Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.14.16.2 (tyrosine hydroxylase)
14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of chronic inhibition of the angiotensin-converting enzyme on dopamine content and release in the striatum was investigated using in vivo microdialysis in awake, freely moving rats. Rats were treated for 1 week with the angiotensin-converting enzyme inhibitor perindopril (1 mg/kg) via the drinking water, whereas the controls were given water alone. One week after perindopril treatment, striatal dopamine dialysate levels in the treated group were markedly elevated compared with control values: control, 233 +/- 43 pg/ml; perindopril, 635 +/- 53 pg/ml (p < 0.001). These results were confirmed by a complementary study in which dopamine content was measured in striatal extracts (3.5 +/- 0.4 micrograms of dopamine/g of tissue for controls compared with 9.2 +/- 2.4 micrograms of dopamine/g of tissue for the treated group; p < 0.05). In the rats that were dialyzed, angiotensin-converting enzyme levels in the striatum were decreased by 50% after perindopril treatment. Levels of dopamine D1 and D2 receptors and of preprotachykinin and tyrosine hydroxylase mRNAs were unchanged after angiotensin-converting enzyme inhibition. A small, but significant, increase was detected in striatal preproenkephalin mRNA levels in the angiotensin-converting enzyme inhibitor-treated group. These results indicate that peripherally administered angiotensin-converting enzyme inhibitors penetrate the blood-brain barrier when given chronically and modulate extracellular dopamine and striatal neuropeptide levels.
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PMID:Angiotensin-converting enzyme modulates dopamine turnover in the striatum. 904 78

Experiments were performed in rats to test the hypothesis that adrenal mRNA levels of tyrosine hydroxylase (TH) and the norepinephrine transporter (NET) would be modified by water deprivation via activation of the sympathetic nervous system. TH and NET mRNA levels were measured using the ribonuclease protection assay. Adrenal TH mRNA was higher (P < 0.001) in water-deprived (921 +/- 39 fg/microgram total RNA) compared with the water-replete rats (657 +/- 45 fg/microgram total RNA). In contrast, water deprivation decreased (P < 0.01) adrenal NET mRNA levels (275 +/- 66 vs. 433 +/- 63 fg/microgram total RNA). The dehydration-induced increase in TH mRNA was prevented by prior splanchnicectomy, but the decrease in NET mRNA was produced even in the absence of adrenal nerves. Water deprivation also increased (P < 0.05) plasma adrenocorticotropic hormone (84 +/- 16 vs. 42 +/- 14 pg/ml) and corticosterone (358 +/- 87 vs. 44 +/- 15 ng/ml) levels. Interestingly, the corticosterone response was reduced (P < 0.05) by unilateral adrenal denervation. These results suggest that water deprivation increases both adrenal medullary and adrenocortical activity at least in part by stimulation of sympathetic nerve activity.
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PMID:Water deprivation and rat adrenal mRNAs for tyrosine hydroxylase and the norepinephrine transporter. 922 5

Previous data have clearly suggested that the posterior pituitary (PP), consisting of neural lobe (NL) and intermediate lobe (IL), has a role in the control of anterior pituitary PRL secretion. However, basic aspects of this regulatory mechanism like (1), the role of an intact hypothalamic innervation of the PP as well as (2) the site of production of previously found PRL releasing substance(s) have not yet been characterized. Denervation of the PP (PPD) is an effective method for having a selective lesion of the innervation of PP, indeed, PPD results in a disappearance of neurosecretory materials from NL and tyrosine hydroxylase (TH) immunoreactivity from IL, leaving blood supply of all three lobes intact. Blood samples were taken from freely moving sham an PP-denervated lactating rats before and after 4-h separation from their pups and during the suckling stimulus. PPD blocks separation-induced depletion but only attenuates suckling induced release of PRL. Furthermore, it doubles plasma level of alpha-MSH during the entire sampling period, which has been used as a marker for in vivo secretory activity of IL cells. Lack of the separation-induced depression in plasma PRL of PPD animals can be partially restored by normalizing the diabetes insipidus with treatment of a vasopressin analogue, 1-desamino-8-D-arginine-vasopressin (dDAVP). In contrast, dDAVP, neither alone nor in combination with oxytocin (OXY), can change PPD-induced elevation of plasma alpha-MSH as well as attenuation of PRL response induced by suckling. It is concluded that: (1) contribution of the THDA system parallel to the confirmed role in the regulation of alpha-MSH seems to be crucial for the depletion of plasma PRL induced by separation but not for the elevation due to suckling stimulus, (2) intact hypothalamic innervations of both NL and IL, regulating water intake and the secretion of alpha-MSH, respectively, are necessary for normal secretory responses of AL during lactation, (3) as well as for the presence of PRF activity in PP, (4) which does not solely responsible for suckling-induced PRL release. Therefore, an interplay between several substances produced by NIL of the pituitary gland must have been responsible for the intact regulation of PRL secretion during lactation.
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PMID:Effect of posterior pituitary denervation (PPD) on prolactin (PRL) and alpha-melanocyte-stimulating hormone (alpha-MSH) secretion of lactating rats. 922 42

