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)

Nurr1 has been implicated as a transcription factor mediating the endogenous neuroprotective mechanism against stroke. We examined the in vivo and in vitro properties of a new human embryonic carcinoma Ntera-2 cell line carrying the human Nurr1 gene (NT2N.Nurr1). Adult Sprague-Dawley rats underwent experimental stroke initially and 14 days later were assigned randomly to receive stereotaxic transplantation of NT2N.Nurr1 cells or infusion of vehicle into their ischemic striatum. Transplantation of NT2N.Nurr1 cells promoted significant attenuation of behavioral impairments over a 56-day period after stroke, characterized by decreased hyperactivity, biased swing activity, and neurologic deficits, as well as significant reduction in ischemic striatal cell loss compared to vehicle-infused stroke animals. Transplanted NT2N.Nurr1 cells survived and expressed neuronal phenotypic markers in the ischemic striatum. In vitro results showed that cultured NT2.Nurr1 cells were already negative for nestin even before retinoic acid treatment, despite strong nestin immunoreactivity in NT2 cells. This indicates Nurr1 triggered a rapid commitment of NT2 cells into a neuronal lineage. Indeed, NT2.Nurr1 cells, at 4 weeks into RA treatment, displayed more abundant tyrosine hydroxylase positive cells than NT2 cells. Parallel ELISA studies showed further that cultured NT2N.Nurr1, but not NT2N cells, secreted glial cell derived neurotrophic factor. The present study shows efficacy of NT2N.Nurr1 cell grafts in ischemic stroke, with in vitro evidence suggesting the cells' excellent neuronal differentiation capability and ability to secrete GDNF as likely mechanisms mediating the observed therapeutic benefits.
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PMID:Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke: in vitro evidence of expedited neuronal differentiation and GDNF secretion. 1733 85

In the central nervous system (CNS), generation of phenotypic diversity within the neuronal lineage is precisely regulated in a spatial and temporal fashion. Neural basic helix-loop-helix (bHLH) transcription factors are cell intrinsic factors that control commitment to neuronal lineage and play an important role in neuronal cell type specification. The ability to differentiate human embryonic stem (hES) cells into neurons provides a good model system to address human neuronal specification. Previous studies have shown neurogenin-2 (Ngn2) to be involved in the development of mesencephalic dopaminergic neurons. Toward the goal of correlating neuronal phenotype with early gene expression pattern, we have characterized the expression of Ngn2 during hES cell differentiation. Our results show that treatment of embryoid bodies (EBs) with retinoic acid (RA) leads to the greatest proportion of tyrosine hydroxylase (TH)-positive cells followed by vasoactive intestinal peptide (VIP)-treated EBs as compared to untreated EBs. This increase in the proportion of TH-positive neurons was correlated with the unique morphology of RA-treated aggregates and the spatial delocalization of the expression of Ngn2 within the EB. Neurospheres derived from RA-treated EBs contained many nestin-positive cells within regions that expressed Ngn2. We show that the extent of nestin-positive cells that arise from the region of Ngn2 expression is correlated with the appearance of TH-positive neurons. Our results show for the first time the expression of Ngn2 during the differentiation of hES cells.
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PMID:Neurospheres derived from human embryoid bodies treated with retinoic Acid show an increase in nestin and ngn2 expression that correlates with the proportion of tyrosine hydroxylase-positive cells. 1778 40

