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)

Neurturin is a neurotrophic factor that is widely expressed in cavernous tissue and retrogradely transported to penis-projecting neurons via its receptor, glial cell line derived neurotrophic factor family receptor alpha-2 (GFRa2). To investigate the influence of aging on neural function on the penis, we examined the expression of GFRa2 mRNA in the major pelvic ganglion and its relationship to neuronal nitric oxide synthase (nNOS)- and tyrosine hydroxylase (TH)-positive neurons. GFRa2 and nNOS mRNA expression levels in RT-PCR showed age-related decreases in 1-, 3-, 6-, 12-, 18- and 24-month-old rats. In situ hybridization also revealed that the number of GFRa2-positive neurons in pelvic ganglia decreased with aging. A double-labeling study revealed the co-expression of GFRa2 and nNOS, which simultaneously decreased in old adult (24 months) and young castrated rats compared with young adult rats (3 months). These results suggest that aging and castration influence the numbers of nNOS- and GFRa2-positive neurons. Higher age might affect not only cavernous tissue but also the neural plasticity of the cavernous nerve related to erectile function.
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PMID:Age-related alteration of neurturin receptor GFRa2 and nNOS in pelvic ganglia. 1614 Apr 23

Glial cell line-derived neurotrophic factor (GDNF) is suggested as a specific neurotrophic factor for midbrain dopamine (DA) neurons, but the molecular mechanism underlying the neuroprotective action of GDNF is not well known. In the present study, we have shown that GDNF increased protein kinase CK2 activity in rat substantia nigra (SN) in a dose-dependent and time-dependent manner. This effect is prevented by prior treatment of the receptor Ret blocker K-252b. Immunostaining results also revealed that CK2 is expressed in TH-positive neurons in mesencephalon culture. Transfection of the wildtype CK2alpha DNA increased, whereas transfection of the catalytically inactive CK2alphaA156 mutant DNA decreased CK2 activity in the SN. CK2alphaA156 mutant DNA also antagonized the enhancing effect of GDNF on CK2 activity. It also antagonized the enhancing effects of GDNF on tyrosine hydroxylase (TH) protein level in the SN, DA turnover in the striatum and rotarod performance in rats. Further, CK2alpha wildtype DNA increased, whereas CK2alphaA156 mutant DNA decreased TH activity in the SN without altering the TH protein level. On the other hand, the DA neuron toxin 1-methyl-4-phenylpyridinium iodide (MPP+) markedly decreased the number of TH-positive neurons and TH protein level in the SN, decreased DA level in the striatum and impaired rotarod performance in rats. Over-expression of the CK2alpha wildtype DNA partially, but significantly, prevented the deteriorating effect of MPP+ on these measures. Prior administration of MPP+ also antagonized the enhancing effect of GDNF on CK2 activity. These results together suggest that the CK2 signaling pathway contributes to the neuroprotective action of GDNF on DA neurons.
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PMID:Molecular mechanism of the neurotrophic effect of GDNF on DA neurons: role of protein kinase CK2. 1629 46

Erythropoietin (EPO), a hematopoietic factor, is also required for normal brain development, and its receptor is localized in brain. Our previous study showed that EPO promotes differentiation of neuronal stem cells into astrocytes. Since astrocytes have influence on the neuronal function, we investigated whether EPO-activated astrocytes could stimulate differentiation of neuronal stem cells into neurons. EPO did not promote neuronal differentiation of neuronal stem cells isolated from 17 day embryos, however, neuronal differentiation was promoted when the neuronal stem cells were co-cultured with astrocyte isolated from post neonatal (Day 1) rat brain. Moreover, neuronal differentiation was further promoted when the neuronal stem cells were cultured with astrocyte culture medium treated by EPO (10U/ml) showing increase of morphological differentiation, and expression of neuronal differentiation marker proteins, neurofilament, and tyrosine hydroxylase. The promoting effect of EPO-treated astrocyte medium was also found in the differentiation of PC12 cells. EPO-promoted morphological differentiation of neuronal stem cells as well as astrocytes was dose dependently reduced by treatment with anti-EPO receptor antibodies in culture with astrocyte culture medium. To clarify whether EPO itself or via production of well-known neurotropic factor could promote neuronal cell differentiation, we determined the level of neurotropic factors in the EPO-treated astrocytes. Compared to untreated astrocytes, EPO-treated astrocytes increased about 2-fold in beta-NGF and 3-4-fold in BMP2, but did not increase BNDF and NT-3 levels. Since the previous study showed that extracellular signal-regulated kinase (ERK) is involved in activation of astrocytes by EPO, we determined whether generation of neurotrophic factor may also be involved with the ERK pathway. In the presence of ERK inhibitor, PD98059, the generation of beta-NGF was diminished in a dose dependent manner consistent with the inhibiting effect on neuronal differentiation. These data demonstrate that EPO promotes neuronal cell differentiation through increased release of beta-NGF and BMP2 from astrocytes, and this effect may be associated with ERK pathway signals.
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PMID:ERK-mediated production of neurotrophic factors by astrocytes promotes neuronal stem cell differentiation by erythropoietin. 1633 49