Tyrosine hydroxylase (TH) (EC 1.14.16.2) activity has been frequently employed as a marker of adrenomedullar catecholamine-synthesizing capacity and, thus, as an indicator of chronic stress exposure in various animal species. We have developed a thin layer chromatography (TLC) procedure for its assay in adrenal glands of rats and large animals that reduces some of the drawbacks of currently employed methods, thereby facilitating routine use. Preparation of tissue samples was adapted for rats and pigs. The activity of the enzyme is expressed as the rate of the TH-catalysed tyrosine hydroxylation to 3,4-dihydroxyphenyl-alanine (DOPA) using tritium-labeled tyrosine, in the presence of cofactors and a DOPA decarboxylase inhibitor. The subsequent separation of the radioactive product (DOPA) from the substrate (tyrosine) is accomplished by TLC on silicagel plates, in a n-butanol/acetic acid/water solvent system (4:1:1). Radioactivity in the scraped zones, in which DOPA has been detected by means of an internal standard, is measured by beta-counting. An advantage of this procedure is its simplicity, reliability, and convenience for routine assays. Levels of endogenous adrenal tyrosine (HPLC assay) are considerably higher in pig (2.5-5 nmol/mg protein) than in rat (0.15 nmol/mg protein); their effects upon assay results being, in both cases, negligible. Michaelis constants estimated by this procedure amounted to 0.9 mmol l(-1) (at 0.7 mM DMPH4) for pig, and 1.1 mmol l(-1) (at 1.5 mM DMPH4) for rat.
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PMID:A rapid assay for tyrosine hydroxylase activity, an indicator of chronic stress in laboratory and domestic animals. 950 18

This study concerns functional recovery of zebrafish following spinal cord transection. Spinal cords were transected at the level of the 14th vertebra, just rostral to the dorsal fin. Recovery was tested at one month after transection when descending fibers start to regrow across the transection site and at three months after transection when fish perform kick and glide swimming. To estimate the rate of regrowth across the lesion site we analysed the tyrosine hydroxylase (TH) and dorsal 5-hydroxytryptamine (5-HT) systems in distal parts of lesioned cords. Both systems have cell bodies in the brainstem and in control fish TH- and dorsal 5-HT-containing fibers descend to all spinal segments. Swimming performance was studied by subjecting lesioned fish to endurance tests in a swimming tunnel with water flowing at a constant rate of 2 or 4.5 body lengths per second (BL/s). At 2 BL/s slow myotomal muscles are active whereas at 4.5 BL/s fast myotomal muscles are recruited. Control fish endured sustained swimming at both speeds for at least 3 hours. As a measure for the condition of the neuromuscular system in trunk and tail, we analysed aerobic metabolic capacities, assessed by NADH-tetrazolium reductase (NADH-TR) histochemistry of myotomal muscle fibers and spinal lateral neuropil. We found that TH- and dorsal 5-HT-immunoreactive fibers were absent in the entire distal part of lesioned cords at one month but at two months after transection they were present at approximately 6000 microns caudally to the site of the lesion. Thus the rate of outgrowth of these fibers is at least 200 microns per day. Sustained swimming at the slow speed (2 BL/s) could be endured for about 14.4 min at one month and for 23.5 min at two months after transection; there was no further improvement in the period that followed. In contrast, in the 10 weeks following transection, fast swimming (4.5 BL/s) could be endured for about 5 to 6 minutes. A significant improvement was gained in the period of 10 to 12 weeks after transection when fish could endure the high speed for almost 15 min. The aerobic capacity of muscle fibers in distal parts of the body was not strongly affected by the lesion. The only important change in aerobic capacity was observed in the neuropil of distal parts of the cords where, at three months after transection, NADH-TR activity was increased to approximately 150% of control values. On the basis of our findings, we assume that it is not the condition of the neuromuscular system, but rather a deficient co-ordination between proximal and distal body parts of lesioned fish that accounts for the relatively poor performances in endurance tests. Furthermore, differences in timing of improvements in swimming at 2 and 4.5 BL/s indicate that the spinal circuitries serving the slow parts of the neuromuscular system recover at an earlier stage than those serving the fast parts.
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PMID:Long term effects of spinal cord transection in zebrafish: swimming performances, and metabolic properties of the neuromuscular system. 958 24