We examined the effects of 7-nitroindazole on the dopaminergic system in mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. The mice received four intraperitoneal injections of MPTP (20 mg/kg) at 2 h-intervals. Administration of 7-nitroindazole showed dose-dependent neuroprotective effects against striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion 7 days after MPTP treatment. Behavioral testing showed that MPTP-treated mice exhibited motor deficits in the catalepsy test after 7 days, but 7-nitroindazole prevented the appearance of motor abnormalities in this test. The MPTP-treated mice exhibited the loss of tyrosine hydroxylase-containing dopaminergic neurons in mice after 1, 3 and 7 days, but 7-nitroindazole-treated mice showed a protective effect. GFAP (glial fibrillary acidic protein)-positive astrocytes were accumulated in the striatum 3 and 7 days and in the substantia nigra 1, 3 and 7 days after MPTP treatment. In contrast, 7-nitroindazole prevented a significant increase in the number of GFAP-positive astrocytes in the striatum and substantia nigra after MPTP treatment. The reactive astrocytes in the striatum and substantia nigra after MPTP treatment increased the production of S100beta protein, which is thought to promote neuronal damage, but 7-nitoindazole suppressed the expression of S100 beta protein. Activation of microglia, with an increase in staining intensity and morphological changes, was observed in the striatum and substantia nigra 1 and 3 days after MPTP treatment, but 7-nitroindazole prevented a significant increase in the number of isolectin B(4) positive microglia in the striatum and substantia nigra. On the other hand, nestin-immunoreactive cells were increased significantly in the striatum 3 and 7 days after MPTP treatment. 7-Nitroindazole treatment facilitated nestin expression in the striatum 7 days after MPTP treatment. Thus, nNOS inhibitor 7-nitroindazole protected dopaminergic neurons against MPTP neurotoxicity in mice and ameliorated neurological deficits. The results suggest that the neuroprotection is mediated though the modulation of glial activation, including the inhibition of S100beta synthesis and the prevention of microglial activation. These results suggest the therapeutic strategy targeted to glial modulation with 7-nitoindazole offers a great potential for the development of new neuroprotective therapies for Parkinson's disease.
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PMID:Protective action of neuronal nitric oxide synthase inhibitor in the MPTP mouse model of Parkinson's disease. 1803 Jun 9

The authors investigated the protective effects of a novel astrocyte-modulating agent, arundic acid, in a 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) mouse model of Parkinson's disease. Male mice received four intraperitoneal (i.p.) injections of MPTP (20 mg/kg) at 2 h intervals. The content of dopamine and its metabolites in the striatum was reduced markedly 7 days after MPTP treatment. The delayed treatment with arundic acid (30 mg/kg, i.p.) administered 3, 4, 5 and 6 days after MPTP treatment did not affect the depletion of dopamine and its metabolites in the striatum. Our immunohistochemical study with anti-tyrosine hydroxylase antibody, anti-neuronal nuclei antibody, anti-glial fibrillary acidic protein antibody, anti-S 100beta antibody and anti-nestin antibody showed that the delayed treatment with arundic acid had a protective effect against MPTP-induced neuronal damage in the striatum and the substantia nigra of mice. Furthermore, this agent ameliorated the severe reductions in number of isolectin reactive microglia in the striatum and the substantia nigra 7 days after MPTP treatment. These results demonstrate that the inhibition of S 100beta synthesis in astrocytes may be the major component of the beneficial effect of arundic acid. Thus, our present findings provide that the therapeutic strategies targeted to astrocytic modulation with arundic acid offers a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with Parkinson's disease.
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PMID:Delayed treatment with arundic acid reduces the MPTP-induced neurotoxicity in mice. 1820 68

