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)

Intraperitoneal injection of GM1 ganglioside or intracerebroventricular infusion of basic fibroblast growth factor (FGF-2) or epidermal growth factor (EGF) partially restored dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum of young MPTP-treated mice. Combined treatments of GM1 ganglioside with FGF-2 or EGF produced a greater restoration of striatal dopamine levels than treatments with GM1 or either of the neurotrophic factors alone. GM1 treatment, but not trophic factor treatments caused significant sparing of substantia nigra pars compacta (SNc) tyrosine hydroxylase (TH)-positive neurons. These results confirm previous findings that GM1 provides trophic support for damaged dopamine neurons and suggests that GM1, FGF-2, and EGF may also enhance dopaminergic function in residual neurons. The results also suggest that a potentially fruitful approach to treating degenerative disorders of the dopamine system may be the use of combined trophic factor therapies.
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PMID:Enhanced restoration of striatal dopamine concentrations by combined GM1 ganglioside and neurotrophic factor treatments. 779 5

The neurotoxic effect of glutamate in cultured mouse mesencephalic dopaminergic neurons was investigated. Neuron-rich cell cultures were prepared from 13-14-day-old fetal mouse ventral mesencephalic tissue. Cultures were exposed to glutamate for 10 min and evaluated for glutamate neurotoxicity (GNT) 18-24 hr later by tyrosine hydroxylase (TH) immunostaining, microtubule associated protein-2 (MAP2) immunostaining, and radiolabeled dopamine uptake assay. In glutamate-exposed cultures, the number of TH-positive neurons and the level of dopamine uptake were reduced to 40% (35-45%) and 50% (47-52%), respectively, of control cultures. The number of MAP2-positive neurons was also reduced to 47%, indicating that the GNT was not restricted or selective to dopaminergic neurons. It is concluded that GNT was mediated by the N-methyl-D-aspartic acid (NMDA) receptor from the following observations: 1) GNT was completely blocked by MK-801, an NMDA receptor antagonist; 2) NMDA itself was as toxic as glutamate; 3) 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate (AMPA/KA) receptor, did not block GNT; 4) kainate did not show neurotoxicity at a low concentration; and 5) two modulators of the NMDA receptor, 7-chlorokynurenic acid and magnesium, were effective in blocking GNT. Protective effects of phorbol myristate acetate, a tumor promoter, and gangliosides (GM1 and GT1b) on GNT were also demonstrated. Possible interactions between GNT and several protein kinase cascades were also investigated. Forskolin, an activator of adenyl cyclase and protein kinase A, showed some protective effect on GNT. But okadaic acid, an inhibitor of phosphatases, and genistein, a tyrosine kinase inhibitor, did not show any protective effect. These results suggest that 1) glutamate is capable of causing neuronal death in the substantia nigra; 2) GNT on dopaminergic neurons is mainly mediated by the NMDA receptor under the conditions of our study; 3) protein kinase C translocation is a key mechanism of GNT; and 4) there is an interplay of a signal transduction system in the pathomechanism of GNT.
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PMID:Glutamate neurotoxicity in mesencephalic dopaminergic neurons in culture. 790 39

GM1 ganglioside is believed to be important in promoting the recovery of neurons from injury. The present study assesses the ability of GM1 to repair or prevent the damage of dopamine neurons caused by the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Treatment of mesencephalic cell cultures with 2.5 microM MPP+ resulted in the loss of 30% of tyrosine hydroxylase (TH) immunoreactive neurons. In contrast, cultures administered 100 microM GM1 ganglioside for 3 days after toxin treatment contained nearly control numbers of TH+ neurons (97%). This reparative effect of GM1 was reflected in parallel increases in TH enzyme activity, dopamine and dopac levels. Cultures sustaining greater insult from higher doses of MPP+ (5.0-10.0 microM) did not benefit from ganglioside treatment, suggesting that rescue by GM1 depended on the degree of initial damage to cells. Moreover, the timing of ganglioside treatment was critical; pretreatment with GM1 alone did not prevent or attenuate the damage caused by subsequent incubation in 2.5 microM MPP+.
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PMID:GM1 ganglioside partially rescues cultured dopaminergic neurons from MPP(+)-induced damage: dependence on initial damage and time of treatment. 791 28

