Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for midbrain dopaminergic neurons. To begin to understand the intracellular signaling pathways used by GDNF, we investigated the role of phosphatidylinositol 3-kinase activity in GDNF-stimulated cellular function and differentiation of dopaminergic neurons. We found that treatment of dopaminergic neuron cultures with 10 ng/ml GDNF induced maximal levels of Ret phosphorylation and produced a profound increase in phosphatidylinositol 3-kinase activity, as measured by western blot analysis and lipid kinase assays. Treatment with 1 microM 2-(4-morpholinyl)-8-phenylchromone (LY294002) or 100 nM wortmannin, two distinct and potent inhibitors of phosphatidylinositol 3-kinase activity, completely inhibited GDNF-induced phosphatidylinositol 3-kinase activation, but did not affect Ret phosphorylation. Furthermore, we examined specific biological functions of dopaminergic neurons: dopamine uptake activity and morphological differentiation of tyrosine hydroxylase-immunoreactive neurons. GDNF significantly increased dopamine uptake activity and promoted robust morphological differentiation. Treatment with LY294002 completely abolished the GDNF-induced increases of dopamine uptake and morphological differentiation of tyrosine hydroxylase-immunoreactive neurons. Our findings show that GDNF-induced differentiation of dopaminergic neurons requires phosphatidylinositol 3-kinase activation.
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PMID:Inhibition of phosphatidylinositol 3-kinase activity blocks cellular differentiation mediated by glial cell line-derived neurotrophic factor in dopaminergic neurons. 979 15

Sympathetic ganglia are composed of noradrenergic and cholinergic neurons. The differentiation of cholinergic sympathetic neurons is characterized by the expression of choline acetyltransferase (ChAT) and vasoactive intestinal peptide (VIP), induced in vitro by a subfamily of cytokines, including LIF, CNTF, GPA, OSM and cardiotrophin-1 (CT-1). To interfere with the function of these neuropoietic cytokines in vivo, antisense RNA for gp130, the common signal-transducing receptor subunit for neuropoietic cytokines, was expressed in chick sympathetic neurons, using retroviral vectors. A strong reduction in the number of VIP-expressing cells, but not of cells expressing ChAT or the adrenergic marker tyrosine hydroxylase (TH), was observed. These results reveal a physiological role of neuropoietic cytokines for the control of VIP expression during the development of cholinergic sympathetic neurons.
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PMID:The specification of sympathetic neurotransmitter phenotype depends on gp130 cytokine receptor signaling. 980 27

Among the dopaminergic neurons in substantia nigra pars compacta and in the ventral tegmental area, subpopulations express the calcium-binding proteins calbindin (CB) and calretinin (CR), and the CB-containing neurons are supposed to be less prone to degeneration in Parkinson's disease. Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for nigrostriatal dopaminergic neurons. Using free-floating roller-tube (FFRT) cultures derived from fetal rat (E14) ventral mesencephalon we found that GDNF (10 ng/ml) significantly increased the number of surviving tyrosine hydroxylase (TH)-immunoreactive neurons. The possible effects of GDNF treatment on CB-immunoreactive (CB-ir) and CR-ir neurons in such cultures were examined in the present study. The neuronal cell densities were measured by quantifying the numbers of CB-ir and CR-ir neurons in areas of sections through the most extensive parts of the spherical cultures. In 4-day-old and 8-day-old cultures GDNF treatment increased the density of CB-ir neurons by 50% and 59%, respectively. Partial co-existence of TH and CB was shown using the method of double immunolabeling. The density of CR-containing neurons was unaffected by GDNF treatment as confirmed by Western blotting for CR. Parallel effects of GDNF treatment were obtained for cultures of human fetal ventral mesencephalon (8 weeks postconception). In conclusion, our findings identify GDNF as a potent factor for fetal rat and human nigral CB-ir neurons able to promote their survival in culture. Referring to a suggested neuroprotective role of CB, the results may be of relevance in the context of neuronal transplantation of patients suffering from severe Parkinson's disease.
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PMID:GDNF increases the density of cells containing calbindin but not of cells containing calretinin in cultured rat and human fetal nigral tissue. 1033 73

