their potential to differentiate into DA neurons. To address this, we expanded NPs derived from mouse embryonic day-12.5 (E12.5) VM or ES cells and compared their developmental properties. Interestingly, expanded ES NPs fully sustain their ability to differentiate to the neuronal as well as to the DA fate. In sharp contrast, VM NPs almost completely lost their ability to become neurons and tyrosine hydroxylase-positive (TH(+)) neurons after expansion. Expanded ES NP-derived TH(+) neurons coexpressed additional DA markers such as dopa decarboxylase and DAT (dopamine transporter). Furthermore, they also expressed other midbrain DA markers, including Nurr1 and Pitx3, and released significant amounts of DA. We also found that these ES NPs can be cryopreserved without losing their proliferative and developmental potential. Finally, we tested the in vivo characteristics of the expanded NPs derived from J1 ES cells with low passage number. When transplanted into the mouse striatum, the expanded NPs as well as control NPs efficiently generated DA neurons expressing mature DA markers, with approximately 10% tumor formation in both cases. We conclude that ES NPs maintain their developmental potential during in vitro expansion, whereas mouse E12.5 VM NPs do not.

Animals↗
PubMed1975

Adaptation of brain monoamine synthesis to hypoxia in the rat.

Oxygen is a substrate in the synthesis of the neurotransmitters, norepinephrine, dopamine, and serotonin. Changes in environmental oxygen appear to cause corresponding alterations in brain monoamine synthesis in vivo. The effect of chronic hypoxia was studied by exposing rats to 10% oxygen for up to 36 h. Brain monoamine synthesis, estimated in vivo, decreased initially and then returned to control levels, despite continued exposure to 10% oxygen. During this apparent adaptation to hypoxia, there were no changes in the concentration of brain serotonin, norepinephrine, dopamine, or tryptophan, while brain tryosine increased after 24 h of exposure. Tyrosine hydroxylase activity in vitro was not altered by the exposure to 10% oxygen. Evidence of hypoxic adaptation in these rats, a rightward shift of their hemoglobin dissociation curves, was found after 24 h of exposure. The adaptation of brain monoamine synthesis to hypoxia appeared to correlate with adaptive changes in brain tissue oxygen rather than any change in the intraneuronal regulation of amine synthesis.

5-Hydroxytryptophan↗
PubMedDate not supplied

Biochemical pathway of melanotic encapsulation of Brugia malayi in the mosquito, Armigeres subalbatus.

The mosquito, Armigeres subalbatus, is naturally resistant to the filarial worm, Brugia malayi, and microfilariae (mf) penetrating the midgut are killed by melanotic encapsulation reactions in the hemocoel within 48 h following ingestion. This vector-parasite system was used to assess changes in hemolymph tyrosine, tyrosine derivatives, and catecholamine-metabolizing enzyme activities using high pressure liquid chromatography with electrochemical detection (HPLC-ED) during melanotic encapsulation reactions against mf. Tyrosine and dopa were detected in the hemolymph of both control and immune-activated (mf-exposed) mosquitoes, but not dopamine or N-acetyl dopamine (NADA). Tyrosine was significantly increased in immune-activated mosquitoes at 6 and 12 h post blood feeding, but was depleted following intrathoracic inoculation of mf in the absence of a blood meal. Dopa also was elevated in immune-activated mosquitoes at 6, 12, and 24 h post-exposure to mf. There were significant increases in phenol oxidase (PO) and dopa decarboxylase (DDC) activities in immune-activated mosquitoes as compared to controls, and these elevated activities were correlated with changes in tyrosine and dopa levels in the hemolymph. No significant differences in N-acetyl transferase (NAT) and dopachrome conversion enzyme (DCE) activities between control and immune-activated mosquitoes were observed. The possible roles these molecules play in melanotic encapsulation reactions of A. subalbatus against mf are discussed.

Animals↗
PubMed1998

Immunocytochemical characterization of quisqualic acid- and N-methyl-D-aspartate-induced excitotoxicity in the retina of chicks.

