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)

Effects of a single injection of either 150 micrograms human recombinant glial cell line-derived neurotrophic factor (rGDNF) or vehicle into the right substantia nigra were analyzed in 12 normal adult female rhesus monkeys. The studies included evaluating whole animal behavior, electrochemical recordings of striatal dopamine release, neurochemical determinations of basal ganglia and nigral monoamine levels, and immunohistochemical staining of the nigrostriatal dopamine system. The behavioral effects over the 3-week observation period following trophic factor administration were small, with blinded observers unable to distinguish between GDNF- and vehicle-treated animals. Quantitative measurements did show that five of six trophic factor recipients experienced some weight loss and four of the six GDNF recipients displayed small, but significant, increases in daytime activity levels. In vivo electrochemical recordings in the ipsilateral caudate and putamen 3 weeks after GDNF administration revealed increased potassium-evoked release of dopamine in trophic factor recipients. In a second series of animals killed at the same time, dopamine levels in the substantia nigra and ventral tegmental area of GDNF recipients were significantly increased, with ipsilateral values more than 200% higher than contralateral and control levels. Levels of the dopamine metabolite HVA were significantly elevated in the substantia nigra, ventral tegmental area, and caudate nucleus ipsilateral to the trophic factor injection. There was a trend toward increased HVA levels in the ipsilateral putamen, nucleus accumbens, and globus pallidus in GDNF-treated animals, but the ratios of HVA to dopamine were not significantly different between vehicle- and GDNF-treated recipients. Although some tissue damage from the delivery of concentrated trophic factor was evident, dopamine neurons remained in an adjacent to the injection site. In the substantia nigra ipsilateral to GDNF administration, dopamine-neuron perikaryal size was significantly increased, along with a significant increase in tyrosine hydroxylase-positive axons and dendrites. We conclude that, in the adult rhesus monkey, a single intranigral GDNF injection induces a significant upregulation of mesencephalic dopamine neurons which lasts for weeks.
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PMID:Morphological and functional effects of intranigrally administered GDNF in normal rhesus monkeys. 884 4

Glial cell line-derived neurotrophic factor (GDNF) is a highly selective neurotrophic factor for midbrain dopaminergic neurons and might thus be of potential use in the therapy of Parkinson's disease. In this study, we present evidence that the survival-promoting action of GDNF on dopaminergic neurons requires the concurrent activation of cAMP-dependent signaling pathways. In serum-free low density cultures of the dissociated embryonic day 15 mesencephalon, dopaminergic neurons undergo constant cell death as evidenced by a 90% reduction in tyrosine hydroxylase-immunoreactive (TH-IR) cell numbers between days 1 and 9 of cultivation. This decline was not affected by GDNF (5 ng/ml) within the initial 3 days of cultivation, but was in part attenuated with prolonged treatment. In contrast, stimulation of 3-day-old mesencephalic cultures with GDNF induced c-fos expression in 73% of all TH-IR neurons, indicative for the early presence of efficient signal-transduction coupling in these neurons. Combined treatment of mesencephalic cultures with dibutyryl cyclic AMP (dbcAMP; 100 microM) and GDNF accelerated the onset of the survival effects of GDNF on dopaminergic neurons, resulting in a 1.5-fold increase in the number of surviving TH-IR neurons at 3 days in vitro. In addition, activation of cAMP-dependent signal pathways significantly potentiated the survival-promoting effects of GDNF on dopaminergic neurons in older cultures. dbcAMP alone had no effect on dopaminergic cell survival. Taken together, our findings suggest that the action of GDNF on midbrain dopaminergic neurons is modulated by other extracellular signals.
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PMID:Effects of glial cell line-derived neurotrophic factor (GDNF) on dopaminergic neurons require concurrent activation of cAMP-dependent signaling pathways. 885 92