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

The immunophilin ligand FK506 (Tacrolimus) is used for prevention of graft rejection following organ transplantation. FK506 is a high-affinity ligand for FK506-binding proteins, an immunophilin subgroup of peptidyl-prolyl-cis/trans-rotamases abundant in the mammalian brain. Here, we demonstrate that FK506 is a potent survival factor that prevents neuronal cell death following axotomy of central intrinsic neurons. Administration of FK506 (2 mg/kg, s.c., per day for two days pre-axotomy and for up to eight days post-axotomy) effectively delayed and reduced the death of axotomized neurons in the substantia nigra pars compacta following transection of the medial forebrain bundle. In saline-treated controls, 75%, 89% and 92% of nigral neurons died after 25, 50 and 60 days post-axotomy, respectively. In contrast, application of FK506 resulted in survival of 46%, 44% and 28% of the axotomized nigral neurons, and the majority of these surviving neurons showed continuous expression of tyrosine hydroxylase, the pacemaker enzyme for dopamine synthesis. Moreover, FK506 significantly reduced the expression of the inducible transcription factor c-Jun and its N-terminal phosphorylation and prevented the axotomy-induced suppression of the constitutive transcription factor ATF-2 in neurons of the substantia nigra and mammillary body. The latter is also axotomized by the coincident transection of the mammillothalamic tract, but the mammillary neurons survive the axotomy. In contradistinction to FK506, the non-immunosuppressive FK506-binding protein ligand GPI-1046 (25 or 12.5 mg/kg, applied once or twice per day for two days pre-axotomy and for eight days post-axotomy) was completely ineffective for all these parameters investigated. Finally, FK506, but not GPI-1046, impressively accelerated the recovery from surgery. Our data provide the first evidence that FK506 acts as a neuroprotective molecule that rescues axotomized otherwise degenerating central intrinsic neurons in the adult mammalian brain by mechanisms that interfere with the transcriptional program of the axotomy-induced cell body response, such as activating transcription factor-2 suppression and c-Jun expression and phosphorylation.
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PMID:The immunophilin ligand FK506, but not GPI-1046, protects against neuronal death and inhibits c-Jun expression in the substantia nigra pars compacta following transection of the rat medial forebrain bundle. 1067 Apr 42

Transplantation of embryonic nigral tissue is used as an experimental therapy for patients with Parkinson's disease but is hampered by a limited survival rate of dopaminergic neurons. Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for nigrostriatal dopaminergic neurons, and the present in vitro study aimed at improving the survival of dopaminergic neurons in porcine mesencephalic brain slice cultures by adding transfected, immortalized, temperature-sensitive GDNF-releasing HiB5 cells (HiB5-GDNF). Embryonic (E27/28) porcine ventral mesencephalic brain slices were placed on membrane inserts in six-well plates with serum-containing medium, and HiB5-GDNF, nontransfected HiB5 cells (HiB5-control), or green fluorescent protein-producing HiB5 cells (HiB5-GFP) were seeded onto each tissue slice. The concentration of GDNF in the coculture medium was 0.49 +/- 0.13 ng/ml at day 9 and 0. 22 +/- 0.05 ng/ml at day 19 (mean +/- SEM) as measured by GDNF ELISA. The decrease in release of GDNF over time was paralleled by a gradual reduction in the number of HiB5-GFP cells expressing the reporter gene (EGFP). At day 12, HPLC analysis revealed that medium from HiB5-GDNF cocultures contained 2.0 times more dopamine than medium from HiB5-control cocultures. At day 21 there was 1.6 times more dopamine. Similar results were obtained for the dopamine metabolite 3,4-dihydroxyphenylacetic acid. At day 21, cell counts showed that HiB5-GDNF cocultures contained 1.5 times more tyrosine hydroxylase immunoreactive neurons than HiB5-control cocultures, which must be compared with a 1.8 fold increase after chronic treatment with rhGDNF (10 ng/ml). In conclusion, the better survival of HiB5-GDNF cocultures is promising for the generation of effective cell lines for local delivery of neurotrophic factors to intracerebral nigral grafts.
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PMID:Improved survival of embryonic porcine dopaminergic neurons in coculture with a conditionally immortalized GDNF-producing hippocampal cell line. 1087 18