Administration of high doses of glutamate (Glu) leads to selective neurodegeneration in discrete brain regions near circumventriclular organs of the early postnatal mouse. The arcuate nucleus-median eminence complex (ARC-ME) appears to be the most Glu-sensitive of these brain regions, perhaps because of the intimate relationships between its neurons and specialized astroglial tanycytes. To investigate the mechanism of Glu-induced neuronal loss, we administered graded doses of the sodium salt of glutamate (MSG) to postnatal mice, measured their plasma Glu concentrations, and performed microscopic analyses of the ARC-ME region 5 h after treatment. Nursing, 7-day-old mouse pups (CD1, Charles River, Hollister, Calif.) were injected subcutaneously with single doses of 0.1-0.5 or 1.0-4.0 mg of MSG per g BW, or with water vehicle alone. Mice were decapitated 5 h later and the brains immediately fixed by immersion in buffered aldehydes. Frontal vibratome tissue sections at comparable levels of the ARC-ME were examined by light microscopy. A dose of 4.0 mg MSG/g BW caused neurodegeneration throughout the ARC region, while 1.0 mg/g MSG resulted in less extensive damage. Injection of 0.2 mg MSG/g BW, which raised plasma Glu concentrations 17-fold after 15 min, was the minimum dose tested at which nuclear and cytoplasmic changes were observed in a small group of subependymal neurons near the lateral recesses of the third ventricle. Higher doses of 0.3-0.5 mg MSG caused injury to additional neurons situated farther laterally, but damage remained confined to the ventral region of the ARC nucleus. Ultrastructural examination showed some subependymal neurons with pyknotic nuclei, reduced cytoplasmic volume, and swollen subcellular organelles, while others had fragmented and condensed nuclear material. Immunostaining for tyrosine hydroxylase indicated that dopamine neurons were spared at the threshold dose, but suffered damage after higher doses of MSG. Immunostaining for Glu receptor subtypes revealed that 0.2 mg MSG/g BW enhanced neuronal expression of NMDAR1 and of GluR2/4, and that higher doses of MSG preferentially increased NMDAR1 expression in injured neurons. These results extend previous reports of Glu sensitivity in the ARC-ME region of 7-day postnatal mice. A dose of 0.2 mg MSG/g BW s.c. causes clear but discrete injury to specific subependymal neurons of undetermined phenotype near the base of the third ventricle. Slightly higher doses of MSG evoke damage of additional neurons confined to the ventral region of the ARC traversed by tanycytes. These same greater amounts of MSG promote dose-related increase in the expression of NMDAR1 more than of GluR2/4 in injured ARC neurons, suggesting that elevated Glu receptor levels may contribute to or be related to neuronal cell death. Taken together with previous findings, the data suggest that Glu responsitivity in the ARC-ME of the postnatal mouse may result from transient developmental conditions involving the numerical ratios and juxtaposition between tanycytes and neurons, expression of Glu receptors, and perhaps other ontogenetic factors which may not persist in the mature adult.
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PMID:Exogenous glutamate enhances glutamate receptor subunit expression during selective neuronal injury in the ventral arcuate nucleus of postnatal mice. 970 74

Thyrotropin-releasing hormone (TRH) has been reported to have some possibilities toward the treatment of affective CNS disorders. However, long term treatments with daily injections are often required. Effects of TRH-SR (sustained release microspheres of TRH) which is encapsulated in copoly (dl-lactic/glycolic acid) using an in-water drying method were investigated in experimental Japanese encephalitis virus (JEV)-induced post-encephalitic parkinsonism rats by a pole test and high performance liquid chromatography (HPLC) with an electrochemical detector (ECD). We have already reported that in adult Fischer rats killed 12 weeks after infection with JEV at the age of 13 days a marked decrease of tyrosine hydroxylase-positive neurons was found in the bilateral substantia nigra. TRH-SR (3 mg/kg per 2 weeks, 4 times injections, subcutaneous [s.c.]) improved bradykinesia observed in the JEV-induced parkinsonism rats. Dopamine (DA) concentrations in the JEV-infected rats were profoundly reduced in the striatum as compared with controls. TRH-SR (3 mg/kg, once, s.c.) increased DA in the striatum 7 days after the injection. Although the pathomechanism of post-encephalitic parkinsonism is different from that of Parkinson's disease and TRH possesses a variety of CNS effects as well, these results suggest that TRH-SR play a possible role in the treatment of Parkinson's disease in addition to post-encephalitic parkinsonism as a supportive drug of L-DOPA.
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PMID:Sustained release dosage of thyrotropin-releasing hormone improves experimental Japanese encephalitis virus-induced parkinsonism in rats. 974 96

