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)

The major neuropathology of Parkinson's disease (PD) is the degeneration of nigrostriatal dopamine (DA), resulting in a deficiency of DA, and of the enzyme tyrosine hydroxylase (TH), which catalyzes the synthesis of L-dopa. The symptomatic treatment of PD consists of replenishing DA by administering L-dopa, which is enzymatically converted to DA in the striatum. The increase of TH activity by modification of the enzyme leads to an increased synthesis of striatal L-dopa, and thereby replenishes the missing DA more efficiently. The activity of TH is increased by protein kinase-dependent phosphorylation of the enzyme or by inhibition of dephosphorylation with specific phosphatase inhibitors. Thus, modification of TH results in an activated form of the enzyme, which might provide a basis for developing new strategies in the treatment of PD. The extraneuronal enzyme, catechol-O-methyl transferase (COMT), inactivates catecholamines by O-methylation, and its inhibition leads to increased levels of striatal DA. The availability of selective and nontoxic COMT inhibitors makes it possible to assess their therapeutic role in treatment of PD. The intraneuronal enzymes, monoamine oxidase (MAO)-A and MAO-B, inactivate catecholamines and other biogenic amines, such as serotonin, by deamination. Inhibition of these enzyme activities leads to increased levels of striatal DA. The irreversible MAO-B inhibitor selegiline was shown to exert antiparkinsonian activity, especially in the early stages of parkinsonism. Selegiline also prevents the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in MPTP-treated mice and monkeys. Its role in the prevention of the disease is under investigation in several clinical centers.
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PMID:The role of the regulatory enzymes of catecholamine synthesis in Parkinson's disease. 834 92

Selegiline, a selective monoamine oxidase type B inhibitor, is beneficial in the treatment of Parkinson's disease. However, this beneficial effect is only transient, and patients must ultimately resort to treatment with standard levodopa therapy. We studied the effects of chronic selegiline treatment on the rat nigrostriatal pathway, to elucidate a neurochemical correlate for this adaptive clinical response. Selegiline treatment for 3, 7, 14, or 21 days decreased tyrosine hydroxylase (the enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis) activity in the cell body regions (substantia nigra) of the nigrostriatal pathway. However, tyrosine hydroxylase activity measurements in the major terminal field region (corpus striatum) of the pathway did not correspond to those in the substantia nigra; in the corpus striatum, tyrosine hydroxylase activity was decreased at 3 and 7 days of treatment and recovered by 14 days. We tested whether the decrease in tyrosine hydroxylase activity was mediated by a decrease in tyrosine hydroxylase mRNA. Northern blot and RNA dot blot analyses (using a tyrosine hydroxylase-specific cDNA probe) of substantia nigra homogenates revealed a significant decrease in tyrosine hydroxylase mRNA at 3, 7, and 14 days of selegiline treatment, compared with controls. Conversely, after 21 days of selegiline, tyrosine hydroxylase mRNA levels were significantly higher (3-fold) than controls; this finding was not reflected in substantia nigra tyrosine hydroxylase activity. The 21-day increase in mRNA may be associated with the rebound in tyrosine hydroxylase activity observed in the corpus striatum. Thus, it is possible that the recovery in tyrosine hydroxylase activity in the corpus striatum is mediated through an increase in tyrosine hydroxylase protein transport from the substantia nigra to the corpus striatum and/or that the tyrosine hydroxylase enzyme exists in a more stabilized state during this period of time. These results demonstrate that monoamine oxidase type B-selective inhibitory doses of selegiline are capable of inducing transient decreases in tyrosine hydroxylase activity and tyrosine hydroxylase mRNA levels. Furthermore, these reversible effects may represent adaptive responses associated with pharmacological tolerance and the transient beneficial actions of this drug in Parkinson's disease.
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PMID:Chronic selegiline administration transiently decreases tyrosine hydroxylase activity and mRNA in the rat nigrostriatal pathway. 135 Mar 20

