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)

Previous research has shown an increase in tyrosine hydroxylase in the ventral tegmental area following chronic morphine and chronic cocaine treatments. Chronic morphine treatment also increases levels of glial fibrillary acidic protein in this brain region. In the present study, we investigated the effects of infusing neurotropic factors (nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4 or ciliary neurotrophic factor) via midline intra-ventral tegmental area cannulae on these biochemical changes. Our studies examined the effects of neurotrophic factor infusion alone, neurotrophic factor infusion followed by morphine treatment, morphine treatment followed by neurotrophic factor infusion, and concurrent neurotrophic factor infusion and cocaine treatment. Brain-derived neurotrophic factor, which by itself tended to decrease tyrosine hydroxylase levels in the ventral tegmental area, prevented the characteristic increase in tyrosine hydroxylase following morphine and cocaine exposure and reversed the increase in rats pretreated with morphine. Neurotrophin-4 and neurotrophin-3 exerted similar effects. In addition, neurotrophin-4 prevented the morphine-induced increase in glial fibrillary acidic protein. In contrast, ciliary neurotrophic factor infusions alone resulted in an increase in tyrosine hydroxylase levels, with no additional increase induced by morphine or cocaine coadministration. Nerve growth factor alone had no effect on tyrosine hydroxylase or glial fibrillary acidic protein levels and did not affect morphine's ability to induce these proteins. We also looked at the effects of intra-ventral tegmental area infusion of neurotrophic factor on cAMP-dependent protein kinase and adenylyl cyclase activity in the nucleus accumbens, both of which are increased by chronic morphine or cocaine exposure. In general, regulation of cAMP-dependent protein kinase and adenylyl cyclase morphine by neurotrophic factors paralleled effects seen in the ventral tegmental area. Intra-ventral tegmental area infusion of brain-derived neurotrophic factor (or neurotrophin-4) alone tended to decrease cAMP-dependent protein kinase and adenylyl cyclase activity in the nucleus accumbens and prevented the morphine-induced increases in these enzymes. These effects were not seen with ciliary neurotrophic factor or nerve growth factor. These studies demonstrate novel interactions within the ventral tegmental area, and its target the nucleus accumbens, between neurotrophic factors and drugs of abuse, which have potentially important implications for the pathophysiology and treatment of drug addiction.
 ...
PMID:Influence of neurotrophic factors on morphine- and cocaine-induced biochemical changes in the mesolimbic dopamine system. 854 3

Growth factors are considered pivotal for the development, maintenance, and function of mesencephalic dopaminergic neurons. Recent studies have identified a plethora of growth factors which support the survival and differentiation of embryonic dopaminergic neurons. However, the exact cellular targets of these growth factors, and, thus, their precise mechanisms of action, remain largely unknown. To identify these cellular targets, we analysed, at the single cell level, growth factor-induced c-fos expression in dissociated mesencephalic cell cultures derived from a fos-lac Z transgenic mouse line. Pharmacological interference with cell-cell communication was utilized to control for direct growth factor effects. beta-Galactosidase-expressing cells were phenotypically characterized by immunocytochemistry to specific neural cell markers. Glia cell line-derived neurotrophic factor, basic fibroblast growth factor, brain-derived neurotrophic factor, and neurotrophin-3 directly induced Fos expression in differently sized, yet overlapping, populations of tyrosine hydroxylase-immunoreactive dopaminergic neurons. In an additional subpopulation of dopaminergic neurons, neurotrophin-3 induced fos-lac Z expression indirectly through a glutamate-mediated activation of N-methyl-D-aspartate receptors. Consistent with their proposed glial-mediated mode of action, transforming growth factor alpha and platelet-derived growth factor induced Fos expression predominantly in glia but only in a very small number of dopaminergic neurons. These findings demonstrate that individual dopaminergic neurons represent the direct targets of different sets of extracellular growth factors. Our findings further establish that growth factors affect dopaminergic neurons by indirect mechanisms which require specific cell-cell communication. These data also suggest a potential role for growth factors in the establishment of the morphological and functional diversity of midbrain dopaminergic neurons.
 ...
PMID:Growth factor-induced c-fos expression defines distinct subsets of midbrain dopaminergic neurons. 878 57

Our previous studies have shown that primary mesencephalic glia secrete factors that promote dopaminergic cell survival and differentiation in vitro. To obtain enough starting material to identify the neurotrophic activity, embryonic day (E)14.5 rat mesencephalic glia were stimulated with acidic fibroblast growth factor to increase number of cells. These cells were replated in the absence of neurons and immortalized by transfection with the SV 40 large T-antigen. Clonal cell lines were established and characterized for immunoreactivity (IR) to various glial and non-glial markers. Media conditioned by these cell lines were tested for survival-promoting effects on dopaminergic neurons in serum-free cultures of the dissociated E14.5 rat mesencephalon. All cell lines expressed IR for the astrocytic marker, GFAP, the oligodendroglial marker, CNP, and for A2B5, a marker for O-2A progenitor cells, but were negative for the neuronal marker, microtubule associated protein-2, and the fibroblast marker, fibronectin. Moreover, treatment of serum-free cultures of the dissociated E14.5 mesencephalon with glial cell line-CM conditioned medium (CM) delayed dopaminergic cell death in a dose-dependent manner, resulting in a maximal twofold to sixfold increase in the number of surviving tyrosine hydroxylase-IR neurons at various days in vitro. This increase in dopaminergic cell survival was not mimicked by GDNF, BDNF or NT-3 within the initial 3 days of cultivation. Moreover, initial biochemical characterization demonstrated that the neurotrophic activity is restricted to the high MW fraction of >50 kD of glial cell line-CM. Since the apparent MW of this factor exceeds the size of most known growth factors, it may represent a novel dopaminergic neurotrophic factor.
 ...
PMID:Evidence for a novel neurotrophic factor for dopaminergic neurons secreted from mesencephalic glial cell lines. 883 92