The weaver mutation in the mouse is a developmental disorder characterized by cerebellar atrophy as well as decreased numbers of substantia nigra dopaminergic neurons and a striatal dopamine loss. Since the nigrostriatal dopamine loss occurs postnatally, the present study was performed to determine whether early intervention with GM1 ganglioside could alter the extent of this dopamine loss. Weaver mice that received injections of GM1 ganglioside (30 mg/kg) daily, beginning at 7-10 days of age, had significantly higher striatal dopamine levels and significantly more tyrosine hydroxylase-positive substantia nigra pars compacta neurons than weaver mice that received only daily saline injections. These results show that GM1 treatment can alter at least some aspects of this inherited developmental disorder. If the weaver defect is related to a deprivation of trophic support for certain midbrain dopaminergic neurons, the presence of GM1 may be able to enhance the survival of these neurons.
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PMID:GM1 ganglioside treatment partially reverses the nigrostriatal dopamine defect in the weaver mutant mouse. 791 61

Parkinson's disease is characterized by the degeneration of melanized dopaminergic neurons of the substantia nigra. The functional capacity of the surviving dopaminergic neurons is affected, as suggested by the subnormal levels of tyrosine hydroxylase messenger RNA and protein found in the remaining cells. The reduced expression of tyrosine hydroxylase may be due to either the evolving neurodegenerative process or its downregulation, possibly secondary to chronic levodopa treatment. The cellular content of tyrosine hydroxylase was determined in the mesencephalon from 16 Macaca fascicularis monkeys, using a semiquantitative immunocytochemical method. Thirteen monkeys were rendered parkinsonian by weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 2 (subacute treatment) or 20 (chronic treatment) weeks. Three of the monkeys received levodopa and 3 others received GM1 ganglioside. The loss of dopaminergic neurons in the mesencephalon of the MPTP-intoxicated monkeys was severe in the substantia nigra, intermediate in cell groups A8 and A10, and almost undetectable in the central gray substance. After both subacute and chronic treatment, the cellular content of tyrosine hydroxylase was reduced by 40% in the surviving neurons of the lesioned substantia nigra, but by less in the other mesencephalic dopaminergic regions. Neuronal survival and tyrosine hydroxylase content in monkeys that had received levodopa were not significantly different. The cellular content of tyrosine hydroxylase was increased in the substantia nigra of the monkeys that received GM1 ganglioside injections. The results show that the decreased expression of tyrosine hydroxylase found in nigral dopaminergic neurons after partial degeneration of the mesostriatal dopaminergic system is not influenced by levodopa treatment and is partially reversed by GM1 ganglioside administration.
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PMID:Decreased tyrosine hydroxylase content in the dopaminergic neurons of MPTP-intoxicated monkeys: effect of levodopa and GM1 ganglioside therapy. 791 99

Brain-derived neurotrophic factor (BDNF) supports the survival of sensory neurons as well as retinal ganglion cells, basal forebrain cholinergic neurons, and mesencephalic dopaminergic neurons in vitro. Here we examined the ability of BDNF to confer protection on cultured dopaminergic neurons against the neurotoxic effects of 6-hydroxyDOPA (TOPA or 2,4,5-trihydroxyphenylalanine), a metabolite of the dopamine pathway suggested to participate in the pathology of Parkinson's disease. Cells prepared from embryonic day 14-15 rat mesencephalon were maintained with 10-50 ng/ml BDNF for 7 days prior to addition of TOPA (10-30 microM) for 24 hr. In BDNF-treated cultures, the extensive loss (> 90%) of tyrosine hydroxylase immunopositive cells was virtually (< 10%) eliminated, while the equally drastic loss (> 90%) of the overall cell population was limited to only a 25-30% recovery. Furthermore, the monosialoganglioside GM1 (1-10 microM), although inactive alone, acted synergistically with subthreshold amounts of BDNF to rescue tyrosine hydroxylase-positive cells against TOPA neurotoxicity. These results add impetus to exploring the therapeutic potential of gangliosides and BDNF in Parkinson's disease.
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PMID:Brain-derived neurotrophic factor selectively rescues mesencephalic dopaminergic neurons from 2,4,5-trihydroxyphenylalanine-induced injury. 809 67