A single, large dose of N-methyl-D-aspartate (NMDA) or quisqualic acid (QA) injected into the chick eye has been shown previously to destroy many retinal amacrine cells and to induce excessive ocular growth accompanied by myopia. The purpose of this study was to identify distinct populations of retinal cells, particularly those believed to be involved in regulating ocular growth, that are sensitive to NMDA or QA. Two pmol of NMDA or 0.2 micromol of QA were injected unilaterally into eyes of 7-day-old chicks, and retinas were prepared for observation 1, 3, or 7 days later. Retinal neurons were identified by using immunocytochemistry, and cells containing fragmented DNA were identified by 3'-nick-end labelling in frozen sections. NMDA and QA destroyed many amacrine cells, including those immunoreactive for vasoactive intestinal polypeptide, Met-enkephalin, and choline acetyltransferase, but they had little effect upon tyrosine hydroxylase-immunoreactive cells. Other cells affected by both QA and NMDA included those immunoreactive for glutamic acid decarboxylase, gamma-aminobutyric acid, parvalbumin, serotonin, and aminohydroxy methylisoxazole propionic acid (AMPA) receptor subunits GluR1 and GluR2/3. Cells largely unaffected by QA or NMDA included bipolar cells immunoreactive for protein kinase C (alpha and beta isoforms) and amacrine cells immunoreactive for glucagon. DNA fragmentation was detected maximally in many amacrine cells and in some bipolar cells 1 day after exposure to QA or NMDA. We propose that excitotoxicity caused by QA and NMDA induces apoptosis in specific populations of amacrine cells and that these actions are responsible for the ocular growth-specific effects of QA and NMDA reported elsewhere.

Animals↗
PubMed1997

Reduced striatal tyrosine hydroxylase activity is not accompanied by change in responsiveness of dopaminergic receptors following chronic treatment with deprenyl.

Deprenyl is the only selective monoamine oxidase B (MAO-B) inhibitor that is in clinical use for the treatment of Parkinson's disease. Our previous studies showed that chronic treatment of rats with low (MAO-B selective) doses of deprenyl inhibited dopamine (DA) re-uptake and enhanced DA release in the striatum. These changes could affect DA synthesis rate by activation of negative feedback loops. Chronic deprenyl treatment has also been suggested to cause down-regulation of release-modulating DA receptors. The effects of chronic and acute treatment with deprenyl on ex vivo striatal tyrosine hydroxylase activity were therefore studied, by determination of steady-state tissue level of DOPA following administration of NSD-1015 (100 mg/kg i.p.). In addition, we assessed changes in the in vivo sensitivity of dopaminergic receptors from the reduction in DOPA extracellular level after systemic apomorphine administration (2.5 mg/kg s.c.), following elevation of microdialysate DOPA by systemic or local aromatic amino acid decarboxylase inhibition with NSD-1015. Chronic treatment with deprenyl (0.25 mg/kg s.c. daily for 21 days) caused a significant reduction in tyrosine hydroxylase activity to 60% of control, with no change in the apomorphine-induced reduction of microdialysate DOPA and DOPAC. The reduction in tyrosine hydroxylase activity is compatible with our previous results showing an increase in striatal DA extracellular level following chronic treatment with deprenyl. The increased extracellular striatal DA level could reduce tyrosine hydroxylase activity through activation of a negative feedback loop, by activation of either presynaptic or postsynaptic DA receptors.

Animals↗
PubMed1992

Co-localization of tyrosine hydroxylase, GABA and neuropeptide Y within axon terminals innervating the intermediate lobe of the frog Rana ridibunda.

Possible co-existence of gamma-aminobutyric acid (GABA), catecholamines, and neuropeptide Y (NPY) in the same nerve terminals of the frog intermediate lobe was investigated by immunocytochemistry at the electron microscopic level. Co-localization of GABA and tyrosine hydroxylase (TH) was studied by using a double immunogold labeling procedure. Co-localization of glutamate decarboxylase (GAD) and NPY was studied by combining, respectively, the peroxidase-antiperoxidase method and a radioimmunocytochemical labeling procedure. Catecholamines and GABA were systematically co-localized in nerve endings of the pars intermedia. Most of the NPY-immunoreactive fibers also contained GAD-like immunoreactivity. However, a few NPY-positive nerve terminals were not immunoreactive for GAD. These data provide evidence for co-existence of a regulatory peptide (NPY) and several neurotransmitters (i.e., GABA and catecholamines) within the same axon terminals in the intermediate lobe. Since GABA, dopamine, and NPY have all been shown to inhibit the activity of frog melanotrope cells, the present findings suggest that these neuroendocrine factors may interact either at the pre-synaptic or post-synaptic level.

Animals↗
PubMed1976

Sympathoadrenal Neurochemistry and early weaning of swine.

Three litters of pigs were weaned at 21 days of age, and 3 others were left with the sow. Pigs were killed at 21, 23, 28, or 39 days of age. Weaned pigs exhibited anxiety, gastrointestinal dysfunction, and decreased rate of body weight gain. Plasma glucose or liver glycogen concentrations were not decreased by weaning. Adrenal gland weights and tyrosine hydroxylase (EC 1.14.3a), dopamine beta-hydroxylase (EC 1.14.2.1), phenethanolamine-N-methyl transferase (EC 2.1.1), and monoamine oxidase (EC 1.4.3.4) activities were increased after weaning. Adrenal catecholamine and cortisol levels and dopa decarboxylase (EC 4.1.1.26) and catechol-o-methyl transferase (EC 2.1.1.6) activities were not significantly altered, although some increases were indicated. Cranial cervical ganglionic choline acetyltransferase (EC 2.3.1.6) and tyrosine hydroxylase activities were increased after weaning. Weaning of swine at 21 days of age is a stressful experience, and many effects persist for at least 18 days; however, growth was no longer impaired 18 days after weaning.

