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 the various neurotrophin family members on the morphological structure of dopaminergic neurons was compared in dissociated cultures of embryonic rat ventral mesencephalon. Cultures were maintained in vitro in the presence of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrohin-4/5 (NT-4/5), nerve growth factor (NGF) or no added growth factors. Three-dimensional reconstructions of 48 neurons were made in each of the experimental groups following immunocytochemical staining for tyrosine hydroxylase to detect dopaminergic neurons. In addition [3H]mazindol binding analyses were carried out in replicate cultures in order to quantify the effects of the neurotrophins on the number of dopamine uptake sites. Among the neurotrophins tested, NT-4/5 influenced the proximal morphological parameters most, as determined by a 36% increase in the soma profile area and 35% in the number of stem neurites. Analysis of neuritic size and complexity in these cultures revealed that combined neuritic length and number of segments/cell were increased by 45 and 40% respectively. A change in neurite complexity in the NT-4/5 treated cultures was further confirmed using Scholl's concentric sphere analysis. In addition, relative to the control, NT-4/5 increased the neuronal differentiation as evidenced by increases in varicosity density and [3H]mazindol binding by 114 and 101% respectively. BDNF and, to a lesser extent, NT-3 also increased both proximal parameters and parameters of differentiation, but were without effect on parameters of neuritic size and complexity. No effects on neuronal structure were observed in NGF treated cultures. These findings demonstrate that BDNF, NT-3 and NT-4/5 influence the morphological differentiation of dopaminergic neurons in vitro, suggesting they may play a role in the structural development and plasticity of these neurons in the mesencephalon.
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PMID:Comparison of the effects of the neurotrophins on the morphological structure of dopaminergic neurons in cultures of rat substantia nigra. 775 59

The neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) were compared for their effects in promoting the survival and/or regulation of expression of phenotypic markers of dopaminergic and GABAergic neurons in cultures derived from embryonic rat ventral mesencephalon. Dopaminergic neuron number and phenotypic expression were monitored by tyrosine hydroxylase (TH) immunocytochemistry, and measurement of high-affinity dopamine uptake activity and dopamine content, respectively. High-affinity GABA uptake, glutamic acid decarboxylase (GAD) activity, and endogenous GABA content were used to detect GABAergic neurons. Seven days of treatment with either BDNF or NT-3 resulted in dose-dependent increases in the number of TH-positive neurons, with maximal responses of 3-fold and 2.3-fold, respectively. Dopamine uptake activity and dopamine content were similarly increased. The effects of BDNF and NT-3 on dopamine uptake activity showed no additivity. NT-4/5 treatment elicited the greatest increase (7-fold) in the number of TH-positive neurons, as well as a 2.6-fold increase in dopamine content. In marked contrast to BDNF or NT-3, NT-4/5 had no effect on dopamine uptake capacity. BDNF, NT-3, or NT-4/5 also produced dose-dependent elevations of 2-3-fold in GABA uptake activity. These effects were not additive. GAD activity was increased by BDNF (1.8-fold) and NT-3 (threefold) treatment, but not by NT-4/5, whereas GABA content was increased to a similar extent by all three neurotrophins. NGF had no effect on any of the parameters measured in this study. Northern analyses indicated that the mRNAs encoding TrkB and TrkC, the functional high-affinity receptors for BDNF and NT-4/5, and NT-3, respectively, are expressed in the substantia nigra of adult rat brain, as well as in cultures of developing ventral mesencephalon. Taken together, our results indicate that BDNF and NT-3 have broadly similar effects in promoting the survival and differentiated phenotype of both dopaminergic and GABAergic neurons of the developing substantia nigra. Although BDNF and NT-4/5 are thought to act through the same high-affinity receptor, TrkB, it is evident that these two neurotrophins have distinct as well as overlapping actions toward mesencephalic dopaminergic or GABAergic neurons.
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PMID:Overlapping and distinct actions of the neurotrophins BDNF, NT-3, and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon. 828 41