Apoptosis is a prerequisite to model the developing nervous system. However, an increased rate of cell death in the adult nervous system underlies neurodegenerative disease and is a hallmark of multiple sclerosis (MS) Alzheimer's- (AD), Parkinson- (PD), or Huntington's disease (HD). Cell surface receptors (e.g., CD95/APO-1/Fas; TNF receptor) and their ligands (CD95-L; TNF) as well as evolutionarily conserved mechanisms involving proteases, mitochondrial factors (e.g. , Bcl-2-related proteins, reactive oxygen species, mitochondrial membrane potential, opening of the permeability transition pore) or p53 participate in the modulation and execution of cell death. Effectors comprise oxidative stress, inflammatory processes, calcium toxicity and survival factor deficiency. Therapeutic agents are being developed to interfere with these events, thus conferring the potential to be neuroprotective. In this context, drugs with anti-oxidative properties, e.g., flupirtine, N-acetylcysteine, idebenone, melatonin, but also novel dopamine agonists (ropinirole and pramipexole) have been shown to protect neuronal cells from apoptosis and thus have been suggested for treating neurodegenerative disorders like AD or PD. Other agents like non-steroidal anti-inflammatory drugs (NSAIDs) partly inhibit cyclooxygenase (COX) expression, as well as having a positive influence on the clinical expression of AD. Distinct cytokines, growth factors and related drug candidates, e.g., nerve growth factor (NGF), or members of the transforming growth factor-beta (TGF-beta ) superfamily, like growth and differentiation factor 5 (GDF-5), are shown to protect tyrosine hydroxylase or dopaminergic neurones from apoptosis. Furthermore, peptidergic cerebrolysin has been found to support the survival of neurones in vitro and in vivo. Treatment with protease inhibitors are suggested as potential targets to prevent DNA fragmentation in dopaminergic neurones of PD patients. Finally, CRIB (cellular replacement by immunoisolatory biocapsule) is an auspicious gene therapeutical approach for human NGF secretion, which has been shown to protect cholinergic neurones from cell death when implanted in the brain. This review summarises and evaluates novel aspects of anti-apoptotic concepts and pharmacological intervention including gene therapeutical approaches currently being proposed or utilised to treat neurodegenerative diseases.
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PMID:Apoptosis modulators in the therapy of neurodegenerative diseases. 1106 Jul 7

Glial cell line-derived neurotrophic factor (GDNF) is a survival factor for several types of neurons, including dopaminergic (DAergic) neurons. GDNF binds with high affinity to the GDNF family receptor alpha-1 (GFRalpha-1), which is highly expressed in the midbrain. Using anatomical and lesion techniques, we demonstrated that GFRalpha-1 was expressed in DAergic and non-DAergic neurons in the rat midbrain. Immunohistochemical characterization of GFRalpha-1-expressing neurons indicated that most of the neurons that were immunopositive for the DAergic marker tyrosine hydroxylase (TH) expressed GFRalpha-1 in the substantia nigra pars compacta (SNC). In contrast, fewer TH-containing neurons expressed GFRalpha-1 in the substantia nigra pars reticulata (SNR) and the ventral tegmental area (VTA). Depletion of GFRalpha-1/TH neurons was observed in the SNC following treatment with the neurotoxin 6-hydroxydopamine (6-OHDA); however, GFRalpha-1 expression remained in some neurons located in the SNR. The gamma-aminobutyric acid (GABA)ergic nature of GFRalpha-1-expressing neurons located in the SNR, which were resistant to (6-hydroxydopamine) 6-OHDA, was established by their expression of glutamic acid decarboxylase (GAD; the synthesizing enzyme for GABA). Further analysis indicated that coexpression of GFRalpha-1 and GAD varied in a rostrocaudal gradient in the SNR, substantia nigra pars lateralis (SNL), and VTA. Midbrain DAergic and GABAergic neurons have been previously classified according to their Ca(2+) binding protein (CaBP) content; thus, we also sought to investigate the proportion of midbrain GFRalpha-1-expressing neurons containing parvalbumin (PV), calbindin (CB), and calretinin (CR) in the midbrain. Although GFRalpha-1 expression was found mainly in CB- and CR-immunoreactive neurons, it was rarely observed in PV-immunolabeled neurons. Analysis of the proportion of GFRalpha-1-expressing neurons for each CaBP subpopulation indicated the coexistence of GFRalpha-1 with CR in the VTA and all subdivisions of the SN; double-labeled GFRalpha-1/CR neurons were distributed in the SNC, SNR, SNL, and VTA. GFRalpha-1/CB neurons were also detected in the SNC, SNL, and VTA. Expression of GFRalpha-1 in DAergic and non-DAergic neurons in the rat SN and VTA suggests that GDNF, via GFRalpha-1, might modulate DAergic and GABAergic functions in the nigrostriatal, mesolimbic, and nigrothalamic circuits of the adult rat.
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PMID:GFRalpha-1 mRNA in dopaminergic and nondopaminergic neurons in the substantia nigra and ventral tegmental area. 1174 38

