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)

A number of presynaptic markers are compromised in the dopaminergic neurons of aged Sprague-Dawley rats (22 months old) compared with young rats (3 months old). Indeed, in the striatum of the aged rats there is a diminished capacity to transport dopamine (DA), to bind the dopamine transporter (DAT) marker mazindol, to bind the vesicular monoamine transporter 2 (VMAT2) marker dihydrotetrabenazine, and to release DA under basal conditions or after induction by K(+) or amphetamine. Furthermore, the expression of DAT and VMAT2 mRNA in the midbrain is suppressed. GM1 ganglioside, 30 mg/kg ip daily, administered for 30 days, restores the afore-mentioned markers to values approaching those for young rats. Taken together with our published observations that GM1 partially restores tyrosine hydroxylase activity and DA metabolism in aged nigrostriatal and mesoaccumbal neurons and improves their morphology, our work suggests that GM1 might act as a dopaminergic neurotrophic factor in the aged brain and be a useful adjuvant for treating age-associated dopaminergic deficits.
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PMID:GM1 enhances dopaminergic markers in the brain of aged rats. 1455 8

Oxidative stress is thought to be a major contributor to the progress of the Parkinson's Disease (PD) because of the high vulnerability of dopaminergic cells against oxidative stress. The present work demonstrates that with the expression of the baculovirus p35 gene, PC12 cells could gain a high resistance against oxidative toxicants, hydrogen peroxide (H(2)O(2)) and 6-hydroxydopamine (6-OHDA). The DNA fragmentation analysis showed that PC12 cells underwent apoptosis after exposure to H(2)O(2) or 6-OHDA, while PP35 cells, a p35-expressing PC12 cell line, did not. Flow cytometric analysis showed that treatment with 150 microM H(2)O(2) or 120 microM 6-OHDA for 24 h caused 52.86% or 66.36% apoptotic cell, respectively, in PC 12 cells, but only 4.26% or 5.80% in PP35 cells. The cell viability measured by 3-(4,5-dimethylthiazal-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay indicated that H(2)O(2) and 6-OHDA induced a dose-dependent cell death on PC12 cells that were greatly remitted on PP35 cells. The viability of PP35 cells was even stronger than that of PC12 cells protected by glial cell line deprived neurotrophic factor (GDNF). The surviving PP35 cells remained normal cell morphology and showed positive with tyrosine hydroxylase (TH) immunocytochemical staining. These results indicate that baculovirus p35 gene possesses remarkable ability to rescue PC12 cells from death in experimental paradigms associated with oxidative stress.
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PMID:Baculovirus p35 gene greatly enhances PC12 cell's resistance against oxidative stress. 1460 15

The aim of this study was to produce dopaminergic neurons in vitro from human embryonic stem (hES) cells following treatment of various neurotrophic factors. MB03 hES cells were induced by retinoic acid (RA) or basic fibroblast growth factor (bFGF), which were further treated with brain derived neurotrophic factor (BDNF) or transforming growth factor (TGF)-alpha in each induction method during neuron differentiation days. At the final differentiation stage (21 days), all treatment groups revealed very similar levels (bFGF, 76-78%; RA, 70-74%) of mature neurons (anti-NF-200) in two induction methods irrespective of the addition of BDNF or TGF-alpha. In addition, immunostaining and HPLC analyses revealed higher levels of tyrosine hydroxylase (20+/-2.3%) and dopamine (265.5+/-62.8 pg/ml) in the bFGF- and TGF-alpha-treated hES cells than in RA- or BDNF-treated hES cells. These data are one of the first reports on the generation of dopaminergic neurons of hES cells in vitro. Also, our results indicate that TGF-alpha may be successfully used in the bFGF induction protocol and yield higher numbers of dopaminergic neurons from hES cells.
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PMID:Generation of dopaminergic neurons in vitro from human embryonic stem cells treated with neurotrophic factors. 1505 Jul 21