Selegiline is a selective and irreversible monoamine B inhibitor with the capacity to increase the level of several antioxidative enzymes in rat brain. It can protect adrenergic neurons against injury induced by neurotoxins such as MPTP, DSP-4 and AF64A in animal studies. In addition, the protective action is not limited to catecholaminergic cells, as selegiline can also minimize the loss of developing motoneurons after axotomy. The aim of this study was to determine whether selegiline can protect peripheral catecholaminergic neurons against the neurotoxic effect of 6-OHDA. This kind of protective effect against 6-OHDA neurotoxicity has not been reported before. Wistar albino male rats aged 4 or 24 months were treated with selegiline or saline solution 1 h before 6-OHDA injection. At 2 weeks after the 6-OHDA injection, the superior cervical ganglia (SCG) and submandibular glands (SMG) were studied using catecholamine histofluorescence and immunohistochemistry for tyrosine hydroxylase (TH). The number of TH-positive cells in the SCG and the length and number of adrenergic nerve fibers in the SMG were quantified. Our findings showed that 6-OHDA caused a reduction of TH immunoreactivity and catecholamine histofluorescence in neuronal somata, as well as a decrease in the number and length of adrenergic nerve fibers in the submandibular gland. Selegiline pretreatment protected SCG neurons and their postganglionic nerve fibers in SMG against these changes in a dose-dependent manner. The mechanism through which selegiline exerts its neuroprotective effect is as yet unknown.
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PMID:Monoamine oxidase B inhibitor selegiline protects young and aged rat peripheral sympathetic neurons against 6-hydroxydopamine-induced neurotoxicity. 874 Feb 26

The ability of selegiline to protect against the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of the conversion of MPTP to 1-methyl-4-phenylpyridinium (MPP+), catalyzed by monoamine oxidase-B. Selegiline, however, has been found to rescue neurons in MPP(+)-treated mice after they have sustained lethal damage independently of monoamine oxidase-B inhibition. In our present study, we investigate whether selegiline can protect and/or rescue MPP(+)-injured dopaminergic neurons in co-cultures of mesencephalic and striatal cells of embryonic C57B1/6 mouse brains. Cells were exposed to selegiline (1, 10, 100 microM) in three different schemes: (i) in control cultures on the 8th day for 48 h; (ii) pretreatment: on the 8th day for 48 h, followed by administration of MPP+ (0.5 microM) on the 9th day for 24 h; (iii) delayed treatment: on the 9th day for 48 h, while MPP+ was administered on the 8th day and remained in culture during treatment with selegiline. In the delayed scheme, selegiline (1 microM) increased dopamine content, number of tyrosine hydroxylase immunoreactive cells and astrocytes in the cultures. We question whether selegiline protects cells injured by a toxic stressor via an astrocyte-mediated mechanism.
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PMID:Selegiline is neuroprotective in primary brain cultures treated with 1-methyl-4-phenylpyridinium. 881 31

The effects of Selegiline hydrochloride (Selegiline HCl) on the intracellular Ca2+ contents of primarily cultured rat striatal, mesencephalic neuronal cells and PC-12 cells were examined by the use of a Ca2+ imaging analyzer. In the former two cell types, Selegiline HCl (10(-5)-10(-6) M) induced a transient inflow of extracellular Ca2+ through the voltage-dependent N-type Ca2+ channel. In addition, all cells indicating an increase in the intracellular Ca2+ content were found to be catecholaminergic neurons which showed a positive reaction with anti-tyrosine hydroxylase antibodies. Furthermore, a transient intracellular influx of Ca2+ was observed in the NGF-pretreated PC-12 cells. From these results, it is suggested that Selegiline HCl elicits various functions, including antioxidation, activation of neurotrophic factor biosynthesis and neuronal protection probably via an unidentified specific proteins of tyrosine hydroxylase-positive neurons.
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PMID:[Effects of selegiline hydrochloride on intracellular Ca2+ contents in cultured neuronal cells]. 998 54

