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 parkinsonian syndrome can be produced in nonhuman primates by administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Parkinsonian-like symptoms induced acutely by MPTP were ameliorated after treatment with GM1 ganglioside, a substance shown to have neurotrophic effects on the damaged dopamine system in rodents. Treatment with GM1 ganglioside also increased striatal dopamine and metabolite levels and enhanced the dopaminergic innervation of the striatum as demonstrated by tyrosine hydroxylase immunohistochemistry. These results suggest that GM1 ganglioside may hold promise as a therapeutic agent for the treatment of Parkinson's disease.
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PMID:Recovery from experimental parkinsonism in primates with GM1 ganglioside treatment. 135 Mar 79

The neurotoxic properties of 2,4,5-trihydroxyphenylalanine (TOPA; the 6-hydroxylated derivative of dopa) was investigated in cultures of central neurons. Application of solutions of TOPA to cerebellar granule cells resulted in a concentration- and time-dependent neuronal death, with prolonged (24 hr) exposure producing a clear left-handed shift in the dose-response relationship from the one observed with a 60-min exposure (LD50: 4 and 29 microM, respectively). This toxicity was largely blocked by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Solutions of TOPA were also toxic to mesencephalic neurons after acute or chronic exposure, displaying the same leftward shift in LD50. This latter preparation contained a minor population of dopaminergic, tyrosine hydroxylase immunopositive cells which were likewise sensitive to the excitotoxic effects of TOPA. Neurotoxic activity of TOPA appeared to depend upon its oxidation in solution, as judged using chemical analysis and reducing agents. The monosialoganglioside GM1 was effective in protecting against neurodegeneration induced by brief or prolonged exposure to solutions of TOPA. These results suggest that an abnormal production or accumulation of TOPA or its oxidation product(s) might be involved in excitotoxicity directed to areas of the brain with dopaminergic innervation, and in other brain areas in Parkinson's disease patients on long-term dopa therapy. The selective action of gangliosides in disrupting the pathological consequences of glutamate receptor activation proposes their use as chemoprophylactic agents for preventing or arresting the neuronal losses accompanying such situations.
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PMID:Characterization of 2,4,5-trihydroxyphenylalanine neurotoxicity in vitro and protective effects of ganglioside GM1: implications for Parkinson's disease. 136 75

The effects of exogenous GM1 ganglioside on depolarization and ligand-induced Ca2+ signaling were investigated in PC12 cells. Cellular responses to K+ depolarization and bradykinin application in control and GM1-treated cells were examined with respect to: 1) changes in the intracellular Ca2+ concentration ([Ca2+]i) measured using fura-2 fluorescence in single cells, and 2) changes in Ca(2+)-dependent protein kinase activity as assayed by two-dimensional phosphopeptide analysis of the site-specific phosphorylation of tyrosine hydroxylase. Pretreatment of cells with GM1 (10 or 100 microM) enhanced K+ depolarization-stimulated increases in [Ca2+]i and in 32PO4 incorporation into tyrosine hydroxylase phosphopeptide T2, a Ca2+/calmodulin-dependent protein kinase II substrate. In contrast, GM1 treatment had no effect on the transient increases in [Ca2+]i evoked by bradykinin or on bradykinin-induced increases in the site-specific phosphorylation of tyrosine hydroxylase. The depolarization-induced and GM1-enhanced increases in [Ca2+]i and T2 phosphorylation were prevented by removal of external Ca2+ or pretreatment with 1 microM nitrendipine, suggesting that these increases result from Ca2+ entry through dihydropyridine-sensitive Ca2+ channels. The ability of exogenous gangliosides to potentiate increases in [Ca2+]i may underlie their diverse neuritogenic and neurotrophic actions in the nervous system.
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PMID:Modulation of a Ca2+ signaling pathway by GM1 ganglioside in PC12 cells. 144 16

We have investigated the ability of exogenous gangliosides to modulate nerve growth factor (NGF) signal transduction in PC12 cells. The effects of exogenous ganglioside GM1 on multiple protein kinase activities were assayed by analyzing site-specific serine phosphorylation of tyrosine hydroxylase (TyrOHase) by two-dimensional phosphopeptide mapping. In the presence of NGF, exogenous GM1 (1-10 microM) increased 32P incorporation into TyrOHase phosphopeptide T2, a Ca2+/calmodulin-dependent protein kinase substrate whose phosphorylation is not normally affected by NGF treatment. In the absence of NGF, GM1 treatment had no significant effects on TyrOHase phosphorylation. The removal of extracellular Ca2+ or blockade of dihydropyridine-sensitive Ca2+ channels prevented the GM1-induced increases in 32P incorporation into phosphopeptide T2. Exogenous GM1 also potentiated K+ depolarization-induced increases in the phosphorylation of TryOHase. These results suggest that the stimulatory effects of exogenous GM1 ganglioside on NGF actions may be due to its ability to potentiate a Ca(2+)-dependent signaling pathway.
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PMID:Stimulation of a Ca(2+)-dependent protein kinase by GM1 ganglioside in nerve growth factor-treated PC12 cells. 167 13