One approach to the treatment of retinal diseases, such as retinitis pigmentosa, is to replace diseased or degenerating cells with healthy cells. Even if all of the problems associated with tissue transplant were to be resolved, the availability of tissue would remain an ongoing problem. We have previously shown that transformed human retinal cells can be grown in a NASA-developed horizontally rotating culture vessel (bioreactor) to form three-dimensional-like structures with the expression of several retinal specific proteins. In this study, we have investigated growth of non-transformed human retinal progenitors (retinal stem cells) in a rotating bioreactor. This rotating culture vessel promotes cell-cell interaction between similar and dissimilar cells. We cultured retinal progenitors (Ret 1-4) alone or as a co-culture with human retinal pigment epithelial cells (RPE, D407) in this system to determine if 3D structures can be generated from non-transformed progenitors. Our second goal was to determine if the formation of 3D structures correlates with the upregulation of neurotrophins, basic fibroblast growth factor (bFGF), transforming growth factor alpha (TGFalpha), ciliary neurotrophic factor (CNTF), and brain-delivered neurotrophic factor (BDNF). These factors have been implicated in progenitor cell proliferation, commitment, differentiation, and survival. We also investigated the expression of the following retinal specific proteins in this system: neuron specific enolase (NSE); tyrosine hydroxylase (TH); D(2)D(3), D(4) receptors; protein kinase-C alpha (PKCalpha), and calbindin. The 3D structures generated were characterized by phase and scanning transmission electron microscopy. Retinal progenitors, cultured alone or as a co-culture in the rotating bioreactor, formed 3D structures with some degree of differentiation, accompanied by the upregulation of bFGF, CNTF, and TGFalpha. Brain-derived neurotrophic factor, which is expressed in vivo in RPE (D407), was not expressed in monolayer cultures of RPE but expressed in the rotating bioreactor-cultured RPE and retinal progenitors (Ret 1-4). Upregulation of neurotrophins was noted in all rotating bioreactor-cultured cells. Also, upregulation of D(4) receptor, calbindin, and PKCalpha was noted in the rotating bioreactor-cultured cells. We conclude that non-transformed retinal progenitors can be grown in the rotating bioreactor to form 3D structures with some degree of differentiation. We relied on molecular and biochemical analysis to characterize differentiation in cells grown in the rotating bioreactor.
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PMID:Enhanced neurotrophin synthesis and molecular differentiation in non-transformed human retinal progenitor cells cultured in a rotating bioreactor. 1649 51

Fibroblast growth factor 2 (FGF-2) was the first growth factor discovered that exerted prominent protective and regenerative effects in an animal model of Parkinson's disease, the MPTP-lesioned dopaminergic nigrostriatal system. To address the putative physiological relevance of endogenous FGF-2 for midbrain dopaminergic neurons, we have analysed densities of tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) and TH-positive fibers in the striatum and amygdala of adult FGF-2-deficient mice. We found that densities of TH-immunoreactive (ir) cells in the SN as well as densities of TH-ir fibers in the striatum and amygdala were unaltered as compared with wild-type littermates. There is evidence to suggest that growth factor deficits do not become apparent unless a system is challenged in a lesioning paradigm. We therefore tested the ability of the nigrostriatal system with respect to its ability to cope with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) intoxication. Treatment with 20 mg/kg MPTP on three consecutive days reduced dopamine levels in the striatum by about 80%. Densities of TH-positive neurons in the SN were reduced by 71%. However, both parameters did not significantly differ between FGF-2(-/-) mice and wild-type littermates. Our results therefore suggest that FGF-2, despite its prominent pharmacological potency as a neurotrophic factor for the dopaminergic nigrostriatal system, is not crucial for maintaining its structural integrity and ability to cope with MPTP intoxication.
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PMID:FGF-2 deficiency does not alter vulnerability of the dopaminergic nigrostriatal system towards MPTP intoxication in mice. 1655 32