The development of noradrenergic locus coeruleus (LC) neurons is subject to regulation by multiple epigenetic signals. To examine the potential regulation of LC ontogeny by opiates and neurotrophins, we studied the effects of morphine and NT-3, NT-4, and BDNF on the survival and differentiation of LC neurons from prenatal rats in dissociated cell culture. Noradrenergic cells were identified and counted following tyrosine hydroxylase (TH) immunocytochemistry, and their state of differentiation was assessed by measuring norepinephrine (NE) uptake. Treating LC cultures with morphine starting on day 1 after plating resulted in a 20% decrease in NE uptake and a small (12%) but significant decrease in the number of TH-immunoreactive (TH +) cells. Application of morphine on day 4 after plating had the same effect on NE uptake without influencing TH + cell number. This effect of morphine was blocked by concomitant exposure to naloxone (an opioid receptor antagonist), and mimicked by exposure to opioid peptides. Treatment of cultures with the neurotrophins, NT-3 or NT-4, increased NE uptake and TH + cell number, as reported previously. Moreover, we show for the first time that brain-derived neurotrophic factor (BDNF) exerts similar effects, with a large (110%) increase in NE uptake and a modest (20%) increase in TH + cell number. Cotreatment of LC cultures with morphine and NT-3 resulted in an attenuation of the NT-3 effect on both NE uptake and the number of TH + cells. In contrast, cotreatment of LC cultures with morphine and NT-4 or BDNF attenuated the neurotrophin effect on TH + cell number but not on NE uptake. Our results raise the possibility that opioid peptides may modulate the influence of neurotrophins on LC neuronal survival and differentiation.
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PMID:Opposing effects of morphine and the neurotrophins, NT-3, NT-4, and BDNF, on locus coeruleus neurons in vitro. 884 66

Neurotrophins, including nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5), have been shown to enhance survival and differentiation of a variety of central neuronal populations, such as those with the dopaminergic, cholinergic, GABAergic phenotype during development. In this paper we present evidence that BDNF, NT-3 and NT-4/5 acting synergistically with dopamine (DA) can artificially induce the full dopaminergic phenotype in rat fetal cerebral cortex which normally has very few dopaminergic neurons in adulthood. Thus, BDNF/DA, NT-3/DA, NT-4/DA elicited a great increase in the number of tyrosine hydroxylase (TH)-immunoreactive cells, which was up to 5-7% of total neuronal population in cultures of fetal rat cortical cells. This stimulatory effect was not dependent on glial proliferation, or on addition of serum to the culture. Pharmacological studies showed that dopamine receptors D1 and D2 were involved in this effect. The TH+ cortical cells possessed other biochemical phenotypic features of dopaminergic neurons. Thus, high-affinity DA uptake was elevated in cortical cultures treated with neurotrophin/DA. Also DA and 3,4-dihydroxyphenlacetic acid production was detected (5.42 +/- 1.24 and 13.72 +/- 2.84 pmol/dish respectively, zero in controls). This show the presence of functionally active TH, aromatic acid decarboxylase and monoamine oxidase. Neurotrophins/DA had no effect on noradrenergic phenotype expression by cortical fetal cells. Taken together, these results support the long-standing view that development of the central nervous system is determined not only by intrinsic genetic programmes, but also involves environmental influences such as the action of growth factors and extracellular neurotransmitter. In this case we report the effect of specific DA phenotype-inducing agents.
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PMID:Induction of dopaminergic neurotransmitter phenotype in rat embryonic cerebrocortex by the synergistic action of neurotrophins and dopamine. 895 97