Intraparenchymal injections of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle in rats destroys the dopaminergic neurons in the pars compacta of the substantia nigra. In other transmitter systems it has been found that axotomy or neurotoxin exposure produces an initial loss of neurotransmitter phenotype, with cell death occurring over a much slower time course. To determine whether this also occurs in dopamine neurons after 6-OHDA, two approaches were utilized. First, the effect of injections of 6-OHDA into the medial forebrain bundle on nigral dopaminergic neurons was studied using combined fluorogold and immunocytochemical labeling. Four weeks after the 6-OHDA injection, there was an 85% reduction in the number of tyrosine hydroxylase (TH)-immunoreactive cells on the lesioned side. In contrast, there was only a 50% reduction in the number of fluorogold-labeled cells on the lesioned side. Second, the time course of the rescue of dopaminergic neurons after 6-OHDA by glial cell line-derived neurotrophic factor (GDNF) was determined using TH immunocytochemistry. Greater numbers of dopamine neurons were rescued 9 weeks after GDNF, compared with counts made 5 weeks after GDNF. Taken together, these results suggest loss of dopaminergic phenotype is greater than cell loss following 6-OHDA injections, and that GDNF restores the phenotype of affected cells.
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PMID:6-hydroxydopamine induces the loss of the dopaminergic phenotype in substantia nigra neurons of the rat. A possible mechanism for restoration of the nigrostriatal circuit mediated by glial cell line-derived neurotrophic factor. 889 30

Growth of mouse neural crest cultures in the presence of glial cell line-derived neurotrophic factor (GDNF) resulted in a dramatic dose-dependent increase in the number of tyrosine hydroxylase (TH)-positive cells that developed when 5% chicken embryo extract was present in the medium. In contrast, growth in the presence of bone morphogenetic protein (BMP)-2, BMP-4, BMP-6, transforming growth factor (TGF) beta 1, TGF-beta 2, and TGF-beta 3 elicited no increase in the number of TH-positive cells. The TH-positive cells that developed in the presence of GDNF had neuronal morphology and contained the middle and low molecular weight neurofilament proteins. Numerous TH-negative cells with the morphology of neurons also were observed in GDNF-treated cultures. Analysis revealed that the period from 6 to 12 days in vitro was the critical time for exposure to GDNF to generate the increase in TH-positive cell number. The growth factors neurotrophin-3 and fibroblast growth factor-2 elicited increases in the number of TH-positive cells similar to that seen in response to GDNF. In contrast, nerve growth factor was unable to substitute for GDNF. These findings extend the previously reported biological activities of GDNF by showing that it can act on mouse neural crest cultures to promote the development of neurons.
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PMID:Glial cell line-derived neurotrophic factor promotes the development of adrenergic neurons in mouse neural crest cultures. 891 81

The neostriatum is one of the areas with relatively high levels of glial cell line-derived neurotrophic factor (GDNF) messenger RNA expression in the developing and adult brain. GDNF expression in the neostriatum has been suggested to be involved in promoting the survival of nigral dopaminergic neurons, acting as a target-derived neurotrophic factor. However, GDNF messenger RNA expression in the striatum starts several days before dopaminergic and other afferent neurons reach the striatum, suggesting additional trophic effects of this factor on striatal neurons. In the present report, we have examined whether GDNF is able to prevent the degeneration of striatal calbindin- and parvalbumin-immunoreactive neurons in a lesion model of Huntington's disease. Fischer 344 rat 3T3 fibroblast cell line expressing high levels of GDNF (F3A-GDNF) was used to assess the protective effect of this factor, on striatal neurons, against excitotoxicity. Quinolinate (34 nmol) was injected at two different coordinates, and calbindin, parvalbumin and tyrosine hydroxylase immunoreactivity were examined seven days after lesion. Dopaminergic afferents were spared after quinolinate injection, but the number of calbindin- and parvalbumin-immunoreactive neurons was decreased. Interestingly, implantation of F3A-GDNF cells increased the density of tyrosine hydroxylase staining in the intact and also in the quinolinate-lesioned striatum. Furthermore, GDNF partially protected calbindin- but not parvalbumin-immunoreactive neurons from quinolinate excitotoxicity. Instead, mock-transfected fibroblasts did not affect any of these parameters. Our results show that GDNF specifically protects a subpopulation of striatal calbindin-immunoreactive neurons against quinolinate lesion, suggesting that GDNF administration may have a potential therapeutic application in the prevention and treatment of striatonigral degenerative disorders.
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PMID:Glial cell line-derived neurotrophic factor protects striatal calbindin-immunoreactive neurons from excitotoxic damage. 893 Oct 1