Adrenal Glands↗
PubMed2004

Female-specific regulation of cuticular hydrocarbon biosynthesis by dopamine in Drosophila melanogaster.

The role of dopamine (DA) is investigated in cuticular hydrocarbon biosynthesis in Drosophila melanogaster with three different approaches: use of DA-deficient mutants (dopa decarboxylase temperature sensitive mutants reared at restrictive temperature, and rescued by dopamine ingestion or by pale mutants partially rescued by a tyrosine hydroxylase construction), pharmacological treatments (tyrosine hydroxylase inhibitors) and topical application on decapitated flies. We report that DA specifically regulates diene hydrocarbon biosynthesis, which is female specific. Our results suggest that DA acts in adult flies within the first hours of imaginal life and that DA production from the brain is crucial for this process. Thus, DA contributes to reproduction in D. melanogaster by acting during a critical period during development of young adults.

Aging↗
PubMed1991

Specific outgrowth from neurons of ventral mesencephalic grafts to the catecholamine-depleted striatum of adult hosts.

Grafts of fetal ventral mesencephalon including substantia nigra have been used to correct some motor deficits produced by unilateral destruction of the dopaminergic nigrostriatal pathway in rats. Histochemical studies have shown that dopaminergic neurons within the graft send processes from the graft to the host neuropil, wherein they form synapses. The results of numerous immunocytochemical studies indicate, however, that a large proportion of neurons in grafts are not catecholaminergic. Whether or not the nondopaminergic neurons in grafts project to the host brain is unknown. The purpose of the present study was to combine immunocytochemistry and retrograde tracing with fluorogold to identify the cell types which project from grafts to the host striatum. Tissue from the ventral mesencephalon of E15 fetuses was placed into the 6-hydroxydopamine denervated striatum of graft recipients. Six weeks to 6 months following transplantation, fluorogold was pressure injected under stereotaxic control immediately adjacent to the ventral mesencephalic grafts; after 4 days CNS tissue was prepared for light microscopic immunocytochemistry. Ventral mesencephalic grafts contained cell bodies immunoreactive for enkephalin, GAD, substance P, and serotonin in addition to those immunoreactive for tyrosine hydroxylase. Some cells of each immunochemically defined type were retrogradely labeled by the fluorogold injection into the host brain. Nevertheless, more catecholaminergic and serotonergic cells projected from grafts to the fluorogold injection site than did other cell types. Since many of the nonmonoaminergic neurons in grafts are probably projection neurons, our results suggest that the extent of neurite outgrowth from grafted cells is influenced by the surrounding target tissue.

Animals↗
PubMed1988

Decrease in tetrahydrobiopterin content and neurotransmitter amine biosynthesis in rat brain by an inhibitor of guanosine triphosphate cyclohydrolase.

To investigate the regulatory role of tetrahydrobiopterin in neurotransmitter amine biosynthesis, 2,4-diamino-6-hydroxypyrimidine, a potent inhibitor of guanosine triphosphate cyclohydrolase which is a rate-limiting enzyme of tetrahydrobiopterin biosynthesis, was administered intraperitoneally to weanling rats. Four h after 4 injections at 4-h intervals, the biopterin contents in plasma and liver were reduced to the level of 9 and 3.5%, respectively, of those in the control group injected with saline; while the contents in the whole brain, neocortex + striatum, diencephalon, and brainstem were 34, 50, 33 and 28%, respectively, of the control level. When in vivo tyrosine and tryptophan hydroxylase activities were measured over a 30-min period after the inhibition of aromatic amino acid decarboxylase, the accumulation of dihydroxyphenylalanine was reduced to 74, 77, 67 and 69% of the control in the whole brain, neocortex + striatum, diencephalon, and brainstem, respectively; and the accumulation of 5-hydroxytryptophan, to 71, 74, 66 and 65% of the control, respectively. On the other hand, 5-hydroxytryptamine and 5-hydroxyindole acetic acid contents were not altered in any brain regions, although norepinephrine and dopamine contents were reduced to approximately 70% of the control in the brainstem and the contents of dopamine metabolites were significantly decreased in the diencephalon and brainstem. Plasma phenylalanine level was significantly elevated, while the plasma tyrosine level was reduced, compared with the control level of these amino acids. These results indicate that the drug-treated rats could be an animal model for tetrahydrobiopterin-deficient disease involving neurological disorder.

5-Hydroxytryptophan↗