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Monoamine-oxidase B (MAO-B) has been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease, since selegiline (L-deprenyl), an irreversible MAO-B inhibitor, prevents MPTP-induced neurotoxicity in numerous species including mice, goldfish and drosophyla. However, one disadvantage of this substance relates to its metabolism to (-)-methamphetamine and (-)-amphetamine. Rasagiline (R-(+)-N-propyl-1-aminoindane) is a novel irrevesible MAO-B-inhibitor, which is not metabolized to metamphetamine and/or amphetamine. The present study compared the effects of high doses of selegiline and rasagiline (10 mg/kg body weight s.c.) on MPTP-induced dopaminergic neurotoxicity in a non-human primate (Callithrix jacchus) model of PD. Groups of four monkeys were assigned to the following six experimental groups: Group I: Saline, Group II: Selegiline/Saline, Group III: Rasagiline/Saline, Group IV: MPTP/Saline, Group V: Rasagiline/MPTP, Group VI: Selegiline/MPTP. Daily treatment with MAO-B-inhibitors (either rasagiline or selegiline, 10 mg/kg body weight s.c.) was initiated four days prior to MPTP-exposure (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of four days) and was continued until the end of the experiment, i.e. 7 days after the cessation of the MPTP-injections, when animals were sacrificed. MPTP-treatment caused distinct behavioural, histological, and biochemical alterations: 1. significant reduction of motor activity assessed by clinical rating and by computerized locomotor activity measurements; 2. substantial loss (approx. 40%) of dopaminergic (tyrosine-hydroxylase-positive) cells in the substantia nigra, pars compacta; and 3. putaminal dopamine depletion of 98% and its metabolites DOPAC (88%) and HVA (96%). Treatment with either rasagiline or selegiline markedly attenuated the neurotoxic effects of MPTP at the behavioural, histological, and at the biochemical levels. There were no significant differences between rasagiline/MPTP and selegiline/MPTP-treated animals in respect to signs of motor impairment, the number of dopaminergic cells in the substantia nigra, and striatal dopamine levels. As expected, both inhibitors decreased the metabolism of dopamine, leading to reduced levels of HVA and DOPAC (by >95% and 45% respectively). In conclusion, rasagiline and selegiline at the dosages employed equally protect against MPTP-toxicity in the common marmoset, suggesting that selegiline-derived metabolites are not important for the neuroprotective effects of high dose selegiline in the non-human MPTP-primate model in the experimental design employed. However, unexpectedly, high dose treatment with both MAO-inhibitors caused a decrease of the cell sizes of nigral tyrosine hydroxylase positive neurons. It remains to be determined, if this histological observation represents potential adverse effects of high dose treatment with monoamine oxidase inhibitors.
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PMID:Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline. 1171 51

The aim of this study was to investigate the effects of selegiline ((-)deprenyl), an irreversible inhibitor of monoaminoxidase-B (MAO-B): (a) on brain acetylcholinesterase (AChE), (Na(+),K(+))-ATPase and Mg(2+)-ATPase activities; (b) total antioxidant status (TAS); (c) learning performance and to evaluate possible correlation between biochemical and behavioral findings after long-term drug administration in aged male rats. Selegiline (0.25mgkg(-1) rat) was administered once every other day for 50 days. Learning parameters were tested through a two-way active avoidance procedure taking place in an Ugo-Basile automated shuttle box device. Enzyme activities and TAS were evaluated spectrophotometrically in brain homogenates of decapitated animals. TAS was significantly lower in aged compared to adult rats and this was reversed by selegiline administration. The decrease of free radical production by selegiline resulted in the stimulation of AChE and (Na(+),K(+))-ATPase. Mg(2+)-ATPase activity was not affected by the drug. Selegiline seems to improve the avoidance performance as compared to control groups. It is concluded that: (a) MAO-B inhibition and/or free radical protection on tyrosine hydroxylase by the drug may increase brain catecholamine concentrations resulting possibly in (Na(+),K(+))-ATPase stimulation; (b) AChE and (Na(+),K(+))-ATPase activation by the drug could modulate brain cholinergic, catecholaminergic and serotoninergic systems as well as the neural excitability and metabolic energy production; and (c) selegiline seems to improve the learning performance of aged rats.
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PMID:Selegiline long-term effects on brain acetylcholinesterase, (Na+,K+)-ATPase activities, antioxidant status and learning performance of aged rats. 1286 Apr 42