After 7 days of treatment with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), 30 mg/kg i.p., tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD) activities are decreased by more than 50% in the mouse striatum. Within 30 days, AAAD activity returns while TH activity remains depressed. TH activity can be restored to near normal by chronic treatment with GM1 ganglioside, 30 mg/kg i.p.
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PMID:Differential recovery of dopamine synthetic enzymes following MPTP and the consequences of GM1 ganglioside treatment. 197 54

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice results in the loss of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) from the mouse striatum and a loss of cells containing tyrosine hydroxylase (TH)-immunoreactivity from the substantia nigra. The cells that remained in the nigra after MPTP treatment were smaller in diameter than normal cells. Treatment with GM1 ganglioside beginning 24 h after establishing the MPTP lesion resulted in partial restoration of DA and DOPAC content in the striatum and an increase in the diameter of the TH-immunoreactive nigra cells. It appears, therefore, that treatment of MPTP-intoxicated mice with GM1 ganglioside results in the partial restoration of both the biochemistry and morphology of dopaminergic neurons.
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PMID:GM1 ganglioside-induced recovery of nigrostriatal dopaminergic neurons after MPTP: an immunohistochemical study. 256 52

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to young (2-3 months) and aging (12 months) C57BL/6 mice (4 x 20 mg/kg, i.p., given 12 h apart) reduced tyrosine hydroxylase (TH)-immunoreactive (IR) fibers in the striatum, and reduced dopamine (DA) concentration to 28% of controls in young, and 16% of controls in aging mouse brain five weeks after administration. Although GM1 ganglioside treatment (30 mg/kg, i.p., daily for 5 weeks) restored striatal dopamine concentration to 74% of the control concentration in young mice, such an apparent recovery was not seen in aging brain. Immunocytochemical analysis also showed marked recovery of TH-IR fibers in the striatum of MPTP-depleted young mice treated with GM1 ganglioside while TH-IR fibers in the striatum of MPTP-depleted aging mice showed no recovery with such treatment. We conclude that treatment of MPTP-depleted young mice with GM1 ganglioside results in partial recovery in the striatal DA system, but such benefits do not extend to aging mice.
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PMID:Exogenous GM1 gangliosides induce partial recovery of the nigrostriatal dopaminergic system in MPTP-treated young mice but not in aging mice. 260 83

The effect of GM1 ganglioside on the recovery of dopaminergic nigro-striatal neurons was studied in rats after unilateral hemitransection. GM1 treatment partially prevented the decrease of tyrosine hydroxylase (TH) activity caused by hemitransection in the substantia nigra ipsilateral to the lesion. Concomitantly a significant increase of TH-immunoreactivity in the substantia nigra was also detected. In particular, chronic treatment with GM1 prevented the disappearance of TH-positive cell bodies in the substantia nigra and induced the appearance of longer TH-positive dendrites with respect to the saline treatment. These data indicate that GM1 treatment maintains the number of dopaminergic cell bodies in the substantia nigra after hemitransection by protecting against retrograde neuronal degeneration.
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PMID:Chronic GM1 ganglioside treatment reduces dopamine cell body degeneration in the substantia nigra after unilateral hemitransection in rat. 614 56

In the present study the topology and the biochemical mechanisms underlying the functional recovery of the dopaminergic nigrostriatal system is further analyzed. Rats with unilateral hemitransection were treated with 30 mg/kg GM1 monosialoganglioside or with its internal ester derivative for different periods of time. GM1 enhances 3H-dopamine uptake in striatal synaptosomes of the lesioned side, and the enhancement of dopamine uptake precedes that of striatal tyrosine hydroxylase activity. The above biochemical effects are accompanied by changes in behavioral- and electrophysiological-related parameters. The effect of GM1 on striatal tyrosine hydroxylase of the lesioned side disappears when the ascending dopaminergic fibers are extensively lesioned. This suggests that the source of regrowing dopaminergic nerve terminals in the striatum of partially lesioned rats resides mainly in the intact axons remaining in the ipsilateral side. When GM1 is injected into partially lesioned rats kept in darkness, no effect on tyrosine hydroxylase activity is observed. This indicates that the mechanism through which GM1 acts involves a normal light-dark cycle.
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PMID:The functional recovery of damaged brain: the effect of GM1 monosialoganglioside. 615 Jan 19

The effect of GM1 ganglioside on the recovery of dopaminergic nigro-striatal neurons was studied in rats after unilateral hemitransection. GM1 treatment favoured the collateral sprouting of dopaminergic axons in the striatum as indicated by the induced increase of tyrosine hydroxylase (TH) activity and immunofluorescence. Concomitantly GM1 partially prevented the decrease of TH activity caused by the hemitransection in the substantia nigra ipsilateral to the lesion. A significant increase of TH immunoreactivity was also detected in the substantia nigra: GM1 prevented the disappearance of TH-positive cell bodies and increased the formation of TH-positive collaterals and dendrites with respect to the saline treatment. The addition of GM1 to embryonic dissociated mesencephalic cell cultures stimulates the expression of dopaminergic characteristics as suggested by the increase of 3H-DA uptake.
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PMID:Effects of gangliosides on the functional recovery of damaged brain. 674 41


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