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for ventral mesencephalic (VM) dopaminergic neurons. Subpopulations of dopaminergic and non-dopaminergic VM neurons express the calcium-binding proteins calbindin (CB) and calretinin (CR). Characterization of the actions of GDNF on distinct subpopulations of VM cells is of great importance for its potential use as a therapeutic molecule and for understanding its role in neuronal development. The present study investigated the effects of GDNF on the survival and morphological differentiation of dopaminergic and non-dopaminergic neurons in primary cultures of embryonic day (E) 18 rat VM. As expected from our results obtained using E14 VM cells, GDNF significantly increased the morphological complexity of E18 CB-immunoreractive (CB-ir), tyrosine hydroxylase (TH)-ir, and CR-ir neurons and also the densities of CB-ir and TH-ir neurons. Interestingly, densities of E18 CR-ir neurons, contrarily to our previous observations on E14 CR-ir neurons, were significantly higher after GDNF treatment (by 1.5-fold). Colocalization analyses demonstrated that GDNF increased the densitiy of dopaminergic neurons expressing CR (TH+/CR+/CB-), while no significant effects were observed for TH-/CR+/CB- cell densities. In contrast, we found that GDNF significantly increased the total fiber length (2-fold), number of primary neurites (1.4-fold), number of branching points (2.5-fold), and the size of neurite field per neuron (1.8-fold) of the non-dopaminergic CR-expressing neurons (TH-/CR+/CB-). These cells were identified as GABA-expressing neurons. In conclusion, our findings recognize GDNF as a potent differentiation factor for the development of VM dopaminergic and non-dopaminergic CR-expressing neurons.
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PMID:Effect of GDNF on differentiation of cultured ventral mesencephalic dopaminergic and non-dopaminergic calretinin-expressing neurons. 1572 14

Activin has previously been shown to act as a nerve cell survival factor and to have neurotrophic effects on neurons. However, the role of activin in regulating neurotransmitter expression in the central nervous system and the exact mechanisms involved in this process are poorly understood. In the present study, we report that activin A and basic fibroblast growth factor (bFGF) synergistically increased the protein level of tyrosine hydroxylase (TH), and also greatly increased the TH mRNA level, in both mouse E14 striatal primary cell cultures and the hippocampal neuronal cell line HT22. Activin A and bFGF cooperatively stimulated nuclear translocation of Smad3 and specifically activated ERK1/2, but not p38 or JNK. Interestingly, a specific inhibitor for MEK, U0126, efficiently blocked the induction of TH promoter activity by activin A and bFGF, indicating that activin A collaborated with bFGF signaling to induce the TH gene through selective activation of ERK-type MAP kinase in mouse striatal and HT22 cells. These data suggest that activin A may act in concert with bFGF for the development of TH-positive neurons.
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PMID:Synergistic activity of activin A and basic fibroblast growth factor on tyrosine hydroxylase expression through Smad3 and ERK1/ERK2 MAPK signaling pathways. 1574 8


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