Rat embryonic mesencephalic cultures were employed to evaluate the consequences of adding GM1 ganglioside to cultures lesioned with the selective neurotoxin 1-methyl-4-phenylpyridinium (MPP+). MPP+ reduced dopamine and DOPAC content, dopamine uptake, aromatic L-amino acid decarboxylase activity, and the number of tyrosine hydroxylase-immunopositive neurons. The immunopositive neurons that remained were aberrant. All of these parameters were partially restored by adding GM1 ganglioside to the cultures. The response to GM1 was not altered by prior treatment of the cultures with cytosine beta-D-arabinofuranoside to reduce the number of glial cells. Dopamine uptake activity restored by GM1 was lost if GM1 was removed from the culture.
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PMID:GM1 ganglioside improves dopaminergic markers of rat mesencephalic cultures treated with MPP+. 810 Dec 12

By means of light and confocal laser microscopical analysis of choleratoxin (CT) binding sites indicating the localization of the ganglioside GM1, evidence has been obtained for the presence of ganglioside GM1 in discrete nerve terminals, some of them identified by synapsin-1 immunoreactivity (IR), with a focal distribution in the nerve terminal membrane. Double immunolabelling studies demonstrate that GM1 positive nerve terminals are associated with tyrosine hydroxylase/fibroblast growth factor-2 (TH/FGF-2) immunoreactive dopamine (DA) perikarya in the zona compacta of the rat substantia nigra. It is suggested that GM1 may be released from these terminals to become incorporated into the nerve cell membrane of the FGF-2-containing DA nigral nerve cells, where they may enhance the activity of neurotrophic factor receptors such as those for FGF-2.
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PMID:Codistribution of choleratoxin binding sites and tyrosine hydroxylase/FGF-2 immunoreactive nigral nerve cells. 810 82

Brain-derived neurotrophic factor (BDNF) has recently been shown to enhance the survival of dopaminergic neurons in cultures derived from the embryonic rat mesencephalon. In the present study BDNF was found to protect cultured dopaminergic neurons from injury induced by acute exposure to the dopaminergic-selective neurotoxin 6-hydroxydopamine. The BDNF effect was concentration (ED50 approximately 10 ng/ml) and time-dependent, as determined by tyrosine hydroxylase immunocytochemistry. More importantly, subthreshold amounts of BDNF were rendered efficacious in the presence of ganglioside GM1: loss of tyrosine hydroxylase positive cells was reduced from 80% to only 20%. Thus GM1 may provide a fruitful treatment strategy for disorders of dopamine function such as Parkinson's disease.
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PMID:Ganglioside GM1 cooperates with brain-derived neurotrophic factor to protect dopaminergic neurons from 6-hydroxydopamine-induced degeneration. 826 58

The protective effect of GM1 ganglioside against nerve cell death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was analyzed in monkey mesencephalon. Administration of GM1 before and during MPTP treatment improved motor performances compared with MPTP-treated animals that received saline rather than GM1. Postmortem analysis revealed that GM1 did not protect dopaminergic cell bodies from MPTP intoxication but resulted in an increased immunoreactivity of tyrosine hydroxylase in the perikarya and processes of the surviving neurons. These data suggest that GM1 may be potentially used as a palliative rather than a curative therapy in Parkinson's disease.
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PMID:Gangliosides and parkinsonism. 841 79


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