Neuronal progenitor cells (NPCs) play an important role in potential regenerative therapeutic strategies for neurodegenerative diseases, such as Parkinson disease. However, survival of transplanted cells is, as yet, limited, and the identification of grafted cells in situ remains difficult. The use of NPCs could be more effective with regard to a better survival and maturation when transfected with one or more neurotrophic factors. Therefore, we investigated the possibility of transfecting mesencephalic neuronal progenitors with different constructs carrying neurotrophic factors or the expression reporters enhanced green fluorescence protein (EGFP) and red fluorescent protein (DsRed). Different techniques for transfection were compared, and the highest transfection rate of up to 47% was achieved by nucleofection. Mesencephalic neuronal progenitors survived the transfection procedure; 6 hours after transfection, viability was approximately 40%, and the transfected cells differentiated into, for example, tyrosine hydroxylase-positive neurons. Within the group of transfected cells, many progenitors and several neurons were found. To provide the progenitor cells with a neurotrophic factor, different isoforms of fibroblast growth factor-2 were introduced. To follow the behavior of the transfected cells in vitro, functional tests such as the cell viability assay (water-soluble tetrazolium salt assay [WST-1]) and the cell proliferation assay (5-bromo-2'-deoxyuridine-enzyme-linked immunosorbent assay) were performed. In addition, these transfected NPCs were viable after transplantation, expressed tyrosine hydroxylase in vivo, and could easily be detected within the host striatum because of their EGFP expression. This study shows that genetic modification of neural progenitors could provide attractive perspectives for new therapeutic concepts in neurodegenerative diseases.
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PMID:Nucleofection is the most efficient nonviral transfection method for neuronal stem cells derived from ventral mesencephali with no changes in cell composition or dopaminergic fate. 1690 96

To investigate the neuroprotective effects of erythropoietin (EPO) in a rodent model of Parkinson disease, we inoculated a nonreplicating herpes simplex virus-based vector expressing EPO (vector DHEPO) into the striatum of mice 1 week prior to, or 2 weeks after, the start of continual administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (4 mg/kg intraperitoneally, 5 of 7 days) for 6 weeks. Inoculation with DHEPO prior to MPTP intoxication preserved behavioral function measured by pellet retrieval and the histological markers of tyrosine hydroxylase-immunoreactive (TH-IR) neuronal cell bodies in the substantia nigra (SN) and TH-IR and dopamine transporter-immunoreactive (DAT-IR) terminals in striatum. Inoculation of DHEPO 2 weeks into a 6-week course of MPTP resulted in improvement of behavioral function and restoration of TH-IR cells in SN and TH- and DAT-IR in the striatum. The effects of vector-produced EPO were similar in magnitude to the effects of vector-mediated expression of glial-derived neurotrophic factor in the same model. These results demonstrate that vector-mediated EPO production may be used to reverse dopaminergic neurodegeneration in the face of continued toxic insult.
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PMID:HSV-mediated delivery of erythropoietin restores dopaminergic function in MPTP-treated mice. 1694 43

Uninfected neurons of the substantia nigra (SN) degenerate in human immunodeficiency virus (HIV)-positive patients through an unknown etiology. The HIV envelope glycoprotein 120 (gp120) causes apoptotic neuronal cell death in the rodent striatum, but its primary neurotoxic mechanism is still under investigation. Previous studies have shown that gp120 causes neurotoxicity in the rat striatum by reducing brain-derived neurotrophic factor (BDNF). Because glial cell line-derived neurotrophic factor (GDNF) and BDNF are neurotrophic factors crucial for the survival of dopaminergic neurons of the SN, we investigated whether gp120 reduces GDNF and BDNF levels concomitantly to induce apoptosis. Rats received a microinjection of gp120 or vehicle into the striatum and were sacrificed at various time intervals. GDNF but not BDNF immunoreactivity was decreased in the SN by 4 days in gp120-treated rats. In these animals, a significant increase in the number of caspase-3- positive neurons, both tyrosine hydroxylase (TH)-positive and -negative, was observed. Analysis of TH immunoreactivity revealed fewer TH-positive neurons and fibers in a medial and lateral portion of cell group A9 of the SN, an area that projects to the striatum, suggesting that gp120 induces retrograde degeneration of nigrostriatal neurons. We propose that dysfunction of the nigrostriatal dopaminergic system associated with HIV may be caused by a reduction of neurotrophic factor expression by gp120.
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PMID:Intrastriatal administration of human immunodeficiency virus-1 glycoprotein 120 reduces glial cell-line derived neurotrophic factor levels and causes apoptosis in the substantia nigra. 1696 4