The adult subventricular zone (SVZ) supports a population of cells that display the hallmarks of stem cells: they are self-renewing and multipotent-capable of generating neurons, oligodendrocytes, and astrocytes. In vivo, these adult neural stem cells (aNSCs) are fated primarily for a gamma-amino butyric acid (GABA)-ergic lineage of olfactory bulb interneurons, a small subpopulation of which is dopaminergic. Here, we investigate the plasticity of aNSCs in vitro, in particular, their ability to generate a specific neuronal lineage, midbrain dopamine neurons. Previous work using mouse embryonic stem (ES) cells showed that introduction of early developmental inductive cues, sonic hedgehog (SHH) and fibroblast growth factor-8 (FGF-8), directed ES cell-derived neuroepithelial cells to generate midbrain dopaminergic neurons, those lost in Parkinson's disease. Placing aNSCs under similar culture conditions, immunocytochemistry and RT-PCR analysis revealed early dopaminergic neuron specification. However, aNSC-derived neurons remained morphologically immature, exhibiting concurrent nestin and tyrosine hydroxylase (TH) expression, with cell death occurring in the final differentiation stage. High-performance liquid chromatography (HPLC) analysis revealed that while aNSC-derived neurons released dopamine, release was not significantly increased following depolarization with K+. In contrast, ES cell-generated TH+ neurons expressed the mature markers MAP2 and NeuN and showed K+-evoked release of dopamine. Reduced culture time of aNSC-derived nestin+ progenitors in FGF-2-containing medium improved survival of TH+ neurons. However, these neurons exhibited characteristics of forebrain dopamine neurons and also expressed low levels of midbrain transcription factors. Together, our data indicate that when presented with in vitro conditions that promote midbrain-specific dopamine neuron specification, aNSCs instead generate forebrain-like dopamine neurons, demonstrating their restricted and prescribed nature.
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PMID:In vitro generation of dopaminergic neurons from adult subventricular zone neural progenitor cells. 1824 23

We studied the histochemical phenotype of carotid body (CB) cells in the adult rat. In addition to tyrosine hydroxylase (TH), type I cells expressed numerous growth factors such as glial cell line-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha), as well as the receptors p75, Ret, epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-alpha (PDGFR-alpha). Type II cells expressed the glial fibrillary acid protein (GFAP), vimentin, the trophic factor bFGF and receptors p75, EGFR and PDGFR-alpha. Both types I and II cells exhibited a positive immunoreaction to markers of neural progenitor cells such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) and nestin, respectively, suggesting that CB contain some immature cells even at the adult stage. The possibility that these cells can be expanded and differentiated into mature neurons should be explored.
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PMID:Immunohistochemical characterization of the rat carotid body. 1828 Jul 99

Sympathetic ganglia are primarily composed of noradrenergic neurons and satellite glial cells. Although both cell types originate from neural crest cells, the identities of the progenitor populations at intermediate stages of the differentiation process remain to be established. Here we report on the identification in vivo of glial and neuronal progenitor cells in postnatal sympathetic ganglia, by using mouse superior cervical ganglia as a model system. There are significant levels of cellular proliferation in mouse superior cervical ganglia during the first 18 days after birth. A majority of the proliferating cells express both nestin and brain lipid-binding protein (BLBP). Bromodeoxyuridine (BrdU) fate-tracing experiments demonstrate that these nestin and BLBP double-positive cells represent a population of glial progenitors for sympathetic satellite cells. The glial differentiation process is characterized by a marked downregulation of nestin and upregulation of S100, with no significant changes in the levels of BLBP expression. We also identify a small number of proliferating cells that express nestin and tyrosine hydroxylase, a key enzyme of catecholamine biosynthesis that defines sympathetic noradrenergic neurons. Together, these results establish nestin as a common marker for sympathetic neuronal and glial progenitor cells and delineate the cellular basis for the generation and maturation of sympathetic satellite cells.
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PMID:Nestin expression defines both glial and neuronal progenitors in postnatal sympathetic ganglia. 1839 38