Previously, this laboratory has shown that human foetal progenitor cells derived from ventral mesencephalon (VM) can be developmentally directed towards a dopaminergic lineage. In the present study, the effects are reported of several as yet untested differentiation/survival factors on the controlled conversion of neural progenitor cells to dopaminergic neurons. Positive immunoreactivity to tyrosine hydroxylase (TH) and raised levels of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), secreted into culture medium, were used to indicate the presence of the dopaminergic neuronal phenotype, i.e., active TH. Incubation with retinoic acid (RA) (0.5 microM) lead to an increase in the number of cultured cells showing positive immunoreactivity for the neuronal marker, microtubule-associated protein (MAP)-2ab. A concomitant increase in TH-positive immunoreactivity was also demonstrated. The brain-derived neurotrophic factor (BDNF) (50 ng/ml), glial-derived neurotrophic factor (GDNF) (10 ng/ml) and interleukin-1 beta (IL-1 beta) (10 ng/ml) also had positive effects in promoting neural progenitor cell differentiation towards the dopaminergic phenotype in the presence of dopamine (10 microM) and forskolin (Fsk) (10 microM). There was no synergy in this effect when progenitor cells were incubated with all of these agents simultaneously. The trans-differentiation potential of the progenitor cells to be directed towards other neurotransmitter phenotypic lineages was also investigated. It was found that, with the right cocktails of agents, serotonin (Ser) (75 microM), acidic fibroblast growth factor (aFGF) (10 ng/ml), BDNF (50 ng/ml) and forskolin (10 microM), these same cells could be directed down the serotonergic cell lineage pathway (as judged by the appearance of tryptophan hydroxylase (TPH) positive immunoreactivity, and synthesis of 5-HT and its metabolites, secreted into the culture medium). However, no cocktail containing noradrenaline (10 nM-500 microM), BDNF (50 ng/ml) and forskolin (10 microM) was found which promoted differentiation towards the noradrenergic cell phenotype as judged by the absence of any TH or D beta H positive immunoreactivity, and no formation of 3,4-dihydroxyphenylethyleneglycol (DOPEG), the principal metabolite of noradrenaline. The controlled trans-differentiation potential of these cell could pave the way for development and harvesting of large numbers of neurons of the appropriate neurotransmitter phenotype for future transplantation therapies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease.
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PMID:The differentiation potential of human foetal neuronal progenitor cells in vitro. 1546 16

In the present study, we investigate the effect of aggressive behavior and release of nerve growth factor (NGF) on brain progenitor cells. We found that the condition of subordination enhances the level of NGF in the subventricular zone and hippocampus whereas dominance elevates brain derived neurotrophic factor (BDNF). It was also found that mRNA-TrkA is over-expressed in the subventricular zone and hippocampus of dominant and subordinate mice, whereas mRNA-TrkB is increased in the subventricular zone of both dominants and subordinates and in the hippocampus of dominant mice. Fighting was also associated with increased presence of proliferating cells in the hippocampus stained with the nuclear marker bromodeoxyuridine (BrdU). Moreover, the brain of subordinate mice displayed tyrosine hydroxylase (TH) immunoreactivity in the wall of the periventricular region of the third ventricles and a marked neuropeptide Y (NPY) presence in the hippocampus co-expressed with BrdU. These results provide additional evidence that agonistic behavior in the aged mouse alters neurotrophin levels and increases brain progenitor cells number. The functional significance of these findings is discussed.
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PMID:Fighting in the aged male mouse increases the expression of TrkA and TrkB in the subventricular zone and in the hippocampus. 1563 86

Brain derived neurotrophic factor (BDNF) expression is significantly reduced in the Parkinson's disease substantia nigra. This neurotrophin has potent affects on dopaminergic neuron survival protecting them from the neurotoxins MPTP and 6-hydroxydopamine (6-OHDA) commonly used to create animal models of Parkinson's disease and also promoting dopaminergic axonal sprouting. In this study, we demonstrate that an antisense oligonucleotide infusion (200 nM for 28 days) to prevent BDNF production in the substantia nigra of rats mimics many features of the classical animal models of Parkinson's disease. 62% of antisense treated rats rotate (P < or = 0.05) in response to dopaminergic receptor stimulation by apomorphine. 40% of substantia nigra pars compacta tyrosine hydroxylase immunoreactive neurons are lost (P < or = 0.00001) and dopamine uptake site density measured by (3)H-mazindol autoradiography is reduced by 34% (P < or = 0.005). Loss of haematoxylin and eosin stained nigral neurons is significant (P < or = 0.0001) but less extensive (34%). These observations indicate that loss of BDNF expression leads both to down regulation of the dopaminergic phenotype and to dopaminergic neuronal death. Therefore, reduced BDNF mRNA expression in Parkinson's disease substantia nigra may contribute directly to the death of nigral dopaminergic neurons and the development of Parkinson's disease.
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PMID:Inhibiting BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons. 1569 37

There is increasing evidence that glial cell line-derived neurotrophic factor (GDNF) plays a role as a limiting, striatal target-derived neurotrophic factor for dopamine neurons of the substantia nigra pars compacta (SNpc) by regulating the magnitude of the first phase of postnatal natural cell death which occurs in these neurons. While it has been shown that GDNF mRNA is relatively abundant in postnatal striatum, the cellular basis of its expression has been unknown. We therefore used nonradioactive in situ hybridization and immunohistochemistry to examine the cellular basis of GDNF mRNA and protein expression, respectively, in postnatal striatum and related structures. We found that GDNF mRNA is expressed within medium-sized striatal neurons. Expression in glia was not observed. At the protein level, regionally, GDNF expression in striatum was observed in striosomal patches, as previously described. At a cellular level a few neurons were observed, but they do not account for the striosomal pattern. This pattern is predominantly due to GDNF-positive neuropil. Some of this neuropil arises from tyrosine hydroxylase-positive nigro-striatal dopaminergic afferents. Astrocytic processes do not appear to contribute to the striosomal pattern. GDNF-positive fibers are identified not only within intrinsic striatal neuropil, but also in fibers within the major striatal efferent targets: the globus pallidus, the entopeduncular nucleus, and the SN pars reticulata. We conclude that during normal postnatal development, medium-sized neurons are the principal source of GDNF within the striatum.
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PMID:Anatomical basis of glial cell line-derived neurotrophic factor expression in the striatum and related basal ganglia during postnatal development of the rat. 1571