The documented trophic actions of the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) upon ventral mesencephalic dopamine neurons in vitro and in vivo are presumed to be mediated through interactions with their high-affinity receptors TrkB (for BDNF and NT-4/5) and TrkC (for NT-3). Although both neurotrophin receptor mRNAs have been detected within the rat ventral midbrain, their specific association with mesencephalic dopaminergic cell bodies remains to be elucidated. The present study was performed to determine the precise organization of trkB and trkC mRNAs within rat ventral midbrain and to discern whether the neurotrophin receptor mRNAs are expressed specifically by dopaminergic neurons. In situ hybridization with isotopically labeled cRNA probes showed that trkB and trkC mRNAs were expressed in all mesencephalic dopamine cell groups, including all subdivisions of the substantia nigra and ventral tegmental area, and in the retrorubral field, rostral and caudal linear raphe nuclei, interfascicular nucleus, and supramammillary region. Combined isotopic/nonisotopic double-labeling in situ hybridization demonstrated that virtually all of the tyrosine hydroxylase (the catecholamine biosynthetic enzyme) mRNA-containing neurons in the ventral midbrain also expressed trkB or trkC mRNAs. Additional perikarya within these regions expressed the neurotrophin receptor mRNAs but were not dopaminergic. The present results demonstrate that essentially all mesencephalic dopaminergic neurons synthesize the neurotrophin receptors TrkB and TrkC and thus exhibit the capacity to respond directly to BDNF and NT-3 in the adult midbrain in vivo. Moreover, because BDNF and NT-3 are produced locally by subpopulations of the dopaminergic cells, the present data support the notion that the neurotrophins can influence the dopaminergic neurons through autocrine or paracrine mechanisms.
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PMID:Expression of trkB and trkC mRNAs by adult midbrain dopamine neurons: a double-label in situ hybridization study. 988 32

The factors that regulate the ontogeny and differentiation of C1 adrenergic neurons located in the rostral ventrolateral medulla (RVLM) are completely unknown. In the present study, we have investigated the effects of a number of neurotrophic factors on the survival of E18-19 rat C1 adrenergic neurons in culture. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were used to study the expression of tyrosine hydroxylase (TH), an enzyme present in all catecholaminergic neurons, and of phenylethanolamine N-methyltransferase (PNMT), the final enzyme in the synthesis of adrenalin, as markers for the C1 RVLM neurons. Our results show that GDNF, CNTF BDNF, NT-3 and NT-4/5 increase the number of TH-immunoreactive neurons surviving in vitro. The effects of NGF, TGFbeta and bFGF were not significant. The E18-19 C1 neurons appeared to loose their ability to express PNMT in culture as examined with immunocytochemistry and RT-PCR, and none of the tested neurotrophic factors was able to sustain or induce this expression. Our results indicate that the adrenergic phenotype of C1 neurons, or the survival of these neurons, is determined by environmental factors other than the neurotrophic factors examined in this study.
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PMID:Neurotrophic requirements of rat embryonic catecholaminergic neurons from the rostral ventrolateral medulla. 1052 67

Free radical formation is considered to be a major cause of dopaminergic (DAergic) cell death in the substantia nigra leading to Parkinson's disease (PD). In this study we employed several radical donors including iron and sodium nitroprusside to induce toxic effects on DAergic neurons cultured from the embryonic rat midbrain floor. Overall cell survival was assessed by assaying LDH, and DAergic neuron survival was monitored by counting tyrosine hydroxylase-positive cells. Our data suggest that the DAergic neuron population is about fourfold more susceptible to free-radical-mediated damage than the total population of midbrain neurons. Application of the neurotrophic factors GDNF and NT-4, for which DAergic neurons have specific receptors, prior to toxin administration protected these neurons from toxin-mediated death, which, fully or in part, occurs under the signs of apoptosis. These findings underscore the importance of GDNF and NT-4 in designing future therapeutical concepts for PD.
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PMID:GDNF and NT-4 protect midbrain dopaminergic neurons from toxic damage by iron and nitric oxide. 1078 44