Nitric oxide (NO), in excess, behaves as a cytotoxic substance mediating the pathological processes that cause neurodegeneration. The NO-induced dopaminergic cell loss causing Parkinson's disease (PD) has been postulated to include the following: an inhibition of cytochrome oxidase, ribonucleotide reductase, mitochondrial complexes I, II, and IV in the respiratory chain, superoxide dismutase, glyceraldehyde-3-phosphate dehydrogenase; activation or initiation of DNA strand breakage, poly(ADP-ribose) synthase, lipid peroxidation, and protein oxidation; release of iron; and increased generation of toxic radicals such as hydroxyl radicals and peroxynitrite. NO is formed by the conversion of L-arginine to L-citrulline by NO synthase (NOS). At least three NOS isoforms have been identified by molecular cloning and biochemical studies: a neuronal NOS or type 1 NOS (nNOS), an immunologic NOS or type 2 NOS (iNOS), and an endothelial NOS or type 3 NOS (eNOS). The enzymatic activities of eNOS or nNOS are induced by phosphorylation triggered by Ca(2+) entering cells and binding to calmodulin. In contrast, the regulation of iNOS seems to depend on de novo synthesis of the enzyme in response to a variety of cytokines, such as interferon-gamma and lipopolysaccharide. The evidence that NO is associated with neurotoxic processes underlying PD comes from studies using experimental models of this disease NOS inhibitors can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Furthermore, NO fosters dopamine depletion, and the said neurotoxicity is averted by nNOS inhibitors such as 7-nitroindazole working on tyrosine hydroxylase-immunoreactive neurons in substantia nigra pars compacta. Moreover, mutant mice lacking the nNOS gene are more resistant to MPTP neurotoxicity when compared with wild-type littermates. Selegiline, an irreversible inhibitor of monoamine oxidase B, is used in PD as a dopaminergic function-enhancing substance. Selegiline and its metabolite, desmethylselegiline, reduce apoptosis by altering the expression of a number of genes, for instance, superoxide dismutase, Bcl-2, Bcl-xl, NOS, c-Jun, and nicotinamide adenine nucleotide dehydrogenase. The selegiline-induced antiapoptotic activity is associated with prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons. As apoptosis is critical to the progression of neurodegenerative disease, including PD, selegiline or selegiline-like compounds to be discovered in the future may be efficacious in treating PD.
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PMID:Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. 1288 Apr 86

1. Retinal dystrophies (RD) comprise a group of clinically and genetically heterogeneous retinal disorders, which typically result in the degeneration of photoreceptors followed by the impairment or loss of vision. Although age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are among the most common forms of RD, currently, there is no effective treatment for either disorder. 2. Recently, abnormal protein accumulation and aggregation due to protein misfolding and proteasome inhibition have been implicated in the pathogenesis of RD. In this paper we describe effects of several factors on protein aggregation and survival of photoreceptor cells. 3. Expression of rhodopsin carrying P23H mutation causes its accumulation in intracellular inclusion bodies in a perinuclear area of photoreceptor cells. beta- and gamma-synucleins and heat shock protein Hsp-70, but not alpha-synuclein, protect cultured ocular cells from mutant opsin accumulation. This effect might be explained by their chaperonic activity. 4. Knock-out of alpha- and gamma-synucleins does not affect gross retinal morphology, but induces tyrosine hydroxylase in the inner prexiform layer of the retina. Selegiline-a monoamine oxidase inhibitor used for the treatment of Parkinson's disease, reduces apoptosis and increases viability in cultured retinal pigment epithelium cells (APRE-19). 5. These results suggest that chaperones and selegiline may be considered promising candidates for the protection of ocular cells from the accumulation of misfolded and aggregated proteins.
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PMID:Protein aggregation in retinal cells and approaches to cell protection. 1639 36

Three brothers, born to parents who were first cousins, were referred for progressive diffuse dystonia. Initial physical examinations revealed minor dysmorphic features, e.g., bifrontal narrowing, downslanting palpebral fissures, low-set ears, upturned nostrils, and microretrognathia, as well as neurodevelopmental delay. Absence of eye contact and head control, diffuse dystonia, hypokinesia, choreoathetosis, tremor, increased deep tendon reflexes, diffuse muscle atrophy, and spasticity were evident during neurologic evaluations. After laboratory investigations, imaging studies, and the exclusion of other causes of childhood dystonia, the children were diagnosed with Segawa syndrome. A molecular analysis of the tyrosine hydroxylase gene revealed a novel P492R (1475 C>G) mutation, further confirming the clinical diagnosis. After 1-month therapy with 2 mg/kg/day l-dopa, no changes in signs were evident. Selegiline was added, which greatly improved the clinical picture. Segawa syndrome in three brothers resulted from a novel mutation in the tyrosine hydroxylase gene. Treatment with a combination of l-dopa and selegiline led to favorable outcomes.
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PMID:Marked improvement in Segawa syndrome after L-dopa and selegiline treatment. 2039 90


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