Dopaminergic cells in the retina express the receptor for brain-derived neurotrophic factor (BDNF), which is the neurotrophic factor that influences the plasticity of synapses in the central nervous system. We sought to determine whether BDNF influences the network of dopaminergic amacrine cells in the axotomized rat retina, by immunocytochemistry with an anti-tyrosine hydroxylase (TH) antiserum. In the control retina, we found two types of TH-immunoreactive amacrine cells, type I and type II, in the inner nuclear layer adjacent to the inner plexiform layer (IPL). The type I amacrine cell varicosities formed ring-like structures in contact with AII amacrine cell somata in stratum 1 of the IPL. In the axotomized retinas, TH-labeled processes formed loose networks of fibers, unlike the dense networks in the control retina, and the ring-like structures were disrupted. In the axotomized retinas treated with BDNF, strong TH-immunoreactive varicosities were present in stratum 1 of the IPL and formed ring-like structures. Our data suggest that BDNF affects the expression of TH immunoreactivity in the axotomized rat retina and may therefore influence the retinal dopaminergic system.
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PMID:Brain-derived neurotrophic factor modulates the dopaminergic network in the rat retina after axotomy. 1607 11

Glial cell-line derived neurotrophic factor (GDNF) is a good candidate agent for restoring functional reinnervation and/or neuroprotection of dopamine (DA) nigrostriatal system and thus for the treatment of Parkinson's disease (PD). Viral delivery is currently the most likely in vivo strategy for delivery of the therapeutic protein into the brain for treatment of neurological diseases. However, one of the important unresolved issues for this strategy is the threshold number of DA nigral neurons and/or of striatal DA terminals necessary for optimal benefit from GDNF therapy. In this study, we examined the intrastriatal neurotrophic effects of long-term GDNF delivery using a lentiviral vector in a new rat model of early PD. Lenti-GDNF was injected into the striatum 4 weeks after partial substantia nigra pars compacta 6-hydroxydopamine-induced lesion. Striatal denervation was evaluated by assessing tyrosine hydroxylase-positive DA fiber density and corroborated by testing motor deficit by means of a staircase test. GDNF treatment restored complete striatal DA innervation in the previously denervated area and this was associated with significant behavioral improvements.
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PMID:Functional reinnervation from remaining DA terminals induced by GDNF lentivirus in a rat model of early Parkinson's disease. 1608 32

Neurturin (NTN) is an important neurotrophic factor for parasympathetic neurons; however, no studies to date have investigated the signalling mechanisms downstream of GFRalpha2 and Ret activation underlying this neurotrophic support. This is particularly important for pelvic parasympathetic neurons, which are prone to injury during surgical procedures such as prostatectomy, and where there are no current therapies for axonal regeneration. To address this issue we have cultured dissociated adult rat pelvic ganglion neurons and also examined the structural changes in pelvic ganglion neurons after axotomy. Axotomised penile neurons deprived of target-derived support had smaller somata than intact neurons. Studies of cultured adult pelvic ganglion neurons also demonstrated that NTN stimulated soma growth. Further experiments showed that NTN reduced the up-regulation of tyrosine hydroxylase expression in cultured pelvic parasympathetic neurons. NTN stimulated the extension of neurites in cultured parasympathetic, but not sympathetic, pelvic ganglion neurons. Inhibition of phosphatidylinositol 3-kinase prevented initiation of neurite outgrowth, whereas inhibition of the mitogen-activated protein kinase and the Src family kinase pathways disrupted NTN-stimulated microtubule assembly. Surprisingly, NTN did not activate the transcription factor cAMP-response element binding protein (CREB), which is typically involved in neurotrophic signalling in sympathetic neurons. This is the first study to identify signalling pathways activated by NTN in adult parasympathetic neurons. Our results may lead to a better understanding of regenerative mechanisms in parasympathetic neurons, especially for those innervating urogenital organs. Our results also indicate that neurotrophic signalling in parasympathetic neurons is different from that in other types of peripheral neurons.
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PMID:Neurturin has multiple neurotrophic effects on adult rat sacral parasympathetic ganglion neurons. 1610 41


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