Transplantation of embryonic dopaminergic neurons is an experimental therapy for Parkinson's disease, but limited tissue availability and suboptimal survival of grafted dopaminergic neurons impede more widespread clinical application. Glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-4/5 (NT-4/5) exert neurotrophic effects on dopaminergic neurons via different receptor systems. In this study, we investigated possible additive or synergistic effects of combined GDNF and NT-4/5 treatment on rat embryonic (embryonic day 14) nigral explant cultures grown for 8 days. Contrary to cultures treated with GDNF alone, cultures exposed to NT-4/5 and GDNF+NT-4/5 were significantly larger than controls (1.6- and 2.0-fold, respectively) and contained significantly more protein (1.6-fold). Treatment with GDNF, NT-4/5 and GDNF+NT-4/5 significantly increased dopamine levels in the culture medium by 1.5-, 2.5- and 4.7-fold, respectively, compared to control levels, and the numbers of surviving tyrosine hydroxylase-immunoreactive neurons increased by 1.7-, 2.1-, and 3.4-fold, respectively. Tyrosine hydroxylase enzyme activity was moderately increased in all treatment groups compared to controls. Counts of nigral neurons containing the calcium-binding protein, calbindin-D28k, revealed a marked increase in these cells by combined GDNF and NT-4/5 treatment. Western blots for neuron-specific enolase suggested an enhanced neuronal content in cultures after combination treatment, whereas the expression of glial markers was unaffected. The release of lactate dehydrogenase into the culture medium was significantly reduced for GDNF+NT-4/5-treated cultures only. These results indicate that combined treatment with GDNF and NT4/5 may be beneficial for embryonic nigral donor tissue either prior to, or in conjunction with, intrastriatal transplantation in Parkinson's disease.
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PMID:Additive effect of glial cell line-derived neurotrophic factor and neurotrophin-4/5 on rat fetal nigral explant cultures. 1173 60

The role of glial cell-line derived neurotrophic factor (GDNF) and neurotrophins in the development of locus coeruleus noradrenergic neurons was evaluated. We found that two neurotrophic factors previously reported to prevent the degeneration of lesioned adult central noradrenergic neurons, GDNF and neurotrophin 3 (NT3), do not play significant roles in the prenatal development of locus coeruleus noradrenergic neurons, as demonstrated by: (1) the lack of alterations in double Gdnf/Nt3 null mutant mice; and (2) the lack of survival-promoting effects of GDNF and/or NT3 in rat E13.5 primary cultures. In contrast, null mutant mice for TrkB, the tyrosine kinase receptor for brain-derived neurotrophic factor and neurotrophin 4, displayed a clear loss of locus coeruleus noradrenergic neurons. In accordance with this, treatment of rat E13.5 primary cultures with TrkB ligands prevented the early loss of noradrenergic neurons and maintained their survival for up to 6 days in vitro. Moreover, an additional 5-10-fold increase in the number of tyrosine hydroxylase positive noradrenergic neurons was detected after 12 hours in culture. This second effect of TrkB ligands involved neither proliferation nor survival, because the number of BrdU- or TUNEL-positive noradrenergic neurons did not change and the effect was elicited by delayed administration of either factor. Because TrkB ligands increased the number of tyrosine hydroxylase-positive cells expressing Phox2a, a paired homeodomain protein required for the development of locus coeruleus noradrenergic neurons, but did not affect the number of Phox2a-positive tyrosine hydroxylase-negative cells, our results suggest that the second effect of TrkB ligands may involve promoting or inducing a noradrenergic phenotype. In summary, our findings suggest that, unlike NT3 and GDNF, TrkB ligands are required and sufficient to promote the development of central noradrenergic neurons.
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PMID:Crucial role of TrkB ligands in the survival and phenotypic differentiation of developing locus coeruleus noradrenergic neurons. 1281 Jun

To assess the effect of NT-4 deprivation on maturation of retinal circuitry, we investigated a mouse with targeted deletion of the gene encoding nt-4 (nt-4(-/-)). In particular, we studied neurons immunostained by an antibody recognizing tyrosine hydroxylase (TH), the rate limiting enzyme for dopamine (DA) synthesis. We found that TH immunopositive processes were altered in the retina of nt-4(-/-). Alteration of TH immunopositive processes in nt-4(-/-) mice resulted in changes of DA turnover, as assessed by high-pressure liquid chromatography measurements. These findings suggest that retinal NT-4 plays a role in the morphological maturation of dopaminergic retinal cells.
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PMID:Specific alterations of tyrosine hydroxylase immunopositive cells in the retina of NT-4 knock out mice. 1735 71


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