Human neural stem cells offer the hope that a cell therapy treatment for Parkinson's disease (PD) could be made widely available. In this study, we describe two clonal human neural cell lines, derived from two different 10-week-old fetal mesencephalic tissues and immortalized with the c-mycER(TAM) transgene. Under the growth control of 4-hydroxytamoxifen, both cell lines display stable long-term growth in culture with a normal karyotype. In vitro, these nestin-positive cells are able to differentiate into tyrosine hydroxylase (TH)-positive neurons and are multipotential. Implantation of the undifferentiated cells into the 6-OHDA substantia nigral lesioned rat model displayed sustained improvements in a number of behavioral tests compared with noncell-implanted, vehicle-injected controls over the course of 6 months. Histological analysis of the brains showed survival of the implanted cells but no evidence of differentiation into TH-positive neurons. An average increase of approximately 26% in host TH immunoreactivity in the lesioned dorsal striatum was observed in the cell-treated groups compared to controls, with no difference in loss of TH cell bodies in the lesioned substantia nigra. Further analysis of the cell lines identified a number of expressed trophic factors, providing a plausible explanation for the effects observed in vivo. The exact mechanisms by which the implanted human neural cell lines provide behavioral improvements in the PD model are not completely understood; however, these findings provide evidence that cell therapy can be a potent treatment for PD acting through a mechanism independent of dopaminergic neuronal cell replacement.
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PMID:Implantation of c-mycER TAM immortalized human mesencephalic-derived clonal cell lines ameliorates behavior dysfunction in a rat model of Parkinson's disease. 1855 88

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) caused by an abnormal rate of apoptosis. Endogenous stem cells in the adult mammalian brain indicate an innate potential for regeneration and possible resource for neuroregeneration in PD. We previously showed that guanosine prevents apoptosis even when administered 48 hr after the toxin 1-methyl-4-phenylpyridinium (MPP(+)). Here, we induced parkinsonism in rats with a proteasome inhibitor. Guanosine treatment reduced apoptosis, increased tyrosine hydroxylase-positive dopaminergic neurons and expression of tyrosine hydroxylase in the SNc, increased cellular proliferation in the SNc and subventricular zone, and ameliorated symptoms. Proliferating cells in the subventricular zone were nestin-positive adult neural progenitor/stem cells. Fibroblast growth factor-2-expressing cells were also increased by guanosine. Thus, guanosine protected cells from apoptosis and stimulated "intrinsic" adult progenitor/stem cells to become dopaminergic neurons in rats with proteasome inhibitor-induced PD. The cellular/molecular mechanisms underlying these effects may open new avenues for development of novel therapeutics for PD.
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PMID:Guanosine improves motor behavior, reduces apoptosis, and stimulates neurogenesis in rats with parkinsonism. 1881 92

In addition to increasing insulin sensitivity and adipogenesis, peroxisome proliferator-activated receptor (PPAR)-gamma agonists cause weight gain and hyperphagia. Given the central role of the brain in the control of energy homeostasis, we sought to determine whether PPARgamma is expressed in key brain areas involved in metabolic regulation. Using immunohistochemistry, PPARgamma distribution and its colocalization with neuron-specific protein markers were investigated in rat and mouse brain sections spanning the hypothalamus, the ventral tegmental area, and the nucleus tractus solitarius. In several brain areas, nuclear PPARgamma immunoreactivity was detected in cells that costained for neuronal nuclei, a neuronal marker. In the hypothalamus, PPARgamma immunoreactivity was observed in a majority of neurons in the arcuate (including both agouti related protein and alpha-MSH containing cells) and ventromedial hypothalamic nuclei and was also present in the hypothalamic paraventricular nucleus, the lateral hypothalamic area, and tyrosine hydroxylase-containing neurons in the ventral tegmental area but was not expressed in the nucleus tractus solitarius. To validate and extend these histochemical findings, we generated mice with neuron-specific PPARgamma deletion using nestin cre-LoxP technology. Compared with littermate controls, neuron-specific PPARgamma knockout mice exhibited dramatic reductions of both hypothalamic PPARgamma mRNA levels and PPARgamma immunoreactivity but showed no differences in food intake or body weight over a 4-wk study period. We conclude that: 1) PPARgamma mRNA and protein are expressed in the hypothalamus, 2) neurons are the predominant source of PPARgamma in the central nervous system, although it is likely expressed by nonneuronal cell types as well, and 3) arcuate nucleus neurons that control energy homeostasis and glucose metabolism are among those in which PPARgamma is expressed.
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PMID:Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis. 1884 32


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