TyrOH is a non-heme iron enzyme which uses molecular oxygen to hydroxylate tyrosine to form L-dihydroxyphenylalanine (L-DOPA), and tetrahydrobiopterin to form 4a-hydroxybiopterin, in the rate-limiting step of the catecholamine biosynthetic pathway. The 2.3 A crystal structure of the catalytic and tetramerization domains of rat tyrosine hydroxylase (TyrOH) in the presence of the cofactor analogue 7,8-dihydrobiopterin and iron shows the mode of pterin binding and the proximity of its hydroxylated 4a carbon to the required iron. The pterin binds on one face of the large active-site cleft, forming an aromatic pi-stacking interaction with Phe300. This phenylalanine residue of TyrOH is found to be hydroxylated in the meta position, most likely through an autocatalytic process, and to consequently form a hydrogen bond to the main-chain carbonyl of Gln310 which anchors Phe300 in the active site. The bound pterin forms hydrogen bonds from N-8 to the main-chain carbonyl of Leu295, from O-4 to Tyr371 and Glu376, from the C-1' OH to the main-chain amides of Leu294 and Leu295, and from the C-2' hydroxyl to an iron-coordinating water. The part of the pterin closest to the iron is the O-4 carbonyl oxygen at a distance of 3.6 A. The iron is 5.6 A from the pterin 4a carbon which is hydroxylated in the enzymatic reaction. No structural changes are observed between the pterin bound and the nonliganded enzyme. On the basis of these structures, molecular oxygen could bind in a bridging position optimally between the pterin C-4a and iron atom prior to substrate hydroxylation. This structure represents the first report of close interactions between pterin and iron in an enzyme active site.
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PMID:Crystal structure of tyrosine hydroxylase with bound cofactor analogue and iron at 2.3 A resolution: self-hydroxylation of Phe300 and the pterin-binding site. 975 29

Normal cellular metabolism produces oxidants which are neutralized within cells by antioxidant enzymes and other antioxidants. An imbalance between oxidants and antioxidants has been postulated to lead to the degeneration of specific populations of neurons in neurodegenerative diseases, e.g. Parkinson's disease. The present study investigates whether overexpression of glutathione peroxidase, the enzyme which metabolizes hydrogen peroxide to water, can prevent or slow down neuronal injury in an animal model of Parkinson's disease. Transgenic mice overexpressing the human glutathione peroxidase gene under the control of the mouse hydroxymethylglutaryl-coenzyme A promoter and genetically matched control mice were injected intracerebroventricularly with the dopaminergic neurotoxin 6-hydroxydopamine. Seven days after injection, the number of tyrosine hydroxylase-positive nigral dopaminergic neurons was decreased by 52.4% and 20.5% in 6-hydroxydopamine-injected control and glutathione peroxidase transgenic mice, respectively. Similarly, 3 days after injection of the neurotoxin, striatal dopamine was decreased by 71.2% and 56.5%, respectively. Overexpression of glutathione peroxidase therefore partially protects dopaminergic neurons against 6-hydroxydopamine-induced toxicity.
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PMID:Attenuation of 6-OHDA-induced neurotoxicity in glutathione peroxidase transgenic mice. 978 16

The aromatic amino acid hydroxylases represent a superfamily of structurally and functionally closely related enzymes, one of those functions being reversible inhibition by catechol derivatives. Here we present the crystal structure of the dimeric catalytic domain (residues 117-424) of human phenylalanine hydroxylase (hPheOH), cocrystallized with various potent and well-known catechol inhibitors and refined at a resolution of 2.0 A. The catechols bind by bidentate coordination to each iron in both subunits of the dimer through the catechol hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex. In addition, Glu330 and Tyr325 are identified as determinant residues in the recognition of the inhibitors. In particular, the interaction with Glu330 conforms to the structural explanation for the pH dependence of catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC). The overall structure of the catechol-bound enzyme is very similar to that of the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms). Most striking is the replacement of two iron-bound water molecules with catechol hydroxyl groups. This change is consistent with a change in the ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to a nearly axial ligand field symmetry as seen upon noradrenaline binding using EPR spectroscopy [Martinez, A., Andersson, K. K., Haavik, J., and Flatmark, T. (1991) Eur. J. Biochem. 198, 675-682]. Crystallographic comparison with the structurally related rat tyrosine hydroxylase binary complex with the oxidized cofactor 7,8-dihydrobiopterin revealed overlapping binding sites for the catechols and the cofactor, compatible with a competitive type of inhibition of the catechols versus BH4. The comparison demonstrates some structural differences at the active site as the potential basis for the different substrate specificity of the two enzymes.
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PMID:Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound catechol inhibitors at 2.0 A resolution. 984 68


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