The ability of transplants of fetal nigral neurons to reverse symptoms in patients with Parkinson's disease is, at least in part, limited by the poor survival of the grafted dopaminergic neurons and the restricted host reinnervation from the graft. Here, we report that glial cell line-derived neurotrophic factor, a novel trophic factor for developing dopaminergic neurons, can increase survival and fibre outgrowth of fetal nigral dopaminergic neurons, and stimulate graft-induced functional recovery after transplantation in a rat model of Parkinson's disease. Injections of rat glial cell line-derived neurotrophic factor adjacent to the graft enhanced graft function, resulting in complete compensation of amphetamine-induced turning behaviour already by two weeks postgrafting as opposed to four weeks in the control group. The total number of surviving tyrosine hydroxylase-positive neurons was about two-fold greater in the glial cell line-derived neurotrophic factor-treated animals compared to the vehicle-injected controls, and the density of tyrosine hydroxylase-positive fibres was found to be increased both in the host striatum (from 37.6 +/- 8.3% to 105.5 +/- 9.7% of intact striatum) as well as inside the graft (55% increase). Moreover, in animals treated with glial cell line-derived neurotrophic factor, the outgrowth of tyrosine hydroxylase-positive fibres was mostly directed towards the injection site. These findings show that supply of exogenous glial cell line-derived neurotrophic factor to the transplantation site improves survival, growth and function of transplanted fetal nigral dopaminergic neurons in the rat Parkinson model.
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PMID:Glial cell line-derived neurotrophic factor increases survival, growth and function of intrastriatal fetal nigral dopaminergic grafts. 893 33

Parkinson's disease (PD) is characterized by the progressive loss of the substantia nigra (SN) dopaminergic neurons projecting to the striatum. Neurotrophic factors may have the potential to prevent or slow down the degenerative process occurring in PD. To that end, we examined whether low amounts of glial cell line-derived neurotrophic factor (GDNF) continuously released from polymer-encapsulated genetically engineered cells are able to prevent the loss of tyrosine hydroxylase immunoreactivity (TH-IR) in SN neurons and ameliorate the amphetamine-induced rotational asymmetry in rats that have been subjected to a unilateral medial forebrain bundle (MFB) axotomy. Baby hamster kidney (BHK) cells transfected with the cDNA for GDNF were encapsulated in a polymer fiber and implanted unilaterally at a location lateral to the MFB and rostral to the SN. ELISA assays before implantation show that the capsules release approximately 5 ng of GDNF/capsule per day. One week later, the MFB was axotomized unilaterally ipsilateral to the capsule placement. Seven days later, the animals were tested for amphetamine-induced rotational asymmetry and killed. The striatum was excised and analyzed either for catecholamine content or TH-IR, while the SN was immunostained for the presence of TH-IR. GDNF did not prevent the loss of dopamine in the striatum. However, GDNF significantly rescued TH-IR neurons in the SN pars compacta. Furthermore, GDNF also significantly reduced the number of turns per minute ipsilateral to the lesion under the influence of amphetamine. Improvement of rotational behavior in the absence of dopaminergic striatal reinnervation may reflect neuronal plasticity in the SN, as suggested by the dendritic sprouting observed in animals receiving GDNF. These results illustrate that the continuous release of low levels of GDNF close to the SN is capable of protecting the nigral dopaminergic neurons from an axotomy-induced lesion and significantly improving pharmacological rotational behavior by a mechanism other than dopaminergic striatal reinnervation.
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PMID:GDNF reduces drug-induced rotational behavior after medial forebrain bundle transection by a mechanism not involving striatal dopamine. 898 58