The locus coeruleus (LC), the main noradrenergic center in the brain, participates in many neural functions, as diverse as memory and motor output, and is severely affected in several neurodegenerative disorders of the CNS. GDNF, a neurotrophic factor initially identified as dopaminotrophic, was found to be expressed in several targets of central noradrenergic neurons in the adult rat brain. Grafting of genetically engineered fibroblasts expressing high levels of GDNF prevented > 80% of the 6-hydroxydopamine-induced degeneration of noradrenergic neurons in the LC in vivo. Moreover, GDNF induced a fasciculated sprouting and increased by 2.5-fold both tyrosine hydroxylase levels and the soma size of lesioned LC neurons. These findings reveal a novel and potent neurotrophic activity of GDNF that may have therapeutic applications in neurodegenerative disorders affecting central noradrenergic neurons, such as Alzheimer's, Parkinson's, and Huntington's diseases.
 ...
PMID:GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo. 884 69

Previous reports have indicated that grafting of fetal ventral mesencephalic tissue to the nigra region of animals unilaterally lesioned with 6-hydroxydopamine (6-OHDA), in conjunction with kainate injection between the nigra and striatum, restores nigrostriatal tyrosine hydroxylase immunoreactivity. Glial-cell-line-derived neurotrophic factor (GDNF), a potent trophic factor for dopaminergic neurons, has been found to be upregulated by kainate. We have investigated the bridging effect of GDNF injection on intra-nigral transplants. Adult Sprague-Dawley rats were anesthetized and unilaterally injected with 6-OHDA into the medial forebrain bundle. The completeness of lesions was tested by measuring methamphetamine-induced rotations. Some 1-2 months after 6-OHDA administration, fetal ventral mesencephalic tissues were grafted into the lesioned nigral area followed by injection of 100 microg GDNF, along a tract from the nigra to striatum. Animals receiving transplantation and GDNF injection showed a significant decrease in rotation 1-3 months after grafting. Immunocytochemical studies indicated that tyrosine-hydroxylase-positive neurons and fibers were present in the nigra and striatum, respectively, after grafting. No effects of similarly injected brain-derived neurotrophic factor were seen. These results indicate that fetal nigral transplantation and GDNF injection restore the nigrostriatal dopaminergic pathway in Parkinsonian animals and support the hypothesis of trophic activity of GDNF on midbrain dopaminergic neurons.
 ...
PMID:GDNF triggers fiber outgrowth of fetal ventral mesencephalic grafts from nigra to striatum in 6-OHDA-lesioned rats. 885 91

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.
 ...
PMID:Effects of glial cell line-derived neurotrophic factor (GDNF) on dopaminergic neurons require concurrent activation of cAMP-dependent signaling pathways. 885 92

The present study examined the effects of encapsulated cells which were genetically modified to secrete human glail-derived neurotrophic factor (hGDNF) on the motor deficits in aged rodents. Prior to implantation, animals were tested on a battery of motor tasks. Spontaneous locomotion and motor coordination was evaluated in young (5 month) and aged (20 months) rats. Aged animals tested for spontaneous locomotor activity were found to be hypoactive relative to young animals. Compared to the young animals the aged animals also: (1) were impaired on a bar pressing task, (2) were unable to descend a wooden pole covered with wire mesh in a coordinated manner, (3) fell more rapidly from a rotating rod and (4) were unable to maintain their balance on a series of wooden beams of varying widths. Following baseline testing, aged animals received either no implant, encapsulated baby hamster kidney fibroblast cells that were modified to produce hGDNF (BHK-hGDNF) or encapsulated BHK cells which were not modified to produce hGDNF (BHK-Control) implanted bilaterally into the striatum. Following surgery, a significant increase in locomotor activity and bar pressing was observed in those aged animals receiving BHK-hGDNF implants. Bar pressing in aged animals receiving BHK-Control cells was improved to a lesser extent and reached the level of performance seen in young rats. No recovery was observed in the animals receiving BHK-Control cell-loaded capsules on any of the other motor tasks. Histological analysis revealed that implants of hGDNF-producing cells produced a marked increase in the density of tyrosine hydroxylase staining in the striatum adjacent to the implant site. This increased staining was not seen in animals receiving BHK-Control cells. Histological analysis also revealed the presence of viable BHK-hGDNF cells within the capsules that continued to produce hGDNF as measured by ELISA. These results indicate that polymer-encapsulated hGDNF-secreting cells survive following implantation into aged rats and may be useful for treating some of the behavioral consequences of aging or disorders characterized by dopaminergic hypofunction.
 ...
PMID:Alleviation of behavioral deficits in aged rodents following implantation of encapsulated GDNF-producing fibroblasts. 893 Mar 14

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.
 ...
PMID:Glial cell line-derived neurotrophic factor protects striatal calbindin-immunoreactive neurons from excitotoxic damage. 893 Oct 1

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.
 ...
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 (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.
 ...
PMID:Neuronal GDNF expression in the adult rat nervous system identified by in situ hybridization. 910 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>