The experiment was to evaluate the therapeutic benefit of transplanted bone marrow stromal cells (BMSCs) transfected with a kind of neurotrophic factor gene, neurturin (NTN) gene, in treating the rat model of Parkinson's disease (PD). The 6-OHDA-lesioned rats were assigned to one of three groups, those receiving BMSCs transfected with NTN gene, those receiving untransfected BMSCs containing a void plasmid and those receiving phosphate buffer solution (PBS). Treatments were injected into the right striatum (6-OHDA-lesioned side). One to six months post-transplantation, apomorphine-induced rotational behavior was observed. One month after transplantation, green fluorescent protein (GFP)/NTN, GFP/glial fibrillary acidic protein (GFAP), GFP/neuron specific enolase (NSE) and GFP/tyrosine hydroxylase (TH) fluorescence determinations of brain sections were carried out. One to six months after transplantation, brain sections containing striatum and substantia nigra were stained for TH. In situ hybridization and Western blots were used to determine NTN mRNA and protein concentration, respectively, in affected brain regions. High performance liquid chromatography (HPLC) was used to measure the dopamine (DA) content in the lesioned striatum 1 and 3 month(s) post-transplantation. The results were shown that: in the first 3 months after transplantation, the number of rotations was lower in NTN-transplant group than the void vector group, and during 1-6 months post-transplantation, the number of rotations was lower in both transplant groups than that in the PBS group (P<0.05). One month after transplantation, we detected GFP/NTN-, GFP/GFAP- and GFP/NSE-labeled cells in the transplantation area of the NTN-transplanted group, but no obvious GFP/TH labeled cells were found. Quantitative analysis of TH-positive cells 1 to 6 months after transplantation indicated that there were no significant differences between groups in survival rates of TH-positive neurons in the lesioned substantia nigra (P>0.05). In situ hybridization and Western blot identified NTN mRNA and protein expression in the transplantation area of the NTN-transplanted group. After transplantation of NTN-expressing cells, DA content in the lesioned striatum was significantly higher in the transgenic group than that in the void vector group or the PBS group (P<0.05). The overall therapeutic effects of the NTN-transplanted group were superior to those of the void plasmid group and the PBS group. The mechanisms by which transgenic therapy treats PD might involve functional enhancement of residual dopaminergic neurons by NTN, which significantly reduces the number of rotations in animals, but not increase the numbers of existing dopaminergic neurons.
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PMID:Transplantation of bone marrow stromal cells containing the neurturin gene in rat model of Parkinson's disease. 1733 73

The transcription factor Nurr1 is essential for the generation of midbrain dopaminergic neurons (mDA). Only a few Nurr1-regulated genes have so far been identified and it remains unclear how Nurr1 influences the development and function of dopaminergic neurons. To identify novel Nurr1 target genes we have used genome-wide expression profiling in rat midbrain primary cultures, enriched in dopaminergic neurons, following up-regulation of Nurr1 expression by depolarization. In this study we demonstrate that following depolarization the hyperexpression of Nurr1 and the brain derived neurotrophic factor (BDNF) are phospholipase C- and protein kinase C-dependent. We show that Bdnf, which encodes a neurotrophin involved also in the phenotypic maturation of mDA neurons, is a novel Nurr1 target gene. By RNA interference experiments we show that a decreased Nurr1 expression is followed by tyrosine hydroxylase and BDNF mRNA and protein down-regulation. Reporter gene assay experiments performed on midbrain primary cultures using four Bdnf promoter constructs show that Bdnf is a direct target gene of Nurr1. Taken together, our findings suggest that Nurr1 might also influence the development and the function of midbrain dopaminergic neurons via direct regulation of Bdnf expression.
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PMID:Bdnf gene is a downstream target of Nurr1 transcription factor in rat midbrain neurons in vitro. 1750 60


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