Glial cell line-derived neurotrophic factor (GDNF) is a member of the TGF-beta superfamily of growth factors with neurotrophic activity on midbrain dopaminergic neurons and on developing and mature motoneurons of the brainstem and spinal cord. To investigate the extent of GDNF dependency of central and peripheral nervous structures during development, we have performed an immunohistochemical analysis of sections from the whole head including brain, peripheral ganglia, developing teeth and tongue, as well as intestines, in mutant mice lacking a part of the third exon that encodes the GDNF protein. As described previously, these null-mutated mice lack most of the enteric nerve plexus and are subject to agenesis or severe dysgenesis of the kidneys. In the present communication, we examined the development of vibrissae and incisor and molar teeth, as well as the innervation of these structures, and found no differences between null-mutated and control mice. A decrease in the immunohistochemical labeling intensity with tyrosine hydroxylase was observed in the superior cervical ganglion (SCG), as well as in the pontine nucleus locus coeruleus, and the sympathetic innervation of blood vessels and glands in the head was significantly decreased. None of the brain nuclei studied exhibited any significant decreases in the total number of neurons, but the packing density of neurons in the nucleus locus coeruleus was decreased. These data indicate that GDNF might be one neurotrophic factor that contributes to the development of central and peripheral noradrenergic neurons.
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PMID:Morphological alterations in the peripheral and central nervous systems of mice lacking glial cell line-derived neurotrophic factor (GDNF): immunohistochemical studies. 899 69

Glial cell line-derived neurotrophic factor has been shown to affect dopaminergic and cholinergic neuron markers and functions in young rats. However, it is not known if the response to exogenous glial cell line-derived neurotrophic factor is augmented during normal aging. Thus, the effects of chronic intraventricular infusions of glial cell line-derived neurotrophic factor were determined in young adult (three-months-old) and aged (24-months-old) Fischer 344 (F344) male rats. The effects of glial cell line-derived neurotrophic factor were compared to the effects of the neurotrophin nerve growth factor. Growth factors were administered at a dose of 10 mg/day for 14 days. Locomotor activity and weight changes were also examined in all rats. Aged F344 rats showed significantly reduced (by 75-80%) locomotor activity compared to young rats. In glial cell line-derived neurotrophic factor-treated aged and young rats there was significantly increased (242% and 149%, respectively) locomotor activity measured at seven days. There was also a significant increase in locomotor activity measured 14 days after the start of infusion. Both glial cell line-derived neurotrophic factor and nerve growth factor reduced weight gain by 10% in young and old F344 rats. Two weeks following the start of nerve growth factor or glial cell line-derived neurotrophic factor administration the brains were used for neurochemical analyses. Glial cell line-derived neurotrophic factor significantly increased tyrosine hydroxylase activity in the substantia nigra and striatum of aged rats and in the substantia nigra of young rats. Nerve growth factor treatment did not significantly affect tyrosine hydroxylase activity. However, glial cell line-derived neurotrophic factor and nerve growth factor increased choline acetyltransferase activity in the septum, hippocampus, striatum and cortex of aged rats and in the hippocampus and striatum of young rats to a comparable degree. These findings indicate that specific dopaminergic and cholinergic neuron populations remain responsive to glial cell line-derived neurotrophic factor during the life span of the rat and may be involved in maintaining phenotypic expression within multiple neuronal populations. Additionally, the glial cell line-derived neurotrophic factor-induced up-regulation of brain neurotransmitter systems may be responsible for increased locomotor activity in F344 rats.
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PMID:Glial cell line-derived neurotrophic factor induces the dopaminergic and cholinergic phenotype and increases locomotor activity in aged Fischer 344 rats. 907 Jul 49

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor which has been purified on the basis of its ability to promote the survival of dopaminergic neurons in vitro. GDNF has subsequently been cloned and its sequence shown to be distantly related to transforming growth factor-beta (TGF-beta). To identify GDNF expressing cells in the adult rat brain, in situ hybridization using a digoxygenin (DIG)-labelled riboprobe has been performed. Our results show that GDNF mRNA is mainly expressed in neurons and that its synthesis is not restricted to dopaminergic areas. It is widely expressed in the cortex, the hippocampus, the striatum, the substantia nigra, the thalamus, the cerebellum and the spinal cord. Neuronal GDNF expression varies among brain regions as determined by the intensity of the in situ signal. Double labelling of the substantia nigra using tyrosine hydroxylase immunohistochemistry, associated with GDNF in situ hybridization, show that the majority of dopaminergic neurons express GDNF. The widespread expression of GDNF throughout the adult brain suggests that its administration in Parkinson's disease should be restricted to the altered structures, in order to avoid possible deleterious side effects.
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PMID:Neuronal GDNF expression in the adult rat nervous system identified by in situ hybridization. 910 88


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